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WO1999006410A1 - Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique - Google Patents

Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique Download PDF

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Publication number
WO1999006410A1
WO1999006410A1 PCT/US1998/016147 US9816147W WO9906410A1 WO 1999006410 A1 WO1999006410 A1 WO 1999006410A1 US 9816147 W US9816147 W US 9816147W WO 9906410 A1 WO9906410 A1 WO 9906410A1
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radicals
alkyl
radical
aryl
heteroaryl
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PCT/US1998/016147
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English (en)
Inventor
David S. Thomson
Kevin Koch
Chan Kou Hwang
Sandra E. Russo-Rodriguez
Conrad Hummel
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Amgen Inc.
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Application filed by Amgen Inc. filed Critical Amgen Inc.
Priority to JP2000505168A priority Critical patent/JP2003524572A/ja
Priority to CA002297988A priority patent/CA2297988A1/fr
Priority to AU87664/98A priority patent/AU8766498A/en
Priority to EP98939182A priority patent/EP1003751A1/fr
Publication of WO1999006410A1 publication Critical patent/WO1999006410A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to metalloproteinase inhibitors and more particularly, relates to novel compounds, composition and method for prophylaxis and treatment of inflammation, tissue degradation and the like.
  • This invention in particular, relates to novel hydroxamic acid substituted fused heterocyclic compounds, compositions containing such compounds and methods of use of such compounds.
  • the subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
  • Metalloproteinase enzymes such as collagenases (e.g., MMP-1, MMP-8 and MMP- 13 ) , stromelysins (e.g., MMP-3, MMP-10, MMp-11 and MMP-7) , gelatinases (e.g., MMP -2 and MMP- 9) and TNF convertase, may contribute to the onset, etiology, or exacerbate disease states which are related to connective tissue degradation, secretion of proinflammatory cytokines and the like.
  • collagenases e.g., MMP-1, MMP-8 and MMP- 13
  • stromelysins e.g., MMP-3, MMP-10, MMp-11 and MMP-7
  • gelatinases e.g., MMP -2 and MMP- 9
  • TNF convertase may contribute to the onset, etiology, or exacerbate disease states which are related to connective tissue degradation, secretion of proinflammatory
  • matrix metalloproteinases such as collagenases, stromelysins and gelatinases, are thought to be involved in the tissue breakdown observed in rheumatoid arthritis; osteoarthritis ; osteopenias (e.g., osteoporosis) ; periodontitis; gingivitis; corneal, epidermal and gastric ulceration; and tumour metastasis, invasion and growth; in neuroinflammatory disorders, such as myelin degradation (e.g., multiple sclerosis); and in angiogenesis dependent diseases, such as arthritic conditions; solid tumor growth; psoriasis; proliferative retinopathies; neovascular glaucoma; ocular tumours; angiofibromas; and hemangiomas .
  • Tumor Necrosis Factor alpha is a proinflammatory cytokine secreted by a variety of cells including monocytes and macrophages in response to many inflammatory stimuli (e.g. lipopolysaccharide - LPS) or external cellular stress (e.g. osmotic shock, peroxide) . Elevated levels of TNF play a major role in mediating many inflammatory disease states.
  • inflammatory stimuli e.g. lipopolysaccharide - LPS
  • external cellular stress e.g. osmotic shock, peroxide
  • Elevated levels of TNF- ⁇ may contribute to the onset, etiology, or exacerbate the following disease states: rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS) ; psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; antiviral therapy including those viruses sensitive to TNF- ⁇ inhibition - HIV-1, HIV- 2, HIV- 3, cytomegalovirus (CMV) , influenza, adenovirus, and the herpes viruses including HSV-1, HSV- 2, and herpes zoster; muscle degeneration; cachexia; Reiter's syndrome; type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; Alzheimer's disease; multiple sclerosis; cerebral malaria;
  • TNF- ⁇ Several approaches have been taken to block the effects of TNF- ⁇ .
  • a second approach to neutralizing TNF- ⁇ utilizing a monoclonal antibody specific to TNF- ⁇ , cA2 has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al Immunological Reviews p.195 -223 (1995)).
  • TNF convertase is thought to be a metalloproteinase enzyme involved in the cellular secretion of TNF- ⁇ (Mohler et al . , Nature 370:218-220, 1994; Gearing et al . , Nature 370:555-557, 1994; McGeehan et al . , Nature 370:558-561, 1994). Inhibition of TNF convertase is thought to be an additional approach to intervene in the cellular secretion of TNF- ⁇ .
  • a metalloproteinase inhibitor was shown to inhibit cellular secretion of TNF- ⁇ , in vitro and in vivo, which was thought to be due to inhibition of TNF convertase (McGeehan et al . , Nature 370:558-561, 1994).
  • TNF- ⁇ is upstream in the cytokine cascade of inflammation wherein elevated levels of TNF- ⁇ lead to elevated levels of other cytokines including IL-1, IL-6 and IL-8
  • inhibiting the secretion of TNF- ⁇ may also reduce levels of other cytokines including but not limited to IL-1, IL-6 or IL-8.
  • TNF- ⁇ is thought to play a role in head trauma, stroke, and ischemia.
  • TNF- ⁇ levels increased in the contused hemisphere (Shohami et al J. Cereb. Blood Flow Metab. 14:615-619 (1994)).
  • the levels of mRNA of TNF- ⁇ increased (Feurstein et al Neurosci. Lett. 164:125-128 (1993)).
  • Administration of TNF- ⁇ into the rat cortex resulted in significant PMN accumulation in capillaries and adherance in small blood vessels.
  • TNF- ⁇ promotes the infiltration of other cytokines (IL-lb, IL-6), and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein Stroke 25:1481-1488 (1994)).
  • TNF- ⁇ may also play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF- ⁇ secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al , J. Immunol. 142:431 (1989)). The role of TNF- ⁇ in the HIV associated states of cachexia and muscle degradation has been discussed (Lahdevirta et al The American J. Med. 85:289 (1988)).
  • WO 97/18194 generically discloses N- (substituted- sulfonyl) thienyl - fused 5-7 membered ring nitrogen containing heterocycle hydroxamic acid compounds for use as inhibitors of matrix metalloproteinases and TNF production.
  • DE 3529960 and DE 3705220 disclose heterocyclic- fused- tetrahydropyridinyl - 2 -carboxylic acid derivatives, such as thieno- fused- tetrahydropyridinyl -2 -carboxylic acid compounds, preparation and use as angiotensin I converting enzyme inhibitors.
  • DE 2800596 discloses the preparation and use for inhibition of agglutination of blood platelets, erythrocyte adhesion and thrombosis of thieno- fused- tetrahydropyridinyl-2 -carboxylic acid derivatives.
  • DE 2812950 disclose the preparation and use for inhibition of agglutination of blood platelets, erythrocyte adhesion, thrombosis, pain and inflammation of thieno- fused-dihydropyridinone derivatives.
  • DE 2949399 discloses the use of thieno- fused- tetrahydropyridine derivatives as intermediates in the preparation of (thieno- fused- tetrahydropyridyl) -fused- tetrahydrothiazole compounds for use as antiviral, analgesic, antipyretic and anti- inflammatory agents.
  • FR 2457869 discloses the use of thieno- fused- tetrahydropyridinyl - 2 -carboxylic acid derivatives as intermediates in the preparation of (thieno- fused- tetrahydropyridyl) - fused-pyrazine compounds for use as sedatives.
  • WO 96/33172 discloses N-arylsulfonyl and N- heteroarylsulfonyl substituted 6 membered ring heterocycle hydroxamic acid derivatives, such as N- arylsulfonyl - and N-heteroarylsulfonyl -piperidinyl - 2 - hydroxamic acid compounds, preparation and use as inhibitors of matrix metalloproteinases and TNF production.
  • EP 606046 discloses N-arylsulfonyl and N- heteroarylsulfonyl substituted 5-6 membered ring heterocycle hydroxamic acid derivatives, such as N- arylsulfonyl - and N-heteroarylsulfonyl -piperidinyl - 2 - hydroxamic acid compounds and N-arylsulfonyl - and N- heteroarylsulfonyl-1, 2 , 3 , 4 - tetrahydroisoquinolinyl -2 - hydroxamic acid compounds, preparation and use as inhibitors of matrix metalloproteinases.
  • the present invention relates to selected metalloproteinase inhibitory compounds, analogs and pharmaceutically acceptable salts and prodrugs thereof.
  • the subject compounds are characterized as hydroxamic acid substituted fused heterocyclic compounds.
  • the subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
  • R is (1) an alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of -OH, -OR 3 , -SR 3 , -C(0)R or
  • aryl, heteroaryl, cycloalkyl or heterocyclyl or (2) aryl or heteroaryl radicals; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl radicals are
  • R is (1) an C 1 -C 12 alkyl, C2-C 12 alkenyl,
  • aryl, heteroaryl, cycloalkyl or heterocyclyl or (2) aryl or heteroaryl radicals; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl radicals are optionally
  • R is (1) an C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of -OH, -OR 3 , -SR 3 , -S(0)R 3 , -S(0) 2 R 3 , -C(0)R 3 , -NR 3 R 4 , aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) aryl or heteroaryl radicals; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl radicals are optionally
  • R is (1) an C 1 -C 12 alkyl or cycloalkyl radical optionally substituted by 1-3 radicals of -OH,
  • aryl, heteroaryl, cycloalkyl or heterocyclyl or (2) aryl or heteroaryl radicals; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl radicals are optionally
  • R is (1) an C 1 -C 12 alkyl or cycloalkyl radical optionally substituted by 1-3 radicals of -OH,
  • R is (1) an C 1 -C 12 alkyl or cycloalkyl radical optionally substituted by 1-2 radicals of -OH,
  • R is (1) an C 1 -C 12 alkyl or cycloalkyl radical optionally substituted by 1-2 radicals of -OH,
  • R is (1) an C 5 -C 12 alkyl radical
  • aryl or heteroaryl radicals optionally substituted by a hydroxy, -OR , - SR , -S(0) 2 R , -NR R , amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, halo, Ci-Cg alkyl or -CF 3 radical; and
  • each R is independently an alkyl, haloalkyl, aryl, heteroaryl, aryl -alkyl or heteroaryl -alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl , alkylsulfonyl , alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
  • each R is independently an Ci-C ⁇ alkyl, Ci-
  • each R is independently an C 1 -C 4 alkyl, -CF 3 , aryl, heteroaryl, aryl -C 1 -C 4 -alkyl or heteroaryl -C 1 -C 4 - alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 ;
  • each R is independently an C 1 -C 4 alkyl, -CF 3 , aryl, heteroaryl, aryl -C 1 -C 2 -alkyl or heteroaryl -C 1 -C 2 - alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 ;
  • each R is independently an C 1 -C 4 alkyl, -CF 3 , aryl, heteroaryl, aryl -C 1 -C 2 - alkyl or heteroaryl -C 1 -C 2 - alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C2 alkoxy, C 1 -C 2 alkylthiol, amino, acetylamino, methylsulfonylamino, C 1 -C 2 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, halo, C 1 -C 2 alkyl, -CF 3 or -OCF 3 ;
  • each R is independently an C 1 -C 4 alkyl, -CF 3 , aryl, heteroaryl, arylmethyl or heteroarylmethyl radical;
  • each R is independently a hydrogen or alkyl radical
  • each R is independently a hydrogen or C ⁇ -C 8
  • each R is independently a hydrogen or C 1 -C 4 alkyl radical; most preferably, each
  • R is independently a hydrogen or methyl radical
  • R is a hydrogen or alkyl radical; preferably, R is a
  • R is a hydrogen radical
  • V is -CHR - or -CHR -CHR - ; wherein R and R are each independently (1) a hydrogen, -OR , -SR , -C(0)R , -0-
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
  • R and R are each independently (1) a 20 21 , , 22 32 31 33 hydrogen, -OR , - SR , -C(0)R , -0-C(0) -NR R , -NR -
  • R and R are each independently (1) hydrogen, -OR 2 °, -SR 21 , -C(0)R 22 , -O-C (0) -NR 3 R 31 , -NR 33 -
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, amino, C 1 -C 4 alkanoylamino, C 1 -C 4 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl , C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloal
  • R and R are each independently (1) a hydrogen, -OR , - SR , -C(0)R , -0-C(0)-NR R ⁇ -NR -
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, methylsulfinyl , methylsulfonyl , Ci- C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • R is (1) a hydrogen, -OR 2 °, -SR 21 , -C(0)R 22 , -0-C(0) -NR R 31 , -NR -
  • R -NR -S(0) 2 "NR R , aryl or heteroaryl radical; or (2) an Ci-C ⁇ alkyl or C 2 -C 8 alkenyl radical optionally substituted with an -0R 2 °, -SR 21 , -C(0)R 22 , -O-C(O)-
  • R is (1) a hydrogen, -OR , - SR ,
  • aryl or heteroaryl radical wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, methylsulfonyl , halo, azido, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • R is (1) a hydrogen, -OR , -O-C(O)-
  • aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, aryloxy, heteroaryloxy, C3.-C 2 alkylthiol, halo, azido, C 1 -C 2 alkyl, -CF 3 or -OCF 3 radicals; and
  • R is (1) a hydrogen, -OR , -O-C(O)-
  • V is -CHR -CHR -, more preferably,
  • R is a hydrogen, hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl
  • R is (1) a hydrogen, -OR , -SR ,
  • aryl or heteroaryl radical wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, methylsulfinyl , methylsulfonyl, C]_- C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals; or
  • R is a hydrogen, hydroxy, C1 . -C 4 alkoxy or C 1 -C 4
  • R is (1) a hydrogen, -OR , -SR ,
  • aryl or heteroaryl radical wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, methylsulfinyl , methylsulfonyl , C_- C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • R is a hydrogen, hydroxy, C 1 -C 4 alkoxy
  • R is (1) a hydrogen, -OR ,
  • -NR -C(0)-OR , -NR -C(0)-NR R , -NR -S(0) 2 -R , aryl or heteroaryl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylthiol, methylsulfonyl , halo, azido, C1 . -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • R is a hydrogen, hydroxy, C 1 -C 4 alkoxy
  • R is (1) a hydrogen, -OR ,
  • R is a hydrogen, hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl radical and R 11 is (1) a hydrogen, -OR , -0-C(0)-NR R , -NR -
  • NR -C(0)-OR , -NR -C(0)-NR R , -NR -S(0) 2 -R , aryl or heteroaryl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, aryloxy, heteroaryloxy, C 1 -C 2 alkylthiol, halo, azido, C 1 -C 2 alkyl, -CF 3 or -OCF 3 radicals; and
  • R is a hydrogen, hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl radical and R is (1) a hydrogen, -OR ,
  • R is (1) a hydrogen, -OR , -0-C(0)-NR R , -NR -
  • each R is independently a hydrogen, -C(0)R , alkyl , alkenyl , cycloalkyl , aryl , heteroaryl , aryl - alkyl, heteroaryl -alkyl, alkanoyl, aroyl or heteroaroyl radical; wherein the alkyl and alkenyl radicals are
  • each R is independently a hydrogen, Ci-C ⁇ alkyl, C 2 -C 8 alkenyl, cycloalkyl, aryl, heteroaryl, aryl -C 1 -C 4 - alkyl, heteroaryl -Ci -C 4 -alkyl , C ⁇ -C 8 alkanoyl, aroyl or heteroaroyl radical; wherein the alkyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl , alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy; 20 preferably, each R is independently a hydrogen, Ci-C ⁇ alkyl, C 2 -C
  • alkenyl radicals are optionally substituted by -C(0)R ; and wherein the cycloalkyl, aryl and heteroaryl radicals are optionally substituted by 1 - 3 radicals of hydroxy,
  • each R is independently a hydrogen
  • cycloalkyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, C 1 -C 4 alkanoylamino, C 1 -C 4 alkylsulfonylamino, Ci-
  • each R is independently a hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyl, aryl, heteroaryl, aryl -C 1 -C 4 - alkyl, heteroaryl -C 1 -C 4 - alkyl , C_- C 4 alkanoyl, aroyl or heteroaroyl radical; wherein the alkyl and alkenyl radicals are optionally substituted by
  • cycloalkyl, aryl and heteroaryl radicals are optionally substituted by 1 - 3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, methylsulfinyl , methylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • each R is independently a hydrogen
  • each R is independently a hydrogen
  • each R is independently an alkyl
  • alkyl -C(0)R aryl, heteroaryl, aryl -alkyl or heteroaryl -alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
  • each R is independently an Ci-Cs alkyl, Ci-
  • each R is independently an C 1 -C 4 alkyl, C 1 -C 4 alkyl -C(0)R , aryl, heteroaryl, aryl-C ⁇ -C - alkyl or heteroaryl -C 1 -C 4 -alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, C 1 -C 4 alkanoylamino, C -C 4 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl , C 1 -C 4 alkylsulfonyl , C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of
  • each R is independently an C 1 -C 4
  • each R is independently an C 1 -C 4
  • each R is independently a hydroxy, alkoxy, aryloxy, aryl -alkoxy, heteroaryloxy, heteroaryl -alkoxy
  • each R is independently a hydroxy, Ci-Cs alkoxy, aryloxy, aryl -Ci -C 4 -alkoxy,
  • each R is independently a hydroxy, C 1 -C 4 alkoxy, aryloxy, aryl -Ci -C 2 -alkoxy,
  • each R is independently
  • R is a hydrogen, alkyl, aryl, aryl -alkyl
  • R is a hydrogen, Ci-C ⁇ alkyl, aryl, aryl -C 1 -C 4 - alkyl, heteroaryl or heteroaryl -C 1 -C 4 -alkyl radical; more
  • R is a hydrogen, C 1 -C 4 alkyl, aryl, aryl - C 1 -C 2 - alkyl, heteroaryl or heteroaryl -C 1 -C 2 -alkyl
  • R is a hydrogen, C 1 -C 2 alkyl, aryl, aryl -C 1 -C 2 -alkyl , heteroaryl or heteroaryl C 1 -C 2 - alkyl radical;
  • R is a hydrogen or alkyl radical; preferably, R is a
  • R is a hydrogen or C 1 -C 4 alkyl radical; and most preferably,
  • R is a hydrogen or C 1 -C 2 alkyl radical
  • 23 24 -NR R represents a heterocyclyl or heteroaryl radical
  • -NR R represents a heteroaryl radical; and wherein the heterocyclyl, aryl and heteroaryl radicals
  • R 22 23 23 24 of R , R and -NR R are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoyl -amino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy; preferably, 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, Ci-C ⁇ alkanoylamino, Ci-C ⁇ alkylsulfonylamino, C 1 -C 4 alkyl -sulfinyl , C 1 -C 4 alkylsulfonyl , C ⁇ -C 8 alkoxycarbonylamino, Ci-C ⁇ alkoxycarbony
  • W-N represents -C(0)-N, -C(0)-CR 15 R 1 -N, -CR 15 R 16 -N or
  • W-N represents -C(O)-
  • CR R -N -CR R -N or -CR R -CR R -N; more preferably, 11 12 when V is -CHR -CHR -, W-N represents -C(0)-N or -
  • CR R -N preferably, -CR R -N; provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in V and W is 0-3; preferably, 0-2; and more preferably, 0-1;
  • R and R are each independently (1) a
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl , alkylsulfonyl , alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
  • R and R are each independently (1) a
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, Ci-C ⁇ alkanoylamino, Ci-Cp, alkylsulfonylamino, Ci- C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, Ci-Cs alkoxycarbonylamino, Ci-Cs alkoxycarbonyl, cyano, halo, azido, Ci-Cs alkyl, Ci-Cs haloalkyl of 1-3 halo radicals or Ci-C ⁇ haloalkoxy of 1-3 halo radicals;
  • R and R are each independently (1) a
  • R is a hydrogen radical; and R is
  • R is (1) a hydrogen, aryl or heteroaryl radical; or (2) an C1-C4 alkyl radical
  • aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C ⁇ -C 2 alkylthiol, amino, acetylamino, C1-C4 alkoxycarbonyl -amino, halo, C1-C4 alkyl, -CF3 or -OCF3 radicals; and
  • R is (1) a hydrogen, aryl or heteroaryl radical; or (2) an C1-C4 alkyl radical optionally substituted with an aryl or heteroaryl radical ; and
  • R and R are each independently (1) a hydrogen, -OR , -SR 1 , -C(0)R 22 , -NR 33 -C (O) -NR 33 -
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl , alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
  • R and R are each independently (1) a hydrogen, -OR 2 °, -SR 21 , -C(0)R 22 , -NR 33 -C (O) -R 31 , -NR 3 -
  • NR R aryl or heteroaryl radical
  • aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, Ci-Cs alkanoylamino, Ci-Cp, alkylsulfonylamino, C 1 -C 4 alkylsulfinyl , C 1 -C 4 alkylsulfonyl , Ci-Cs alkoxycarbonylamino, Ci-Cs alkoxycarbonyl, cyano, halo, azido, C 1 -C13 alkyl, Ci-Cs haloalkyl of 1-3 halo radicals or Ci-Cs haloalkoxy of 1 3 halo radicals;
  • R and R are each independently (1) a
  • NR R aryl or heteroaryl radical; or (2) an C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted with an -OR , - SR , -C(0)R 22 , -NR -C (0) -R 31 , 0 -NR -C(0)-OR , -NR -C(0)-NR R 1 , -NR -S(0) -R 3 °, -NR 3 -
  • S(0) 2 _ NR R aryl or heteroaryl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, C 1 -C 4 alkanoylamino, C 1 -C 4 5 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl , C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1- 3 halo radicals; 0
  • R is a hydrogen radical, and R is (1) a hydrogen, -0R 2 °, -SR 21 , -C(0)R 22 , -NR 33 -C (0) -
  • S(0) 2 _ NR R aryl or heteroaryl radical; wherein the aryl and heteroaryl radicals are optionally substituted 0 by 1-3 radicals of hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, methylsulfinyl, methylsulfonyl , C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals;
  • R is (1) a hydrogen, -OR , -NR -C(O)-
  • R -NR -S(0) 2 "R , aryl or heteroaryl radical; or (2) an C 1 -C 4 alkyl radical optionally substituted with an -NR -C(0)-R , -NR 3 -S(0) 2 -R 3 °, aryl or heteroaryl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthiol, amino, acetylamino, methylsulfonyl , C 1 -C 4 alkoxycarbonylamino, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals; and
  • R is a hydrogen, hydroxy or C 1 -C 4 alkyl radical
  • one of -CR R - or -CR R - represent a cycloalkylene or heterocyclylene radical
  • X is O, Y is CR and Z is N;
  • X is S, Y is CR and Z is CR ;
  • X is S, Y is CR and Z is CR ; or Y is 0, X is CR and Z is CR ; or
  • Y is S, X is CR and Z is CR ;
  • Z is S, X is CR and Y is CR ;
  • Z is 0, X is N and Y is CR ; or .. , , , 15 16 17 18 preferably, when W-N represents -CR R -N or -CR R -
  • R , R , R , R , R or R is other than a hydrogen
  • R , R , R or R is other than a hydrogen radical
  • R is other than a hydrogen radical
  • R , R and R are each independently -B-A, provided that the combined total number of aryl,
  • R and R is 0-3; preferably 0-2; and more preferably,
  • R is a radical of hydrogen, halo, C 1 -C 2 alkoxy, amino, C 1 -C 2 alkylamino, di-(C ⁇ -C 2 alkyl)amino, C 1 -C 2 alkanoylamino, amidino, amido, carboxy, or C 1 -C 4 alkyl optionally substituted by amino, C 1 -C 2 alkylamino, di- (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, hydroxy, Ci- C 2 alkoxy, 1-3 halo radicals, amidino, amido or carboxy
  • R is a radical of hydrogen, halo, C 1 -C 2 alkoxy, -CF 3 or C 1 -C 4 alkyl optionally substituted by hydroxy or C 1 -C 2 alkoxy radical; and most
  • R is a radical of hydrogen, halo, C 1 -C 2 alkoxy, -CF 3 or methyl;
  • R is independently a radical of hydrogen, halo, C1-C 2 alkoxy, amino, C 1 -C 2 alkylamino, di- (C 1 -C2 alkyl) amino, C 1 -C 2 alkanoylamino, amidino, amido, carboxy, or C 1 -C 4 alkyl optionally substituted by amino, C1-C2 alkylamino, di-(C ⁇ -C 2 alkyl)amino, C 1 -C 2 alkanoylamino, hydroxy, C 1 -C 2 alkoxy, 1-3 halo radicals, amidino, amido or carboxy radical;
  • R is independently -B-A when R is a hydrogen, hydroxy, C 1 -C 2 alkoxy or C 1 -C 4 alkyl radical;
  • R is independently a radical of hydrogen, halo, C 1 -C 2 alkoxy, -CF 3 or C 1 -C 4 alkyl optionally substituted by hydroxy or C 1 -C 2 alkoxy radical;
  • R is independently -B-A when R is a hydrogen, hydroxy, C 1 -C 2 alkoxy or C 1 -C 4 alkyl radical;
  • R is independently a radical of hydrogen, halo, C 1 -C 2 alkoxy, -CF 3 or methyl radical;
  • R is independently -B-A when R and R are each independently a hydrogen, hydroxy, C ⁇ -C 2 alkoxy or
  • R is independently a radical of hydrogen, halo, C 1 -C 2 alkoxy, amino, C 1 -C 2 alkylamino, di- (C 1 -C 2 alkyl ) amino , C ⁇ -C 2 alkanoylamino, amidino, amido, carboxy, or C 1 -C 4 alkyl optionally substituted by amino, C1-C2 alkylamino, di-(C ⁇ -C 2 alkyl)amino, C 1 -C 2 alkanoylamino, hydroxy, C ⁇ -C alkoxy, 1-3 halo radicals, amidino, amido or carboxy radical;
  • R is independently -B-A when R and
  • R is independently a radical of hydrogen, halo, C 1 -C 2 alkoxy, -CF 3 or C 1 -C 4 alkyl optionally substituted by hydroxy or C 1 -C 2 alkoxy radical;
  • R is independently -B-A when R and
  • R is independently a radical of hydrogen, halo, C -C 2 alkoxy, -CF 3 or methyl;
  • each B is independently a (1) bond; (2) alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and/or (b) 1- 2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy; (3) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino
  • each B is independently a (1) bond;
  • Ci- Cs alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted by (a) 1-3 radicals of amino, Ci- C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, and/or (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di - (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbon
  • each B is independently a (1) bond;
  • Ci-C ⁇ alkyl radical optionally substituted by (a) a radical of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C -C 4 alkyl
  • each B is independently a (1) bond; (2) C 1 -C 4 alkyl radical optionally substituted by (a) a radical of amino, C 1 -C 2 alkylamino, di- (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy or C 1 -C 2 alkoxy and/or (b)
  • halo radicals and/or (c) a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-2 radicals of amino, C 1 -C 2 alkylamino, di-(C ⁇ -C 2 alkyl) amino, C]_-C alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C ⁇ -C 2 alkylsulfonylamino, hydroxy,
  • each B is independently a (1) bond; (2) C 1 -C 4 alkyl radical; or (3) aryl or heteroaryl radical optionally substituted by a radical of amino, C 1 -C 2 alkylamino, di-(C ⁇ -C 2 alkyl)amino, C 1 -C 2 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 2 alkylsulfonylamino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, halo, C 1 -C 4 alkyl, -CF3 or -OCF 3 radicals; and most preferably, each B is independently a bond, C 1 -C 4 alkyl, aryl or heteroaryl radical; and
  • each A is independently a (1) hydrogen radical
  • each A is independently a (1) hydrogen radical; (2) halo, cyano or nitro radical; (3) -C(O)-
  • each A is independently a (1) hydrogen radical; (2) halo radical; (3) -C(0)-R 3 °, -C(0) -C(0)-NR R or -C(NR ) -NR R radical; (4) -OR radical; (5) -SR 31 , -S(0) 2 -R 3 ° or - S (0) 2 -NR 32 R 1 radical;
  • each A is independently a (1) hydrogen radical; (2) halo radical; (3) -C(0)-R , -C(0)-OR ,
  • each A is independently a hydrogen, halo, -C(0)-R 3 °, -C(0)-OR 31 or -C (0) -NR 32 R 31 radical;
  • each R is independently (1) alkyl, alkenyl or alkynyl radicals optionally
  • cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of amino, C 3. -C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or
  • each R is independently selected from the group consisting of: (C1-C4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl , hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; 30 more preferably, each R is independently
  • cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl , hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C2.-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl , hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals;
  • each R is independently (1) Ci-Cg alkyl radical optionally substituted by 1-3
  • each R is independently (1) -CF 3 or C 1 -C 4 alkyl radical optionally substituted
  • each R is independently (1) heterocyclyl radical optionally substituted by 1-2 radicals of (C 1 -C 4 alkoxy) carbonyl , hydroxy or C 1 -C 4 alkyl; or (2) heteroaryl radicals optionally substituted by 1-2 radicals of amino, C 1 -C 2 alkylamino, di- (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals; and most
  • each R is independently a heterocyclyl radical optionally substituted by C 1 -C 4 alkyl; 31 , 30 each R is independently hydrogen radical or R ;
  • each R is independently hydrogen radical or (1) -CF 3 or C 1 -C 4 alkyl radical optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy or aryl -Ci -C 2 -alkoxy, aryl or heteroaryl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, C1-C 2 alkylamino, di-(C ⁇ -C 2 alkyl)amino, C 1 -C 2 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 5 alkanoyl, (C 1 -C 4 alkoxy) carbonyl , hydroxy, C 1 -C 4 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals; (2) cycloalkyl radical optionally substituted by 1-2 radicals of hydroxy or C 1
  • each R is independently hydrogen radical or (1) C 1 -C 4 alkyl radical optionally substituted by 1-2 radicals of aryl or heteroaryl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by a hydroxy, C 1 -C 4 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radical; or (2) cycloalkyl radical optionally substituted by 1-2 radicals of hydroxy or C 1 -C 4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by a hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3 radicals; and
  • each R is independently (1) hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo; or (3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or
  • each R is independently (1) hydrogen radicals; (2) Ci-Cs alkyl, C 2 -C 8 alkenyl or C 2 - C 8 alkynyl radicals optionally substituted by 1 - 3 radicals of amino, C 1 -C 4 alkylamino, di - (C 1 -C 4 - alkyl) amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano or halo; or (3) aryl, heteroaryl, aryl-C ⁇ -C 4 - alkyl, heteroaryl -C 1 -C 4 -alkyl , heterocyclyl, heterocyclyl -C 1 -C 4 -alkyl, C 3 -C 8 cycloalkyl or C 3 -C 8 - cycloalkyl-C ⁇ -C 4 - alkyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkyl
  • each R is independently a hydrogen or C 1 -C 4 alkyl radical
  • each R is independently (1) hydrogen radical; (2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl which is optionally substituted by 1 - 3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoyl - amino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl , alkylsulfonyl,
  • each R is independently (1) hydrogen radical; (2) C 1 -C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl which is optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl , cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; or (3) heterocyclyl,
  • R is independently a hydrogen or C 1 -C 4 alkyl radical
  • each R is independently a hydrogen or methyl radical
  • each R is independently hydrogen, alkyl, heteroaryl, aryl, arylalkyl or heteroarylalkyl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of cyano, halo, alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 4 .
  • each R is independently hydrogen or C 1 -C 4 alkyl, aryl, heteroaryl, aryl -C 1 -C 4 - alkyl or heteroaryl -C 1 -C 4 - alkyl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C
  • each R is independently a hydrogen or C 1 -C 4 alkyl radical.
  • the compounds of this invention have in general several asymmetric centers and are depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers .
  • the absolute configuration of the hydroxamic acid group is (R) .
  • Compounds of interest include the following:
  • Alkyl alone or in combination, means a straight -chain or branched- chain alkyl radical containing preferably 1- 15 carbon atoms (C 1 -C 15 ) , more preferably 1-8 carbon atoms (Ci-C ⁇ ) 1 even more preferably 1-6 carbon atoms (Ci-Cfs) , yet more preferably 1-4 carbon atoms (C 1 -C 4 ) , still more preferably 1-3 carbon atoms (C 1 -C 3 ) , and most preferably 1-2 carbon atoms (C 1 -C 2 ) •
  • Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl , iso- a yl, hexyl, octyl and the like.
  • Alkenyl alone or in combination, means a straight- chain or branched- chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C 2 -C 15 ), more preferably 2-8 carbon atoms (C 2 "Cs), even more preferably 2-6 carbon atoms (C 2 -C 6 ) , yet more preferably 2-4 carbon atoms (C 2 -C 4 ) , and still more preferably 2-3 carbon atoms (C 2 -C 3 ).
  • alkenyl radicals include ethenyl, propenyl , 2 -methylpropenyl , 1,4- butadienyl and the like.
  • Alkynyl alone or in combination, means a straight - chain or branched chain hydrocarbon radical having one or more triple bonds, preferably 1-2 triple bonds and more preferably one triple bond, and containing preferably 2-15 carbon atoms (C 2 -C 15 ), more preferably 2-8 carbon atoms (C 2 -C1 3 ), even more preferably 2-6 carbon atoms (C 2 -C 6 ), yet more preferably 2-4 carbon atoms (C 2 -C 4 ) , and still more preferably 2-3 carbon atoms (C 2 -C 3 ).
  • alkynyl radicals include ethynyl , propynyl (propargyl) , butynyl and the like.
  • Alkoxy alone or in combination, means a radical of the type "R-0-" wherein “R” is an alkyl radical as defined above and "0" is an oxygen atom.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy and the like.
  • Alkoxycarbonyl alone or in combination, means a radical of the type “R-O-C(O)-” wherein “R-0-” is an alkoxy radical as defined above and “C (0) " is a carbonyl radical .
  • Alkoxycarbonylamino alone or in combination, means a radical of the type “R-O-C (0) -NH-” wherein “R-O-C(O)” is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl , cycloalkyl, cycloalkylalkyl and the like.
  • Alkylthio alone or in combination, means a radical of the type "R-S-" wherein "R” is an alkyl radical as defined above and “S” is a sulfur atom.
  • alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec -butylthio, tert-butylthio and the like.
  • Alkylsulfinyl means a radical of the type “R-S(O)-" wherein "R” is an alkyl radical as defined above and “S(O)” is a mono-oxygenated sulfur atom.
  • alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl , isopropylsulfinyl, n-butylsulfinyl , iso-butylsulfinyl , sec -butylsulfinyl, tert-butylsulfinyl and the like.
  • Alkylsulfonyl means a radical of the type “R-S(0) 2 -" wherein “R” is an alkyl radical as defined above and “S(0) 2 " is a di - oxygenated sulfur atom.
  • alkylsulfonyl radicals include methylsulfonyl , ethylsulfonyl , n-propylsulfonyl , isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
  • Alkylsulfonylamino alone or in combination, means a radical of the type “R-S (0) 2 -NH- " wherein "R-S(0) 2 -” is an alkylsulfonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
  • Aryl alone or in combination, means a phenyl, biphenyl or naphthyl radical which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl , alkylsulfonyl and the like.
  • aryl radicals are phenyl, p-tolyl, 4 -methoxyphenyl , 4-(tert- butoxy) phenyl , 3 -methyl -4 -methoxyphenyl , 4 -CF 3 -phenyl , 4 - fluorophenyl , 4 -chlorophenyl , 3 -nitrophenyl , 3- aminophenyl , 3 -acetamidophenyl , 4 -acetamidophenyl , 2- methyl - 3 -acetamidophenyl , 2 -methyl - 3 -aminophenyl , 3- methyl -4 -aminophenyl, 2 -amino- 3 -methyIpheny1 , 2,4- dimethyl - 3 - aminophenyl , 4 -hydroxypheny1 , 3 -methyl -4- hydroxyphenyl , 4 - (4 -methoxyphenyl
  • Aryl - alkyl means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl , dibenzylmethyl , hydroxyphenylmethyl , methylphenylmethyl , diphenylmethyl , dichlorophenylmethyl , 2 - naphthylmethyl , 4 -methoxyphenylmethyl and the like.
  • Aryl - alkoxy means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2 -phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4- methoxyphenylmethoxy and the like.
  • Aryloxy alone or in combination, means a radical of the type "R-0-" wherein “R” is an aryl radical as defined above.
  • Aroyl alone or in combination, means a radical of the type "R-C(O)-" wherein “R” is an aryl radical as defined above and “-C(O)-” is a carbonyl.
  • Alkanoyl alone or in combination, means a radical of the type "R-C(O)-" wherein "R” is an alkyl radical as defined above and "-C(O)-” is a carbonyl radical.
  • alkanoyl radicals include acetyl , trifluoroacetyl, hydroxyacetyl , propionyl, butyryl, valeryl, 4 -methylvaleryl , and the like.
  • Alkanoylamino alone or in combination, means a radical of the type "R-C(0)-NH-" wherein "R-C(O)-" is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
  • Aminocarbonylamino means an amino substituted carbonyl substituted on a second amino (ureido) radical, wherein each amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
  • Bicyclic as used herein is intended to include both fused ring systems, such as naphthyl and ⁇ -carbolinyl , and substituted ring systems, such as biphenyl, phenylpyridyl, naphthyl and diphenylpiperazinyl .
  • Cycloalkyl alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic alkyl radical, preferably monocyclic, containing preferably 3-10 carbon atoms (C 3 -C 10 ) , more preferably 3-8 carbon atoms (C 3 - C ⁇ ) / even more preferably 3-6 carbon atoms (C 3 -C 6 ), which is optionally be benzo fused and which is optionally substituted as defined herein with respect to the definition of aryl.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl , cycloheptyl, octahydronaphthyl , tetrahydronaphthyl , dimethoxytetrahydronaphthyl , 2 , 3 -dihydro- IH- indenyl and the like.
  • Cycloalkylene is a cycloalkyl gem divalent radical, wherein cycloalkyl is as defined above.
  • cycloalkylene is monocyclic, containing preferably 3-10 carbon atoms (C 3 -C 10 ), more preferably 3-8 carbon atoms (C 3 -C 8 ) , even more preferably 3-6 carbon atoms (C 3 -C 6 ).
  • Cycloalkylalkyl alone or in combination, means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
  • Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl , cyclopentylmethyl , cyclohexylmethyl , 1- cyclopentylethyl, 1-cyclohexylethyl , 2- cyclopentylethyl , 2 - cyclohexylethyl , hydroxycyclopentylpropyl , tetrahydronaphthylpropyl , cyclohexylbutyl and the like.
  • Heteroatoms means nitrogen, oxygen and sulfur heteroatoms .
  • Heterocyclyl alone or in combination, means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4 , more preferably 1 to 3 , even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring.
  • Heterocyclyl is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N- oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems.
  • Heterocyclyl radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N- alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals.
  • heterocyclyl is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo- fused and optionally substituted by 1-2 oxo or thioxo radicals.
  • heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl , 4 -benzyl -piperazin- 1-yl, pyrimidinyl, tetrahydrofuryl , pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl , tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2 , 3 -dihydroindolyl, tetrahydroquinolinyl , 1,2,3, 4- tetrahydroisoquinolinyl, 1,2,3,4 - tetrahydro- 1- oxo-isoquinolinyl, 2 , 3 -dihydrobenzofuryl , benzopyranyl , methylenedioxyphenyl, ethylenedioxyphenyl and the
  • Heterocyclylene is a heterocyclyl gem divalent radical on a ring carbon atom, wherein heterocyclyl is as defined above.
  • heterocyclylene is a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-3, more preferably 1-2, most preferably 1, ring members are oxygen, sulfur or nitrogen heteroatoms.
  • Heterocyclylalkyl alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heterocyclyl radical as defined above, such as pyrrolidinylmethyl , tetrahydrothienylmethyl , piperidinylethyl and the like.
  • Heteroaryl alone or in combination, means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3 , even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally benzo fused or saturated carbocyclic fused, preferably 3-4 carbon atoms (C 3 -C 4 ) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl and heterocyclyl.
  • heteroaryl is a radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C 3 -C 4 - carbocyclic - fused.
  • heteroaryl groups include imidazolyl , 1 -benzyloxycarbonylimidazol - 4 -yl , pyrrolyl , pyrazolyl, pyridyl, 2 - (1 -piperidinyl) pyridyl, 2- (4- benzyl piperazin- 1 -yl) - 1 -pyridinyl , pyrazinyl, triazolyl, furyl, thienyl , oxazolyl , thiazolyl, indolyl, quinolinyl, 1 -oxido- 2 -quinolinyl , isoquinolinyl , 5,6,7, 8- tetrahydroquinolyl, 5,6,7, 8- tetrahydroiso- quinolinyl, quinoxalinyl , benzothiazolyl , ⁇ -carbolinyl , benzofuryl, benzimidazolyl ,
  • Heteroaroyl alone or in combination, means a radical of the type "R-C(O)-" wherein “R” is an heteroaryl radical as defined above and “-C(O)-” is a carbonyl.
  • Heteroaryl - alkyl means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3 -furyl - propyl, 2 -pyrrolylpropyl, chloroquinolinylmethyl , 2- thienylethyl, pyridylmethyl , 1-imidazolylethyl and the like.
  • Halogen and "halo”, alone or in combination, means fluoro, chloro, bromo or iodo radicals.
  • Haloalkyl alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals.
  • haloalkyl radicals include 1, 1, 1- trifluoroethyl, chloromethyl , 1-bromoethyl, fluoromethyl , difluoro- methyl, trifluoromethyl, bis (trifluoromethyl) methyl and the like.
  • Haloalkoxy alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals.
  • haloalkoxy radicals include 2 , 2 , 2 - trifluoroethoxy, chloromethoxy, 2 -bromoethoxy, fluoromethoxy, difluoro- methoxy, trifluoromethoxy, bis (trifluoromethyl) methoxy and the like.
  • Sulfinyl alone or in combination, means a diradical of the type “-S(O)-” wherein “S (O) " is a mono -oxygenated sulfur atom.
  • Sulfonyl alone or in combination, means a diradical of the type “-S(0) 2 -” wherein “S(0) 2 " is a di- oxygenated sulfur atom.
  • leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9 - (9 -phenylfluorenyl) , phenanthrenyl , durenyl and the like.
  • Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
  • Suitable acyl, alkoxycarbonyl and aralkoxy- carbonyl groups include benzyloxycarbonyl , t-butoxy- carbonyl , iso-butoxycarbonyl , benzoyl, substituted benzoyl, butyryl, acetyl, tri - fluoroacetyl , tri- chloro acetyl, phthaloyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1, 2 -bis (methylene) benzene, phthalimidyl , succinimidyl , maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • the heterocyclic groups can be mono-, di- or tri -substituted, such as nitrophthalimidyl .
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • aralkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
  • Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups.
  • Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri- isopropylsilyl, tert-butyldimethyl- silyl, dimethylphenylsilyl, 1, 2 -bis (dimethylsilyl) - benzene, 1, 2 -bis (dimethylsilyl) ethane and diphenyl- methylsilyl.
  • Silylation of an amino groups provide mono- or di-silylamino groups.
  • Silylation of amino- alcohol compounds can lead to a N,N,0- tri -silyl derivative.
  • Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
  • Suitable silylating agents are, for example, trimethyl- silyl chloride, tert-buty- dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
  • Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
  • Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
  • Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine.
  • a protecting group such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxycarbonyl protecting group can be removed utilizing an inorgan
  • Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4- methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
  • Procedures for preparing the compounds of this invention are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R) .
  • the compounds having one stereochemistry e.g., (R)
  • Sulfonamide (4) (when R 9 is H) may be halogenated, such as iodinated, and then carbonylated (See for example Schoenberg, A., et al, J. Org. Chem., 19 . , 3318, (1974))) and subsequently derivatised, amidated (See for example Corey, E.J. and Hegedus , L.S., J.Am. Chem. Soc. , 9_1, 1233 (1969) ) , arylated or alkylated (See for example Stille, J.K., Angew.
  • an appropriately substituted heterocyclic carboxaldehyde (6) (Scheme II) may be condensed, under basic conditions, with a glycine to give the hydroxy amino acid (7) (See for example Dullaghan, M.E. and Nord, F.F., J.Am.Chem. Soc . , 71, 5455 (1951) ) .
  • the hydroxy amino acid (7) is then protected (for example, esterified) to yield the protected amino acid (8) .
  • Cyclization of the protected amino acid (8) under acidic conditions with an appropriately functionalized aldehyde or ketone (2) can furnish the bicyclic intermediate (9) .
  • Sulfonylation, using Schotten-Baumann conditions, of the bicyclic intermediate (9) can give the sulfonamide (10a) .
  • Sulfonamide (10a) can be readily converted into the corresponding hydroxamic acid (11) , where R 11 is -OH, using procedures well known to those skilled in the art.
  • Sulfonamide (10b) can be readily converted into the corresponding hydroxamic acid (11) using procedures well known to those skilled in the art.
  • halogenating agents for example PC1 5 , PBr 3 , and the like
  • hydroxy amino acid (7) may be converted with nucleophiles, electrophiles and the like as described above or under Mitsonobu conditions to yield the amino acid intermediate (12) (Scheme III) .
  • the amino acid intermediate (12) may subsequently be cyclised, sulfonylated and converted to hydroxamic acids using the aforementioned procedures to give hydroxamic acid (11) .
  • sulfonamides (10a) or (10b) may be halogenated, such as iodinated, and then carbonylated (See for example Schoenberg, A., et al, J. Org. Chem., ⁇ , 3318, (1974))) and subsequently derivatised, amidated (See for example Corey, E.J. and Hegedus, L.S., J. Am.Chem. Soc . , _1, 1233 (1969)), arylated or alkylated (See for example Stille, J.K., Angew. Int. Ed. Engl . , 21, 508 (1986)) to yield sulfonamides (10a) or (10b) where R 9 is other than H.
  • halogenated such as iodinated
  • carbonylated See for example Schoenberg, A., et al, J. Org. Chem., ⁇ , 3318, (1974)
  • amidated See for example Corey, E.J
  • a second general synthesis useful for the preparation of the novel compounds of this invention is illustrated in Scheme IV whereby an appropriately substituted heterocycle (13) or (14) is cyclized into bicyclic intermediate (15) in the presence of a base, such as KOH in THF, potassium carbonate in DMF, and the like, where L a and L b are each a leaving group, such as chloro, bromo, iodo, mesylate, tosylate and the like, or -V-L a is an appropriately substituted ketone or aldehyde group, or -V-L a or -W-L b is an appropriately substituted unsaturated aldehyde, ketone, ester, amide, nitrile or the like Michael reaction acceptor, or other cyclization method well known to those skilled in the art.
  • a base such as KOH in THF, potassium carbonate in DMF, and the like
  • L a and L b are each a leaving group, such as chloro, bromo,
  • the bicyclic intermediate (15) can be prepared in two steps from a protected amino acid (16) ⁇ wherein the R -S0 2 - group is introduced after cyclization with the amino group (-NH 2 ) (see Scheme V).
  • R , R , R , R , R , R and R may be introduced prior to or after the cyclization step provided the radicals do not interfer with, compete with or inhibit the cyclization reaction.
  • R , R , R , R , R and R may be introduced prior to or after the cyclization step provided the radicals do not interfer with, compete with or inhibit the cyclization reaction.
  • One skilled in the art is well versed in such matters and knows when and how to introduce the various groups and utilize protecting groups to prevent such deleterious effects.
  • the intermediates (13) , (14) and (16) are readily prepared from commercially available starting materials, for example as shown in Scheme VI, wherein P 1 and P 2 are protecting groups, L a and L b are leaving groups, A 1 is a radical that can converted into -W-L b and A 2 is a radical that can be converted into -V-L a .
  • a third general synthesis useful for the preparation of the novel compounds of this invention is cyclization reactions, such as Friedel -Crafts and the like reactions, directly onto the heterocyclic ring as illustrated in Scheme VII, whereby an appropriately substituted heterocycle (17) or (18) is cyclized into bicyclic intermediate (15) by nucleophilic displacement of the leaving group L a or L b , such as in the presence of acid or a Friedel -Crafts reagent, such as tin chloride, aluminum chloride and the like, or other nucleophilic reaction conditions, such as formation of an anion on the ring, for example, metal halogen exchange and the like.
  • cyclization reactions such as Friedel -Crafts and the like reactions
  • -W-L b and -V-L a are groups containing an electrophilic group, such as halogen (CI, Br, I) , ester, carboxylic acid, carboxylic acid halide, aldehyde, ketone, nitrile and the like.
  • Heterocycle (17) can be prepared from the sulfonamide (19) by reaction with L b -W-L c or A 1 -! wherein A 1 is a radical that can be coverted into -W-L b and wherein L c is a leaving group similar to L a and L b .
  • Sulfonamide (19) can be readily prepared from the corresponding protected or unprotected amino acid by reaction with the appropriate sulfonyl chloride (R -S0 2 -
  • amino acid is either commercially available or is readily prepared from commercially available starting materials using methods well known to those skilled in the art.
  • Heterocycle (18) can be prepared by coupling the electrophile (20) with the sulfonamide (21) in the presence of a base, such as potassium carbonate and the like.
  • the radical A 2 may be used in place of -V-L in sulfonamide (21) to avoid reaction of -V-L a with the sulfonamide group, in which event A 2 is converted into -V-L a after reaction of the electrophile (20) with the sulfonamide (21) .
  • Electrophiles (20) are either commercially available or is readily prepared from commercially available starting materials using methods well known to those skilled in the art.
  • Sulfonamide (21) can be prepared from the corresponding protected or unprotected amino acid by reaction with the appropriate sulfonyl chloride (R - S0 2 -C1) or the like.
  • the amino acid is either commercially available or is readily prepared from commercially available starting materials using methods well knoen to those skilled in the art.
  • the carboxylic acid intermediate (23) can be selectively reduced to an aldehyde using appropriate reducing agents, such as DIBAL-H and the like, which is converted into the sulfonamide imine (24) by reaction of the aldehyde with the the sulfonamide
  • the sulfonamide imine (24) can then be reacted with a carbon nucleophile which can be converted into a carboxylic acid or ester, such as cyanide anion followed by hydrolysis, 1,3-dithiane anion followed by deprotection and oxidation, and the like, to yield the protected or unprotected sulfonamide intermediate (22) .
  • a carbon nucleophile which can be converted into a carboxylic acid or ester, such as cyanide anion followed by hydrolysis, 1,3-dithiane anion followed by deprotection and oxidation, and the like, to yield the protected or unprotected sulfonamide intermediate (22) .
  • the substituted protected carboxylic acid intermediate (23) is commercially available or may be readily prepared from commercially available starting materials using methods well known to those skilled in the art.
  • an appropriately 3 , 4 -substituted thiophene carboxaldehye (25) wherein P 2 is a hydroxy protecting group
  • P 2 is a hydroxy protecting group
  • a protected N- sulphonylated glycine (26) wherein P ⁇ is a carboxylic acid protecting group such as an ester and the like, to give beta-hydroxy amino acid (27) (see for example Dikshit, D.K., et al . Tet . Lett. 1988, 29(25), 3109- 3110) .
  • the beta-hydroxy amino acid (27) may then be protected with a hydroxy protecting group P 3 such as by acylation of the beta-hydroxy group and separated into threo and erythro diastereomers.
  • P 2 may then be removed and Mitsonobu cyclization conditions can give intermediate (28) .
  • P x may then be removed, a hydroxamic acid formed and P 3 removed to give (29a) utilizing methodology familiar to one skilled in the art.
  • (28) may be deprotected to the beta-hydroxy acid and converted to beta-carbamoyl hydroxamate (29b) or other substituted oxy group (i.e., -OR 20 ) compound (29c) again utilizing methodology familiar to one skilled in the art.
  • Scheme XI illustrates an alternative general synthesis (Claisen ring contraction) useful for the preparation of the novel compounds of this invention as illustrated in Scheme IV whereby an appropriately substituted heterocycle (14) is cyclized into bicyclic intermediate (15).
  • R e is a leaving group, such as bromine atom
  • the coupling can be performed utilizing PdCl 2 (PPh 3 ) 2 catalyzed Stille reaction (Stille, Chem. Int. Ed. Engl. 25:508-524 (1986); and Stille et al., J. Am. Chem. Soc. 101:4992-4998 (1979)).
  • the lactone (34) is then prepared from the Z- allylic alcohol (33) .
  • Many methods that are available to form medium to large lactones (Meng et al . , "Topics in Current Chemistry, Ring Closure Methods in the
  • the lactone (34) can be prepared from the Z-allylic alcohol (33) utilizing Mukaiyama's reagent (Mukaiyama et al . , Chem. Lett. 1976:49-50; and Mukaiyama, Chem. Int. Ed. Engl. 18:707-721 (1979)) under high dilution conditions (Funk et al., J. Org. Chem. 49:4320-4322 (1984); Cooper et al . , J. Chem. Soc, Chem. Commun., 1987:1220; and Cooper et al . , Tet. Lett. 28:3031 (1987)).
  • Claisen ring contraction of the lactone (34) can be effected by treatment of the lactone with various combinations of reagents including TBDMSC1/LDA, TBDMSOTf/LHMDS and TBDMSOTf/KHMDS, such as in THF at about -78°C (Ireland et al . , J. Am. Chem. Soc. 98:2868- 2877 (1976)) followed by heating the reaction, for example to reflux, to give the Claisen product as a protected carboxylic acid which can be deprotected, such as with , to yield the heterocycle carboxylic acid (35) . Any silyl ester of the heterocycle carboxylic acid (35) produced in the reaction can be removed by treatment with aqueous K 2 C0 3 in THF-MeOH to give the free the heterocycle carboxylic acid (35) .
  • the relative stereochemistry between the vinyl and carboxylic acid groups of the heterocycle carboxylic acid (35) may be cis (Abelman et al . , J. Am. Chem. Soc. 104:4030-4032 (1982); Funk et al . , Tetrahedron 42:2831- 2845 (1986); and Corey et al . , J. Am. Chem. Soc. 118:1229-1230 (1996)).
  • the carboxylic acid group of the heterocycle carboxylic acid (35) or the corresponding ester can be epimerized, for example by treatment with base, and the resulting cis and trans diasteriomers can be separated and the R and S enantiomers can be separated using methods well known to those skilled in the art.
  • the 2 - trimethylsilylethyl protecting group can be removed from the carboxylic acid group without substantial epimerization from the cis stereochemistry with fluoride in the presence of DMAP.
  • the hydroxamic acids (I) of this invention can then be prepared from the heterocycle carboxylic acid (35) using PyBroP,
  • the alkene group of the heterocycle carboxylic acid (35) can be functionalize using methods well known in the art to produce a variety of groups .
  • Suzuki et al . Chem. Rev. 95:2457-2483 (1995)
  • coupling of the hydroboration product of an ester of heterocycle carboxylic acid (35) with iodobenzene can yield heterocycles substituted with a phenethyl group.
  • This functionalization can be carried out in one pot by hydroboration with 9-BBN in THF, to give a terminally substituted alkyl borane that is then treated with iodobenzene, K 2 C0 3 and catalytic PdCl 2 (dppf).
  • Sulfonyl halides can be prepared by the reaction of a suitable alkyl, aryl, heteroaryl, heterocyclyl and the like Grignard or lithium reagents with sulfuryl chloride, or sulfur dioxide followed by oxidation with a halogen, preferably chlorine.
  • Alkyl, heteroaryl, heterocyclyl, aryl and the like Grignard or lithium reagents can be prepared from their corresponding halide (such as chloro or bromo) compounds which are commercially available or readily prepared from commercially available starting materials using known methods in the art.
  • mercaptans may be oxidized to sulfonyl chlorides using chlorine in the presence of water under carefully controlled conditions.
  • sulfonic acids may be converted into sulfonyl halides using reagents such as PCI5, SOCI 2 , C1C(0)C(0)C1 and the like, and also to anhydrides using suitable dehydrating reagents.
  • the sulfonic acids are either commercially available or may be prepared using procedures well known in the art from commercially available starting materials.
  • sulfinyl halides or sulfenyl halides can be utilized to prepare compounds wherein the sulfonyl moiety is replaced by an sulfinyl or thio moiety, respectively.
  • Arylsulfonic acids, benzo fused heterocyclyl sulfonic acids or heteroaryl sulfonic acids can be prepared by sulfonation of the aromatic ring by well known methods in the art, such as by reaction with sulfuric acid, SO 3 , SO 3 complexes, such as DMF(S0 3 ), pyridine (SO 3 ) , N,N-dimethylacetamide (SO 3 ) , and the like.
  • sulfonyl halides are prepared from such aromatic compounds by reaction with DMF(S0 3 ) and SOCI 2 or C1C (0) C (0) CI . The reactions may be performed stepwise or in a single pot.
  • Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides, heterocyclylhalides , heteroarylhalides , and the like are commercially available or can be readily prepared from starting materials commercially available using standard methods well known in the art.
  • Thioether derivatives can be converted into the corresponding sulfone or sulfoxide by oxidizing the thioether derivative with a suitable oxidation agent in a suitable solvent.
  • suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate) , meta- chloroperoxybenzoic acid, periodic acid and the like, including mixtures thereof.
  • Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof .
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985) .
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl) , and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl) .
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl) , and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl) .
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
  • Step A 4 , 5 , 6 , 7 - tetrahydro- thieno [3 , 2 -ci pyridine- 6 (R) - carboxylic acid»HCl Hydrogen chloride (IN, 0.3 ml, 2.9 mmole) was added into a mixture of 3 - (2 - thienyl) -D-alanine (500 mg, 2.9 mmole) and formaldehyde (37%, 0.72 ml, 8.8 mmole) in 5 ml of water. The reaction mixture was then heated to 90°C for 3 hr.
  • Step B methyl 4 , 5 , 6 , 7 - tetrahydro- thieno [3 , 2 -ci pyridine- 6 -carboxylate*HCl
  • Step C methyl 5 - (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydro- thieno T3 , 2 -ci yridine- 6 -carboxylate*HCl
  • N,N-dimethylformamide (5 ml) was stirred at 25°C for 3 hr. The N, N-dimethylformamide was then removed under reduced pressure and the residue was subjected to column chromatography (ethylacetate:hexane, 1:1) yielding methyl 5- (4 -methoxyphenylsulfonyl) -4 , 5, 6 , 7 -tetrahydrothieno [3 , 2 -c] pyridine- 6 -carboxylate hydrochloride salt (390 mg, 54%): 1H NMR (CDCI3, 400 MHz), ppm: 7.78(d,
  • Step D 5 - (4 -methoxyphenylsulfonyl) -4.5 , 6 , 7 - tetrahydrothieno [3 , 2 -ci yridine- 6 -carboxylic acid
  • Step E 5- (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 -tetrahydrothieno [3 , 2 -ci pyridine- 6 -hydroxamic acid
  • Step A threo ⁇ - 2 - thienylserine
  • thiophene- 2 -carboxaldehyde 44.4g, 0.39mol
  • absolute ethanol 80.0ml, 4.9M
  • glycine 14.8g, 0.20mol
  • the resulting suspension was cooled to 0°C, at which time a solution of potassium hydroxide (22.2g, 0.39mol) in absolute ethanol (120.0, 3.3M) was introduced in a dropwise manner.
  • the reaction mixture was kept at -10°C for ninety minutes. The yellow solid which had precipitated during this time was collected via filtration and washed with ethanol.
  • Step B 4.5 , 6 , 7 - tetrahydro- 7 -hvdroxy- thieno [3.2 - ci pyridine- 6 -carboxylic acid hydrogen sulfate salt
  • Step C 5- (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydro- 7 -hydroxy- thieno [3 , 2 -ci pyridine- 6 -carboxylic acid
  • the 1,4-dioxane was removed in vacuo and the remaining residue was diluted with water and ethyl acetate. The layers were separated. The aqueous phase was acidified to a pH of about 2 using 2M HCl and the product was extracted into ethyl acetate (twice) .
  • Step D 5 - (4 -methoxyphenylsulfonyl) -4.5 , 6 , 7 - tetrahydro - 7 - acetoxy- thieno T3 , 2 - ci pyridine- 6 - carboxylic acid
  • Step E 5 - (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahvdro- 7 -acetoxy- thieno f3.2-cl pyridine-6 -hydroxamic acid
  • 5- (4-methoxybenzenesulfonyl) - 4,5,6,7 -tetrahydro- 7 -acetoxy- thieno [3 , 2 -c] pyridine- 6 - carboxylic acid (0.19g, 0.46mmol) in dichloromethane (20.0ml) was added hydroxylamine hydrochloride (0.77g, 9.20mmol) at 0°C under nitrogen.
  • Step A DL-cis 2 - (2 - thienyl) serine
  • 2-thiophene arboxaldehyde (488. Og, 4.35mol) in absolute ethanol (900ml)
  • glycine 98.5% purity, 165.8g, 2.17mol
  • the resulting suspension was cooled to 0°C.
  • a solution of potassium hydroxide (87.9% purity, 277.6g, 4.35mol) in absolute ethanol (1.3L) was then added dropwise over 7.5 hours. During this time, the reaction became homogeneous and shortly after a precipitate formed.
  • Step B DL-cis 7 -hvdroxy-4.5.6 , 7 - tetrahydro- thieno r3.2 - cl pyridine- 6 -carboxylic acid
  • Step C DL-cis-7 -hvdroxy-5- (4 -methoxyphenylsulfonyl) - 4,5,6, 7- tetrahydro- thieno [3 , 2-cl pyridine- 6 -carboxylic acid
  • a suspension of DL-cis 7 -hydroxy-4 , 5 , 6 , 7 - tetrahydrothieno [3 , 2 -c] pyridine- 6 -carboxylic acid (35. Og, 175.9 mmol) in 9% sodium carbonate (440.0ml) was cooled to 0°C.
  • Step D DL-cis 7 -acetoxy- 5 - (4 -methoxyphenylsulfonyl) - 4,5,6,7- tetrahydrothieno [3 , 2 -ci pyridine- 6 -carboxylic acid
  • Step E DL-cis 7 -Hydroxy- 5 - (4 -methoxyphenylsulfonyl) - 4,5,6, 7- tetrahydrothieno ⁇ 3 ,2-cl pyridine- 6 -hydroxamic acid
  • DL-cis 7 -acetoxy- 5 - (4 -methoxy phenylsulfonyl) -4,5,6,7- tetrahydrothieno [3,2-c] pyridine- 6 -carboxylic acid 5.3g, 12.9mmol
  • dichloromethane 60ml
  • oxalyl chloride (12.9ml of a 2M dichloromethane solution, 25.8mmol
  • Step A DL-cis 7- (N-benzylaminocarbonyloxy) -5- (4- methoxyphenylsulfonyl) -4,5,6, 7 -tetrahydrothieno- [3 , 2-cl ⁇ pyridinyl - 6 -carboxylic acid
  • Step B DL-cis-7- (N-benzylaminocarbonyloxy) - 5- (4- methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- f3 , 2 -cl - pyridinyl -6 -hydroxamic acid
  • DL-cis 7 - (N-benzylamino carbonyloxy) - 5 - (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3,2-c] -pyridinyl - 6 -carboxylic acid (O.llg, 0.22mmol) in anhydrous dichloromethane was added oxalyl chloride (0.22ml, 0.44mmol) at 0°C, under argon.
  • Step A DL-cis 7 - (N-phenylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6, 7 - tetrahydrothieno- T3 , 2 -ci - pyridinyl - 6 -carboxylic acid
  • DL-cis 7 - (N-phenylamino carbonyloxy) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridinyl -6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -4 , 5, 6, 7 -tetrahydrothieno [3 , 2 -c] pyridine- 6- carboxylic acid in the same manner as DL-cis 7-(N- benzylaminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) - 4, 5, 6, 7- tetrahydrothieno- [3,2-c] -pyridinyl - 6 -carboxylic acid.
  • Step B DL-cis 7 - (N-phenylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-cl - pyridinyl -6 -hydroxamic acid
  • DL-cis 7- (N-phenylaminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] -pyridinyl -6 - hydroxamic acid was prepared in the same manner as DL- cis 7- (N-benzylaminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5, 6, 7 -tetrahydrothieno- [3,2-c] -pyridinyl
  • Step A DL-cis 7 - (N-methylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -cl - pyridinyl- 6 -carboxylic acid
  • DL-cis 7 - (N-methylamino carbonyloxy) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridinyl -6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine-6 - carboxylic acid in the same manner as DL-cis 7-(N- benzylaminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) - 4, 5, 6, 7 -tetrahydrothieno- [3,2-c] -pyridinyl -6 -carboxylic acid.
  • Step B DL-cis 7 - (N-methylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6,7 -tetrahydrothieno- [3 , 2-cl ⁇ pyridinyl - 6 -hydroxamic acid
  • DL-cis 7- (N-methylaminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7- tetrahydrothieno- [3,2-c] -pyridinyl- 6- hydroxamic acid was prepared in the same manner as DL- cis 7- (N-benzylaminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] -pyridinyl - 6 - hydroxamic acid.
  • Step A DL-cis 7 - (N- isopropylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 -tetrahydrothieno- f3,2-c1 - pyridinyl- 6 -carboxylic acid
  • DL-cis 7 - (N- isopropyl aminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridinyl -6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6- carboxylic acid in the same manner as
  • Step B DL-cis 7 - (N- isopropylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-cl ⁇ pyridinyl- 6 -hydroxamic acid
  • DL-cis 7- (N-isopropylaminocarbonyloxy) -5- (4- methoxypheny1 sulfonyl ) -4,5,6,7- tetrahydrothieno - [3,2- c] -pyridinyl - 6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c
  • Step A DL-cis 7 - (N- (4 -phenoxyphenyl ) aminocarbonyloxy) 5- (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- T3,2-c1 -pyridinyl -6 -carboxylic acid
  • DL-cis 7-(N-(4- phenoxyphenyl) aminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] -pyridinyl -6 - carboxylic acid was prepared from DL-cis 7 -hydroxy- 5 - (4 - methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno [3 , 2 - c] pyridine- 6 -carboxylic acid in the same manner as DL- cis 7- (N-benzylaminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 -tetrahydrothieno- [3,2-c]
  • Step B DL-cis 7 - (N- (4 -phenoxyphenyl) aminocarbonyloxy) - 5- (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno - [3,2-cl -pyridinyl -6 -hydroxamic acid
  • DL-cis 7- N- (4 -phenoxyphenyl) aminocarbonyloxy) -5- (4- methoxyphenylsulfonyl) -4 , 5 , 6, 7 -tetrahydrothieno- [3,2-c] - pyridinyl- 6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) -5- (4- methoxyphenylsulfonyl) -4 , 5 , 6 , 7 -tetrahydrothieno- [3,2-c] - pyridinyl- 6 -hydroxamic acid.
  • Step B DL-cis 7 - (N- (1 -phenylethyl) aminocarbonyloxy) - 5 - (4 -methoxyphenylsulfonyl) -4,5,6, 7 - tetrahydrothieno- [3,2- cl -pyridinyl- 6 -hydroxamic acid
  • DL-cis 7- (N- (1 -phenylethyl) aminocarbonyloxy) -5- (4- methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 -tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid.
  • Step A DL-cis 7 - (N- (4 -methoxyphenyl) aminocarbonyloxy) - 5 - (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3,2-cl -pyridinyl -6 -carboxylic acid Utilizing 4 -methoxyphenyl isocyanate, DL-cis 7-(N-(4- methoxyphenyl) aminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] -pyridinyl - 6 - carboxylic acid was prepared from DL-cis 7 -hydroxy- 5 - (4 - methoxyphenyl sulfonyl) -4 , 5, 6 , 7- tetrahydrothieno [3 , 2-c]
  • Step B DL-cis 7 - (N- (4 -methoxyphenyl) aminocarbonyloxy) -
  • DL-cis 7- (N- (4 -methoxyphenyl) aminocarbonyloxy) -5- (4- methoxyphenylsulfonyl) -4 , 5 , 6, 7 -tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5- (4 - methoxyphenylsulfonyl) -4 , 5, 6, 7 -tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid.
  • Step A DL-cis 7 - (N- (phenethyl) aminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6,7 -tetrahydrothieno- [3 , 2 -cl - pyridinyl -6 -carboxylic acid
  • DL-cis 7 - (N- (phenethyl) aminocarbonyloxy) -5- (4 -methoxyphenyl sulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridinyl -6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6 - carboxylic acid in the same manner as DL-cis 7-(N- benzylaminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) - 4, 5, 6, - tetrahydrothieno- [3,2-c] -pyridinyl -6 -carboxylic acid.
  • Step B DL-cis 7 - (N- (phenethyl) aminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6,7 -tetrahydrothieno- [3 , 2 -cl - pyridinyl -6 -hydroxamic acid
  • pyridinyl -6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6, 7 -tetrahydrothieno- [3,2-c
  • Step A DL-cis 7 - (N-cvclohexylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6, 7 - tetrahydrothieno- [3 , 2-cl - pyridinyl - 6 -carboxylic acid
  • DL-cis 7 - (N- cyclohexyl aminocarbonyloxy) - 5 - (4 -methoxyphenyl sulfonyl ) -4,5,6,7- tetrahydrothieno- [3 , 2-c] -pyridinyl -6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6 - carboxylic acid in the same manner as DL-cis 7-(N- benzylaminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) - 4 , 5 , 6 , 7 -tetrahydrothieno- [3,2-c] -pyridinyl- 6 -carboxylic acid.
  • Step B DL-cis 7 - (N-cvclohexylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5.6, 7 - tetrahydrothieno- [3 , 2-cl ⁇ pyridinyl -6 -hydroxamic acid
  • DL-cis 7- (N-cyclohexylaminocarbonyloxy) -5- (4 -methoxy phenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] - pyridinyl - 6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] • pyridinyl - 6 -hydroxamic acid.
  • Step A DL-cis 7 - (N- (2 -biphenyl) aminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4,5,6, 7 -tetrahydrothieno- [3.2-cl - pyridinyl -6 -carboxylic acid
  • DL-cis 7 - (N- (2 -biphenyl) aminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridinyl- 6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -4,5,6, 7- tetrahydrothieno [3 , 2-c] pyridine- 6- carboxylic acid in the same manner as DL-cis 7-(N- benzylaminocarbonyloxy) -5- (4 -methoxyphenylsulfonyl) - 4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] -pyridinyl - 6 - carboxylic acid
  • Step B DL-cis 7 - (N- (2 -biphenyl) aminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4.5,6,7 -tetrahydrothieno- [3 , 2 -cl - pyridinyl -6 -hydroxamic acid
  • DL-cis 7- (N- (2 -biphenyl) aminocarbonyloxy) -5- (4 -methoxy phenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid was prepared in the same manner as DL-cis 7 - (N-benzylaminocarbonyloxy) - 5 - (4 - methoxyphenylsulfonyl) -4 , 5, 6 , 7 -tetrahydrothieno- [3,2-c] - pyridinyl -6 -hydroxamic acid.
  • Step A DL-cis 7 - (N- (4 -butoxycarbonylphenyl) amino carbonyloxy) -5- (4 -methoxyphenylsulfonyl) -4,5,6.7- tetrahvdrothieno- [3.2-cl -pyridinyl-6-carboxylic acid Utilizing 4 -butoxycarbonylphenyl isocyanate, DL-cis 7- (N- (4 -butoxycarbonylphenyl) aminocarbonyloxy) -5- (4- methoxy phenylsulfonyl) -4 , 5 , 6, 7 -tetrahydrothieno- [3,2- cl -pyridinyl - 6 -carboxylic acid was prepared from DL-cis 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -4, 5, 6, 7- tetrahydrothieno [3 , 2 -c] pyr
  • Step B DL-cis 7 - (N- (4 -butoxycarbonylphenyl) amino carbonyloxy) -5 - (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno- r3.2-cl -pyridinyl - 6 -hydroxamic acid
  • Step A cis -7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) - 6 - (methoxycarbonyl ) -4,5,6,7- tetrahydrothieno [3,2- cl pyridine
  • Step B cis- 2 -iodo- 7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -6- (methoxycarbonyl) -4.5 , 6 , 7- tetrahydrothieno [3 , 2-cl pyridine
  • Step C cis-7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) -2 - (N- benzyl -N-methylaminocarbonyl) -6- (methoxycarbonyl) - 4 , 5 , 6 , 7 - tetrahydrothieno- f3, 2-cl -pyridine
  • a mixture of 2 - iodo- 7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl) -6- (methoxycarbonyl) - 4 , 5 , 6 , 7 - tetrahydrothieno [3 , 2-c] pyridine (509 mg, 1.0 mmole), N-methyl -N-benzyl amine (3.0 mL) and nickel tetracarbonyl (0.39 mL, 3 mmole) was stirred well and heated at 55 °C under argon atomsphere for 2 h
  • Step D cis-7 -hvdroxy-5- (4 -methoxyphenylsulfonyl) -2 - (N- benzyl-N-methylaminocarbonyl) -4,5,6, 7 - tetrahydrothieno- [3,2-cl -pyridine- 6 -carboxylic acid
  • cis-7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -2- (N-benzyl-N-methylaminocarbonyl) -6- (methoxy carbonyl) -4, 5, 6, 7- tetrahydrothieno- [3, 2-c] -pyridine 530 mg, 1.0 mmole) in THF (4.0 mL) and H 2 0 (4.0 mL) at 25°C was added LiOH-H 2 0 (124 mg, 3.0 mmole) in one portion.
  • Step E cis - 7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) - 2 - (N- benzyl-N-methylaminocarbonyl) -4,5,6,7 - tetrahydrothieno - [3,2-cl -pyridine- 6 -hydroxamic acid
  • cis - 7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl) -2 - (N-benzyl -N-methylaminocarbonyl) -4,5,6,7- tetrahydrothieno- [3 , 2 -c] -pyridine- 6 -carboxylic acid (516 mg, 1.0 mmole) in DMF (5.0 mL) at 25 °C was sequentially added hydroxylamine hydrochloride (209 mg, 3.0 mmole), N,N- diisopropylethylamine (0.7 L,
  • Step A cis- 2 - iodo -7 -hvdroxy- 5 - (4 -methoxyphenyl sulfonyl) -4,5,6, 7 - tetrahydrothieno [3 , 2 -cl pyridine- 6- carboxylic acid cis-2 -Iodo-7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) - 4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6 -carboxylic acid was prepared from cis- 7 -hydroxy- 5 - ( -methoxyphenyl sulfonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6- carboxylic acid in the same manner as cis - 2 - iodo- 7 - hydroxy- 5- (4 -methoxy phenylsulfonyl) -6
  • Step B cis - 7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) -2 - phenyl-4 , 5 , 6 , 7- tetrahydrothieno- [3,2-cl -pyridine- 6- carboxylic acid
  • Step C cis-7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) -2 - phenyl -4,5.6,7- tetrahydrothieno- T3 , 2 -cl -pyridine- 6 - hydroxamic acid cis-7 -Hydroxy- 5- (4 -methoxyphenylsulfonyl) - 2 -phenyl -
  • Step B cis - 7 -hydroxy- 5 - (4 -methoxyphenylsulfonyl) - 2 - (methoxycarbonyl) -4,5,6,7 -tetrahydrothieno [3 , 2 -cl pyridine- 6 -carboxylic acid
  • a suspension of cis-7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl) -2, 6 -bis (methoxycarbonyl) -4,5,6, 7- tetrahydro thieno [3, 2-c] pyridine (441 mg, 1.0 mmole) in THF (5 mL) and H 2 0 (5 mL) was added LiOH-H 2 0 (46 mg, 1.1 mmole) in one portion.
  • Step C cis- 7 -hydroxy- 5- ( -methoxyphenylsulfonyl) -2 - (methoxycarbonyl ) -4,5,6,7- tetrahydrothieno
  • 3-cl pyridine- 6 -hydroxamic acid cis-7 -Hydroxy- 5- (4 -methoxyphenylsulfonyl) -2- (methoxy carbonyl) -4,5,6,7 -tetrahydrothieno [3,2-c] pyridine- 6- hydroxamic acid was prepared from cis-7 -hydroxy- 5- (4 - methoxyphenylsulfonyl) -2- (methoxycarbonyl) -4,5,6,7- tetrahydrothieno [3 , 2 -c] pyridine- 6 -carboxylic acid in the same manner as cis-7 -hydroxy- 5 - (4 -methoxyphenyl sulfonyl
  • cis -7 -hydroxy- 5- (4 -methoxyphenyl sulfonyl) -2- (4 -morpholinocarbonyl) -4 , 5 , 6 , 7 - tetrahydro thieno- [3 , 2-c] -pyridine-6 -hydroxamic acid was prepared from cis- 2 - iodo -7 -hydroxy- 5- (4 -methoxyphenylsulfonyl) -6- (methoxycarbonyl ) -4,5,6,7- tetrahydrothieno [3,2-c] pyridine in the same manner as cis-7 -hydroxy- 5- (4- methoxyphenylsulfonyl) -2- (N-benzyl - -methylamino carbonyl) -4, 5, 6, 7 -tetrahydrothieno- [3,2-c] -pyridinyl-6- hydroxamic acid: White solid;
  • Step A 3 - Phenyl -2 - thien- 3 -yl -acrylic acid
  • Step B 3 - Phenyl -2 - thien-3 -yl -propionic acid
  • Step C Methyl 3 -Phenyl - 2 - thien- 3 -yl -propionate
  • Step D 3 - henyl - 2 - thiophen- 3 -yl -propionaldehvde
  • a stirred cooled (-78°C) solution of methyl 3 -phenyl - 2-thien-3-yl-propionate (8.3 g,33.73 mmol) in 65 mL anhydrous toluene under Argon was added a pre- cooled (-78°C) solution of diisobutylaluminum hydride (52.5 mL of a 1 M solution in toluene, 52.5 mmol) dropwise, via cannula, so the internal temperature of the reaction does not rise above -65°C.
  • Step E 2 -Hydroxy-4 -phenyl-3 - thien-3 -yl -butyronitrile
  • ammonium chloride (1.79 g, 33.5 mmol)
  • concentrated ammonium hydroxide (20 mL, 143.79 mmol)
  • 3 -phenyl -2 - thiophen- 3-yl-propionaldehyde (6.19 g, 29.44 mmol) in 60 mL of diethyl ether.
  • the mixture was capped tightly before removing the ice bath and was stirred at room temperature overnight.
  • Step F 2 -Hydroxy- 4 -phenyl - 3 - thien- 3 -yl -butyric acid
  • a suspension of 2 -hydroxy- 4 -phenyl - 3 - thien- 3 -yl - butyronitrile (7.74 g, 29.44 mmol) in 75 mL concentrated hydrochloric acid was heated to reflux for 2 hours.
  • the mixture was cooled to room temperature, and treated with concentrated aq potassium hydroxide to pH 5-6.
  • Step G Methyl 2 -hvdro ⁇ y-4 -phenyl - 3 - thien- 3 -yl -butyrate
  • 2 -hydroxy- 4 -phenyl - 3 - thien- 3 - yl-butyric acid 4.2 g, 16 mmol
  • the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, and water.
  • the combined organic phases were dried (magnesium sulfate) , filtered and evaporated to afford crude product.
  • Step H Methyl 2 - (4 -methoxyphenylsulfonyl) amino- 4 - phenyl -3 -thien- 3 -yl -butyrate
  • triphenylphosphine 2.91 g, 11 mmol
  • diisopropyl azodicarboxylate 2 mL, 11.2 mmol
  • Step I Methyl 4 - (N- carboxymethyl -N- (4 -methoxyphenyl sulfonyl) -amino) -4 -phenyl-3 - thien-3 -yl-butyrate
  • a solution of the crude methyl 2- (4- methoxyphenylsulfonyl) amino -4 -phenyl -3 - thien- 3 -yl- butyrate (single diastereomer) in 60 mL of tetrahydrofuran:N,N-dimethylformamide (2:1) was added a solution of potassium bis- (trimethylsilyl) amide in toluene (4.64 mL of a 0.5 M solution, 2.32 mmol) dropwise with stirring under Argon.
  • Step J Methyl 4 -benzyl - 6 - (4 -methoxyphenylsulfonyl) - 8 - oxo -5 ,6.7, 8- tetrahydro -4H- thieno [2 , 3 , di azepine- 5- carboxylate; and Methyl 4 -benzyl - 6 - (4 -methoxyphenyl sulfonyl ) -4,5,6,7- tetrahydrothieno [2.3. - cl pyridine - 5 - carboxylate
  • Step K 4 -Benzyl-6- (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydrothieno [2.3. - cl pyridine- 5 -hydroxamic acid
  • methyl 4 -benzyl- 6 - (4 -methoxy phenylsulfonyl) -4,5,6, 7 - tetrahydrothieno [2.3. -c] pyridine- 5 -carboxylate (16.6 mg, 0.036 mmol) in 2 L of methanol was added 1 mL of IN NaOH. The reaction was stirred overnight at room temperature before removing the methanol under reduced pressure.
  • Step A N- (3 - Phenyl - 2 - thien- 3 -yl -propylidene) -4 - methoxyphenylsulfonamide
  • 15.0 g 3 -phenyl -2 - thien-3 -yl -propion aldehyde 69.4 mmol
  • 12.3 g of freshly activated powdered 5 A sieves 400 mg of Amberlyst 15 resin and 18.2 g (97.2 mmol, 1.4 eq) of p-methoxyphenylsulfonamide.
  • the reaction was refluxed with a Dean- stark trap under Argon atmosphere for two days.
  • Step B N- (1 -Cvano- 3 -phenyl -2 - thien-3 -ylpropyl) -4 - methoxyphenylsulfonamide
  • Step C 2 - (4 -Methoxyphenylsulfonylamino) -4-phenyl-3 - thien- 3 -yl -butyric acid
  • Step D Methyl 2 - (4 -methoxyphenylsulfonyl) amino-4 - phenyl - 3 - thien- 3 -yl -butyrate
  • Step A Methyl 4 -Benzyl - 6 - (4 -methoxyphenylsulfonyl) - 5,6,7,8 - tetrahydro -4H- thieno [2 , 3 -dl azepine- 5 -carboxylate To a stirred solution of methyl 4 -benzyl - 6 - (4 -methoxy- phenylsulfonyl) - 8 -oxo- 5 , 6 , 7 , 8 - tetrahydro- 4H- thieno
  • Step B 4 -Benzyl - 6 - (4 -methoxyphenylsulfonyl) - 5 , 6 , 7 , 8 - tetrahydro-4H- thieno [2 , 3 -dl azepine- 5 -carboxylic acid
  • azepine- 5- carboxylate 24.8 mg, 0.053 mmol
  • 2 mL of methanol was added 2 mL of 1 N NaOH.
  • Step C 4-Benzyl-6- (4 -methoxyphenylsulfonyl) -5 , 6 , 7 , 8- tetrahydro- 4H- thieno [2 , 3-dl azepine- 5 -hydroxamic acid
  • 4 -benzyl - 6 - (4 -methoxyphenylsulfonyl) - 5,6,7, 8- tetrahydro-4H- thieno [2, 3 -d] azepine- 5 -carboxylic acid (22.4 mg, 0.049 mmol) in 2.4 mL of anhydrous dichloromethane cooled to 0°C was added hydroxylamine hydrochloride (26 mg, 0.37 mmol), PyBrOP (Bromo-tris- pyrrolidino-phosphonium hexafluorophosphate, 82 mg, 0.175 mmol), and N,N- diisopropyleth
  • Step A 4 -Benzyl -9 - (4 -methoxyphenylsulfonyl) - 11 -oxa- 3 - thia-9-aza-tricvclo[6.2.2.0 0 ' °ldodeca-2 (6) .4 -dien-12 -one
  • azepine- 5 -carboxylate as a mixture of two diastereomers, (83.6 mg, 0.17 mmol) in 8 mL of anhydrous methanol was added sodium borohydride (3.6 mg, 0.095 mmol) .
  • Step B (+/-) 4 -Benzyl -8 -cis -hvdroxy- 6- (4- methoxyphenylsulfonyl) -5,6,7, 8 - tetrahydro-4H- thieno T2.3 , dl azepine- 5 -hydroxamic acid
  • sodium methoxide (16 mg, 0.29 mmol)
  • Step A Methyl 4 -benzyl - 8 -hydroxy- 6 - (4 -methoxyphenyl sulfonyl) -5,6,7, 8 - tetrahydro-4H- thieno [2 , 3 , dl azepine- 5- carboxylate
  • Step B-l 4 -benzyl - 8 - ( tert-butyldimethylsilyloxy) - 6 - (4 - methoxyphenylsulfonyl) -5,6,7.8 - tetrahydro-4H- thieno [2 , 3 , dl azepine- 5- carboxylic acid (From Step A Faster Diastereomer)
  • azepine- 5 -carboxylate 205 mg, 0.42 mmol
  • 30 mL of methanol was added 18 mL of IN aqueous sodium hydroxide.
  • the aqueous layer was extracted with dichloromethane and ethyl acetate, and the combined organic layers were dried (sodium sulfate) , filtered and concentrated to an oil.
  • the oil was dissolved in 2.5 mL of methanol and stirred with 290 mg (2 mmol) of anhydrous potassium carbonate for 2 hours at ambient temperature.
  • the methanol was evaporated, aqueous ammonium chloride and 300 ⁇ L of glacial acetic acid were added (pH ⁇ 5) , and extracted with several portions of ethyl acetate.
  • Step B-2 4-benzyl-8- ( tert-butyldimethylsilyloxy) -6- (4- methoxyphenylsulfonyl) -5,6.7,8- tetrahydro- 4H- thieno [2 , 3 , dl azepine- 5 -carboxylic acid (From Step A Slower Diastereomer)
  • Step C-l 4 -cis-benzyl - 8 -cis - ( tert-butyldimethyl silyloxy) -6- (4 -methoxyphenylsulfonyl) -5,6,7,8- tetrahvdro-4H- thieno [2 , 3 , dl azepine- 5 -hydroxamic acid (From Step B Faster Diastereomer) 4-Benzyl-8- (tert-butyldimethylsilyloxy) -6- (4-methoxy phenylsulfonyl) -5,6,7, 8 - tetrahydro-4H- thieno [2 , 3 , d] azepine- 5 -carboxylic acid (the faster eluting diastereomer, 48 mg, 0.08 mmol) was dried by co- evaporation with anhydrous toluene and dissolved in 4 mL of an
  • Step C-2 4- trans -benzyl -8- ( tert-butyldimethyl silyloxy) - 6 - (4 -methoxyphenylsulfonyl) -5.6,7,8- tetrahvdro-4H- thieno [2 , 3 , dl azepine- 5 -hydroxamic acid (From Step B Slower Diastereomer) Analogous procedures were carried out with the slower eluting diastereomer of 4 -benzyl - 8 - (tert-butyldimethyl silyloxy) -6- (4 -methoxyphenylsulfonyl) -5,6,7,8- tetrahydro-4H- thieno [2 , 3 , d] azepine- 5 -carboxylic acid to yield 4 - trans -benzyl- 8 - (tert-butyldimethyl silyloxy) -6-
  • Step D-l 4 -cis-benzyl- 8-cis- (hvdroxy) -6 - (4 -methoxy phenylsulfonyl) -5.6.7, 8 - tetrahydro-4H- thieno [2 , 3. dl azepine- 5 -hydroxamic acid (From Faster Diastereomer of Step C)
  • Step D-2 4 - trans -benzyl - 8 - (hvdroxy) - 6 - (4 -methoxyphenyl sulfonyl) -5,6,7, 8 - tetrahydro-4H- thieno T2 , 3 ,dl azepine- 5- hydroxamic acid (From Slower Diastereomer of Step C) Analogous procedures were carried out with the slower eluting diastereomer of 4 -trans-benzyl - 8 - (tert-butyl dimethylsilyloxy) -6- (4 -methoxyphenylsulfonyl) -5,6,7,8- tetrahydro-4H- thieno [2 , 3 , d] azepine- 5 -hydroxamic acid to yield 4 - trans -benzyl - 8 - (tert-butyldimethyl silyloxy) -6- (4 -methoxy
  • Step A 4 -Benzyl - thiophene- 3 -carboxaldevde 3 -Benzyl -4 -bromo- thiophene (12.7g, 50.1 mmol) is dissolved in 100 ml dry diethylether and cooled to -70°C. Butyllithiu (22.0 ml, 2.5 M in Hexane) is added drop-wise at -70°C and the reaction is stirred for 5 minutes. Dimethylformamide (DMF) is added in one shot and the reaction mixture is stirred for 15 min. and then allowed to warm to 0°C. The reaction mixture is quenched with water and neutralized. The organic phase is separated and the water phase is extracted twice with diethylether.
  • DMF dimethylformamide
  • Step C Methyl 3 - (4 -Benzyl - thien-3 -yl) -2 - (tert- butoxycarbonylamino) propionate
  • Methyl 3- (4 -benzyl - thien- 3 -yl) -2- (tert-butoxycarbonyl amino) acrylate (3.43 g, 9.2 mmol) is dissolved in 30 ml benzene/ethanol 4:1.
  • the reaction solution is hydrogenated under shaking at 50°C at 60 psi using Chlorotris (triphenylphosphine) rhodium (I) (Wilkinson' s catalyst). Initially, 25% (160 mg. 0.17 mmol) of the total amount (640 mg, 0.69 mmol) of the Wilkinson's catalyst is added and thereafter every 8-10 hours another 25% of the catalyst is added.
  • the reaction is complete after 48 hours.
  • the solvent is evaporated and the obtained dark oil is purified by flash- chromatography, Hexane/Ethylacetate (gradient 5-18%): Cal. 376.5, found (MH) + 376.2.
  • Step A 2 - Iodo- 5 - (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydro- thieno [3 , 2 -cl pyridine- 6 -carboxylic acid 5- (4 -Methoxyphenylsulfonyl) -4,5,6, 7 - tetrahydrothieno [3 , 2 -c] pyridine- 6 -carboxylic acid (1.19 g, 3.4 mmol) is dissolved in 60 ml dry Tetrahydrofuran (THF) and cooled to -78°C.
  • THF Tetrahydrofuran
  • a solution of lithium diisopropyla ide (3.55 ml, 7.1 mmol) in 5 ml THF is added drop-wise to the reaction mixture.
  • the reaction is stirred for 20 min.
  • Iodine (0.86 g, 3.4 mmol) in 20 ml THF is added drop-wise to the reaction solution.
  • the reaction is allowed to warm to room temp. ( ⁇ lh) and is quenched with sat. NH 4 C1- solution.
  • the organic phase is separated and the water phase is extracted twice with ethylacetate (50 ml) .
  • the water phase is acidified and extracted one more time with ethylacetate.
  • Step B 2 -Iodo- 5- (4 -methoxyphenylsulfonyl) -4, 5, 6,7- tetrahvdro- thieno [3,2-cl pyridine- 6 -carboxylic acid benzhydryloxy- amide
  • To 2 -iodo- 5- (4 -Methoxyphenylsulfonyl) -4,5,6,7- tetrahydrothieno [3 , 2-c] pyridine- 6 -carboxylic acid (1.62 g, 3.37 mmol) in 25 ml dry Dimethylformamide (DMF) is added 0-benzhydryl -hydroxylamine (0.95 g, 4.05 mmol), 1- hydroxyybenzotriazole (HOBt) (0.52 g, 3.37 mmol) and 1- (3 -dimethylaminopropyl) - 3 -ethyl -carbodiimide hydrogen chloride (EDC) (0.
  • Step C 2 - (methoxycarbonyl) -5- (4 -methoxyphenyl sulfonyl) -4.5.6,7 -tetrahydro- thieno [2 , 3 -cl pyridine- 6 - carboxylic acid benzhydryloxy- amide
  • Tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.02 mmol) is added and the reaction solution is saturated with carbon monoxide (CO) .
  • the reaction is refluxed over night at 70°C.
  • Evaporation of the solvents and flash- chromatography (Hexane/Ethylacetate; 3:2) afforded 2- (methoxycarbonyl) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7- tetrahydro- thieno [2 , 3 -c] pyridine- 6 -carboxylic acid benzhydryloxy-amide: Cal 593.7, found 592.8.
  • Step D 2- (methoxycarbonyl) -5- (4 -methoxyphenyl sulfonyl) -4,5,6, 7 - tetrahydro- thieno ⁇ 2 .3 -cl pyridine- 6 - hydroxamic acid
  • Step E 2 -carboxy- 5 - (4 -methoxyphenylsulfonyl) -4 , 5 , 6 , 7 - tetrahydro- thieno [2 , 3 -cl pyridine- 6 -hydroxamic acid 2- (Methoxycarbonyl) -5- (4 -methoxyphenylsulfonyl) -4,5,6,7' tetrahydro- thieno [2, 3- c] pyridine- 6 -hydroxamic acid (20 mg, 0.047 mmol) in 4 ml tetrahydrofuran/water (1:1) is stirred at room temp, for 1.5 h.
  • reaction mixture is acidified with 2N HCl to pH 3.
  • the organic phase is separated and the water phase is extracted twice with ethyl acetate.
  • the solvents are evaporated and the remaining solid is lyophilized to yield 2 -carboxy- 5- (4 - methoxyphenylsulfonyl) -4,5,6, 7 - tetrahydrothieno [2, 3-c] pyridine- 6 -hydroxamic acid: Cal. 412.5, found (MH) + 413.0.
  • Step A 5 - (4 -methoxyphenylsulfonyl) -2 -pyrid- 2 -yl - 4,5,6,7 -tetrahydro- thieno [3.2 -cl pyridine- 6 -carboxylic acid benzhvdryloxy- amide
  • Step B 5 - (4 -methoxyphenylsulfonyl) - 2 -pyrid- 2 -yl - 4,5,6,7- tetrahydro- thieno F3 , 2 -cl pyridine- 6 -hydroxamic acid
  • Step A 5 - (4 -methoxyphenylsulfonyl) -2 -pyrid- 3 -yl - 4,5,6,7 -tetrahydro- thieno [3 , 2 -cl pyridine- 6 -carboxylic acid benzhydryloxy- amide
  • Step B 5 - (4 -methoxyphenylsulfonyl) -2 -pyrid- 3 -yl - 4,5,6,7 -tetrahydro- thieno [3.2 -cl pyridine- 6 -hydroxamic acid
  • Step A 2 -Amino-3 - (4 -benzylthien- 3 -yl) -3 -hvdroxy- propionic acid
  • Step B 3 -Benzyl -4 -hydroxy-4 , 5 , 6 , 7 - tetrahydrothieno [2 , 3 - cl pyridine- 5 - carboxylic acid 2 -Amino- 3 - (4 -benzylthien- 3 -yl) -3 -hydroxy-propionic acid (880 mg, 3.17 mmol) is suspended in 25.4 ml of 0.25 N sulfuric acid and formaldehyde (2.57 ml, 12.33 M) was added. The mixture was stirred for 2 h at room temp.
  • reaction suspension is then filtered through a small fritted glass funnel and the obtained white powder is washed with diethylether and dried at high vacuum to yield 3 -benzyl -4 -hydroxy-4 ,5,6,7- tetrahydro- thieno [2,3- c] pyridine- 5 -carboxylic acid: Cal. 290.3, found (MH) + 290.2.
  • Step C 3 -Benzyl -4 -hydroxy- 6 - (4 -methoxyphenylsulfonyl) -
  • aqueous layer is acidified (pH 0-1, 6N HCl) and the water phase is extracted three more times with ethyl acetate.
  • the combined organic extracts are dried with MgS0 4 and the solvent is evaporated to give 3 -benzyl -4 -hydroxy- 6 - (4 -methoxyphenylsulfonyl) - 4,5,6,7 -tetrahydro- thieno [2, 3 -c] pyridine- 5 -carboxylic acid as an oil: Cal. 458.5, found (M-H) " 458.2.
  • Step D 4 -Acetoxy- 3 -benzyl -4 -hydroxy- 6 - (4 -methoxyphenyl sulfonyl) -4.5,6,7 - tetrahydro- thieno [2 , 3 -cl pyridine- 5 - carboxylic acid
  • Step E 4 -Acetoxy- 3 -benzyl -4 -hydroxy- 6 - (4 -methoxyphenyl sulfonyl) -4,5,6, 7 - tetrahydro- thieno [2 , 3 -cl pyridine- 5 - hydroxamic acid
  • DCM dichloromethane
  • Step F 4 -Hydroxy- 3 -benzyl -4 -hydroxy- 6 - (4 -methoxyphenyl sulfonyl) -4,5.6.7 - tetrahydro- thieno [2 , 3 -cl pyridine- 5 - hydroxamic acid
  • Step A Methyl (4 -Methoxyphenylsulfonylamino) acetate Glycine methyl ester hydrochloride (25 g, 0.2 mol) was dissolved in 200 -mL of anhydrous methylene chloride. The solution was cooled to 0°C on ice. Triethylamine (40.5 g, 0.4 mol) was added and the solution allowed to stir for an additional 15 minutes. 4 -Methoxybenzene sulfonyl chloride was added and the reaction allowed to warm slowly to room temperature and stir overnight. The reaction mixture was washed twice with 2M ammonium chloride then brine.
  • Step B Methyl N- (2 - (3 -bromothien-2 -yl) ethyl) -N- (4 - methoxy phenylsulfonyl) aminoacetate
  • Step C Methyl N- (4 -methoxyphenylsulfonyl) -N- (2 - (3 - vinylthien- 2 -yl) ethyl) aminoacetate
  • Methyl N- (2- (3 -bromothien-2 -yl) ethyl) -N- (4 -methoxy phenylsulfonyl) aminoacetate (1.86 g, 4.15 mmol) in toluene (28 mL) was treated with tributyl (vinyl) tin (3.1 mL, 10.6 mmol) .
  • the solution was heated to reflux for 5 minutes and then treated with dichlorbis (triphenyl phosphine) palladium (II) (250 mg, 0.36 mmol).
  • the reaction mixture was stirred at reflux for 18 hrs and then cooled to 25 °C.
  • the mixture was diluted with diethyl ether and treated with 10% aqueous potassium fluoride for 30 minutes. Filtration through a plug of celite removed solids. The liquid phases of the filtrate were separated and the organic layer was washed with 10% aqueous potassium fluoride, dried (Na 2 S0 4 ) and concentrated.
  • Step D Methyl N- (2 - (3 - formylthien- 2 -yl) ethyl) -N- (4 - methoxyphenylsulfonyl) aminoacetate
  • the mixture was then treated with a second portion of sodium metaperiodate (130 mg, 0.6 mmol) and stirred for 30 minutes at 25 °C.
  • the THF was then evaporated and the mixture was diluted with H 2 0 and the product was extracted into ethyl acetate.
  • Step E N- (2 - (3 - formylthien- 2 -yl) ethyl) -N- (4 - methoxyphenylsulfonyl) aminoacetic acid

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Abstract

Cette invention concerne de nouveaux composés hétérocycliques hybrides et substitués par de l'acide hydroxamique qui correspondent à la formule (I) et sont efficaces pour la prophylaxie et le traitement d'inflammations, de la dégradation tissulaire et des affections apparentées. Cette invention concerne de nouveaux composés, des analogues, des promédicaments et leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques ainsi que des procédés pour la prophylaxie et le traitement d'inflammations, de la dégradation tissulaire et des affections apparentées. L'invention se rapporte également à des processus permettant d'obtenir ces composés ainsi qu'à des produits intermédiaires utiles dans ces processus (I).
PCT/US1998/016147 1997-08-04 1998-08-04 Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique WO1999006410A1 (fr)

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JP2000505168A JP2003524572A (ja) 1997-08-04 1998-08-04 ヒドロキサム酸置換縮合複素環メタロプロテイナーゼ阻害剤
CA002297988A CA2297988A1 (fr) 1997-08-04 1998-08-04 Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique
AU87664/98A AU8766498A (en) 1997-08-04 1998-08-04 Hydroxamic acid substituted fused heterocyclic metalloproteinase inhibitors
EP98939182A EP1003751A1 (fr) 1997-08-04 1998-08-04 Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique

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WO2000023443A1 (fr) * 1998-10-22 2000-04-27 Akzo Nobel N.V. Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives
EP1065209A1 (fr) * 1999-07-01 2001-01-03 Adir Et Compagnie Nouveaux inhibiteurs de métalloprotéases, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
SG121932A1 (en) * 2005-07-27 2006-05-26 Takenaka Corp Mobile building platform
WO2006077013A1 (fr) 2005-01-19 2006-07-27 Sanofi-Aventis Derives de tetrahydrofurane en tant qu'inhibiteurs de metalloproteinases matricielles
EP1723148A2 (fr) * 2004-01-31 2006-11-22 Sanofi-Aventis Deutschland GmbH Derives de thieno-iminoacide en tant qu'inhibiteurs de metalloproteinases matricielles
JP2006528637A (ja) * 2003-07-23 2006-12-21 エックス−セプター セラピューティクス， インコーポレイテッド 薬剤としてのアゼピン誘導体
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
WO2009037001A2 (fr) 2007-09-19 2009-03-26 4Sc Ag Nouvelles pyridines tétrahydrocondensées
US7576198B1 (en) * 1999-09-02 2009-08-18 Shionogi & Co., Ltd. Integrase inhibitors containing aromatic heterocycle derivatives
WO2010007027A1 (fr) * 2008-07-14 2010-01-21 Novartis Ag Inhibiteurs sélectifs de mmp-12 et mmp-13 à base d’acide hydroxamique
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies
CN113387959A (zh) * 2021-06-24 2021-09-14 烟台理工学院 一种噻吩并[3,2-c]吡啶-6-羧酸甲酯的合成方法

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WO1997018194A1 (fr) * 1995-11-13 1997-05-22 Hoechst Aktiengesellschaft ACIDES α-IMINOHYDROXAMIQUES ET CARBOXILIQUES CYCLIQUES ET HETEROCYCLIQUES SUBSTITUES EN POSITION N
EP0803505A1 (fr) * 1996-04-26 1997-10-29 Adir Et Compagnie Nouveaux inhibiteurs de métalloprotéases, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

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Publication number Priority date Publication date Assignee Title
WO1997018194A1 (fr) * 1995-11-13 1997-05-22 Hoechst Aktiengesellschaft ACIDES α-IMINOHYDROXAMIQUES ET CARBOXILIQUES CYCLIQUES ET HETEROCYCLIQUES SUBSTITUES EN POSITION N
EP0803505A1 (fr) * 1996-04-26 1997-10-29 Adir Et Compagnie Nouveaux inhibiteurs de métalloprotéases, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023443A1 (fr) * 1998-10-22 2000-04-27 Akzo Nobel N.V. Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives
EP1065209A1 (fr) * 1999-07-01 2001-01-03 Adir Et Compagnie Nouveaux inhibiteurs de métalloprotéases, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
FR2795730A1 (fr) * 1999-07-01 2001-01-05 Adir Nouveaux inhibiteurs de metalloproteases, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
KR100472521B1 (ko) * 1999-07-01 2005-03-08 르 라보레또레 쎄르비에르 신규한 메탈로프로테아제 억제제, 이들을 제조하는 방법 및 이들을 함유하는 약제학적 조성물
US7576198B1 (en) * 1999-09-02 2009-08-18 Shionogi & Co., Ltd. Integrase inhibitors containing aromatic heterocycle derivatives
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
JP2006528637A (ja) * 2003-07-23 2006-12-21 エックス−セプター セラピューティクス， インコーポレイテッド 薬剤としてのアゼピン誘導体
EP1723148A2 (fr) * 2004-01-31 2006-11-22 Sanofi-Aventis Deutschland GmbH Derives de thieno-iminoacide en tant qu'inhibiteurs de metalloproteinases matricielles
WO2006077013A1 (fr) 2005-01-19 2006-07-27 Sanofi-Aventis Derives de tetrahydrofurane en tant qu'inhibiteurs de metalloproteinases matricielles
US8039481B2 (en) 2005-01-19 2011-10-18 Sanofi-Aventis Tetrahydrofuran derivatives for use as inhibitors of matrix metalloproteinases
KR101315788B1 (ko) * 2005-01-19 2013-10-14 사노피 매트릭스 메탈로프로테이나제의 억제제로서 사용하기 위한테트라하이드로푸란 유도체
SG121932A1 (en) * 2005-07-27 2006-05-26 Takenaka Corp Mobile building platform
WO2009037001A2 (fr) 2007-09-19 2009-03-26 4Sc Ag Nouvelles pyridines tétrahydrocondensées
WO2010007027A1 (fr) * 2008-07-14 2010-01-21 Novartis Ag Inhibiteurs sélectifs de mmp-12 et mmp-13 à base d’acide hydroxamique
US8841291B2 (en) 2008-07-14 2014-09-23 Novartis Ag Selective hydroxamic acid based MMP-12 and MMP-13 inhibitors
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies
CN113387959A (zh) * 2021-06-24 2021-09-14 烟台理工学院 一种噻吩并[3,2-c]吡啶-6-羧酸甲酯的合成方法

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