WO1999067230A1 - INHIBITORS OF α4β1 MEDIATED CELL ADHESION - Google Patents

INHIBITORS OF α4β1 MEDIATED CELL ADHESION Download PDF

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Publication number
WO1999067230A1
WO1999067230A1 PCT/US1999/014233 US9914233W WO9967230A1 WO 1999067230 A1 WO1999067230 A1 WO 1999067230A1 US 9914233 W US9914233 W US 9914233W WO 9967230 A1 WO9967230 A1 WO 9967230A1
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WIPO (PCT)
Prior art keywords
alkyl
hydrogen
attached
carbon atom
formula
Prior art date
Application number
PCT/US1999/014233
Other languages
French (fr)
Inventor
James R. Blinn
Robert A. Chrusciel
Jed F. Fisher
Steven P. Tanis
Edward William Thomas
Thomas J. Lobl
Bradley R. Teegarden
Original Assignee
Pharmacia & Upjohn Company
Tanabe Seiyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia & Upjohn Company, Tanabe Seiyaku Co., Ltd. filed Critical Pharmacia & Upjohn Company
Priority to US09/720,088 priority Critical patent/US6685617B1/en
Priority to JP2000555884A priority patent/JP2002518491A/en
Priority to MXPA00012765A priority patent/MXPA00012765A/en
Priority to AU47116/99A priority patent/AU764553B2/en
Priority to KR1020007014696A priority patent/KR20010083065A/en
Priority to CA002342778A priority patent/CA2342778A1/en
Priority to NZ509010A priority patent/NZ509010A/en
Priority to EP99930614A priority patent/EP1089989A1/en
Publication of WO1999067230A1 publication Critical patent/WO1999067230A1/en

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • the present invention relates to small molecules that are potent inhibitors of ⁇ 4 ⁇ , mediated adhesion to either VCAM or CS-1 and which are useful for the treatment of inflammatory diseases.
  • the extracellular matrix is the major component of connective tissue which provides structural integrity, and promotes cell migration and differentiation. As part of these functions, extracellular matrix molecules such as fibronectin, collagen, laminin, von Willebrand factor, thrombospondin, fibrinogen, and tenascin have been shown to support adhesion of cells in vitro. This adhesive interaction is critical for a number of biological processes including hemostasis, thrombosis, wound healing, tumor metastasis, immunity and inflammation.
  • Fibronectin is the prototype ECM molecule.
  • the major cell attachment site in the fibronectin molecule has been reproduced synthetically with the amino acid sequence arginine-glycine-aspartic acid, or RGD using single letter nomenclature.
  • Peptides containing the RGD sequence which either inhibit or promote cell adhesion have been described (US Patent Nos. 4,589,881; 4,661,111; 4,517,686; 4,683,291; 4,578,079; 4,614,517; and 4,792,525).
  • the receptors which recognize these sites on FN belong to a gene superfamily called integrins which consist of heterodimeric complexes of non-covalently associated alpha and beta subunits.
  • a common ⁇ subunit combines with unique I subunits to form an adhesion receptor of defined specificity.
  • 8 ⁇ subunits have been identified which can dimerize with 16 distinct I subunits forming 22 distinct integrins.
  • the ⁇ l subfamily also known as the VLA family (Very Late Activation Antigens), binds to ECM molecules such as FN, collagen and laminin.
  • Vascular endothelial cells form the interface between blood and tissues and control the passage of leukocytes as well as plasma fluid into tissues.
  • a variety of signals generated at the site of inflammation can activate both endothelial cells as well as circulating leukocytes so that they become more adhesive to one another. Following this initial adhesion the leukocytes migrate into the tissues to perform host defense functions.
  • adhesion molecules have been identified which are involved in leukocyte-endothelial interactions.
  • ⁇ 4 ⁇ interacts with a cytokine inducible protein on endothelial cells termed vascular cell adhesion molecule (VCAM). Further involved in the leukocyte-endothelial adhesion process is the ⁇ 2 integrin subfamily.
  • ⁇ 2 integrins include CDl la/CD18, CDl lb/CD18, and CDl lc/CD18.
  • the ⁇ 7 subunit associates with ⁇ 4 to form a unique 4 ⁇ 7 heterodimer which binds to FN, to VCAM, and to Mucosal Addressin Cell Adhesion Molecule- 1 (MAdCAM) (Ruegg et al, J. Cell.Biol 117:179 (1992); Andrew et al., J Immunol. 153:3847 (1994); Briskin et al., Nature 363:461 (1993); Shyjan et al, J Immunol. 156:2851 (1996)).
  • MAdCAM Mucosal Addressin Cell Adhesion Molecule- 1
  • ⁇ 4 integrins are widely expressed on different cell types including hematopoietic progenitors, lymphocytes, natural killer cells, monocytes, eosinophils, basophils, and mast cells (Helmer, M. E., Annu. Rev. Immunol. 8:365 (1990)).
  • Other molecules on endothelial cells which bind to the leukocytes include ICAM-1, ICAM-2, E-selectin and P-selectin (Carlos and Harlan, Immunol. Rev.
  • ⁇ 4 ⁇ plays a critical role in the pathogenesis of a variety of diseases.
  • Monoclonal antibodies directed against ⁇ 4 have been tested in a variety of disease models.
  • Anti- 4 antibodies block adhesion of lymphocytes to synovial endothelial cells; this adhesion plays a potential role in rheumatoid arthritis (van Dinther-Janssen et al, J Immunol. 147:4207 (1991)).
  • ⁇ 4 has also been implicated with respect to rheumatoid arthritis in separate studies (Laffon et al, J. Clin. Invest. 88:546 (1991); Morales-Ducret et al, J Immunol.
  • ⁇ 4 is also implicated in atherosclerosis due to its endothelial expression during atherogenesis (Cybulsky et al, Science 251:788 (1991)).
  • the migration of leukocytes to an inflammatory site can also be blocked by anti- ⁇ 4 antibodies.
  • inhibitors of leukocyte endothelial adhesion may block the costimulatory signals mediated by integrins and thus inhibit overproduction of inflammatory cytokines.
  • ⁇ 4 ⁇ , -mediated conditions include the inflammatory disorders rheumatoid arthritis, allergic disorders, asthma, spontaneous chronic colitis, insulitis, contact hypersensitivity response, atherosclerosis and autoimmune encephalomyelitis. These studies illustrate that small molecules that are potent inhibitors of ⁇ 4 ⁇ , mediated adhesion to either VCAM-1 or CS-1 may be used as a form of treatment in numerous inflammatory diseases.
  • these inflammatory conditions could be expanded to include adult respiratory distress syndrome, AIDS, cardiovascular diseases, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, allograft rejection, reperfusion injury, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including metastasis of neoplastic or cancerous growth, wound healing enhancement, treatment of certain eye diseases such as detaching retina, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, ulcerative colitis, regional enteritis and other autoimmune diseases. Accordingly, a compound which could inhibit these conditions is desirable.
  • the present invention particularly provides: A compound of the formula:
  • R may occur one to four times and each occurrence is independently hydrogen or C,. 6 alkyl.
  • R 2 is hydrogen, pyridyl, C,. 6 alkyl, (C,_ 6 alkyl)-CO 2 -R ⁇ , or -CO 2 -R ⁇ .
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
  • R 3 is hydrogen, phenyl, C,. 6 alkyl, C 3 . 6 alkenyl, C 7. , 7 arylalkyl , (C,. 6 alkyl)-CO 2 -R, rule (C 2 . 6 alkenyl)-CO 2 -R ⁇ , (C,. 6 alkyl)-CO-C,. 6 alkyl, (C,. 6 alkyl)-O-C,. 6 alkyl, (C,. 6 alkyl)-OH, (C,. 6 alkyl)-CN, adamantyl or one of the following
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R n , NH 2 , NHOH, -O-(C 7 . I0 arylalkyl), or is of the formula:
  • R 5 is a formula of the following:
  • Rj is N or CH
  • R 7 is hydrogen or halogen
  • R 8 is -NH-Y,-, -OCH 2 -, or
  • R may occur one to three times and is a halogen, C,. 6 alkoxy, C,. 6 alkyl or trifluoromethyl, R, 0 is C,. 6 alkyl, or (C,_ 6 alkyl)-OH, or hydrogen, R n is hydrogen or C,_ 6 alkyl, R 12 is C,. 6 alkyl or the following formula:
  • W is (C,. 6 alkyl)
  • X is S, O, or CH 2
  • / is 1, 2, or 3
  • m is 1 or 2
  • n is 0 or 1
  • o is 0 or X
  • p is 0 or 1
  • q is 0 or 1
  • r is 0, 1, 2 or 3.
  • R 5 is a formula of the following:
  • R 7 is hydrogen or Cl.
  • R 2 is hydrogen or C,. 6 alkyl. Additionally, R, and R 2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
  • n is
  • R is hydrogen or C,. 3 alkyl
  • R 2 is hydrogen or C alkyl.
  • R, and R 2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same atom and form a ring of 5-8 atoms of the formula:
  • R 3 is hydrogen, C,. 6 alkyl, C 7 . 17 arylalkyl, (C,. 6 alkyl)-OH, (C,. 6 alkyl)-CO 2 -R ⁇ , (C,. 6 alkyl)-CN, adamantyl, phenyl, or one of the following:
  • R 4 is -O-R ⁇ , NH 2 , NHOH, or R 4 is of the formula: , R ⁇ is hydrogen or CH 3 and X is S or O.
  • R, and R 2 are hydrogen, and R 3 is(C 2 . 6 alkenyl)-CO 2 -R n , (C,. 6 alkyl)-O-C,. 3 alkyl, (C,. 6 alkyl)-CO 2 R ⁇ , or one of the following:
  • R 4 is O-R ⁇
  • Ro is CH
  • R n is hydrogen
  • R 7 is hydrogen
  • X is S
  • Y is -CO-
  • / is 1.
  • R, and R 2 are hydrogen
  • R 3 is C,. 6 alkyl, (C,. 6 alkyl)-CO 2 -R n , (C 2 . 6 alkenyiyCO.-R,,, (C, .6 alkyl)-CO-C, .6 alkyl, (C,. 6 alkyl)-O-C,. 3 alkyl, (C,. 6 alkyl)-CN, or one of the following:
  • W is C,. 3 alkyl
  • X is CH 2
  • R is hydrogen
  • R 2 is (C alkyl)-CO 2 -R ⁇ , or CO 2 -R u
  • R 3 is hydrogen, C,. 3 alkyl, or C 2 . 7 alkenyl
  • R 4 is OH
  • R n is hydrogen
  • R 7 is hydrogen
  • / is 1
  • m is 1
  • n o is 0, and/? is 1.
  • the compound of the present invention is represented by the following formula
  • R, and R 2 are hydrogen
  • R 3 is C,. 6 alkyl, (C,. 6 alkyl)-CO 2 R, rule (C w alkenyl)-CO 2 R punishment, (C,. 6 alkyl)-O-C,. 3 alkyl, or one of the following:
  • R is hydrogen or C,. 3 alkyl and R 2 is hydrogen or C alkyl. Additionally, R, and R 2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms, or be attached to the same atom and form a ring of 5-8 atoms of the formula:
  • R 3 is hydrogen, C,. 6 alkyl, C 7 . I7 arylalkyl, (C,. 6 alkyl)-OH, (C,. 6 alkyl)-CO 2 -R ⁇ , (C,. 6 alkyl)-CN, adamantyl, phenyl, or one of the following:
  • R 4 is -O-R ⁇ , NH 2 , NHOH, or R 4 is of the formula — ⁇ -CH 2 -
  • R n is hydrogen or C,. 6 alkyl
  • X is S or O.
  • the compound of the present invention is represented by the following formula (I-a):
  • R may occur one to four times and each occurrence is independently hydrogen or C,. 6 alkyl
  • R 2 is hydrogen, pyridyl, C,. 6 alkyl, (C,. 6 alkyl)- CO 2 -R ⁇ , or -CO 2 -R ⁇ .
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
  • R 3 is hydrogen, phenyl, C,. 6 alkyl, C 3 . 5 alkenyl, C 7 . 17 arylalkyl , (C,. 6 alkyl)-CO 2 -R fate, (C 2 . 6 alkenyl)-CO 2 -R u , (C,. 6 alkyl)-CO-C,. 6 alkyl, (C,. 6 alkyl)-O-C,. 6 alkyl, (C,. 6 alkyl)-OH, (C,_ 6 alkyl)-CN, adamantyl or one of the following:
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R, rule NH 2 , NHOH, -O-(C 7 ., 0 arylalkyl), or is of the formula
  • R 5 is a formula of the following:
  • R ⁇ is N or CH
  • R 7 is hydrogen or halogen
  • R g is -NH-Y,-, -OCH 2 -, or -CONH-, R,
  • R 10 is C,. 6 alkyl, or (C,. 6 alkyl)-OH
  • R, is hydrogen or C,_ 6 alkyl
  • R, 2 is C,. 6 alkyl or the following formula:
  • R 13 is N or CH
  • W is (C,. 6 alkyl)
  • X is S, O, or CH 2
  • Z is O, CH 2 , or N-Rêt, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3.
  • This particular embodiment of the present invention has the provisos that
  • R 3 cannot be hydrogen
  • the compound has an IC 50 value of less than 5 ⁇ M in a Jurkat CS-1 assay and/or an IC 50 value of less than 50 ⁇ M in a Jurkat EC assay;
  • R may occur one to four times and each occurrence is independently hydrogen or C,. 6 alkyl.
  • R 2 is hydrogen, pyridyl, C,. 6 alkyl, (C,. 6 alkyl)-CO 2 -R n , or -CO 2 -R ⁇ .
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached.
  • R 3 is hydrogen, phenyl, C,.
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R,,, NH 2 , NHOH, -O-(C 7 . 10 arylalkyl), or R 4 is of the formula: - ⁇ -CH 2 till
  • R 5 is a formula of the following:
  • ⁇ is N or CH
  • R 7 is hydrogen or halogen
  • R 8 is -NHCO-
  • R may occur one to three times and is a halogen, C,. 6 alkoxy, C,. 6 alkyl or trifluoromethyl
  • R 10 is C,. 6 alkyl, or (C,. 6 alkyl)-OH, or hydrogen
  • R ⁇ is hydrogen or C,. 6 alkyl
  • R 12 is C,. 6 alkyl or the following formula:
  • R 13 is N or CH
  • W is (C,. 6 alkyl)
  • X is S, O, or CH 2
  • Z is O, CH 2 , or N-R réelle
  • / is 1, 2, or 3
  • m is 1 or 2
  • n is 0 or 1
  • o is 0 or X
  • p is 0 or 1
  • q is 0 or 1
  • r is 0, 1, 2 or 3.
  • R may occur one to four times and each occurrence is independently hydrogen or C,. 6 alkyl
  • R 2 is hydrogen, pyridyl, C,. 6 alkyl, (C,_ 6 alkyl)-CO 2 -R u , or -CO 2 -R u .
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached.
  • R 3 is hydrogen, phenyl, C,. 6 alkyl, C 3 . 6 alkenyl, C 7 . I7 arylalkyl ,
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R, rule NH 2 , NHOH, -O-(C 7 . 10 arylalkyl), or is of the formula -O-CHz-i ⁇
  • R 5 is a formula of the following:
  • R 7 is hydrogen or halogen
  • R 8 is -NHCO-
  • R may occur one to three times and is a halogen, C,_ 6 alkoxy, C,. 6 alkyl or trifluoromethyl
  • R 10 is C,. 6 alkyl, or (C,. 6 alkyl)-OH, or hydrogen
  • R u is hydrogen or C,. 6 alkyl
  • R 12 is C,. 6 alkyl or the following formula:
  • R,j is N or CH
  • W is (C,. 6 alkyl)
  • X is S, O, or CH 2
  • Z is O, CH 2 , or N-R
  • m is 1 or 2
  • n is 0 or 1
  • o is 0 or X
  • p is 0 or 1
  • q is 0 or 1
  • r is 0, 1, 2 or 3.
  • R 3 cannot be hydrogen
  • the compound has an IC 50 value of less than 5 ⁇ M in a Jurkat CS-1 assay and/or an IC 50 value of less than 50 ⁇ M in a Jurkat EC assay.
  • R may occur one to four times and each occurrence is independently hydrogen or C,_ 6 alkyl
  • R ⁇ is hydrogen, pyridyl, C, profession 6 alkyl, (C,_ 6 alkyl)-CO 2 -R ⁇ , or -CO 2 -R ⁇
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached.
  • R 3 is hydrogen, phenyl, C,.
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R n , NH 2 , NHOH, -O-(C 7 ., 0 arylalkyl), or R 4 is of the formula:
  • R 5 is a formula of the following:
  • R 7 is hydrogen or halogen
  • R 8 is -OCH 2 -
  • R_ may occur one to three times and is a halogen, C, profession 6 alkoxy, C,. 6 alkyl or trifluoromethyl
  • R 10 is C,. 6 alkyl, (C,. 6 alkyl)-OH, or hydrogen
  • R ⁇ is hydrogen or C,. 6 alkyl
  • R, 2 is C,. 6 alkyl or the following formula:
  • R 13 is N or CH
  • W is (C, .6 alkyl)
  • X is S, O, or CH 2
  • Z is O, CH 2 , or N-R ⁇ , / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or 1 , p is 0 or 1 , q is 0 or 1 , and r is 0, 1 , 2 or 3.
  • This particular embodiment has the following provisos:
  • R 3 cannot be hydrogen
  • R 3 is phenyl, C,_ 6 alkyl, C 7 . 17 arylalkyl, (C, .6 alkyl)-CO 2 -R, ,, (C,. 6 alkyl)-O- C,. 6 alkyl or (C,. 6 alkyl)-OH, o is 0;
  • R may occur one to four times and each occurrence is independently hydrogen or C,. 6 alkyl
  • R 2 is hydrogen, pyridyl, C,. 6 alkyl, (C,. 6 alkyl)-CO 2 -R u , or -CO 2 -R u .
  • R, and R 2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
  • R 3 is hydrogen, phenyl, C,. 6 alkyl, C 3.6 alkenyl, C 7 . 17 arylalkyl ,
  • R 2 and R 3 -(Y) 0 - may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
  • R 4 is -O-R n , NH 2 , NHOH, -O-(C 7 . 10 arylalkyl), or is of the formula
  • R 5 is a formula of the following:
  • R 7 is hydrogen or halogen
  • R 8 is -OCH 2 -
  • R, may occur one to three times and is a halogen, C,_ 6 alkoxy, C,. 6 alkyl or trifluoromethyl
  • R, 0 is C,. 6 alkyl, or (C,_ 6 alkyl)-OH
  • R ⁇ is hydrogen or C,. 6 alkyl
  • R 12 is C,_ 6 alkyl or the following formula:
  • R I3 is N or CH
  • W is (C,. 6 alkyl)
  • X is S, O, or CH 2
  • Z is O, CH 2 , or N-Rêt, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3.
  • This particular embodiment of the present invention has the provisos that:
  • R 3 cannot be hydrogen
  • the compound has an IC 50 value of less than 5 ⁇ M in a Jurkat CS-1 assay and or an IC 50 value of less than 50 ⁇ M in a Jurkat EC assay;
  • the desired compound of the present invention may be clinically used either in a free form or in the form of pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include acid-addition salts with inorganic acid or organic acid (e.g., hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate), salt with inorganic base, organic base or amino acid (e.g., triethylamine salt, a salt with lysine, an alkali metal salt, an alkali earth metal salt and the like).
  • the compound may also be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined above and a pharmaceutically acceptable carrier or diluent.
  • the compound can also be used for treating or preventing ⁇ 4 ⁇ , adhesion mediated conditions in a mammal such as a human.
  • This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained above.
  • This method can be used to treat such inflammatory conditions as rheumatoid arthritis, asthma, allergy conditions, adult respiratory distress syndrome, AIDS, cardiovascular diseases, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, allograft rejection, reperfusion injury, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including metastasis of neoplastic or cancerous growth, wound healing enhancement, treatment of certain eye diseases such as detaching retina, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, ulcerative colitis, atherosclerosis, regional enteritis and other autoimmune diseases.
  • inflammatory conditions as rheumatoid arthritis, asthma, allergy conditions, adult respiratory distress syndrome, AIDS, cardiovascular diseases,
  • the compounds and compositions containing the compounds according to the present invention are particularly useful in treating or preventing 4 ⁇ , adhesion mediated conditions in a mammal such as a human.
  • the present inventors have found that the compounds and compositions containing the compounds according to the present invention are most useful in the treatment of asthma.
  • the desired compound of the present invention or pharmaceutically acceptable salts thereof may be administered either orally or parenterally, and it may be used as a suitable pharmaceutical preparation, for example, a tablet, a granule, a capsule, a powder, an injection, and an inhalation by a conventional process.
  • the dose of the desired compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on an administration method, age, body weight, and state of a patient, but, in general, the daily dose is preferably about 0.1 to 100 mg/kg/day, however, 1 to 100 mg kg/day may also be suitable.
  • compositions containing the compounds of the present invention can be prepared to provide for an excellent means for administering in aerosol form for inhalation therapy. Accordingly, the present invention will provide for self- propelling compositions containing the compounds of the present invention.
  • Propellants employed should be non-toxic and have a vapor pressure suitable for the conditions under which administration occurs.
  • These propellants can be fluorinated or fluorochlorinated lower saturated aliphatic hydrocarbons.
  • the preferred propellants of this type are the halogenated alkanes containing not more than two carbon atoms and at least one fluorine atom. Illustrative of these are trichloromonofluoromethane, dichlorodifluoromethane, monochlorotrifluoromethane, dichloromonofluoromethane and l,2-dichloro-l,l,2,2-tetrafluoroethane. These compounds are available from E.I. duPont de Nemours and Company under the trade name "Freon”. These propellants may be employed singularly or in admixture.
  • an organic solvent may also be employed.
  • the organic solvent must be non-toxic and without undesirable effects on inhalation in the amount present in the aerosol produced.
  • the solvent should be substantially anhydrous, completely miscible with the propellant or mixture of propellants employed and have a suitable boiling point. Examples of such solvents included non-toxic aliphatic alcohols such as ethanol; ethers such as ethyl ether and vinyl ether; ketones such as acetone; and suitable halogenated lower alkanes.
  • the composition may also optionally contain a non- toxic hygroscopic glycol. The glycol must be substantially miscible with the organic solvent and the propellant employed. Satisfactory glycols include propylene glycol, triethylene glycol, glycerol, butylene glycol and hexylene glycol.
  • compositions As indicated previously, the compounds of formula (I) can be formulated into pharmaceutical compositions.
  • the particular disease in question In determining when a compound of formula (I) is indicated for the treatment of a given disease, the particular disease in question, its severity, as well as the age, sex, weight, and condition of the subject to be treated, must be taken into consideration and this perusal is to be determined by the skill of the attendant physician.
  • the amount of a compound of formula (I) required to achieve a therapeutic effect will, of course, vary both with the particular compound, the route of administration, the patient under treatment, and the particular disorder or disease being treated.
  • a suitable daily dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a mammalian subject suffering from, or likely to suffer from, any condition as described hereinbefore is 0.1 mg to 100 mg of the compound of formula I, per kilogram body weight of the mammalian subject.
  • the dose may be in the range of 0.5 to 500 mg of the compound per kilogram body weight, the most preferred dosage being 0.5 to 50 mg/kg of mammal body weight administered two to three times daily.
  • a suitable dose may be in the range of 0.1 ⁇ g to 100 ⁇ g of the compound per kilogram, typically about 0.1 ⁇ g/kg.
  • a suitable dose of a compound of Formula (I), or a physiologically acceptable salt thereof may be as specified in the preceding paragraph, but most preferably is from 1 mg to 10 mg of the compound per kilogram, the most preferred dosage being from 1 mg to 5 mg/kg of mammal body weight, for example, from 1 to 2 mg/kg.
  • a unit dosage of an orally administrable composition encompassed by the present invention contains less than about 1.0 g of a formula (I) compound.
  • formulation, both for human and veterinary use, of the present invention may be presented to the mammal by inhalation.
  • the dose may be in the range of 0.5 to 500 mg of the compound, per kg body weight.
  • the most preferred dosage being 0.5 to 50 mg/kg of mammal body weight administered two to three times daily.
  • the compounds and compositions of the present invention can be administered to patients suffering from a condition listed herein in an amount which is effective to fully or partially alleviate undesired symptoms of the condition.
  • the symptoms may be caused by inappropriate cell adhesion mediated by ⁇ 4 ⁇ , integrins.
  • Such inappropriate cell adhesion would typically be expected to occur as a result of increased VCAM-1 and/or CS-1 expression on the surface of endothelial cells.
  • Increased VCAM-1 and/or CS-1 expression can be due to a normal inflammation response or due to abnormal inflammatory states.
  • an effective dose of a compound of the invention may reduce the increased cell adhesion due to increased VCAM-1 expression by endothelial cells.
  • Reducing the adhesion observed in the disease state by 50% can be considered an effective reduction in adhesion. More preferably, a reduction in adhesion by 90%, is achieved. Most preferably adhesion mediated by VCAM-l/ ⁇ 4 ⁇ , and/or CS-1 interaction is abolished by an effective dose.
  • effect of the compound can be observed or a decrease in white cell infiltration into tissues or a site of injury.
  • the compounds or compositions of the present invention are administered to provide a dose effective to reduce or eliminate inappropriate cell adhesion or to alleviate undesired symptoms. While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier thereof. Such formulations constitute a further feature of the present invention.
  • the formulations, both for human and veterinary medical use, of the present invention comprise an active ingredient of formula (I), in association with a pharmaceutically acceptable carrier thereof and optionally other therapeutic ingredient(s), which are generally known to be effective in treating the disease or condition encountered.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the formulations include those in a form suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), intra-articular, topical, nasal inhalation (e.g., with an aerosol) or buccal administration. Such formulation are understood to include long-acting formulations known in the art.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods may include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid.
  • Formulations for other uses could involve a nonaqueous liquid; in the form of an oil-in-water emulsion or a water-in-oil emulsion; in the form of an aerosol; or in the form of a cream or ointment or impregnated into a transdermal patch for use in administering the active ingredient transdermally, to a patient in need thereof.
  • the active ingredient of the present inventive compositions may also be administered to a patient in need thereof in the form of a bolus, electuary, or paste.
  • the practitioner is referred to "Remington: The Science and Practice of Pharmacy,"
  • BCECF-AM 2',7'-bis-(2-carboxyethyl)-5-(and 6-) carboxyfluorescein acetoxy- methyl ester
  • BOP-C1 Bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • BOP Reagent Benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate
  • DMEM Dulbecco's Minimal Eagle's Media
  • HATU N-[(Dimethylamino)-lH-l ,2,3-triazolo[4,5-Z>]-pyridin-l - ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
  • HBTU O-Benzotriazol- 1 -yl- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
  • HSA Human serum albumin
  • Me Methyl meq: milliequivalent
  • PBS Phosphate buffered saline
  • Phenyl SPDP 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide ester t-Bu: t-butyl
  • the representative compounds according to the present invention are prepared as described below.
  • the compounds of the present invention are prepared in a similar manner.
  • R A _, and R ⁇ . 2 are defined independently as R,.
  • Scheme A describes a general method for the preparation of examples of the formula A-5, A-6, A-7, A-8, A-9 and A-10.
  • a commercially available or readily prepared sulfur containing amino acid of structure A-l (for the synthesis of ⁇ , ⁇ -disubstituted cysteine amino acids see: Stanfield, G.F.; Hruby, V.J. Synth. Commun.1988, 18, 531 and references therein) is condensed with formaldehyde to afford the thiazolidine-4-carboxylic acid of general formula A-2 (for the condensation of aldehydes with cysteine or similar sulfur containing amino acids see for example: (a) Ratner, S.; Clark, H.T. J. Am. Chem. Soc.
  • the amine group may be reacted with a variety of electrophilic reagents such as: (1) commercially available or readily prepared sulfonyl chlorides (for the synthesis of sulfonyl chlorides see for examples: (a) Roblin, R.O.; Clapp, J.W. J. Am. Chem. Soc. 1950, 72, 4890. (b) Gilbert, E.E. in Sulfonation and Related Reactions Olah, G.A., Ed. John Wiley and Sons, New York; 1965. (c) Park, Y.J.; Shin, H.H.; Kin, Y.H.
  • electrophilic reagents such as: (1) commercially available or readily prepared sulfonyl chlorides (for the synthesis of sulfonyl chlorides see for examples: (a) Roblin, R.O.; Clapp, J.W. J. Am. Chem. Soc. 1950, 72, 4890. (b) Gilbert, E.E. in
  • D-Cysteine hydrochloride monohydrate (A-1, where R A _, and R A réelle 2 are the same and equal to H and stereochemistry is (S)) (35.04 g, 0.19 mol) was dissolved in formaldehyde (40 wt% solution in water, 38 mL) and the reaction mixture allowed to stir for 18 h at ambient temperature. The mixture was cooled (0-5°C ) and absolute ethanol (93 mL) and pyridine (57 mL) were added.
  • a solution of A-2 (Scheme A where R A _, and R A . 2 are the same and equal to H and stereochemistry is (S)) (24.6 g, 0.185 mol) and di-t-butyl dicarbonate (44.4 g, 0.2 mol) in THF (1 L) was heated to reflux for 18 h. Volatiles were removed in vacuo and the residue partitioned between ethyl acetate and 0.1 N NaOH. The aqueous layer was washed with ethyl acetate, made acidic with 1.0 N HCl (pH 3-4) and then extracted with ethyl acetate.
  • A-4 (where R 5 is 4-[(2,6-dichlorobenzoyl)- aminojphenyl, and stereochemistry is (S)) (10 g, 24.8 mmol) was added followed by 4- methylmorpholine (2.72 mL, 24.8 mmol).
  • the reaction mixture was gradually warmed to ambient temperature, stirred an additional 18 h and diluted with CH 2 C1 2 and 0.1 N HCl.
  • the organic layer was separated and washed with 0.1 N HCl, sat. aqueous NaHCO 3 , brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)) (2.0 g, 3.86 mmol) in anhydrous THF (50 mL) was added methanesulfonyl chloride (2.99 mL, 38.6 mmol) followed by pyridine (6.24 mL, 77.2 mmol).
  • R 3 is 2-(l- piperidinyl)ethyl
  • Y is CO 2 -
  • R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
  • Example 13 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1267, 1260, 1216, 1195, 1162, 799 cm 1 ; ⁇ NMR (CDC1 3 ) ⁇ 7.56 (2 H), 7.46 (1 H), 7.33 (3 H), 7.13 (2 H), 6.94 (1 H), 4.75 (3 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.14 (3 H), 1.43 (9 H); 13 C NMR (DMSO-d 6 ) ⁇ 171.6, 171.5, 170.7, 170.1, 161.7, 152.6, 137.0, 136.9, 136.2, 132.6, 132.6, 131.2, 131.0, 129.3, 128.1, 119.1, 79.7, 78.2, 61.5, 53.4, 53.3, 51.8, 49.3, 49.1,
  • Example 14 was prepared from example 13 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3285, 1665, 1607, 1562, 1538, 1516, 1432, 1413, 1394, 1327, 1259, 1217, 1195, 1162, 799 cm 1 ; 'H NMR (DMSO-d 6 ) ⁇ 12.70 (1 H), 10.67 (1 H), 8.14 (1 H), 7.51 (5 H), 7.20 (2 H), 4.56 (1 H), 4.35 (3 H), 2.98 (3 H), 1.22 (9 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.5, 170.1, 169.9, 161.6, 152.6, 136.9, 136.3, 133.0, 131.2, 131.0, 129.4, 128.1, 119.1, 79.8, 79.7.
  • Example 15 was prepared as described in Scheme A from L-cysteine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1744, 1666, 1606, 1561, 1538, 1515, 1445, 1431, 1414, 1345, 1325, 1270, 1216, 1194, 1184 cm “ '; ⁇ NMR (CDC1 3 ) ⁇ 7.55 (2 H), 7.36 (4 H), 7.13 (2 H), 6.95 (1 H), 4.74 (3 H), 4.21 (3 H), 3.75 (3 H), 3.40 (1 H), 3.13 (3 H), 1.26 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.2, 169.4, 162.3, 136.2, 135.8, 132.4, 132.2, 131.0, 130.3, 130.1, 129.9, 128.2, 128.0, 127.9, 120.2, 62.9, 62.7, 53.2, 52.5, 37.1, 14.5, 14.3; MS (ESI+) for C 24 H 25 Cl 2 N 3
  • Example 16 was prepared from example 15 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 1664, 1606, 1561, 1539, 1516, 1445, 1431, 1414, 1346, 1327, 1271, 1217, 1195, 799 cm '1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.80 (1 H), 10.69 (1 H), 8.26 (1 H), 7.51 (5 H), 7.19 (2 H), 4.62 (2 H), 4.37 (2 H), 3.94 (2 H), 2.96 (3 H), 1.11 (3 H); 1 C NMR (DMSO-d 6 ) ⁇ 172.5, 169.6, 161.7, 153.5, 136.9, 136.3, 133.0, 131.2, 131.0, 129.5, 128.1, 1 19.1, 61.2, 53.4, 52.5, 35.9, 22.3, 14.3; MS (ESI+) for
  • Example 17 was prepared as described in Scheme A from L-penicillamine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1747, 1666, 1606, 1562, 1537, 1516, 1432, 1413, 1324, 1268, 1259, 1213, 1195, 1161, 1142 cm ' '; 'H NMR (CDC1 3 ) ⁇ 7.56 (2 H), 7.34 (4 H), 7.21 (2 H), 6.44 (1 H), 4.94 (1 H), 4.60 (2 H), 4.08 (1 H), 3.70 (3 H), 3.10 (2 H), 1.53 (3 H), 1.42 (9 H), 1.25 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.4, 162.3, 136.3, 135.8, 132.6, 132.4, 131.0, 130.2, 130.0, 128.2, 120.5, 120.3, 120.2, 72.7, 63.9, 60.4, 52.9, 52.3, 48.3, 38.0, 30.3, 28.1, 23.9, 21.0,
  • Example 18 was prepared as described in Scheme A from D-cysteine using 9- fluorenylmethyl chloroformate to form the requisite carbamate.
  • Physical data as follows: IR (mull) 3280, 1750, 1692, 1671, 1604, 1560, 1538, 1515, 1441, 1430, 1422, 1346, 1320, 1222, 1118 cm -'; ⁇ NMR (DMSO-d 6 ) ⁇ 8.59 (1 H), 7.87 (2 H), 7.49 (12 H), 4.65 (3 H), 4.26 (4 H), 3.52 (3 H), 2.96 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 171.4, 161.8, 143.5, 140.6, 137.0, 136.3, 132.5, 131.2, 131.1, 129.5, 128.1, 127.6, 127.1, 125.2, 125.1, 120.0, 119.2, 70.6, 70.0, 63.8, 63.2, 53.3, 53.1, 46.4, 36.2, 25.4; MS (ESI+) for C 36 H 31 Cl
  • Example 19 was prepared from example 18 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1672, 1606, 1561, 1533, 1517, 1431, 1413, 1347, 1324, 1269, 1218, 1195, 1116, 760, 742 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.71 (1 H), 8.32 (1 H), 7.87 (2 H), 7.47 (13 H), 7.16 (2 H), 4.62 (2 H), 4.15 (5 H), 2.90 (4 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.4, 169.2, 161.8, 143.6, 140.6, 137.0, 136.3, 133.0, 131.3, 131.1, 129.7, 129.6, 128.9, 128.2, 127.7, 127.1, 126.8, 125.2, 121.3, 120.1, 120.0, 119.2, 53.4, 48.4,
  • Example 20 was prepared as described in Scheme A from D-cysteine using benzyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1748, 1694, 1690, 1673, 1610, 1561, 1542, 1517, 1441, 1430, 1408, 1355, 1324, 1269, 1217 cm “ '; ⁇ NMR (CDC1 3 ) ⁇ 7.50 (2 H), 7.33 (9 H), 7.09 (2 H), 6.75 (1 H), 5.19 (2 H), 4.78 (3 H), 4.38 (3 H), 3.73 (3 H), 3.20 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 171.4, 162.3, 136.3, 135.9, 135.7, 132.5, 132.4, 131.0, 130.0, 128.7, 128.4, 128.2, 128.1, 120.4, 68.2, 63.3, 53.2, 52.5, 37.2; MS (ESI+) for C 29 H 27 Cl 2 N 3 O 6 S m/z 637.8 (
  • Example 21 was prepared from example 20 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3290, 3034, 1666, 1606, 1562, 1537, 1516, 1431, 1413, 1351, 1326, 1270, 1215, 1195, 799 cm “1 ; 'H NMR (DMSO-d 6 ) ⁇ 12.85 (1 H), 10.65 (1 H), 7.39 (10 H), 7.18 (2 H), 4.98 (2 H), 4.65 (2 H), 4.55 (1 H), 4.33 (1 H), 3.06 (1 H), 2.83 (2 H); 13 C NMR (CD 3 OD) ⁇ 172.6, 163.7, 154.4, 136.8, 136.2, 136.1, 131.9, 130.9, 129.6, 128.1, 127.9, 127.8, 127.7, 127.6, 120.0, 67.5, 66.7, 53.4, 36.5; MS (ESI-) for C 28 H 25 Cl 2 N 3 O 6 S m/z 599.7 (M-H) " ; MS (FAB)
  • Example 22 was prepared as described in Scheme A from D-cysteine using 1 -adamantyl fluoroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3284, 3271, 1747, 1690, 1684, 1666, 1557, 1532, 1436, 1412, 1355, 1298, 1194, 1053, 799 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.67 (1 H), 8.41 (1 H), 7.53 (5 H), 7.17 (2 H), 4.51 (3 H), 4.23 (1 H), 3.63 (3 H), 3.22 (1 H), 3.04 (1 H), 2.90 (1 H), 2.75 (1 H), 2.01 (9 H), 1.56 (6 H); 1 3 C NMR (DMSO-d 6 ) ⁇ 172.1, 162.3, 152.7, 137.6, 136.9, 133.2, 131.8, 131.6, 130.0, 128.7, 119.8, 53.8, 52.4, 36.7, 36.1, 30.6; MS (ESI+) for
  • Example 23 was prepared from example 22 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 1667, 1606, 1562, 1537, 1516, 1431, 1412, 1353, 1326. 1299, 1274, 1220, 1194, 1049 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.70 (1 H), 10.67 (1 H), 8.21 (1 H), 7.58 (5 H), 7.17 (2 H), 4.51 (3 H), 4.22 (1 H), 3.20 (1 H), 3.04 (1 H), 2.88 (1 H), 2.76 (1 H), 2.07 (9 H), 1.12 (6 H); 13 C NMR (DMSO-d 5 ) ⁇ 173.1, 162.3, 152.7, 137.5, 136.9, 133.8, 131.8, 131.6, 130.1, 128.7, 119.7, 80.0, 53.8, 36.8, 36.1, 30.6; MS (ESI+) for C 3 ,H 33 Cl 2 N 3 O 6 S m/z 645.8 (M+H)
  • Example 24 was prepared as described in Scheme A from D-cysteine using 4-(2- hydroxyethyl)morpholine to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1705, 1679, 1605, 1536, 1515, 1431, 1414, 1344, 1323, 1269, 1216, 1194, 1183, 1 1 17 cm "1 H NMR (300 MHz, CDC1 3 ) ⁇ 7.82 (1 H), 7.56 (2 H), 7.31 (3 H), 7.12
  • Example 25 was prepared from example 24 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3278, 1667, 1606, 1562, 1541, 1515, 1431, 1413, 1351, 1326, 1270, 1195, 1134, 1118, 799 cm “1 ; 'H NMR (300 MHz, DMSO-d 6 ) ⁇ 10.64 (1 H), 8.25 (1 H), 7.50 (5 H), 7.16 (2 H), 4.60 (2 H), 4.44 (1 H), 4.27 (1 H), 4.06 (2 H), 3.51 (4 H), 3.43 (2 H), 3.29 (4 H), 2.42 (4 H); 13 C NMR (75 MHz, DMSO-d 6 ) ⁇ 173.0, 172.4, 169.8, 162.3, 137.5, 136.8, 133.5, 131.7, 130.1, 128.6, 119.7, 66.6, 63.3, 57.0, 53.7, 36.7, 21.5; MS (FAB) m/z (rel.
  • Example 26 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 3293, 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1260, 1216, 1195, 1162, 799 cm " '; 'H NMR (CDC1 3 ) ⁇ 7.55 (2 H), 7.37 (4 H), 7.14 (2 H), 4.89 (1 H), 4.66 (2 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.24 (3 H), 1.44 (9 H); 13 C NMR (CDC1 3 ) ⁇ 171.2, 169.8, 162.3, 136.3, 135.8, 132.4, 132.3, 131.0, 130.2, 130.1, 129.9, 128.2, 128.1, 127.9, 120.5, 120.2, 120.1, 82.2, 53.2, 52.5, 37.3, 31.0, 28.4, 28.2; MS (ESI+
  • Example 27 was prepared from example 26 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3286, 1665, 1606, 1562, 1538, 1516, 1432, 1413, 1394, 1326, 1259, 1216, 1195, 1161, 799 cm 1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.70 (1 H), 10.63 (1 H), 8.13 (1 H), 7.51 (5 H), 7.20 (2 H), 4.45 (4 H), 2.96 (3 H), 1.23 (9 H); 13 C NMR (DMSO-d 6 ) ⁇ 173.1, 170.5, 162.3, 153.2, 137.5, 136.9, 131.8, 131.6, 130.0, 128.7, 119.7, 80.4, 62.2, 54.0, 49.8, 36.5, 28.3, 21.5; MS (ESI+) for C 25 H 27 Cl 2 N 3 O 6 S m/z 567.9 (M+H) + ; MS (ESI-) for C 25 H 27 Cl 2 N 3 O 6 S m
  • Example 28 [S-(R*,R*)] ⁇ l-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-5,5-dimethyl-3-thiazolidinecarboxylic acid 3-( , 1- dimethylethyl) ester (Scheme A, A-7: where R A _, and R A . 2 are the same and equal to CH 3 , R 3 is t-butyl, Y is CO 2 , R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 28 was prepared as described in Scheme A from D-penicillamine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1744, 1707, 1688, 1678, 1657, 1606, 1562, 1541, 1516, 1431, 1414, 1326, 1253, 1161, 1140 cm “ '; ⁇ NMR (CDC1 3 ) ⁇ 7.58 (2 H), 7.36 (3 H), 7.14 (2 H), 6.55 (1 H), 4.87 (1 H), 4.56 (2 H), 4.10 (1 H), 3.72 (3 H), 3.08 (2 H), 1.53 (3 H), 1.44 (9 H), 1.40 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.6, 162.3, 153.6, 136.4, 135.8, 132.6, 132.4, 131.0, 130.1, 129.9, 129.8, 128.2, 120.7, 120.5, 120.3, 81.7, 73.0, 52.8, 52.6, 52.4, 48.4, 39.8, 39.5,
  • Example 29 was prepared from example 28 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1739, 1666, 1606, 1562, 1535, 1516, 1432, 1413, 1394, 1325, 1270, 1260, 1194, 1160, 799 cm “1 ; 'H NMR (DMSO-d 6 ) ⁇ 12.62 (1 H), 10.62 (1 H), 8.18 (1 H), 7.51 (5 H), 7.19 (2 H), 4.50 (3 H), 4.24 (1 H), 2.91 (2 H), 1.33 (12 H), 1.04 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.8, 168.7, 161.9, 153.2, 137.2, 136.5, 133.1, 131.4, 131.3, 129.6, 128.3, 119.5, 80.0, 70.9, 53.7, 48.5, 37.0, 30.7, 28.1, 27.9, 24.6; MS (ESI+) for C 27 H 31 Cl 2 N 3 O 6 S m/z 595.9 (M+H) + ;
  • Example 30 was prepared as described in Scheme A from D-penicillamine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3292, 1748, 1666, 1606, 1562, 1538, 1516, 1445, 1431, 1414, 1341, 1325, 1271, 1212, 1194 cm “ '; 'H NMR (CDC1 3 ) ⁇ 7.57 (2 H), 7.37 (4 H), 7.1 1 (2 H), 6.49 (1 H), 4.86 (1 H), 4.59 (2 H), 4.14 (3 H), 3.75 (3 H), 3.09 (2 H), 1.60 (3 H), 1.54 (3 H), 1.23 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.6, 162.3, 154.5, 136.3, 135.8, 132.6, 132.4, 131.1, 130.2, 130.1, 129.8, 128.2, 120.5, 120.4, 72.7, 62.5, 52.7, 52.5, 37.3, 30.2, 23.7, 14.6, 14.1; MS (ESI
  • Example 31 was prepared from example 30 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 3070, 1666, 1606, 1562, 1538, 1516, 1431, 1414, 1342, 1328, 1271, 1213, 1194, 799 cm 1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.58 (1 H), 10.63 (1 H), 8.22 (1 H), 7.51 (5 H), 7.20 (2 H), 4.51 (3 H), 3.95 (3 H), 3.04 (1 H), 2.86 (1 H), 1.35 (3 H), 1.16 (6 H); ,3 C NMR (DMSO-d 6 ) ⁇ 223.3, 184.1, 183.9, 172.8, 168.4, 161.7, 136.9, 136.3, 133.1, 131.2, 131.0, 129.4, 128.1, 119.2, 70.6, 61.1, 53.6, 53.4, 48.6, 36.2, 30.1, 25.4, 24.3, 21.0, 14.1; MS (ESI+) for C 25 H 27 Cl 2 N 3 O 6
  • R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
  • Example 32 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (liq.) 1745, 1702, 1565, 1511, 1467, 1439, 1368, 1299, 1241, 1197, 1177, 1162, 1017, 778, 768 cm “ '; ⁇ NMR (CDC1 3 ) ⁇ 7.36 (2 H), 7.25 (1 H), 7.06 (2 H), 6.94 (2 H), 5.23 (2 H), 4.75 (3 H), 4.12 (1 H), 3.72 (3 H), 3.37 (1 H), 3.14 (3 H), 1.45 (9 H); 13 C NMR (CDC1 3 ) ⁇ 171.5, 157.9, 136.9, 132.0, 130.3, 128.4, 128.2, 115.0, 81.9, 65.1, 62.8, 53.2, 52.3, 49.2, 36.9, 28.1, 27.9; MS (ESI+) for C 26 H 30 C1 2 N 2 O 6
  • Example 33 was prepared from example 32 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1734, 1704, 1676, 1612, 1565, 1511, 1439, 1393, 1300, 1241, 1 196, 1178, 1162, 777, 769 cm “1 ; 'H NMR (DMSO-d 6 ) ⁇ 8.24 (1 H), 7.50 (3 H), 7.13 (2 H), 6.93 (2 H), 5.16 (2 H), 4.52 (3 H), 4.21 (1 H), 2.91 (4 H), 1.31 (9 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.7, 169.7, 157.1, 152.6, 135.9, 131.7, 131.5.
  • Example was prepared as described in Scheme A from D-cysteine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3282, 1742, 1705, 1692, 1664, 1562, 1509, 1436, 1352, 1343, 1236, 1196, 1175, 1015, 786 cm “1 ; ⁇ NMR (CDC1 3 ) ⁇ 7.37 (2 H), 7.25 (1 H), 7.05 (2 H), 6.94 (2 H), 6.74 (1 H), 5.23 (2 H), 4.77 (3 H), 4.34 (1 H), 4.18 (2 H), 3.74 (3 H), 3.37 (1 H), 3.13 (3 H), 1.31 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.6, 171.4, 158.0, 137.0, 132.1, 130.5, 130.4, 128.5, 128.2, 115.0, 65.2, 63.6, 63.2, 62.7, 53.6, 53.2, 52.4, 36.9, 14.5; MS (ESI+) for C 24 H 26 Cl
  • Example 35 was prepared from example 34 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1709, 1675, 1612, 1565, 1511, 1439, 1416, 1346,
  • Example 36 was prepared as described in Scheme A from D-cysteine using 4-(2- hydroxyethyl)morpholine to form the requisite carbamate. Physical data as follows: mp 138-140°C; IR (mull) 3286, 1743, 1705, 1660, 1559, 1513, 1435, 1428, 1302, 1245, 1226,
  • Example 37 was prepared from example 36 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1710, 1610, 1585, 1565, 1511, 1439, 1408, 1351,
  • Example 38 was prepared as described in Scheme A from D-cysteine using 2- pyridinemethanol to form the requisite carbamate. Physical data as follows: mp 123- 125°C; IR (mull) 3334, 1728, 1709, 1668, 1531, 1511. 1441, 1405. 1345.
  • Example 39 was prepared as described in Scheme A from D-cysteine using l-(2- hydroxyethyl)pyrrolidine to form the requisite carbamate. Physical data as follows: mp 130-132°C; IR (mull) 1745. 1702. 1661, 1556, 1513, 1435, 1426, 1303. 1245, 1226, 1214,
  • R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (R, S)).
  • Example 40 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1746, 1702, 1611. 1565, 1511, 1439, 1299, 1241, 1197, 1177, 1162, 1118, 1016, 777, 768 cm “1 ; ⁇ NMR (CDC1 3 ) ⁇ 7.39 (2 H), 7.25 (1 H), 6.93 (2 H), 6.93 (2 H), 5.24 (2 H), 4.72 (3 H), 4.20 (1 H).
  • Example 41 was prepared from example 40 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1737, 1705, 1679, 1612, 1565, 1512, 1439, 1300,
  • Example 42 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(ethylsulfonyl) ⁇ -thiazolidinyl]carbonyl]-
  • Example 42 was prepared as described in Scheme A from D-cysteine using ethanesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1743, 1666, 1605, 1561, 1535. 1515. 1432. 1413, 1328, 1269. 1219. 1 195, 1 146.
  • Example 43 4—[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(ethylsulfonyl)- -thiazolidinyl]carbonyl]-
  • Example 43 was prepared from example 42 by the procedure described in preparation 6.. Physical data as follows: IR (mull) 1734, 1664. 1605, 1562, 1536, 1516, 1432, 1414, 1330, 1272. 1234, 1195, 1146, 799, 781 cm 1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.91 (1 H), 10.65 (1 H), 8.15 (1 H), 7.51 (5 H), 7.17 (2 H), 4.77 (2 H), 4.43 (1 H), 4.29 (1 H). 3.94 (6 H),
  • R 3 is 2-(5- triflouromethylpyridyl)
  • Y is SO 2
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 44 was prepared as described in Scheme A from D-cysteine using 2-(5- triflouromethylpyridyl)sulfonyl chloride to form the requisite sulfonamide.
  • Physical data as follows: IR (mull) 1745, 1668, 1603, 1535, 1515, 1432, 1413, 1327, 1219, 1179, 1142, 1108, 1073, 1016, 616 cm “ '; 'H NMR (CDC1 3 ) ⁇ 8.76 (1 H), 8.17 (2 H), 7.90 (1 H), 7.51 (2 H), 7.32 (4 H), 7.17 (2 H), 5.18 (1 H), 4.96 (1 H), 4.66 (1 H), 4.31 (1 H), 3.78 (3 H), 3.52 (1 H), 3.15 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.3.
  • Example 45 was prepared from example 44 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1740. 1666, 1602, 1562, 1533, 1517, 1432. 1354, 1327, 1 179, 1 143, 1 108, 1074, 1016. 613 cm “ '; ⁇ NMR (DMSO-d 6 ) ⁇ 10.63 (1 H), 9.24 (1 H), 8.54 (1 H), 8.46 (1 H), 8.18 (1 H). 7.50 (5 H), 7.17 (2 H), 5.00 (1 H), 4.74 (1 H), 4.42 (2 H), 3.04 (2 H), 2.90 (1 H). 2.78 (1 H); l3 C NMR (DMSO-d 6 ) ⁇ 172.8, 168.9, 162.3, 159.0.
  • Example 46 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(phenylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where R A ., and R 2 are the same and equal to H. R 3 is phenyl, Y is SO 2 , R, is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 46 was prepared as described in Scheme A from D-cysteine using benzenesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1744. 1668, 1604, 1531, 1515. 1432, 1413, 1355, 1324. 1268. 1220. 1 195. 1167, 1090. 730 cm “ '; ⁇ NMR (CDC1,) ⁇ 7.84 (2 H), 7.65 (5 H), 7.45 (1 H), 7.30 (6 H), 4.90 (1 H). 4.63 (2 H), 4.37 (1 H), 3.75 (3 H). 3.32 (1 H), 3.15 (2 H), 2.53 (1 H); 13 C NMR (CDCl 3 ) ⁇ 171.2, 168.2, 162.4.
  • Example 47 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(phenylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where R A _, and R A _ 2 are the same and equal to H. R 3 is phenyl, Y is SO 2 , R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 47 was prepared from example 46 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1735, 1666. 1605. 1562, 1533, 1516, 1432, 1414,
  • Example 48 was prepared as described in Scheme A from D-cysteine using 5- dimethylamino- 1 -napthalenesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1744, 1684, 1605, 1562, 1533, 1515. 1431. 1412, 1350, 1324, 1231, 1202, 1163, 1 145.
  • Example 49 was prepared from example 48 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1666. 1605. 1587, 1577, 1562, 1532, 1516, 1431, 1412, 1395, 1325, 1163, 1 145, 798, 631 cm “ '; ⁇ NMR (DMSO-d 6 ) ⁇ 10.60 (1 H), 8.54 (1 H), 8.28 (2 H), 7.54 (8 H), 7.25 (1 H), 6.93 (2 H), 4.95 (1 H), 4.84 (1 H), 4.39 (1 H), 4.17 (1 H), 2.95 (2 H), 2.80 (7 H), 2.54 (1 H); 13 C NMR (DMSO-d 6 ) ⁇ 167.2, 161.7, 151.4, 136.6.
  • Example 50 O-[(2,6-Dichlorophenyl)methyl]-N-[[(4S)-3- ⁇ methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-tyrosine methyl ester (Scheme A. A-7: where R A _, and R ⁇ . 2 are the same and equal to H, R 3 is methyl, Y is SO 2 , R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
  • Example 50 was prepared as described in Scheme A from D-cysteine using methanesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1742. 1680, 161 1, 1564, 1510, 1439, 1345. 1299, 1240, 1 179, 1 158, 1016, 976, 779. 768 cm '1 ; 'H NMR (CDC1 3 ) ⁇ 7.36 (2 H), 7.24 (1 H), 7.08 (3 H), 6.97 (2 H), 5.25 (2 H), 4.77 (3 H), 4.29 (1 H), 3.74 (3 H). 3.43 (1 H). 3.53 (1 H), 3.10 (2 H). 2.93 (3 H); 13 C NMR (CDC.,) ⁇ 171.4.
  • Example 51 O-[(2,6-Dichlorophenyl)methyl]-N-[[(4S)-3- ⁇ methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-tyrosine (Scheme A, A-8: where R , and R A . 2 are the same and equal to H. R 3 is methyl, Y is SO 2 , R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
  • Example 51 was prepared from example 50 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1737, 1675, 161 1, 1565, 151 1. 1439, 1345, 1300,
  • Example 52 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[( 1.1 -dimethy lethy l)amino]carbonyl] thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where R A ., and R A . 2 are the same and equal to H, R 3 is t-butyl, Y is CONH-, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 52 was prepared from example 6 by the procedure described in preparation 6. Physical properties as follows: IR (mull) 3289. 1728, 1664, 1607, 1580. 1561, 1536, 1432, 1414, 1394, 1326, 1270, 1242, 1213, 1 195 cm '1 ; ⁇ NMR (300 MHz. CD 3 OD) ⁇
  • Example 53 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[(diethylamino)carbonyl] ⁇ r- thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where R A ., and R ⁇ . 2 are the same and equal to H, R 3 is ethyl, Y is CON(CH 2 CH 3 )-, R 5 is 4-[(2,6-dichlorobenzoyl)amino] phenyl and stereochemistry is (S, s».
  • Example 53 was prepared from example 7 by the procedure described in preparation 6. Physical properties as follows: IR (mull) 3269, 1734, 1663, 1607. 1562. 1535. 1515, 1431, 1415, 1348. 1325. 1269, 1213, 1195, 799 cm '1 ; ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.57 (2 H), 7.35 (3 H). 7.09 (2 H), 5.09 (1 H), 4.76 (1 H), 4.38 (2 H), 3.31 (3 H), 3.13 (5 H), 1.05 (6 H); 13 C NMR (75 MHz, CD 3 OD) ⁇ 176.6. 173.9, 167.1, 166.3, 140.7, 140.1, 136.1, 134.6, 133.8.
  • Example 54 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[methyl[2-(2- pyridinyl)ethyl]amino]carbonyl]-4-thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A. A-7: where R A. , and R A . 2 are the same and equal to H, R 3 is 2-(2-pyridyl)ethyl, Y is CON(CH 3 )-, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 54 was prepared as described in Scheme A from D-cysteine using 2-(2- methylaminoethyl)pyridine to form the requisite urea. Physical data as follows: mp 80- 90°C (dec); IR (mull) 1743, 1665, 1606, 1561. 1538. 1514, 1489, 1432, 1413, 1395, 1323, 1268. 1216. 1 195, 799 cm “ ': ⁇ NMR (300 MHz. DMSO-d 6 ) ⁇ 8.44 (1 H), 8.34 (1 H), 7.66 (1 H), 7.51 (5 H), 7.19 (4 H), 4.72 (1 H), 4.48 (1 H).
  • Y is CON(CH 3 )-
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S,
  • Example 55 was prepared from example 54 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1682, 1656, 1606, 1561, 1540, 1513, 1432, 1413,
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S,
  • Example 56 was prepared as described in Scheme A from D-cysteine using morpholine to form the requisite urea. Physical data as follows: mp 223-225°C; ⁇ H NMR (300 MHz, DMSO-d 6 ) ⁇ 10.66 (1 H), 8.25 (1 H), 7.51 (5 H), 7.16 (2 H), 4.81 (1 H), 4.60 (1 H), 4.50 (1 H), 4.28 (1 H), 3.64 (3 H), 3.53 (4 H), 3.09 (8 H); 13 C NMR (75 MHz, DMSO-d 6 ) 172.1. 170.3, 162.3, 161.4, 137.6. 136.8, 133.3, 131.8.
  • Example 57 N-[[(4S)-3-[[Bis(2-hydroxyethyl)amino]carbonyl] ⁇ l-thiazolidin>l]carbonyl] ⁇ l— [(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme A, A-7: where R A ., and R A . 2 are the same and equal to H, R 3 is 2-hydroxyethyl and Y is CON(CH 2 CH 2 OH). R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 57 was prepared as described in Scheme A from D-cysteine using diethanolamine to form the requisite urea. Physical data as follows: mp 105-107°C; IR (mull) 3284. 1743, 1662. 1608, 1561, 1539. 1516, 1432, 1414, 1355, 1326, 1270, 1217,
  • Example 58 was prepared from example 57 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3281 , 3196, 1724, 1660, 1608, 1580, 1561 , 1542,
  • Example 59 was prepared as described in Scheme A from D-cysteine using methyl glutaryl chloride to form the requisite amide. Physical data as follows: IR (mull) 3266, 1741, 1734, 1685, 1678, 1630, 1610. 1560, 1545, 1441, 1435, 1414, 1327. 1268, 1227 cm “ 1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.65 (1 H). 8.43 (1 H), 7.50 (5 H), 7.15 (2 H), 4.72 (2 H), 4.44 (2 H), 3.63 (3 H), 3.56 (3 H), 3.10 (4 H).
  • Example 60 was prepared from example 59 by the procedure described in preparation 12. Physical data as follows: IR (mull) 3271. 3193. 3124, 1725. 1661, 1607. 1561. 1539, 1516, 1432, 1414, 1327, 1271, 1195, 799 cm “ '; 'H NMR (DMSO-d 6 ) ⁇ 12.40 (1 H), 10.63 (1 H), 8.31 (1 H). 7.50 (5 H), 7.16 (2 H), 4.75 (2 H), 4.34 (2 H), 2.95 (4 H), 2.15 (4 H), 1.66 (2 H); 13 C NMR (CD 3 CN) ⁇ 175.0, 172.7, 172.6. 171.0. 163.5, 137.8, 137.0. 134.4, 132.7, 132.3, 131.1, 130.9, 129.1.
  • Example 61 N-[[(4S)-3-Acetyl-4-thiazolidinyl]carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L- phenylalanine methyl ester (Scheme A, A-7: where R 1 and R A . 2 are the same and equal to H. R 3 is CH 3 , Y is CO, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
  • Example 61 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3260, 3067, 1748, 1686. 1623, 1608, 1561.
  • Example 62 was prepared from example 61 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3070, 1747, 1682, 1663, 1625. 1608, 1580, 1561, 1548, 1514, 1443, 1431, 1416, 1278, 1220 cm '; 'H NMR (DMSO-d 6 ) ⁇ 12.48 (1 H), 10.63 (1 H), 8.29 (1 H), 7.50 (5 H), 4.73 (2 H), 4.34 (2 H), 2.97 (4 H), 1.93 (3 H); 1 3 C NMR (DMSO-d 6 ) ⁇ 172.4, 169.6, 169.2, 168.5, 168.0, 161.7, 136.9, 136.3, 133.2, 133.0, 131.2, 129.6, 128.1, 1 19.2, 62.2, 61.0, 53.5, 53.3, 49.3, 48.4, 36.3, 35.7, 35.0, 33.1, 22.4, 20.9; MS (ESI-) for C 22 H 2 ,Cl 2 N 3 O 5 S m/z
  • Example 63 was prepared as described in Scheme A from D-penicillamine using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3264, 3198, 3071, 1721 , 1660, 1608, 1562, 1541, 1516, 1432, 1415, 1327, 1270, 1195, 799 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.62 (1 H), 8.15 (1 H).
  • Example 64 was prepared as described in Scheme A from D-cysteine using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3073, 3031, 1725, 1640, 1612. 1585. 1565, 1535, 1511, 1439, 1300, 1241. 1 196, 1179, 768 cm “ '; ⁇ NMR (DMSO-d 6 ) ⁇ 8.26 (1 H), 7.53 (2 H), 7.44 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.75 (2 H), 4.40 (2 H), 4.20 (1 H), 2.81 (4 H), 2.32 (2 H).
  • Example 65 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1744. 1657, 1612, 1585, 1564, 1511, 1438, 1405, 1352, 1299, 1240, 1 197, 1179, 1016, 768 cm “1 ; 'H NMR (CDC1 3 ) ⁇ 7.36 (2 H), 7.24 (1 H), 6.97 (5 H), 5.24 (2 H), 5.04 (1 H), 4.78 (1 H), 4.50 (2 H), 3.74 (3 H), 3.45 (1 H), 3.17 (3 H), 2.02 (3 H); 13 C NMR (CDC1 3 ) ⁇ 172.7, 171.6, 171.4, 169.8, 168.9, 168.7, 157.8, 136.9, 131.9, 130.3, 129.9, 128.6, 128.4, 1 14.9, 65.1, 61.6, 56.0, 53.6, 53.3, 49.6, 36.7, 31.7, 22.5;
  • Example 66 was prepared from example 65 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1730, 1646, 1612, 1585, 1565, 151 1, 1439, 1414, 1299, 1240, 1 196, 1179, 1016, 779, 768 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 8.26 (1 H), 7.54 (2 H), 7.44 (1 H), 7.13 (2 H), 6.92 (2 H), 5.16 (2 H), 4.72 (2 H), 4.31 (2 H), 2.91 (5 H), 1.92 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.6.
  • Example 67 was prepared as described in Scheme A from L-cysteine using methyl succinyl chloride to form the requisite amide. Physical data as follows: 'H NMR (CD 3 CN) ⁇ 8.86 (1 H), 7.55 (2 H), 7.42 (3 H), 7.24 (2 H), 7.1 1 (1 H), 4.90 (1 H), 4.65 (2 H), 4.33 (1 H), 3.14 (3 H), 2.47 (6 H), 1.80 (1 H); 13 C NMR (CD 3 CN) ⁇ 174.7, 172.6, 172.3, 170.7, 163.4.
  • Example 67 was prepared as described in Scheme A from L-cysteine using methyl glutaryl chloride to form the requisite amide. Physical data as follows: 'H NMR (CD 3 CN) ⁇ 8.85 (1 H), 7.55 (2 H), 7.44 (3 H), 7.17 (3 H), 4.86 (1 H), 4.64 (2 H), 4.34 (1 H), 3.64 (1 H), 3.13 (3 H), 2.27 (4 H), 1.79 (4 H).; 1 C NMR (CD 3 CN) ⁇ 175.0, 172.9. 172.7, 170.6, 163.4, 137.7. 137.0, 134.2, 132.7, 132.2, 131.0. 129.1, 120.7, 68.2, 63.1, 54.2. 49.8.
  • Example 69 N-[[(4R)-3-Acetyl-4-thiazolidinyl]carbonyl] ⁇ l— [(2,6-dichlorobenzoyl)amino]-L- phenylalanine methyl ester (Scheme A, A-7: where R A ., and R A . 2 are the same and equal to H, R, is CH 3 , Y is CO, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
  • Example 69 was prepared as described in Scheme A from L-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3268, 1743. 1662, 1607, 1561, 1538, 1515, 1431, 1413, 1354. 1324. 1270, 1217, 1195, 799 cm '1 ; 'H NMR (CDC1 3 ) ⁇ 7.56 (3 H), 7.31 (4 H), 7.14 (2 H), 4.92 (2 H), 4.49 (1 H), 4.29 (1 H), 3.77 (3 H), 3.54 (1 H), 3.26 (1 H), 3.00 (2 H), 2.1 1 (3 H); 13 C NMR (CDC1 3 ) ⁇ 171.5.
  • Example 70 N-[[(4R)-3-Acetyl-4—thiazolidinyl]carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L- phenylalanine (Scheme A, A-8: where R A ., and R A . 2 are the same and equal to H. R 3 is CHvisor Y is CO, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
  • Exam ⁇ le70 was prepared from example 69 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 3068, 1727, 1661, 1607, 1561, 1540, 1516, 1444, 1431, 1414, 1327, 1271, 1218, 1195 cm '1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 12.78 (1 H), 10.67 (1 H), 8.27 (1 H), 7.49 (4 H), 7.19 (2 H), 4.75 (2 H), 4.45 (3 H), 3.01 (3 H), 1.96 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 172.6, 172.3, 169.4, 168.6, 168.2, 161.7, 136.9.
  • Example 71 4— [(2,6-Dichlorobenzoyl)amino]-N-[[(4R)-4-thiazolidinyl]carbonyl]-L-phenylalanine monohydrochloride salt (Scheme A, A-10: where R A ., and R A . 2 are the same and equal to H, R 5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
  • Example 71 was prepared as described in Scheme A from L-cysteine. Physical data as follows: IR (mull) 3249, 3190, 3036, 1729. 1662. 1605. 1578, 1562, 1541, 1516, 1432, 1414, 1328, 1271, 1 195 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.71 (1 H), 8.83 (1 H). 7.56 (5 H), 7.24 (2 H), 4.50 (1 H), 4.25 (1 H), 4.21 (2 H), 3.62 (1 H), 3.01 (4 H); l3 C NMR (DMSO- d 6 ) ⁇ 172.0, 166.8, 161.8, 137.7, 132.7, 131.3, 131.0.
  • R B .,, R B . 2 , R B . 3 , and R B ⁇ are defined as R, and in addition R B . 3 and R B . 4 may be attached to the same carbon atom and form a cyclic ring of 5-8 atoms of the formula:
  • R B . 5 is defined as OH or O-(C, ⁇ alkyl)
  • Scheme B describes a general method for the preparation of thiazolidine-4- carboxylic acid derivatives of general structure B-6.
  • B-7 and B-8 which are disubstituted at the 2 position (i.e., R B . 3 and R B ⁇ , are not equal to H).
  • the nitrogen is derivatized immediately after forming the heterocyclic ring.
  • the amine group may be reacted with a variety of electrophilic reagents such as sulfonyl chlorides, carbonates, chloroformates. isocyanates, phosgene (or a suitable equivalent) and an amine. acid chlorides, and carboxylic acid anhydrides as described in Scheme A for the reaction of A-6.
  • electrophilic reagents such as sulfonyl chlorides, carbonates, chloroformates. isocyanates, phosgene (or a suitable equivalent) and an amine. acid chlorides, and carboxylic acid anhydrides as described in Scheme A for the reaction of A-6.
  • Preparation 16 is provided as a specific example of the synthesis of a compound of general structure B-4.
  • R 5 is OCH 3
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (1.93 g, 4.77 mmol) was added followed by 4- methylmorpholine (520 ⁇ L, 4.77 mmol).
  • the reaction mixture was gradually warmed to room temperature, stirred an additional 18 h and diluted with CH 2 CL.
  • the organic layer was separated and washed with 0.1 N HCl. sat. aqueous NaHCO 3 , brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Example 73 was prepared from example 72 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1738, 1665, 1606. 1562. 1535, 1516, 1432, 1413, 1347, 1259, 1213, 1 194. 1167, 799, 777 cm '1 ; 'H NMR (CD 3 CN) ⁇ 8.89 (1 H), 7.54 (2 H), 7.41 (3 H). 7.25 (2 H). 4.66 (2 H), 3.15 (4 H), 1.72 (3 H). 1.70 (3 H), 1.35 (9 H); 13 C NMR (CD 3 CN) ⁇ 177.3. 171.8, 163.4, 137.9, 137.1, 133.9. 132.7, 132.3. 131.3, 129.1, 120.7, 81.2. 79.3, 68.0.
  • Example 74 was prepared from example 73 by the procedure described in preparation 4. Physical data as follows: IR (mull) 3244, 3192, 3049, 1726, 1664, 1605, 1578, 1562, 1541, 1516, 1432, 1414, 1327, 1195, 799 cm '1 ; 'H NMR (DMSO-d 6 ) ⁇ 13.00 (1 H), 10.69 (1 H), 7.52 (6 H), 7.24 (2 H), 4.52 (2 H), 3.12 (2 H), 2.93 (1 H), 1.62 (9 H); l3 C NMR (CD 3 OD) ⁇ 166.9, 136.8, 136.0. 133.5.
  • Example 75 was prepared as described in Scheme B from D-cysteine and acetone using di- t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1686. 1666, 1605, 1537, 1515, 1432, 1413, 1349, 1325, 1259, 1213, 1206. 1 195, 1169 cm “ '; ⁇ NMR (CDC1 3 ) ⁇ 7.56 (2 H), 7.32 (3 H), 7.16 (2 H), 6.92 (1 H), 4.83 (2 H), 3.73 (3 H), 3.20 (4 H), 1.78 (6 H), 1.45 (9 H); l3 C NMR (CDC1 3 ) ⁇ 171.6, 170.0. 136.2, 132.6, 132.4. 131.0.
  • Example 76 [S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2-dimethyl-3- thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme B, B-7: where R B ., and R B . 2 are the same and equal to H, R B .
  • R B- are the same and equal to CH 3 , Y is CO 2 , R 3 is t-butyl, R 5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 76 was prepared from example 75 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3280, 1739, 1665, 1606, 1562. 1535, 1516, 1432, 1413, 1348, 1272, 1259. 1 195. 1 167, 799 cm “ '; 'H NMR (CD,CN) ⁇ 8.83 (1 H), 7.55 (2 H), 7.43 (3 H), 7.22 (2 H), 6.83 (1 H), 4.68 (2 H), 3.07 (5 H), 1.73 (6 H), 1.40 (9 H); l3 C NMR (CD 3 CN) ⁇ 172.6.
  • R B ⁇ together form a carbocyclic ring of 5 atoms
  • Y is CO 2
  • R 3 is ethyl
  • R 5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 77 was prepared as described in Scheme B from D-cysteine and cyclopentanone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1760, 1739, 1694, 1656. 1607, 1560, 1543, 1517, 1445. 1429, 141 1, 1334, 1273, 1253, 1116 cm “ '; ⁇ NMR (CDC1,) ⁇ 7.56 (2 H), 7.44 (1 H). 7.34 (3 H), 7.11 (2 H), 6.70 (1 H), 4.84 (2 H), 4.14 (2 H), 3.74 (3 H), 3.12 (4 H). 2.67 (1 H).
  • Example 78 [S-(R* ,R*)]-3-[ [[ 1 -Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-l-thia-4— azaspiro[4.4]nonane-4- carboxylic acid 4-ethyl ester (Scheme B, B-7: where R B _, and R B _ 2 are the same and equal to H, R B . 3 and R B .
  • Example 78 was prepared from example 77 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 1664, 1606, 1562, 1537, 1515, 1445, 1432,
  • R 3 and R B ⁇ together form a carbocyclic ring of 6 atoms
  • Y is CO 2
  • R 3 is ethyl
  • R is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S. S)).
  • Example 79 was prepared as described in Scheme B from D-cysteine and cyclohexanone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1704, 1683, 1668, 1607, 1561, 1538, 1514, 1431, 1413, 1327, 1269, 1213, 1 196, 1117 cm '; ⁇ NMR (CDC1 3 ) ⁇ 7.57 (2 H), 7.46 (1 H), 7.33 (3 H), 7.1 1 (2 H), 6.72 (1 H), 4.88 (2 H), 4.14 (2 H), 3.74 (3 H), 3.13 (4 H), 2.51 (1 H), 1.69 (8 H), 1.22 (5 H); 13 C NMR (CDCl 3 ) ⁇ 171.4, 170.7, 168.1, 162.3, 136.3, 135.7, 132.4, 131.0, 128.2, 120.3, 66.9, 62.8, 62.0, 55.1, 53.1, 52.5, 42.0, 39.9, 37.3, 36.9.
  • Example 80 was prepared from example 79 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 1710, 1664, 1606. 1562. 1537, 1515, 1432, 1413, 1329, 1272. 1256. 1 195, 1 1 17, 800 cm “ '; 'H NMR (CDC1 3 ) ⁇ 8.07 (1 H), 7.62 (2 H), 7.24 (3 H), 7.14 (2 H), 6.75 (1 H), 4.88 (2 H), 4.12 (3 H), 3.14 (4 H), 2.74 (1 H), 2.50 (1 H), 1.69 (6 H), 1.19 (5 H); ' 3 C NMR (CDCl 3 ) ⁇ 175.4, 175.1.
  • Example 81 was prepared as described in Scheme B from D-penicillamine and acetone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1748, 1666, 1606, 1562, 1538. 1516, 1432, 1413, 1327, 1275. 1233. 1215, 1195, 1080.
  • R 3 is t-butyl, R, is 4-[(2.6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S. S)).
  • Example 82 was prepared from example 81 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3275, 1750, 1735. 1678, 1666, 1609, 1562, 1543,
  • Example 83 N-[[(4S)-3-Acetyl-2.2-dimethyl- -thiazolidinyl]carbonyl] ⁇ l-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme B, B-6: where R B ., and R B . 2 are the same and equal to H, R B _ 3 and R B ⁇ , are the same and equal to CH 3 , Y is CO, R 3 is methyl, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
  • Example 83 was prepared as described in Scheme B from D-cysteine and acetone using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1745, 1682, 1662, 1628, 1610, 1579.
  • Example 84 was prepared from example 83 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3279, 1723, 1661, 1608, 1562, 1542, 1516, 1432, 1413. 1349. 1329. 1270, 1238, 1207, 1 195 cm '1 ; 'H NMR (DMSO-d 6 ) ⁇ 12.47 (1 H), 10.62 (1 H), 7.51 (5 H), 7.18 (2 H), 4.80 (1 H), 4.67 (1 H), 4.47 (1 H), 2.98 (3 H), 1.68 (9 H); 13 C NMR (DMSO-d 6 ) ⁇ 184.2, 172.6, 171.9, 169.8, 169.2, 167.8, 136.9, 136.3. 133.1, 131.2, 131.0.
  • Example 85 was prepared as described in Scheme B from D-cysteine and acetone using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3264. 3125. 3071, 1724, 1658, 1607, 1562, 1537. 1517, 1432, 1414, 1326, 1241. 1195, 1181 cm '1 ; 'H NMR (DMSO-d 6 ) ⁇ 12.31 (1 H), 10.65 (1 H), 8.20 (1 H), 7.50 (5 H), 7.19 (2 H), 5.81 (1 H), 4.50 (1 H), 3.02 (3 H), 2.30 (3 H). 1.71 (6 H); 13 C NMR (DMSO-d 6 ) ⁇ 174.1. 172.8. 169.4.
  • Example 86 was prepared as described in Scheme B from D-penicillamine and acetone using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3287, 1741 , 1660. 1608, 1562, 1540, 1516, 1432, 1413, 1323, 1267, 1241, 1225,
  • Example 87 N-[[(4S)-3-Acetyl-2.2.5,5-tetramethyl-4-thiazolidinyl]carbonyl]- ⁇ -[(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme B. B-6: where R B .,, R B . 2 , R B . 3 and R BJ
  • Example 87 was prepared as described in Scheme B from D-penicillamine and acetone using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1741. 1692. 1676. 1629, 1606, 1563. 1538, 1516, 1431, 1410, 1352. 1320, 1276, 1251, 1223 cm “1 ; ⁇ NMR (DMSO-d 6 ) ⁇ 10.70 (1 H), 8.57 (1 H), 7.56 (4 H).
  • Example 88 was prepared as described in Scheme B from D-penicillamine and acetone using methyl glutaryl chloride to form the requisite amide. Physical data as follows: ⁇ NMR (DMSO-d 6 ) ⁇ 10.65 (1 H), 8.45 (1 H), 7.53 (5 H), 7.22 (2 H), 4.51 (1 H), 3.11 (3 H), 2.77 (1 H), 2.21 (4 H), 1.89 (3 H), 1.82 (3 H), 1.1 1 (2 H), 1.48 (3 H), 0.77 (3 H); 13 C NMR (DMSO-d 6 ) ⁇ 184.2, 174.2, 173.1, 170.1, 168.7, 161.7, 137.0, 136.3. 133.1, 131.3, 131.1, 129.4, 128.1, 1 19.2, 74.9, 73.0, 53.8.
  • R ⁇ ., R ⁇ , and Rc_ 3 are defined independently as R,.
  • R ⁇ is defined as R 2 .
  • Scheme C describes a method for the preparation of examples of the formula C-10.
  • Commercially available Rink Amide MBHA resin is deprotected under standard solid- phase peptide synthesis conditions (Atherton. E.; Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) to afford the amine of formula C-2.
  • Acylation with a commercially available or readily prepared amino acid residue of general C-3 affords the resin bound derivative of formula C-4.
  • Removal of the Fmoc group under standard conditions provides amine of general structure C-5 which is acylated with a commercially available or readily prepared thiazolidine-4-carboxylic acid of general formula C-6 to afford the resin bound intermediate C-7.
  • Standard Fmoc deprotection affords the resin bound amine of general formula C-8 which may be reacted with a variety of electrophilic reagents as described in Scheme A to afford resin bound amides, ureas, sulfonamides and carbamates of general structure C-9.
  • Preparation 18 details an example of the reaction of a mixed carbonate to afford a carbamate of general structure C-9 (where Y is equal to CO 2 ).
  • Standard acidolysis affords the amide of general structure C-10.
  • R 5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) , which was diluted with methylene chloride (10 mL). To this mixture was added a solution of the mixed carbonate prepared from 4-(2-hydroxyethyl)morpholine (2.14 mL, 17.7 mmol) and N,N- disuccinimidyl carbonate (4.53 g, 17.7 mmol) as described in preparation 8 in methylene chloride (20 mL) followed by triethylamine (0.33 mL, 2.36 mmol).
  • Resin C-9 was swelled with a minimum of methylene chloride (ca. 2 mL) and suspended with 95 % aqueous TFA (20 mL). The mixture was mixed by magnetic stirring for lh and filtered. The resin was washed with additional TFA (2 X 5 mL), followed by methylene chloride and methanol. The combined filtrates were evaporated in vacuo, and partioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried (MgSO 4 ), filtered and evaporated in vacuo.
  • Example 90 was prepared as described in Scheme C. Physical data as follows: IR (mull)
  • R D .don R D . 2 , and R D . 3 are defined independently as R,.
  • R D ⁇ is defined as R 2 .
  • Scheme D describes a method for the preparation of examples of general formula D-9.
  • N- ⁇ -Fmoc protected amino acids of general structure D-1 are coupled with O(tert-butyl)hydroxylamine (D-2) under standard coupling conditions as previously referenced to afford the t-butyl hydroxamate of general structure D-3.
  • Standard Fmoc deprotection affords the intermediate amine of formula D-4.
  • Coupling of this amine with a commercially available or readily prepared N- ⁇ -Fmoc- thiazolidine-4-carboxylic acid of general structure D-5 affords the pseudodipeptide intermediate of general structure D-6.
  • Standard Fmoc deprotection affords the intermediate amine of general structure D-7 which may be reacted under the variety of conditions described in Scheme A to afford amides, carbamates, sulfonamides and ureas of general structure D-8.
  • Preparation 22 provides a specific example of the reaction of an amine of general structure D-7 with a carbonate to afford a carbamate of general structure D-8.
  • Mild acidolysis affords the hydroxamate of general structure D-9.
  • the mixture was stirred at 0-5 °C for 1 hour, gradually allowed to warm to room temperature and stirred an additional 2 h.
  • the mixture was diluted with methylene chloride and 0.25 N HCl, the organic layer separated and washed with saturated aqueous NaHCO 3 , and brine, dried (MgSO 4 ), filtered and evaporated in vacuo.
  • R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) (500 mg, 0.67 mmol) in anhydrous DMF (7 mL) was added diethylamine (0.70 mL, 6.55 mmol) at ambient temperature. The solution was stirred for 90 min and volatiles were removed in vacuo.
  • R 5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S) (350 mg, 0.67 mmol), triethylamine (0.10 m, 0.74 mmol) and DMAP (1 mg) in CH 2 C1 2 (4 mL). The reaction mixture was stirred overnight and diluted with CH 2 C1 2 (15 mL). Propylamine (8.6 mL, 100.5 mmol) was slowly added (exothermic) and the solution stirred vigorously for 15 min, then diluted with water.
  • Example 92 was prepared as described in Scheme D from Fmoc-Tyr(2,6-Cl 2 -Bn) using ethyl chloroformate to provide the requisite carbamate. Physical properties as follows: IR (mull) 3278, 1654, 1612, 1585, 1564, 1547, 1511, 1439, 1347, 1237, 1195, 1179, 1022, 782, 769 cm “ '; ⁇ NMR (300 MHz , CDC1 3 ) ⁇ 7.39 (3 H), 7.17 (2 H), 6.94 (2 H), 5.24 (2 H), 4.53 (4 H), 4.18 (2 H), 3.15 (2 H), 2.87 (2 H), 1.28 (3 H); 13 C NMR (75 MHz , CD 3 OD) ⁇ 172.7, 170.1, 159.4, 156.2, 138.1, 133.7, 132.1, 131.6, 130.8, 129.8, 115.9, 66.3.
  • Example 93 (Scheme D, D-9: where R D .,, R D . 2 , R D _ 3 and R D.4 are the same and equal to proton, R 3 is 2- (l-piperidinyl)ethyl, R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO 2 and stereochemistry is (S, S)).
  • Example 93 was prepared as described in Scheme D from Fmoc-Tyr(2,6-Cl 2 -Bn) using 1- (2-hydroxyethyl)piperidine to provide the requisite carbamate. Physical properties as follows: IR (mull) 3276, 1707, 1653, 1611, 1584, 1564, 1511, 1439, 1237, 1195, 1179, 1 144, 11 13, 1093, 1021 cm ' '; ⁇ NMR (300 MHz, DMSO-dtf) ⁇ 7.54 (2 H), 7.44 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.58 (2 H), 4.36 (1 H), 4.25 (1 H), 4.00 (3 H), 2.76 (3 H), 2.31 (3 H), 1.62 (1 H), 1.42 (3 H), 1.26 (8 H); 13 C NMR (75 MHz, DMSO-d 6 ) ⁇ 172.2, 168.9, 167.3, 157.0, 135.9, 131.7, 131.4, 130.2, 129.9,
  • Raney-Nickel (20g of a 50%> slurry in H2O) was washed with abs. EtOH (3x25mL) and suspended in abs. EtOH (50mL), and a solution of E-2 (Scheme E, where stereochemistry is (S)) (9.34g, 28.2mmol) in abs. EtOH (50mL) was added.
  • the Ra-Ni was removed by filtration, and the filtrate was evaporated in vacuo.
  • the residue was dissolved in EtO Ac (lOOmL), 5% Pt/C (3. Og) was added, and the mixture was hydrogenated under 50 psi H2 for 12 h.
  • the catalyst was removed by filtration and the filtrate was evaporated in vacuo.
  • Example 95 was prepared as described in Scheme E from E-1 (Scheme E where stereochemistry is (R) prepared by the method of Rapoport (J. Am. Chem. Soc. 1984, 106,
  • R F . 3 is defined as proton or C,. 6 alkyl.
  • Scheme F describes a general method for the preparation of examples of the formula F-4, F-5, F-6, F-7, and F-8.
  • a commercially available or readily prepared sulfur containing amino acid of structure F-1 is condensed with amino acid derivative F-2 under standard peptide synthesis conditions as described in Scheme A.
  • Deprotection of the carbamate from F-3 provides the useful intermediate F-4.
  • the amine group may be reacted with a variety of electrophilic reagents as described in Scheme A to provide esters of general structure F-5.
  • Mild base hydrolysis provides acids of structure F-6.
  • Mild hydrolysis of esters of general structure F-3 provides acid of formula F-7.
  • mild acidolysis of compounds of general structure F-3 afford the amino acid of general structure F-8.
  • R F . 3 is CH 3
  • R 3 is CH 2 CH 2 CO 2 CH 3
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl
  • Y is CO-
  • stereochemistry is (R, S)) (490 mg, 0.80 mmol) in THF (20 mL) and MeOH (6 mL) was added a solution of LiOH»H 2 O (178 mg, 4.25 mmol) in H 2 O (6 mL). After 22 h, the mixture was concentrated in vacuo.
  • ester F-3 (Scheme F, where R F _, and R F . 2 are the same and equal to proton, R F . 3 is CH 3 , R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)) (656 mg, 1.02 mmol) in MeOH (25 mL) was added K 2 CO 3 (550 mg, 4 mmol) and H 2 O (13 mL). After 3 h, volatiles were partially removed and the solution diluted with 10% HCl (20 mL) causing precipitation of a solid.
  • F-2 Scheme F where R F _, and R F.2 are the same and equal to proton, R F _ 3 is t-butyl, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (2.02 g, 4.94 mmol) was added, the reaction allowed to warm to ambient temperature and stirred for 24 h. Volatiles were removed in vacuo and the residue partitioned between methylene chloride and 2.5%) aqueous HCl. The organic layer was separated and washed with sat. aqueous NaHCO 3 , dried and concentrated in vacuo.
  • Example 102 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(3R)-4-[ 1 -oxo-3-( 1 H-tetrazol-5-yl)propyl]-3- thiomo ⁇ holinyl]carbonyl]-L-phenylalanine methyl ester (Scheme F, F-5: where R F _, and R F _ 2 are the same and equal to proton, R F.3 is CH 3 , R 3 is 2- (5-lH-tetrazolyl)ethyl, R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is (R, S)).
  • Example 102 was prepared as described in Scheme F using lH-tetrazole-5-propanoic acid (Hutchinson, D.W.; Naylor, M. Nucleic Acids Res. 1985, 13, 8519) to form the requisite amide.
  • Example 103 was prepared from example 102 by the procedure described in preparation 34. Physical data as follows: IR (mull) 3376, 3296, 3267, 3127, 1746, 1683, 1669, 1641,
  • R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl
  • Y is CO-, and stereochemistry is
  • Example 104 was prepared as described in Scheme F using 3-cyanopropanoic acid (readily prepared from commercially available 3-cyanopropanoic acid) to form the requisite amide.
  • Physical data as follows: IR (mull) 2251 , 1735, 1655, 1612, 1585, 1565, 1512, 1439, 1298, 1240, 1196, 1179, 1016, 1000, 779, 768 cm “1 ; 'H NMR (300 MHz, CDC1 3 ) ⁇ 2.40 (12 H), 4.88 (1 H), 5.22 (2 H), 6.72 (1 H), 6.96 (2 H), 7.23 (5 H).
  • Example 105 [R-(R*,S*)]-3-[[[l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]- phenyl]ethyl]amino]carbonyl]- ⁇ -oxo ⁇ J— thiomo ⁇ holinebutanoic acid (Scheme F, F-6: where R F ., and R F . 2 are the same and equal to proton, R F _ 3 is proton, R 3 is CH 2 CH 2 CO 2 H, R 5 is 4-[(2,6-dichlorophenyl)methoxy] ⁇ henyl , Y is CO-, and stereochemistry is (R, S)).
  • Example 105 was prepared as described in Scheme F using mowo-methyl succinate to form the requisite amide. Physical data as follows: IR (mull) 3031, 1726, 1646, 1612, 1585, 1565, 1511, 1439, 1421, 1297, 1240, 1 196, 1 179, 1016, 768 cm '1 ; ⁇ NMR (300 MHz, DMSO-dtf) ⁇ 2.62 (8 H), 3.64 (3 H), 4.39 (2 H), 5.20 (2 H), 6.92 (2 H), 7.15 (2 H), 7.50 (3 H), 7.98 (2 H); 13 C NMR (75 MHz, DMSO-dtf) ⁇ 174.5, 173.2, 171.9, 168.9, 136.5, 132.3, 132.0, 130.8, 130.7, 129.2, 114.8, 65.3, 54.3, 52.5, 36.0, 29.7, 28.0, 27.0; MS (FAB) m/z (rel.
  • Rg., and R G _ 2 are defined independently as H or CH 3 ;
  • R G _ 3 is defined as H, C,. 6 alkyl or C 3 . 6 alkenyl; and g is defined as 0 or 2.
  • Scheme G describes a general method to prepare lactam examples of general structures G-5 and G-6.
  • Readily prepared lactams of general structure G-l may be alkylated by the reaction of an appropriate alkylating in the presence of a suitable base as described in preparation 37 to provide intermediates of general structure G-2.
  • Mild hydrolysis provides the monoacid of general structure G-3 which may be condensed with an amino acyl intermediate of structure G-4 as described in Scheme A.
  • Full hydrolysis of the diester of general structure G-5 affords the diacid of structure G-6.
  • Example 108 2-[3-[[(l S)-l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-l-(3-methyl-2-butenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R ⁇ is CH 3 , R ⁇ is l-(3-methyl-2-butenyl), R 5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
  • Example 108 was prepared as described in Scheme G using l-bromo-3-methyl-2-butene to form the requisite N-alkyl lactam. Physical data as follows: IR (mull) 32.95, 29.52, 1740, 1678, 1662, 1564, 1538, 1512, 1439, 1414, 1300, 1279, 1240, 1199, 1178, 1017, 768 cm '1 ; 'H NMR (300 MHz, CDC1 3 ) ⁇ 1.64 (3 H), 1.70 (3 H), 2.06 (12 H), 3.09 (2 H), 3.66 (3 H), 3.74 (2 H), 3.74 (3 H), 4.85 (1 H), 5.20 (1 H), 5.24 (2 H), 6.95 (2 H), 7.02 (2 H), 7.25 (1 H), 7.36 (2 H); 13 C NMR (75 MHz, CDC1 3 ) ⁇ 174.7, 173.3, 172.1, 172.0, 171.3, 158.1, 137.0, 135.1, 132.1, 130.5, 130.3, 128.5, 128.3,
  • Example 109 was prepared from example 108 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3290, 2921, 1726, 1635, 1585, 1565, 1545, 1511, 1439, 1419, 1341, 1299, 1240, 1197, 1179, 780, 768 cm '; 'H NMR (300 MHz, DMSO- d ⁇ j) ⁇ 1.57 (3 H), 1.62 (3 H), 1.72 (6 H), 2.02 (6 H), 2.77 (1 H), 2.98 (1 H), 3.55 (2 H), 5.05 (1 H), 5.16 (2 H), 6.94 (2 H), 7.15 (2 H), 7.49 (2 H), 7.54 (2 H), 8.15 (1 H); 13 C NMR (75 MHz, DMSO-dtf) ⁇ 174.6, 174.3, 173.6, 173.56, 172.2, 157.6, 136.5, 134.0, 132.2, 132.0, 130.6, 129.2, 121.1, 121.0, 114.7, 65.2, 65.0, 54.1, 54.0, 37.1,
  • Example 110 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3- ⁇ )xopropyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R Q _ 2 and R Q.3 are equal to CH 3 , R 5 is 4-[(2,6-dichlorobenzoyl)- aminojphenyl, g is equal to 2 and stereochemistry is (S)).
  • Example 110 was prepared as described in Scheme G using iodomethane to form the requisite N-alkyl lactam. Physical data as follows: IR (mull) 3258, 2922, 1738, 1662, 1606, 1561, 1539, 1515, 1432, 1414, 1401, 1323, 1268, 1196, 1177, 799 cm '1 ; 'H NMR (300 MHz, CDC1 3 ) ⁇ 2.01 (12 H), 2.61 (3 H), 3.09 (2 H), 3.64 (3 H), 3.75 (3 H), 4.84 (1 H), 6.15 (1 H), 7.09 (2 H), 2.31 (3 H), 7.58 (2 H), 7.99 (1 H);MS (EI) m/z (rel.
  • Example 111 2-[3-[[(lS)-l-Carboxy-2-[4— [(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]-3-oxo- propyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid (Scheme G, G-6: where R ⁇ is CH 3 , R 5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, g is equal to 2 and stereochemistry is (S)).
  • Example 11 1 was prepared from example 110 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3265, 3056, 2925, 1724, 1658, 1609, 1579, 1561, 1542, 1516, 1432, 1414, 1327, 1271, 1217, 1195, 800 cm '1 ; ⁇ NMR (300 MHz, DMSO- d ⁇ y) ⁇ 1.89 (12 H), 2.49 (3 H), 2.78 (1 H), 2.99 (1 H), 4.38 (1 H), 7.18 (2 H), 7.51 (5 H), 8.17 (1 H), 10.64 (1 H); MS (FAB) m/z (rel. intensity) 580.5 (M+H, 68).
  • Example 112 2-[3-[[(lS)-l-[[4-[(2,6-Dichloro ⁇ henyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where ⁇ is CH 3 , R ⁇ is proton, R5 is 4-[(2,6-dichlorophenyl)- methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
  • Example 112 was prepared as described in Scheme G. Physical data as follows: IR (mull) 3276, 3029, 1738, 1686, 1564, 1538, 151 1, 1439, 1299, 1279, 1239, 1197, 1178, 1016, 767, cm '1 ; ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 1.85 (6 H), 2.24 (2 H), 2.35 (4 H), 3.03 (2 H), 3.66 (3 H), 3.74 (3 H), 4.82 (1 H), 5.24 (2 H), 6.50 (2 H), 6.95 (2 H), 7.05 (2 H), 7.27 (1 H), 7.37 (2 H); MS (EI) m/z (rel. intensity) 578 (M+, 0.2); Anal. Calcd for
  • Example 113 was prepared from example 112 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3294, 3033, 1716, 1647, 1585, 1565, 1544, 1511, 1439, 1420, 1299, 1240, 1197, 1179, 768 cm '1 ; 'H NMR (300 MHz, DMSO-dtf) ⁇ 1.60 (6 H), 2.12 (6 H), 2.78 (1 H), 2.99 (1 H), 4.36 (1 H), 5.19 (2 H), 6.97 (2 H), 7.17 (2 H), 7.45 (1 H), 7.58 (2 H), 7.70 (1 H), 8.22 (1 H); MS (FAB) m/z (rel. intensity) 551 (M+H, 99); Anal.
  • Example 114 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R ⁇ is CH 3 , R, ⁇ is proton, R 5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl, g is equal to 2 and stereochemistry is (S)).
  • Example 114 was prepared as described in Scheme G. Physical data as follows: ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 1.81 (6 H), 2.27 (6 H), 3.10 (2 H), 3.63 (3 H), 3.75 (3 H), 4.89 (1 H), 6.46 (1 H), 6.58 (1 H), 7.10 (2 H), 7.26 (3 H), 7.58 (2 H), 8.14 (1 H); MS (FAB) m/z 592
  • Example 115 was prepared from example 114 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3272, 3195, 3121, 3063, 2953, 2923, 2868, 2855, 1715, 1659, 1608, 1579, 1561, 1541, 1516, 1456, 1432, 1414, 1377, 1367, 1326, 1271,
  • Example 116 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxoproline (Scheme G, G-5: where R ⁇ and R G - 3 are equal to proton, R5 is 4-[(2,6-dichlorophenyl)- methoxyjphenyl, g is equal to 0 and stereochemistry is (S)).
  • Example 115 was prepared as described in Scheme G from 2-carboxy-5-oxo-2- pyrrolidinepropanoic acid (Majer, Z.; Kajtar, M.; Tichy, M.; Blaha, K. Coll. Czech. Chem. Commun. 1982, 47, 950).
  • Example 117 2-[3-[[( 1 S)- 1 -Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]-3- oxo-propyl]-5-oxoproline (Scheme G. G-6: where R ⁇ is proton, R 5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, g is equal to 0 and stereochemistry is (S)).
  • Example 116 was prepared from example 115 by the procedure described in preparation
  • Scheme H teaches a general method for the preparation of 6-chloroazatyrosine examples of structures H-4 and H-5, by adaption of the methodology for the preparation of protected azatyrosine reagents as described by Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012-12013 and references cited therein.
  • regioselective iodination of 2-chloro-3-pyridinol gives the chloro-iodopyridinol H-2, that is O-alkylated as exemplified by the synthesis of H-3.
  • Example 118 was prepared as described in Scheme A from D-cysteine using the product of preparation 44 as amino acid intermediate A-4. Physical properties as follows: TLC (1:1 hexanes/EtOAc) RfO.27; l R NMR (CDCI3, 300 MHz) ⁇ 8.43 (IH), 7.74 (IH),
  • Example 119 was prepared from example 118 by the procedure described in preparation 12. Physical data as follows: mp 93-95 °C; TLC (600:400:2 EtOAc/hexanes/HCO 2 H) Rf
  • Scheme I teaches a general method for the preparation of azatyrosine reagents 1-3, 1-4, 1-5, 1-6 and 1-7, by adaptation of the methodology for the preparation of protected azatyrosine reagents as described by Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012-12013 and references cited therein.
  • O-protection of chloroiodopyridinol I-l (identical to H-2) is followed by reaction with the organozinc, derived from a suitably protected ⁇ -iodoalanine, to provide the protected 6-chloroazatyrosine 1-3.
  • Reductive dehalogenation of 1-3 gives 1-4, that is 0-deprotected to give 1-5.
  • Reagent 1-5 is O- alkylated, as exemplified by the preparation of 1-6.
  • N-deprotection of 1-6 gives the aminoester 1-7, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples of this invention.
  • This reaction mixture is stirred for 4 h at 45 °C. It is cooled to 0 °C, quenched with sat'd aq ⁇ H4CI, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4CI and brine.
  • Example 120 was prepared as described in Scheme A from D-cysteine using the product of preparation 49 as amino acid intermediate A-4. Physical properties as follows: TLC (1 : 1 hexanes/EtOAc) Rf 0.22; ] H NMR (CDCI3, 300 MHz) ⁇ 8.28 (2H), 7.38 (2H), 7.28 (2H), 7.09 (IH), 5.29 (2H), 4.90-4.74 (3H), 4.40 (IH), 3.67 (3H), 3.38-3.22 (3H), 1.61 (2H),
  • Example 121 was prepared from example 120 by the procedure described in preparation 12. Physical data as follows: mp 92-94°; TLC (500:500:3 hexanes/EtOAc/HCO 2 H) Rf
  • Scheme J teaches a general method for the preparation of ⁇ r ⁇ -acylamino derivatives of aza-phenylalanine.
  • bis-acylation of 2-amino-5-iodopyridine J-1 gives the imide J-2, that is reacted with the organozinc, derived from a suitably protected ⁇ -iodoalanine, to provide the protected acylamino azaphenylalanine J-3.
  • N-deprotection of J-3 gives the aminoester J-4, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples of this invention.

Abstract

The present invention relates to compound of formula (I), that are potent inhibitors of α4β1 mediated adhesion to either VCAM or CS-1 and which could be useful for the treatment of inflammatory diseases. Specifically, the molecules of the present invention can be used for treating or preventing α4β1 adhesion mediated conditions in a mammal such as a human. This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained in the present specification.

Description

INHIBITORS OF α4β, MEDIATED CELL ADHESION
Background of the Invention
Field of the Invention
The present invention relates to small molecules that are potent inhibitors of α4β, mediated adhesion to either VCAM or CS-1 and which are useful for the treatment of inflammatory diseases.
Description of Related Art
The extracellular matrix (ECM) is the major component of connective tissue which provides structural integrity, and promotes cell migration and differentiation. As part of these functions, extracellular matrix molecules such as fibronectin, collagen, laminin, von Willebrand factor, thrombospondin, fibrinogen, and tenascin have been shown to support adhesion of cells in vitro. This adhesive interaction is critical for a number of biological processes including hemostasis, thrombosis, wound healing, tumor metastasis, immunity and inflammation.
Fibronectin (FN) is the prototype ECM molecule. The major cell attachment site in the fibronectin molecule has been reproduced synthetically with the amino acid sequence arginine-glycine-aspartic acid, or RGD using single letter nomenclature. Peptides containing the RGD sequence which either inhibit or promote cell adhesion have been described (US Patent Nos. 4,589,881; 4,661,111; 4,517,686; 4,683,291; 4,578,079; 4,614,517; and 4,792,525). Changes in the peptide as small as the exchange of alanine for glycine or glutamic acid for aspartic acid, which constitute the addition of a single methyl or methylene group to the tripeptide, eliminates these activities (Pierschbacher et al., Proc. Natl. Acad. Sci. USA 81:5985 (1984)). Recently, a second FN cell binding domain has been identified within the alternatively spliced region of the A chain of the molecule, known as the connecting segment 1 (CS-1). The most active cell-binding site within this alternatively spliced region is composed of 25 amino acids where the carboxy terminus contains the sequence EILDVPST. The amino acid sequence EILDVPST forms a recognition motif on FN for cell surface receptors. (Wayner et al, J. Cell Biol. 109:1321 (1989); Guan et al., Cell 60:53 (1990)).
The receptors which recognize these sites on FN belong to a gene superfamily called integrins which consist of heterodimeric complexes of non-covalently associated alpha and beta subunits. A common β subunit combines with unique I subunits to form an adhesion receptor of defined specificity. To date, 8 β subunits have been identified which can dimerize with 16 distinct I subunits forming 22 distinct integrins. The βl subfamily, also known as the VLA family (Very Late Activation Antigens), binds to ECM molecules such as FN, collagen and laminin. For reviews, see, Hynes, Cell 48:549 (1987); Hemler, Annu. Rev.
Immunol. 8:365 (1990). Leukocyte interaction with FN at the two spatially separate binding domains is mediated by two distinct integrins. The RGD site is recognized by the integrin α5β„ while, EILDV is recognized by α4β, (Pytela et al., Cell 40:191 (1985); Wayner et al., J.
Cell Biol 109:1321 (1989); Guan et al, Cell 60:53 (1990)). Vascular endothelial cells form the interface between blood and tissues and control the passage of leukocytes as well as plasma fluid into tissues. A variety of signals generated at the site of inflammation can activate both endothelial cells as well as circulating leukocytes so that they become more adhesive to one another. Following this initial adhesion the leukocytes migrate into the tissues to perform host defense functions. Several adhesion molecules have been identified which are involved in leukocyte-endothelial interactions.
In the β, subfamily, in addition to binding to fibronectin, α4β, interacts with a cytokine inducible protein on endothelial cells termed vascular cell adhesion molecule (VCAM). Further involved in the leukocyte-endothelial adhesion process is the β2 integrin subfamily. β2 integrins include CDl la/CD18, CDl lb/CD18, and CDl lc/CD18. In addition, the β7 subunit associates with α4 to form a unique 4β7 heterodimer which binds to FN, to VCAM, and to Mucosal Addressin Cell Adhesion Molecule- 1 (MAdCAM) (Ruegg et al, J. Cell.Biol 117:179 (1992); Andrew et al., J Immunol. 153:3847 (1994); Briskin et al., Nature 363:461 (1993); Shyjan et al, J Immunol. 156:2851 (1996)). α4 integrins are widely expressed on different cell types including hematopoietic progenitors, lymphocytes, natural killer cells, monocytes, eosinophils, basophils, and mast cells (Helmer, M. E., Annu. Rev. Immunol. 8:365 (1990)). Other molecules on endothelial cells which bind to the leukocytes include ICAM-1, ICAM-2, E-selectin and P-selectin (Carlos and Harlan, Immunol. Rev. 114:1 (1990); Osborn, L., Cell 62:3 (1990); Springer T., Nature 346:425 (1990); Geng et al., Nature 347:757 (1990); Stoolman, Cell 56:907 (1989)).
A number of in vitro and in vivo studies indicate that α4β, plays a critical role in the pathogenesis of a variety of diseases. Monoclonal antibodies directed against α4 have been tested in a variety of disease models. Anti- 4 antibodies block adhesion of lymphocytes to synovial endothelial cells; this adhesion plays a potential role in rheumatoid arthritis (van Dinther-Janssen et al, J Immunol. 147:4207 (1991)). α4 has also been implicated with respect to rheumatoid arthritis in separate studies (Laffon et al, J. Clin. Invest. 88:546 (1991); Morales-Ducret et al, J Immunol. 149:1424 (1992)). A significant number of studies have evaluated the role of α4 in allergy and asthma. For example, monoclonal antibodies to α4 block adhesion of basophils and eosinophils to cytokine activated endothelial cells (Walsh et al, J. Immunol. 146:3419 (1991); Bochner et al, J. Exp. Med. 173:1553 (1991)). Monoclonal antibodies to α4 were also effective in several lung antigen challenge models (Abraham et al, J Clin. Invest. 93:776 (1994); Weg et al, J Exp. Med. 177:561 (1993)). The cotton-top tamarin, which experiences spontaneous chronic colitis, showed a significant attenuation of their colitis when anti-α4 antibody was administered (Podolsky et al, J Clin. Invest. 92:372 (1993); Bell et al, J. Immunol. 151:4790 (1993)). In a rat and mouse model, autoimmune encephalomyelitis was blocked by anti-α4 antibody (Yednock et al, Nature 356:63 (1992); Baron et al, J. Exp. Med. 177:57 (1993)). Anti-α4 monoclonal antibodies also inhibit insulitis and delay the onset of diabetes in the non-obese diabetic mouse (Baron et al, J. Clin. Invest. 93:1700 (1994); Yang et al, Proc. Natl. Acad. Sci. USA 90:10494 (1993); Burkly et al. Diabetes 43:529 (1994)). α4 is also implicated in atherosclerosis due to its endothelial expression during atherogenesis (Cybulsky et al, Science 251:788 (1991)). The migration of leukocytes to an inflammatory site can also be blocked by anti-α4 antibodies. In addition to the blocking of migration, inhibitors of leukocyte endothelial adhesion may block the costimulatory signals mediated by integrins and thus inhibit overproduction of inflammatory cytokines. In a separate set of experiments not using anti-α4 antibodies, the peptides GRDGSP or EILDV were tested against contact hypersensitivity response. The contact hypersensitivity response was found to be blocked by GRDGSP or EILDV suggesting that both α4β, and α5β, are involved in this inflammatory response.
Other ailments which may involve α4β, -mediated conditions include the inflammatory disorders rheumatoid arthritis, allergic disorders, asthma, spontaneous chronic colitis, insulitis, contact hypersensitivity response, atherosclerosis and autoimmune encephalomyelitis. These studies illustrate that small molecules that are potent inhibitors of α4β, mediated adhesion to either VCAM-1 or CS-1 may be used as a form of treatment in numerous inflammatory diseases. However, these inflammatory conditions could be expanded to include adult respiratory distress syndrome, AIDS, cardiovascular diseases, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, allograft rejection, reperfusion injury, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including metastasis of neoplastic or cancerous growth, wound healing enhancement, treatment of certain eye diseases such as detaching retina, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, ulcerative colitis, regional enteritis and other autoimmune diseases. Accordingly, a compound which could inhibit these conditions is desirable.
Summary of the Invention
The present invention particularly provides: A compound of the formula:
Figure imgf000006_0001
Iπ the above formula (I), R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl. Also in the above formula (I), R2 is hydrogen, pyridyl, C,.6 alkyl, (C,_6 alkyl)-CO2-Rπ, or -CO2-Rπ. In addition, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000007_0001
together with the carbon atom to which they are attached.
In the above formula (I), R3 is hydrogen, phenyl, C,.6 alkyl, C3.6 alkenyl, C7.,7 arylalkyl , (C,.6 alkyl)-CO2-R,„ (C2.6 alkenyl)-CO2-Rπ, (C,.6 alkyl)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CN, adamantyl or one of the following
Figure imgf000007_0002
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000008_0001
In the above formula (I), R4 is -O-Rn, NH2, NHOH, -O-(C7.I0 arylalkyl), or is of the formula:
Figure imgf000008_0002
In the above formula (I), R5 is a formula of the following:
Figure imgf000008_0003
In the above, Rj, is N or CH, R7 is hydrogen or halogen, R8 is -NH-Y,-, -OCH2-, or
-CONH-, R, may occur one to three times and is a halogen, C,.6 alkoxy, C,.6 alkyl or trifluoromethyl, R,0 is C,.6 alkyl, or (C,_6 alkyl)-OH, or hydrogen, Rn is hydrogen or C,_6 alkyl, R12 is C,.6 alkyl or the following formula:
Figure imgf000008_0004
In the above formula (I), W is (C,.6 alkyl), X is S, O, or CH2, Y and Y, are independently -CO-, -C(=O)O-, -SO2-, or -C(=O)N(R10)- and Z is O, CH2, or N-R„.
In the above, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3.
The above formula (I) has the provisos that: (1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; and (4) the compound is not
Figure imgf000009_0001
In another embodiment of the present invention, R5 is a formula of the following:
Figure imgf000009_0002
wherein R7 is hydrogen or Cl.
In another embodiment of the present invention, R2 is hydrogen or C,.6 alkyl. Additionally, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000009_0003
together with the carbon atom to which they are attached. Also, in this embodiment, n is
Figure imgf000009_0004
In yet another embodiment of the present invention, R, is hydrogen or C,.3 alkyl, and R2 is hydrogen or C alkyl. Additionally, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000009_0005
together with the carbon atom to which they are attached. Also in this embodiment, R3 is hydrogen, C,.6 alkyl, C7.17 arylalkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CO2-Rπ, (C,.6 alkyl)-CN, adamantyl, phenyl, or one of the following:
Figure imgf000010_0001
-(Cι_6 alkyl)-
Figure imgf000010_0002
Additionally, in this embodiment, R4 is -O-Rπ , NH2, NHOH, or R4 is of the formula:
Figure imgf000010_0003
, Rπ is hydrogen or CH3 and X is S or O. In another embodiment, R, and R2 are hydrogen, and R3 is(C2.6 alkenyl)-CO2-Rn, (C,.6 alkyl)-O-C,.3 alkyl, (C,.6 alkyl)-CO2Rπ, or one of the following:
Figure imgf000010_0004
- NO, HN-N fl ^Cθ2- n ^ ' ^ -C02-R^
Also, in this embodiment, R4 is O-Rπ, Ro is CH, Rn is hydrogen, and R7 is hydrogen. Additionally, X is S, Y is -CO-, and / is 1.
In another embodiment of the present invention, R, and R2 are hydrogen, and R3 is C,.6 alkyl, (C,.6 alkyl)-CO2-Rn, (C2.6 alkenyiyCO.-R,,, (C,.6 alkyl)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.3 alkyl, (C,.6 alkyl)-CN, or one of the following:
Figure imgf000011_0001
Additionally, R4 is OH, R^ is CH, R, , is hydrogen, R7 is hydrogen, X is CH2, and Y is - CO- or -C(=O)NH-.
In another embodiment of the present invention, W is (C,.3 alkyl), X is CH2, Y is -C(=O)O-, R, is hydrogen, R2 is hydrogen, (C,.3 alkyl)-CO2-Rπ, or -CO2-R,„ R3 is hydrogen, C7.10 arylalkyl, C,.6 alkyl, or (C,_6 alkyl)-CO2-Rn, R4 is OH, R^ is CH, Rn is hydrogen, R7 is hydrogen, / is 1 or 3, and n is 0.
In another embodiment of the present invention, W is C,.3 alkyl, X is CH2, R, is hydrogen, R2 is (C alkyl)-CO2-Rπ, or CO2-Ru, R3 is hydrogen, C,.3 alkyl, or C2.7 alkenyl, R4 is OH, is CH, Rn is hydrogen, R7 is hydrogen, / is 1, m is 1, n is 1, o is 0, and/? is 1. In another embodiment, the compound of the present invention is represented by the following formula
Figure imgf000011_0002
In another embodiment of the present invention, R, and R2 are hydrogen, and R3 is C,.6 alkyl, (C,.6 alkyl)-CO2R,„ (Cw alkenyl)-CO2R„, (C,.6 alkyl)-O-C,.3 alkyl, or one of the following:
Figure imgf000012_0001
NO, HN-N
H Cθ2-Rιι "CO2- 11
Additionally, in this embodiment, R4 is O-Ru, R^ is CH, Rπ is hydrogen or C,.6 alkyl, R7 is hydrogen, X is S, Y is -C(=O)O-, and / is 1.
In another embodiment of the present invention, R, is hydrogen or C,.3 alkyl and R2 is hydrogen or C alkyl. Additionally, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms, or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000012_0002
together with the carbon atom to which they are attached. In this embodiment, R3 is hydrogen, C,.6 alkyl, C7.I7 arylalkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CO2-Rπ, (C,.6 alkyl)-CN, adamantyl, phenyl, or one of the following:
Figure imgf000012_0003
Additionally, in this embodiment, R4 is -O-Rπ , NH2, NHOH, or R4 is of the formula — θ-CH2-
^N . Also, Rn is hydrogen or C,.6 alkyl, and X is S or O. In yet another embodiment, the compound of the present invention is represented by the following formula (I-a):
Figure imgf000013_0001
In the above formula (I-a), R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl, and R2 is hydrogen, pyridyl, C,.6 alkyl, (C,.6 alkyl)- CO2-Rπ, or -CO2-Rπ. Additionally, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000013_0002
together with the carbon atom to which they are attached. Additionally, in this embodiment, R3 is hydrogen, phenyl, C,.6 alkyl, C3.5 alkenyl, C7.17 arylalkyl , (C,.6 alkyl)-CO2-R„, (C2.6 alkenyl)-CO2-Ru, (C,.6 alkyl)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,_6 alkyl)-CN, adamantyl or one of the following:
-(C].6 alkyl)-N Z (Ci-6
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0001
Figure imgf000014_0004
lkyθ2
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000014_0005
Additionally, R4 is -O-R,„ NH2, NHOH, -O-(C7.,0 arylalkyl), or is of the formula
-θ-CH2-
Also, in this embodiment, R5 is a formula of the following:
Figure imgf000014_0006
Additionally, in this embodiment, R^ is N or CH, R7 is hydrogen or halogen, Rg is -NH-Y,-, -OCH2-, or -CONH-, R,, may occur one to three times and is a halogen, C,.6 alkoxy, C,.6 alkyl or trifluoromethyl, R10 is C,.6 alkyl, or (C,.6 alkyl)-OH, or hydrogen, R, is hydrogen or C,_6 alkyl, R,2 is C,.6 alkyl or the following formula:
Figure imgf000015_0001
, R13 is N or CH, W is (C,.6 alkyl), X is S, O, or CH2, Y and Y, are independently -CO-, -C(=O)O-, -SO2-, or -C(=O)N(R10)-, Z is O, CH2, or N-R„, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3. This particular embodiment of the present invention has the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2;
(4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and/or an IC50 value of less than 50μM in a Jurkat EC assay; and
(5) the compound is not
Figure imgf000015_0002
In yet another embodiment of the compound of formula (I), R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl. Also, R2 is hydrogen, pyridyl, C,.6 alkyl, (C,.6 alkyl)-CO2-Rn, or -CO2-Rπ. Additionally, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000016_0001
together with the carbon atom to which they are attached. In this embodiment, R3 is hydrogen, phenyl, C,.6 alkyl, C3.6 alkenyl, C7.I7 arylalkyl , (C,.6 alkyl)-CO2-R„, (C2.6 alkenyl)-CO2-Rn, (C,.6 alkyl)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CN, adamantyl or one of the following:
-(C1-6 a
Figure imgf000016_0002
Figure imgf000016_0003
O. N
^ \^.NO? HN-
C07-R, , H CO2-R11 \\ T * ^^C02-R„ OO I
N(C1-3aIkyI)2
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000016_0004
In this embodiment, R4 is -O-R,,, NH2, NHOH, -O-(C7.10 arylalkyl), or R4 is of the formula: -θ-CH2 „
N •
Also, in this embodiment, R5 is a formula of the following:
Figure imgf000017_0001
Additionally, in this embodiment, ^ is N or CH, R7 is hydrogen or halogen, R8 is -NHCO-, R, may occur one to three times and is a halogen, C,.6 alkoxy, C,.6 alkyl or trifluoromethyl, R10 is C,.6 alkyl, or (C,.6 alkyl)-OH, or hydrogen, Rπ is hydrogen or C,.6 alkyl, R12 is C,.6 alkyl or the following formula:
Figure imgf000017_0002
, R13 is N or CH, W is (C,.6 alkyl), X is S, O, or CH2, Y is -CO-, -C(=O)O-, -C(=O)N(RIO)-, Z is O, CH2, or N-R„, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3. In this embodiment, the following provisos apply: (1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl; and
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2.
In yet another embodiment of the compound of formula (I-a), R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl, and R2 is hydrogen, pyridyl, C,.6 alkyl, (C,_6 alkyl)-CO2-Ru, or -CO2-Ru. Additionally, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000018_0001
together with the carbon atom to which they are attached. Additionally, in this embodiment, R3 is hydrogen, phenyl, C,.6 alkyl, C3.6 alkenyl, C7.I7 arylalkyl ,
(C,.6 alkyl)-CO2-Ru, (C2.6 alkenyl)-CO2-R1„ (C,.6 alkyl)-CO-C,.6 alkyl,
(C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CN, adamantyl or one of the following:
Figure imgf000018_0002
kyl)2
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000018_0003
Additionally, R4 is -O-R,„ NH2, NHOH, -O-(C7.10 arylalkyl), or is of the formula -O-CHz-i}
N'
Also, in this embodiment, R5 is a formula of the following:
Figure imgf000019_0001
Additionally, in this embodiment, is N or CH, R7 is hydrogen or halogen, R8 is -NHCO-, R, may occur one to three times and is a halogen, C,_6 alkoxy, C,.6 alkyl or trifluoromethyl, R10 is C,.6 alkyl, or (C,.6 alkyl)-OH, or hydrogen, Ru is hydrogen or C,.6 alkyl,R12 is C,.6 alkyl or the following formula:
Figure imgf000019_0002
, R,j is N or CH, W is (C,.6 alkyl), X is S, O, or CH2, Y is -CO-, -C(=O)O- or -C(=O)N(R,0)-, Z is O, CH2, or N-R,„ / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3. This particular embodiment of the present invention has the provisos that
(1) when Y is -C(=O)O-. R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; and (4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and/or an IC50 value of less than 50μM in a Jurkat EC assay.
In another embodiment of the compound of formula (I), R, may occur one to four times and each occurrence is independently hydrogen or C,_6 alkyl, R^ is hydrogen, pyridyl, C,„6 alkyl, (C,_6 alkyl)-CO2-Rπ, or -CO2-Rπ. Additionally, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000020_0001
together with the carbon atom to which they are attached. Also, in this embodiment, R3 is hydrogen, phenyl, C,.6 alkyl, C3.6 alkenyl, C7.17 arylalkyl , (C,.6 alkyl)-CO2-Rn, (C2.6 alkenyl)-CO2-R,„ (C,.6 alkyl)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CN, adamantyl or one of the following:
(Cι-6 -(Cι.6 alkyl)-
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000020_0005
In this embodiment, R4 is -O-Rn, NH2, NHOH, -O-(C7.,0 arylalkyl), or R4 is of the formula:
Figure imgf000020_0006
In this embodiment, R5 is a formula of the following:
Figure imgf000021_0001
Also, in this particular embodiment, is N or CH, R7 is hydrogen or halogen, R8 is -OCH2-, R_, may occur one to three times and is a halogen, C,„6 alkoxy, C,.6 alkyl or trifluoromethyl, R10 is C,.6 alkyl, (C,.6 alkyl)-OH, or hydrogen, Rπ is hydrogen or C,.6 alkyl, R,2 is C,.6 alkyl or the following formula:
Figure imgf000021_0002
, R13 is N or CH, W is (C,.6 alkyl), X is S, O, or CH2, Y is -CO-, -C(=O)O- or -C(=O)N(R10)-, Z is O, CH2, or N-Rπ, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or 1 , p is 0 or 1 , q is 0 or 1 , and r is 0, 1 , 2 or 3. This particular embodiment has the following provisos:
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2;
(4) when R3 is phenyl, C,_6 alkyl, C7.17 arylalkyl, (C,.6 alkyl)-CO2-R, ,, (C,.6 alkyl)-O- C,.6 alkyl or (C,.6 alkyl)-OH, o is 0; and
(5) the compound is not
Figure imgf000021_0003
In yet another embodiment of the compound of formula (I-a), R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl, and R2 is hydrogen, pyridyl, C,.6 alkyl, (C,.6 alkyl)-CO2-Ru, or -CO2-Ru. Additionally, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000022_0001
together with the carbon atom to which they are attached. Additionally, in this embodiment, R3 is hydrogen, phenyl, C,.6 alkyl, C3.6 alkenyl, C7.17 arylalkyl ,
(C,.6 alkyl)-CO2-Rπ, (CM alkenyl)-CO2-R„, (C,.6 alkyl)-CO-C,.6 alkyl,
(C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)-OH, (C,.6 alkyl)-CN, adamantyl or one of the following:
Figure imgf000022_0002
In addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000023_0001
Additionally, R4 is -O-Rn, NH2, NHOH, -O-(C7.10 arylalkyl), or is of the formula
-O-CH2- ,
^N
Also, in this embodiment, R5 is a formula of the following:
Figure imgf000023_0002
Additionally, in this embodiment, is N or CH, R7 is hydrogen or halogen, R8 is -OCH2-, R,, may occur one to three times and is a halogen, C,_6 alkoxy, C,.6 alkyl or trifluoromethyl, R,0 is C,.6 alkyl, or (C,_6 alkyl)-OH, or hydrogen, Rπ is hydrogen or C,.6 alkyl, R12 is C,_6 alkyl or the following formula:
Figure imgf000023_0003
, RI3 is N or CH, W is (C,.6 alkyl), X is S, O, or CH2, Y is -CO-, -C(=O)O- or -C(=O)N(R10)-, Z is O, CH2, or N-R„, / is 1, 2, or 3, m is 1 or 2, n is 0 or 1, o is 0 or X,p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3. This particular embodiment of the present invention has the provisos that:
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2;
(4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and or an IC50 value of less than 50μM in a Jurkat EC assay;
(5) when R3 is phenyl, C,_6 alkyl, C7.17 arylalkyl, (C,.6 alkyl)-CO2-Rn, (C,.6 alkyl)-O- C,.6 alkyl or (C,.6 alkyl)-OH, o is 0; and (6) the compound is not
Figure imgf000024_0001
In the above formula (I) the absolute stereochemistry for the bond leading to R5 is shown, however the absolute stereochemistry has not been shown for all examples which follow. It is understood that all other formulas also follow this type of absolute stereochemistry unless otherwise stated. Additionally, it is to be understood by those of skill in the art that the present invention embodies stereochemical configurations other than those shown. Specifically, the present invention embodies all configurations including the various stereoisomers. Compounds which do not meet the absolute stereochemistry in formula (I) should meet an activity threshold in various assays, to be explained below, which can ensure their efficacy as useful molecules. The present invention includes mixtures, such as racemic mixtures, which contain molecules having the claimed stereochemistry.
The desired compound of the present invention may be clinically used either in a free form or in the form of pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include acid-addition salts with inorganic acid or organic acid (e.g., hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate), salt with inorganic base, organic base or amino acid (e.g., triethylamine salt, a salt with lysine, an alkali metal salt, an alkali earth metal salt and the like). The compound may also be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined above and a pharmaceutically acceptable carrier or diluent.
The compound can also be used for treating or preventing α4β, adhesion mediated conditions in a mammal such as a human. This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained above.
This method can be used to treat such inflammatory conditions as rheumatoid arthritis, asthma, allergy conditions, adult respiratory distress syndrome, AIDS, cardiovascular diseases, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, allograft rejection, reperfusion injury, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including metastasis of neoplastic or cancerous growth, wound healing enhancement, treatment of certain eye diseases such as detaching retina, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, ulcerative colitis, atherosclerosis, regional enteritis and other autoimmune diseases.
As mentioned above, the compounds and compositions containing the compounds according to the present invention are particularly useful in treating or preventing 4β, adhesion mediated conditions in a mammal such as a human. The present inventors have found that the compounds and compositions containing the compounds according to the present invention are most useful in the treatment of asthma.
The desired compound of the present invention or pharmaceutically acceptable salts thereof may be administered either orally or parenterally, and it may be used as a suitable pharmaceutical preparation, for example, a tablet, a granule, a capsule, a powder, an injection, and an inhalation by a conventional process.
The dose of the desired compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on an administration method, age, body weight, and state of a patient, but, in general, the daily dose is preferably about 0.1 to 100 mg/kg/day, however, 1 to 100 mg kg/day may also be suitable. Preferred routes of administration for asthma:
It is preferred that the compound of the present invention be administered in the form of an Aerosol. However, other routes of administration include intravenous, oral, intramuscular, and subcutaneous. In the case of aerosol administration, compositions containing the compounds of the present invention can be prepared to provide for an excellent means for administering in aerosol form for inhalation therapy. Accordingly, the present invention will provide for self- propelling compositions containing the compounds of the present invention.
Propellants employed should be non-toxic and have a vapor pressure suitable for the conditions under which administration occurs. These propellants can be fluorinated or fluorochlorinated lower saturated aliphatic hydrocarbons. The preferred propellants of this type are the halogenated alkanes containing not more than two carbon atoms and at least one fluorine atom. Illustrative of these are trichloromonofluoromethane, dichlorodifluoromethane, monochlorotrifluoromethane, dichloromonofluoromethane and l,2-dichloro-l,l,2,2-tetrafluoroethane. These compounds are available from E.I. duPont de Nemours and Company under the trade name "Freon". These propellants may be employed singularly or in admixture.
In addition to the propellant. an organic solvent may also be employed. The organic solvent must be non-toxic and without undesirable effects on inhalation in the amount present in the aerosol produced. In addition, the solvent should be substantially anhydrous, completely miscible with the propellant or mixture of propellants employed and have a suitable boiling point. Examples of such solvents included non-toxic aliphatic alcohols such as ethanol; ethers such as ethyl ether and vinyl ether; ketones such as acetone; and suitable halogenated lower alkanes. In addition to the organic solvent, the composition may also optionally contain a non- toxic hygroscopic glycol. The glycol must be substantially miscible with the organic solvent and the propellant employed. Satisfactory glycols include propylene glycol, triethylene glycol, glycerol, butylene glycol and hexylene glycol.
The above indicated methods of administration and formulation of aerosol compositions should not be viewed as limiting. The compounds of the present invention can be formulated in anyway deemed suitable to one of ordinary skill in the art so as to obtain the desired effects.
Pharmaceutical Compositions As indicated previously, the compounds of formula (I) can be formulated into pharmaceutical compositions. In determining when a compound of formula (I) is indicated for the treatment of a given disease, the particular disease in question, its severity, as well as the age, sex, weight, and condition of the subject to be treated, must be taken into consideration and this perusal is to be determined by the skill of the attendant physician. For medical use, the amount of a compound of formula (I) required to achieve a therapeutic effect will, of course, vary both with the particular compound, the route of administration, the patient under treatment, and the particular disorder or disease being treated. A suitable daily dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a mammalian subject suffering from, or likely to suffer from, any condition as described hereinbefore is 0.1 mg to 100 mg of the compound of formula I, per kilogram body weight of the mammalian subject. In the case of systematic administration, the dose may be in the range of 0.5 to 500 mg of the compound per kilogram body weight, the most preferred dosage being 0.5 to 50 mg/kg of mammal body weight administered two to three times daily. In the case of topical administration, e.g., to the skin or eye, a suitable dose may be in the range of 0.1 μg to 100 μg of the compound per kilogram, typically about 0.1 μg/kg.
In the case of oral dosing, a suitable dose of a compound of Formula (I), or a physiologically acceptable salt thereof, may be as specified in the preceding paragraph, but most preferably is from 1 mg to 10 mg of the compound per kilogram, the most preferred dosage being from 1 mg to 5 mg/kg of mammal body weight, for example, from 1 to 2 mg/kg. Most preferably, a unit dosage of an orally administrable composition encompassed by the present invention contains less than about 1.0 g of a formula (I) compound.
It is understood that formulation, both for human and veterinary use, of the present invention may be presented to the mammal by inhalation. To achieve therapeutic effect, the dose may be in the range of 0.5 to 500 mg of the compound, per kg body weight. The most preferred dosage being 0.5 to 50 mg/kg of mammal body weight administered two to three times daily.
It is understood that the ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount of a compound of formula (I) to prevent or arrest the progress of the condition for which treatment is administered. In so proceeding, the physician or veterinarian could employ relatively low doses at first, subsequently increasing the dose until a maximum response is obtained.
The compounds and compositions of the present invention can be administered to patients suffering from a condition listed herein in an amount which is effective to fully or partially alleviate undesired symptoms of the condition. The symptoms may be caused by inappropriate cell adhesion mediated by α4β, integrins. Such inappropriate cell adhesion would typically be expected to occur as a result of increased VCAM-1 and/or CS-1 expression on the surface of endothelial cells. Increased VCAM-1 and/or CS-1 expression can be due to a normal inflammation response or due to abnormal inflammatory states. In either case, an effective dose of a compound of the invention may reduce the increased cell adhesion due to increased VCAM-1 expression by endothelial cells. Reducing the adhesion observed in the disease state by 50% can be considered an effective reduction in adhesion. More preferably, a reduction in adhesion by 90%, is achieved. Most preferably adhesion mediated by VCAM-l/α4β, and/or CS-1 interaction is abolished by an effective dose. Clinically, in some instances, effect of the compound can be observed or a decrease in white cell infiltration into tissues or a site of injury. To achieve a therapeutic effect, then, the compounds or compositions of the present invention are administered to provide a dose effective to reduce or eliminate inappropriate cell adhesion or to alleviate undesired symptoms. While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier thereof. Such formulations constitute a further feature of the present invention.
The formulations, both for human and veterinary medical use, of the present invention comprise an active ingredient of formula (I), in association with a pharmaceutically acceptable carrier thereof and optionally other therapeutic ingredient(s), which are generally known to be effective in treating the disease or condition encountered. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The formulations include those in a form suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), intra-articular, topical, nasal inhalation (e.g., with an aerosol) or buccal administration. Such formulation are understood to include long-acting formulations known in the art.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods may include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form.
Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid. Formulations for other uses could involve a nonaqueous liquid; in the form of an oil-in-water emulsion or a water-in-oil emulsion; in the form of an aerosol; or in the form of a cream or ointment or impregnated into a transdermal patch for use in administering the active ingredient transdermally, to a patient in need thereof. The active ingredient of the present inventive compositions may also be administered to a patient in need thereof in the form of a bolus, electuary, or paste. The practitioner is referred to "Remington: The Science and Practice of Pharmacy,"
19th Edition, c. 1995 by the Philadelphia College of Pharmacy and Science, as a comprehensive tome on pharmaceutical preparations. Abbreviations
Ac2O: Acetic anhydride
EtOAc: Ethyl acetate
BCECF-AM: 2',7'-bis-(2-carboxyethyl)-5-(and 6-) carboxyfluorescein acetoxy- methyl ester
BOP-C1: Bis (2-oxo-3-oxazolidinyl) phosphinic chloride
BOP Reagent: Benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate
DMEM: Dulbecco's Minimal Eagle's Media
DMF: Dimethyl formamide
DIEA: Diisopropylethylamine
EDC: 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et: Ethyl
EtOH: Ethanol
HATU: N-[(Dimethylamino)-lH-l ,2,3-triazolo[4,5-Z>]-pyridin-l - ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
HBSS: Hank's Balanced Salt Solution
HBTU: O-Benzotriazol- 1 -yl-Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate
HOBT (HOBt): 1 -Hydroxybenzotriazole
HSA: Human serum albumin
LDA: Lithium diisopropylamide
Me: Methyl meq: milliequivalent
MeOH: Methanol n-Bu: n-Butyl
NMP: 1 -Methyl-2-pyrrolidinone
PBS: Phosphate buffered saline
Pd-C: Palladium on charcoal
Ph: Phenyl SPDP: 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide ester t-Bu: t-butyl
THF: Tetrahydrofuran
TFA: Trifluoroacetic acid DMSO: dimethyl sulfoxide
HO At: l-hydroxy-7-azabenzotriazole
DMAP: 4-dimethylaminopyridine
FMOC: 9-fluorenylmethoxycarbonyl
Bn: benzyl PyBOP: (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate
BOC: tert-butoxycarbonyl
The representative compounds according to the present invention are prepared as described below. The compounds of the present invention are prepared in a similar manner.
Scheme A
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000032_0004
Figure imgf000032_0005
Figure imgf000032_0006
RA_, and RΛ.2 are defined independently as R,.
Scheme A describes a general method for the preparation of examples of the formula A-5, A-6, A-7, A-8, A-9 and A-10. A commercially available or readily prepared sulfur containing amino acid of structure A-l (for the synthesis of β,β-disubstituted cysteine amino acids see: Stanfield, G.F.; Hruby, V.J. Synth. Commun.1988, 18, 531 and references therein) is condensed with formaldehyde to afford the thiazolidine-4-carboxylic acid of general formula A-2 (for the condensation of aldehydes with cysteine or similar sulfur containing amino acids see for example: (a) Ratner, S.; Clark, H.T. J. Am. Chem. Soc. 1937, 59, 200. (b) Lewis, N.J.; Inloes, R.L.; Hes, J.; Matthews, R.H.; Milo, G. J. Med. Chem. 1978, 21, 1070. (c) Oya, M.; Baba, T.; Kato, E.; Kawashima, Y.; Watanbe, T.
Chem. Pharm. Bull. 1982, 30, 440.). Standard protection affords carbamate A-3 which is readily condensed with amino acid derivative A-4 under standard peptide synthesis conditions to provide the psuedodipeptide A-5 (for a review of procedures of peptide synthesis see: Bodansky, M.; Bodansky, A. The Practice of Peptide Synthesis; Springer- Verlag: Berlin, 1984). Deprotection of the carbamate from A-5 provides the useful intermediate A-6. The amine group may be reacted with a variety of electrophilic reagents such as: (1) commercially available or readily prepared sulfonyl chlorides (for the synthesis of sulfonyl chlorides see for examples: (a) Roblin, R.O.; Clapp, J.W. J. Am. Chem. Soc. 1950, 72, 4890. (b) Gilbert, E.E. in Sulfonation and Related Reactions Olah, G.A., Ed. John Wiley and Sons, New York; 1965. (c) Park, Y.J.; Shin, H.H.; Kin, Y.H.
Chem Lett. 1992, 1483. (d) Kim, D.; Ko, Y.K.; Kim, S.H. Synthesis, 1992, 1203.) to afford sulfonamides of general structure A-7 where Y is SO2- (preparation 5); (2) carbonates or chloro formates to afford carbamates of general structure A-7 where Y is CO2- (preparations 2, 7, 8); (3) isocyanates to afford ureas of general structure A-7 where Y is CONHR3 (preparation 9); (4) phosgene or a suitable equivalent and an amine to afford ureas of general structure A-7 where Y is CON(C,.6alkyl)R3- (preparation 10, also see for example: Nowick, J.S.; Homes, D.L.; Noronha, G.; Smith, E.M.; Tram, M.N.; Huang, S. J. Org. Chem. 1996, 61, 3929.); (5) acid chlorides and carboxylic anhydrides to provide amides of structure A-7 where Y is CO- (preparation 11). Mild base hydrolysis of monoesters of general structure A-7 (preparation 6) or diesters of general structure A-7 (preparation 12) affords the acids of general structure A-8. Mild base hydrolysis of the ester of general structure A-5 provides acid A-9 (preparation 6 or 13) which may be further deprotected to afford the amino acid A-10 (preparation 14).
Preparation 1 (Scheme A, A-2: where RA., and RA_2 are the same and equal to H and stereochemistry is
s— Ϊ
VY OH o
D-Cysteine hydrochloride monohydrate (A-1, where RA_, and RA„2 are the same and equal to H and stereochemistry is (S)) (35.04 g, 0.19 mol) was dissolved in formaldehyde (40 wt% solution in water, 38 mL) and the reaction mixture allowed to stir for 18 h at ambient temperature. The mixture was cooled (0-5°C ) and absolute ethanol (93 mL) and pyridine (57 mL) were added. After one hour, the precipitate was collected by filtration, washed with cold absolute ethanol followed by diethyl ether and dried in vacuo to afford the title compound (24.6 g) as a white crystalline solid: mp 181-184 °C (Lit. 194-196 °C; Lewis, N.J.; Inoles, R.L.; Hes, J. J. Med. Chem. 1978, 21, 1070.); Η NMR (DMSO-d6) δ 4.22 (1 H), 4.04 (1 H), 3.86 (1 H), 3.09 (1 H), 2.24 (1 H); MS (ESI+) for C4H7NO2S m/z 134.0 (M+H)+. Preparation 2
(Scheme A, A-3: where RA., and RA.2 are the same and equal to H, R3 is /-butyl and stereochemistry is (S))
Figure imgf000034_0001
A solution of A-2 (Scheme A where RA_, and RA.2 are the same and equal to H and stereochemistry is (S)) (24.6 g, 0.185 mol) and di-t-butyl dicarbonate (44.4 g, 0.2 mol) in THF (1 L) was heated to reflux for 18 h. Volatiles were removed in vacuo and the residue partitioned between ethyl acetate and 0.1 N NaOH. The aqueous layer was washed with ethyl acetate, made acidic with 1.0 N HCl (pH 3-4) and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization of the white solid from hexane/methylene chloride provided the title compound (31.8 g) as white crystals: mp 132-134 °C; [a]25 D = 117° (c 0.66, ethanol); IR (mull) 3002, 1747, 1635, 1421, 1404, 1393, 1310, 1215, 1198, 1166, 1144, 1122 , 894, 862, 774 cm'1; Η NMR (DMSO-d6) δ 4.57 (2 H), 4.28 (1 H), 3.09 (1 H), 1.35 (9 H); 13C NMR (DMSO-d6) δ 171.8, 152.5, 79.8, 60.9, 48.4, 47.7, 33.8, 32.6, 27.7; MS (ESI+) for C9H15NO4S m/z 234.2 (M+H)+; MS (ESI-) for C9H15NO4S m/z 232.1 (M-H)' ; Anal. Calcd for C9H15NO4S: C, 46.34; H, 6.48; N, 6.00. Found: C, 46.27; H, 6.48; N, 6.03.
Preparation 3, Example 1
[S-(R*,R*)]^r-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme A, A-5: where RA_, and RA.2 are the same and equal to H, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000035_0001
To a cooled (0-5°C ) suspension of A-3 (Scheme A where RA., and RA.2 are the same and equal to H, R3 is t-butyl and stereochemistry is (S)) (8.67 g, 37.2 mmol) and HOBT (5.69 g, 37.2 mmol) in CH2C12 (60 mL) was added a solution of EDC (7.12 g, 37.2 mmol) in CH2C12 (140 mL). After 30 min at 0-5°C , A-4 (where R5 is 4-[(2,6-dichlorobenzoyl)- aminojphenyl, and stereochemistry is (S)) (10 g, 24.8 mmol) was added followed by 4- methylmorpholine (2.72 mL, 24.8 mmol). The reaction mixture was gradually warmed to ambient temperature, stirred an additional 18 h and diluted with CH2C12 and 0.1 N HCl. The organic layer was separated and washed with 0.1 N HCl, sat. aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue using hexane/ethyl acetate (50%) as eluant afforded the title compound (13.9 g) as a white solid. Recrystallization from acetone/hexane afforded a crystalline solid: mp 222-224°C; IR (mull) 3282, 3254, 1738, 1714, 1707, 1678, 1662, 1610, 1562, 1545, 1431, 1414, 1287, 1256, 784 cm"1; 'H NMR (CDC13) δ 7.57 (2 H), 7.34 (5 H), 7.14 (2 H), 4.74 (3 H), 4.30 (1 H), 3.74 (3 H), 3.37 (1 H), 3.15 (3 H), 1.45 (9 H); l3C NMR (DMSO-d6) δ 172.1, 162.3, 153.2, 137.6, 136.9, 133.2, 131.8, 131.7, 130.1, 128.7, 119.8, 80.4, 62.2, 53.7, 52.4, 36.7, 28.3; MS (ESI+) for C26H29Cl2N3O6S m/z 604.3 (M+Na)+; Anal. Calcd for C25H29Cl3N3O6S: C, 53.61; H, 5.02; N, 7.21. Found C, 53.82; H, 4.81; N, 7.22. Preparation 4
(Scheme A, A-6: where RA., and RA.2 are the same and equal to H, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000036_0001
To a cooled (5-10°C ) solution of A-5 (Scheme A where RA., and RA.2 are the same and equal to H, R3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)) (3.3 g, 5.67 mmol) in dioxane (34 mL) was added a solution of HCl in dioxane (4 M, 140 mL) in a dropwise manner over 30 min. After an additional 30 min at 0-5°C , the ice bath was removed and the reaction mixture stirred 1 h at ambient temperature. The volatiles were removed in vacuo to afford the title compound (2.94 g) as a light yellow solid: "H NMR (DMSO-d6) δ 10.70 (1 H), 9.1 (1 H), 7.52 (5 H), 7.18 (2 H), 4.64 (1 H), 4.37 (1 H), 4.21 (2 H), 3.67 (3 H), 3.10 (1 H), 2.89 (1 H), 2.70 (1 H); 1 C NMR (DMSO- d6) δ 172.1, 162.3, 153.2, 137.6, 136.9, 133.2, 131.8, 131.7, 130.1, 128.7, 119.8, 80.4, 62.2, 53.7, 52.4, 36.7, 28.3; MS (ESI+) for C2IH21Cl2N3O4S m/z 482.1 (M+H)+. Preparation 5 and Example 2. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is methyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, Sj).
Figure imgf000037_0001
To a cooled (0-5°C ) solution of A-6 (Scheme A, where RA_, and RA_2 are the same and equal to H, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)) (2.0 g, 3.86 mmol) in anhydrous THF (50 mL) was added methanesulfonyl chloride (2.99 mL, 38.6 mmol) followed by pyridine (6.24 mL, 77.2 mmol). After 1 h at 0-5°C , the ice bath was removed and the solution stirred at ambient temperature for 2 h then diluted with ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer washed with sat. aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/methylene chloride/hexane (1 :1 :1) and isopropanol (0.1%) as eluant afforded the title compound (1.99 g) as an amorphous powder: IR (mull) 1742, 1666, 1605, 1562, 1534, 1515, 1432, 1413, 1344, 1327, 1269, 1218, 1195, 1156, 780 cm"1; Η NMR (300 MHz, CDC13) δ 7.55 (3 H), 7.33 (3 H), 7.12 (3 H), 4.84 (1 H), 4.69 (1 H), 4.61 (1 H), 4.29 (1 H), 3.74 (3 H), 3.50 (1 H), 3.29 (1 H), 3.14 (2 H), 2.92 (3 H); 13C NMR (75 MHz, CDC13) δ 171.2, 168.1, 162.4, 136.5, 135.9, 132.3, 132.2, 130.8, 130.0, 128.1, 120.6, 64.9, 53.2, 52.5, 51.8, 37.2, 34.1; MS (ESI+) for C22H23Cl2N3O6S2 m/z 559.8 (M+H)τ; HRMS (FAB) calcd for C^CL^O^+H, 560.0483, found 560.0504; Anal. Calcd for C22H23Cl2N3O6S2: C, 47.15; H, 4.14; N, 7.50. Found: C, 46.88; H, 4.32; N, 7.16. Preparation 6 and Example 3. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is methyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000038_0001
To a cooled (0-5°C ) solution of A-7 (Scheme A, where RA., and RA.2 are the same and equal to H, R3 is methyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, 5)) (1.75 g, 3.12 mmol) in THF (100 mL) and water (10 mL) was added an 0.1 N aqueous solution of NaOH (34.3 mL, 3.43 mmol) via a syringe pump over 1 h. After an additional 45 min at 0-5°C, the reaction mixture was diluted with ethyl acetate and acidified with 0.25 N HCl to a pH of ca. 3. The organic layer was separated, washed with water and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride and methanol (0-5%) as eluant provided a solid which was lyophilized from glacial acetic acid to provide the title compound (1.42g) as an amorphous powder: [α]25 D = 103° (c 0.97, ethanol); IR (mull) 3291, 1736, 1666, 1605, 1562, 1534, 1516, 1432, 1414, 1339, 1270, 1195, 1154, 799, 780 cm-1. 'H NMR (300 MHz, CD3OD) δ 7.58 (2 H), 7.45 (3 H), 7.25 (2 H), 4.72 (2 H), 4.37 (1 H), 3.17
(5 H), 2.99 (3 H); 13C NMR (75 MHz, CD3OD) δ 174.1, 171.6, 165.2, 138.3, 137.7, 134.8, 133.4, 132.4, 131.2, 129.4, 121.6, 66.2, 55.0, 52.9, 37.9, 37.5, 35.7; MS (ESI+) for C21H21Cl2N3O6S2 m/z 545.8 (M+H)+; HRMS (FAB) calcd for C2,H21CL2N3O6S2+H, 546.0327, found 546.0358. Anal. Calcd for C21H2ICl2N3O6S2: C, 46.16; H, 3.87; N, 7.69. Found: C, 46.24; H, 4.04; N, 7.33. Preparation 7 and Example 4. [S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000039_0001
To a cooled (0-5°C ) solution of A-6 (where RA_, and RA.2 are the same and equal to H, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)) (1.25 g, 2.40 mmol) in anhydrous THF (30 mL) was added ethyl chloro formate (340 μL, 3.60 mmol) followed by triethylamine (810 μL, 5.79 mmol). After 1 h at 0-5°C , the ice bath was removed and the solution stirred at ambient temperature for 2 h then diluted with ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer washed with sat. aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/methylene chloride/hexane (1 :1 :1) and isopropanol (0.1 %) as eluant afforded the title compound (1.10 g) as an amorphous powder: Η NMR (300 MHz, CDC13) δ 7.59 (2 H), 7.30 (3 H), 7.10 (2 H), 4.81 (1 H), 4.72 (2 H), 4.38 (1 H), 4.11 (2 H), 3.19 (4 H), 1.25 (3 H); 13C NMR (75 MHz, CDC13) δ 171.6, 163.0, 136.9, 136.2, 132.3, 132.1, 130.7, 129.8, 128.0, 120.3, 63.0, 62.8, 57.1, 53.2, 52.5, 37.0, 14.4; MS (ESI+) for C24H25Cl2N3O6S m/z 554.2 (M+H)+; MS (FAB) m/z (rel. intensity) 554 (MH+, 99), 557 (29), 556 (76), 555 (45), 554 (99), 349 (35), 245 (27), 175 (35), 173 (52), 160 (93), 88 (38); HRMS (FAB) calcd for C24H25CL2N3O6S +H, 554.0919, found 554.0908. Anal. Calcd for C24H25Cl2N3O6S: C, 51.99; H, 4.55; N, 7.58.
Found: C, 52.05; H, 4.67; N, 7.44. Preparation 8 and Example 5 . [S-(R*,R*)]^r-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(l-piperidinyl)ethyl] ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-(l- piperidinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000040_0001
The title compound was prepared by a modification of the literature procedure of Ghosh, A.K.; Duong, T.T.; McKee, S.P.; Thompson, W.J. Tetrahedron Lett. 1992, 33, 2781. To a solution of 1 -(2-hydroxyethyl)piperidine (5.11 g, 39.6 mmol) in CH3CN (220 mL) at ambient temperature was added N,N-disuccinimidyl carbonate (10.13 g, 39.6 mmol) and triethylamine (16.6 mL, 118.8 mmol). The solution was stirred at room temperature for 4 h and concentrated in vacuo to give a viscous oil. The oil was dissolved in a minimal amount of methylene chloride (50 mL) and added to a solution of A-6 (Scheme A, where RA_, and RA_2 are the same and equal to H, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) (2.0 g, 3.96 mmol), triethylamine (0.60 mL) and DMAP (5 mg) in CH2C12 (10 mL). The solution was stirred overnight and an additional 5 equivalents of carbonate in methylene chloride (10 mL) [prepared as described above from N,N- disuccinimidyl carbonate (5.6 g, 19.8 mmol), triethylamine (8.3 mL, 59.4 mmol), and 1- (2-hydroxyethyl)piperidine (2.56 g, 19.8 mmol)] were added . After 3 h at room temperature, propylamine (30 mL, 0.71 mol) was slowly added (exothermic) and the solution diluted with CH2C12. The resulting solution was stirred vigorously for 15 min. and diluted with water. The organic layer was separated and washed with 0.1 M HCl, sat. aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/methylene chloride (3:1) as eluant followed by trituration in hexanes afforded the title compound (1.54 g, 62%) as an white powder: IR (mulι) 1745, 1704, 1660, 1553, 1512, 1435, 1426, 1397, 1303, 1245, 1227,
1212, 1173, 1019, 765 cm "'; Η NMR (300 MHz, DMSO-d6) δ 8.42 (1 H), 7.54 (2 H), 7.44 (1 H), 7.13 (2 H), 6.94 (2 H), 5.17 (2 H), 4.59 (2 H), 4.48 (1 H), 4.26 (1 H), 4.02 (2 H), 3.63 (3 H), 3.19 (2 H), 3.19 (1 H), 2.82 (3 H), 2.35 (4 H), 1.36 (6 H); l3C NMR (75 MHz, DMSO-d5) δ 172.2, 170.0, 157.7, 153.9, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 114.8, 65.3, 63.6, 57.3, 54.6, 53.9, 52.4, 36.4, 26.0, 24.3; MS (ESI+) for C29H35Cl2N3O6S m/z 623.9 (M+H)+; Anal. Calcd for C29H35Cl2N3O6S: C, 55.77; H, 5.65; N, 6.73. Found: C, 55.48; H, 5.73; N, 6.91. Preparation 9 and Example 6.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[((l,l- limethylethyl)amino)carbonyl]- thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA_, and RA_2 are the same and equal to H, R3 is t-butyl, Y is CONH-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000041_0001
To a cooled (0-5°C ) solution of A-6 (Scheme A, where Rχ_, and RA.2 are the same and equal to H, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5", 5)) (140 mg, 0.27 mmol) in anhydrous THF (6 mL) was added tert-butyl isocyanate (0.62 mL, 5.4 mmol) followed by 4-dimethylaminopyridine (5 mg, 0.04 mmol). After 0.5 h at 0-5°C, the ice bath was removed and the solution stirred at ambient temperature for 16 h. Additional tert-butyl isocyanate (0.62 mL, 5.4 mmol) was added and the solution warmed to 50°C for 4 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and 0.25 N HCl. The layers separated and the organic layer washed with sat. aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/methylene chloride (1 :1 :1) and isopropanol (0.1%) as eluant afforded the title compound (150 mg) as an amorphous powder: 'H NMR (300 MHz, CDC13) δ 7.93 (1 H), 7.54 (2 H), 7.26 (4 H), 7.09 (2 H), 4.74 (2 H), 4.66 (1 H), 4.41 (1 H), 4.23 (1 H), 3.70 (3 H), 3.28 (1 H), 3.09 (3 H), 1.31 (9 H); l3C NMR (75 MHz, CDCl3) δ 171.4, 170.6, 162.4, 155.5, 136.3, 135.9, 132.5, 132.3, 130.8, 129.9, 128.1, 120.6, 62.7, 53.2, 52.4, 51.5, 49.0, 37.0, 32.9, 29.2; MS (ESI+) for C26H30C12N4O5S m/z 581.0 (M+H)+, 603.0 (M+Na)+; MS (FAB) m/z (rel. intensity) 581 (MH+, 23), 482 (50), 97 (36), 88 (36), 83 (45), 69 (99), 57 (81), 55 (79), 43 (50), 43 (69), 41 (50). HRMS (FAB) calcd for C26H30CL2N4O5S +H1 581.1392, found 581.1376.
Preparation 10 and Example 7. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[(diethylamino)carbonyl]^:l- thiazoIidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CON(CH2CH3)-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000042_0001
The title compound was prepared by a modification of the literature procedure of Majer, P.; Randad, R.S. J. Org Chem. 1994, 59, 1937. A cooled (0-5°C ) solution of A-6 (Scheme A, where RA_, and RA_2 are the same and equal to H, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)) (200 mg, 0.39 mmol) and triethylamine (56 μL, 0.40 mmol) in anhydrous methylene chloride (10 mL) was added to triphosgene (47 mg, 0.16 mmol) followed by additional triethylamine (56 μL, 0.40 mmol). After 0.5 h at 0-5°C , the ice bath was removed and the solution stirred at ambient temperature for 2 h. The solution was re-cooled (0-5°C ) and diethylamine (1.20 mL,
11.70 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) were added. After 0.5 h at 0-5°C , the ice bath was removed and the solution stirred at ambient temperature for 16 h. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer washed with sat. aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/methylene chloride/hexane (1 :1 :1) and isopropanol (0.1 %) as eluant afforded the title compound (200 mg) as an amorphous solid: Η NMR (300 MHz, CDC13) δ 7.86 (1 H), 7.55 (2 H), 7.30 (3 H), 7.03 (2 H), 6.90 (1 H), 5.09 (1 H), 4.83 (1 H), 4.33 (2 H), 3.76 (3 H), 3.34 (3 H), 3.1 1 (5 H), 1.08 (6 H); ,3C NMR (CDCl3) δ 171.1, 169.6, 162.3, 162.2, 136.5, 135.9, 132.3, 132.1, 130.9, 129.9, 128.1, 120.3, 64.7, 53.4, 52.7, 52.5, 42.0, 37.0, 32.4, 13.1 ; MS (ESI+) for C26H30N4OSS m/z 580.9 (M+H)+; HRMS (El) calcd for C26H30CL2N4O5S 580.1314, found 580.1297. Anal. Calcd for C26H30C12N4O5S: C, 53.70; H, 5.20; N, 9.63. Found: C, 53.63; H, 5.33; N, 9.36.
Preparation 11 and Example 8. [S-(R*,R*)]^τ-[[[l-[[4-[(2,6-dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-γ-oxo-3-thiazolidinebutanoic acid 3-methyl ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is CH2CH2CO2CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000043_0001
To a cooled (0-5°C ) solution of A-6 (Scheme A, where RA., and RA_2 are the same and equal to H, R5 is 4-[(2,6-dichlorobenzoyl)amino] phenyl and stereochemistry is (S, S)) (1.03 g, 1.72 mmol) in anhydrous CH2C12 (25 mL) was added triethylamine (460 μL, 3.27 mmol) followed by methyl succinyl chloride (320 μL, 2.58 mmol). After 1 h at 0-5°C, the ice bath was removed and the solution stirred at ambient temperature for 2 h then diluted with 1 N HCl. The organic layer was separated, washed with sat. aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization of the yellow solid from ethanol/water provided the title compound (824 mg) as a light yellow solid: mp 221-223 °C; IR (mull) 3275, 1748, 1731, 1687, 1626, 1610, 1561, 1542, 1517, 1430, 1416, 1326 , 1268, 1224, 1193 cm"1; Η NMR (DMSO-d6) δ 10.64 (1 H), 8.59 (1 H), 8.24 (1 H), 7.50 (5 H), 7.16 (2 H), 4.75 (2 H), 4.51 (2 H), 4.23 (1 H), 3.63 (3 H), 3.56 (3 H), 2.87 (5 H); 13C NMR (DMSO-d6) δ 172.9, 171.6, 169.9, 169.5, 161.9, 137.2, 136.5, 133.0, 132.8, 131.3, 129.8, 128.3, 119.4, 61.6, 53.6, 52.1, 51.4, 48.6, 36.4, 35.7, 35.2, 33.1, 29.0, 28.9, 28.5; MS (ESI+) for C26H27Cl2N3O7S m/z 596.0 (M+H)+; MS (ESI-) for C26H27Cl2N3O7S m/z 593.9 (M-H)"; Anal. Calcd for C26H27Cl2N3O7S: C, 52.35; H, 4.56; N, 7.04. Found: C, 52.11; H, 4.47; N, 6.96. Preparation 12 and Example 9.
[S-{R*,R*)]- -[[[l-Carboxy-2-[4-[(2,6- lichlorobenzoyl)- amino]phenyl]ethyl]amino]carbonyl]-γ-oxo-3-thiazolidinebutanoic acid (Scheme A, A-8: where RA_, and RA_2 are the same and equal to H, R3 is CH2CH2CO2CO2H, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000044_0001
To a cooled (0-5°C ) solution of A-7 (Scheme A where RA_, and RA.2 are the same and equal to H, R3 is CH2CH2CO2CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)) (130 mg, 0.22 mmol) in anhydrous THF (5 mL) and MeOH (1 mL) was added an aqueous (2 mL) solution of lithium hydroxide monohydrate (23 mg, 0.55 mmol) via a syringe pump over 1 h. After an additional 1 h at 0-5°C, the ice bath was removed and the solution stirred 2 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and 0.1 N HCl and the organic layer was separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. Lyophilization of the residue from glacial acetic acid afforded the title compound (101 mg) as a white amorphous powder: Η NMR (CD3CN) δ 8.87 (1 H), 7.55 (2 H), 7.42 (3 H), 7.22 (2 H), 7.16 (1 H), 4.95 (1 H), 4.52 (3 H), 3.12 (5 H), 2.55 (5 H); 13C NMR (CD3CN) δ 173.8, 171.7, 171.1, 169.8, 162.5, 136.7, 136.0, 133.5, 131.7, 131.3, 130.1, 129.2, 128.2, 119.7, 62.4, 53.6, 48.8, 36.2, 32.4, 29.1, 28.6; MS (ESI-) for C24H23Cl2N3O7S m/z 566.1 (M-H)"; Anal. Calcd for C24H23Cl2N3O7S: C, 50.31; H, 4.13; N, 7.33. Found: C, 50.13; H, 4.37; N, 6.93.
Preparation 13 and Example 10.
[S-(R*,R*)]^τ-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]- phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-0,1-dimethylethyl) esιer
(Scheme A, A-9: where RA.[ and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000045_0001
To a cooled (0-5°C ) of A-5 (Scheme A where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)) (150 mg, 0.26 mmol) in anhydrous THF (5 mL) and MeOH (1 mL) was added an aqueous (2 mL) solution of lithium hydroxide monohydrate (14 mg, 0.325 mmol) via syringe pump over 1 h. After an additional 1 h at 0-5 °C , the ice bath was removed and the solution stirred 2 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and 0.1 N HCl, the organic layer separated and washed with water, dried (Na2SO4), filtered and concentrated in vacuo. Lyophilization of the residue from glacial acetic acid afforded the title compound (142 mg) as an amorphous powder: IR (mull) 3285, 1735, 1666, 1606, 1562, 1539, 1516, 1432, 1413, 1394, 1326, 1259 , 1219, 1195, 1161 cm"1; 'H NMR (DMF-d7) δ 10.71 (1 H), 8.36 (1 H), 7.91 (2 H), 7.72 (3 H), 7.47 (2 H), 4.88 (3 H), 4.51 (1 H), 3.40 (3 H), 3.22 (2 H), 1.57 (9 H); 13C NMR (DMF-d7) δ
173.3, 163.1, 162.9, 162.7, 162.3, 154.0, 138.3, 137.5, 134.2, 132.3, 131.9, 130.6, 128.9, 120.0, 80.9, 63.1, 54.5, 49.9, 37.4, 28.3; MS (FAB) m/z (rel. intensity) 568 (MH+, 23), 570 (14), 568 (23), 471 (13), 470 ( 65), 469 (23), 468 (99), 466 (23), 175 (19), 88 (17), 57 (42); HRMS (FAB) calcd for C25H27Cl2N3O6S+H, 568.1075, found 568.1071; MS (ESI-) for C25H27Cl2N3O6S m/z 565.8 (M-H)"; Anal. Calcd for C25H27Cl2N3O6S • 0.26 H2O: C, 52.38; H, 4.84; N, 7.33. Found: C, 52.07; H, 5.12; N, 7.46; % Water (KF): 0.83.
Preparation 14 and Example 11. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-4-thiazolidinyl]carbonyl]-L-phenylalanine monohydrochloride salt (Scheme A, A-10: where RA_, and RA.2 are the same and equal to H, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000046_0001
To a cooled (5-10°C ) solution of A-9 (Scheme A where RA_, and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)) (193 mg, 0.34 mmol) in dioxane (2 mL) was added a solution of HCl in dioxane (4 M, 8 mL) in a dropwise manner over 30 min. After an additional 3.5 h at 0-5°C, the reaction mixture was concentrated in vacuo. Lyophilization of the residue from water afforded the title compound (158 mg) as an amorphous powder: IR (mull) 3248, 3191, 3048, 1731, 1664, 1605, 1577, 1562, 1541, 1516, 1431, 1414, 1327, 1195, 799 cm"1; 'H NMR (DMF-d7) δ 9.11 (1 H), 7.76 (2 H), 7.60 (3 H), 7.35 (2 H), 4.66 (2 H), 4.46 (2 H), 3.55 (3 H), 3.24 (2 H), 3.10 (2 H); 13C NMR (DMF-d7) δ 172.8, 167.6, 163.1, 162.9, 162.7, 162.3, 138.5, 137.5, 133.8, 132.3, 131.9, 130.6, 128.9, 120.0, 63.8, 54.8, 50.0, 37.3; MS (FAB) m/z (rel. intensity) 468 (MH+, 99), 544 (18), 528 (15), 472 (13), 471 ( 16), 470 (70), 469 (24), 468 (99), 175 (14), 173 (16), 88 (18); HRMS (FAB) calcd for C20H19C12N3O4S+H, 468.0551, found 468.0556. Example 12.
[S-<R*>R*)]- -[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- ethyl ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000047_0001
Example 12 was prepared from example 4 by the procedure described in preparation 6. Physical properties as follows: mp 1 18-121°C; [α]25 D = 106° (c 0.88, ethanol); IR (mull) 3283, 3196, 1665, 1606, 1561, 1539, 1516, 1431, 1414, 1345, 1327, 1271, 1219, 1195, 799 cm"1; Η NMR (300 MHz, CD3OD) δ 7.59 (2 H), 7.44 (3 H), 7.22 (2 H), 4.69 (1 H), 4.64 (1 H), 4.41 (1 H), 3.24 (3 H), 2.95 (2 H), 1.26 (3 H); 13C NMR (75 MHz, CDC13) δ 172.4, 171.5, 163.0, 154.8, 136.7, 136.6, 132.4, 132.1, 130.6, 129.9, 127.9, 120.3, 63.0, 62.7, 53.1, 36.7, 14.3; MS (FAB) m/z (rel. intensity) 540 (MH+, 59), 544 (12), 543 (17), 542 (53), 540 (59), 160 (32), 123 (15), 118 (20), 107 (99), 95 (11), 23 (21); HRMS (FAB) calcd for C23H23CL2N3O6S +H, 540.0762, found 540.0730. Anal. Calcd for C23H23Cl2N3O6S: C, 51.12; H, 4.29; N, 7.78. Found: C, 50.77; H, 4.43; N, 7.68. Example 13.
[R-(R*,S*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme A, A-7: where RA_, and RA_2 are the same and equal to H, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000048_0001
Example 13 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1267, 1260, 1216, 1195, 1162, 799 cm 1; Η NMR (CDC13) δ 7.56 (2 H), 7.46 (1 H), 7.33 (3 H), 7.13 (2 H), 6.94 (1 H), 4.75 (3 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.14 (3 H), 1.43 (9 H); 13C NMR (DMSO-d6) δ 171.6, 171.5, 170.7, 170.1, 161.7, 152.6, 137.0, 136.9, 136.2, 132.6, 132.6, 131.2, 131.0, 129.3, 128.1, 119.1, 79.7, 78.2, 61.5, 53.4, 53.3, 51.8, 49.3, 49.1, 35.8, 27.6; MS (ESI+) for C26H29Cl2N3O6S m/z 604 (M+Na)+; MS (ESI-) for C26H29Cl2N3O6S m/z 580 (M-H)"; Anal. Calcd for C26H29Cl2N3O6S • 0.17 H2O: C, 53.34; H, 5.05; N, 7.18. Found: C, 53.47; H, 5.14; N, 7.15. % Water (KF): 0.51.
Example 14. [R-(R*,S*)]^r-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
(1,1-dimethylethyl) ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000048_0002
Example 14 was prepared from example 13 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3285, 1665, 1607, 1562, 1538, 1516, 1432, 1413, 1394, 1327, 1259, 1217, 1195, 1162, 799 cm 1; 'H NMR (DMSO-d6) δ 12.70 (1 H), 10.67 (1 H), 8.14 (1 H), 7.51 (5 H), 7.20 (2 H), 4.56 (1 H), 4.35 (3 H), 2.98 (3 H), 1.22 (9 H); 13C NMR (DMSO-d6) δ 172.5, 170.1, 169.9, 161.6, 152.6, 136.9, 136.3, 133.0, 131.2, 131.0, 129.4, 128.1, 119.1, 79.8, 79.7. 61.6, 53.4, 49.2, 48.3, 35.9, 27.6, 20.9; HRMS (FAB) calcd for C25H27Cl2N3O6S+H, 568.1075, found 568.1058; MS (ESI+) for C25H27Cl2N3O6S m/z 567.8 (M+H)+; MS (ESI-) for C25H27Cl2N3O6S m/z 565.8 (M-H)"; Anal. Calcd for C25H27Cl2N3O6S • 0.24 H2O: C, 52.43; H, 4.84; N, 7.34. Found: C, 52.23; H, 4.76; N, 7.24. % Water (KF): 0.75.
Example 15. [R-(R*,S*)]^l-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
(Scheme A, A-7: where RA., and RA„2 are the same and equal to H, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000049_0001
Example 15 was prepared as described in Scheme A from L-cysteine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1744, 1666, 1606, 1561, 1538, 1515, 1445, 1431, 1414, 1345, 1325, 1270, 1216, 1194, 1184 cm" '; Η NMR (CDC13) δ 7.55 (2 H), 7.36 (4 H), 7.13 (2 H), 6.95 (1 H), 4.74 (3 H), 4.21 (3 H), 3.75 (3 H), 3.40 (1 H), 3.13 (3 H), 1.26 (3 H); 13C NMR (CDC13) δ 171.2, 169.4, 162.3, 136.2, 135.8, 132.4, 132.2, 131.0, 130.3, 130.1, 129.9, 128.2, 128.0, 127.9, 120.2, 62.9, 62.7, 53.2, 52.5, 37.1, 14.5, 14.3; MS (ESI+) for C24H25Cl2N3O6S m/z 553.8 (M+H)"; MS (ESI-) for C24H25Cl2N3O6S m/z 551.8 (M-H)"; Anal. Calcd for C24H25Cl2N3O6S • 0.24 H2O: C, 51.59; H, 4.60; N, 7.52. Found: C, 51.89; H, 4.62; N, 7.51. % Water (KF): 0.77. Example 16.
[R-(R*,S*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- ethyl ester (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000050_0001
Example 16 was prepared from example 15 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 1664, 1606, 1561, 1539, 1516, 1445, 1431, 1414, 1346, 1327, 1271, 1217, 1195, 799 cm'1; Η NMR (DMSO-d6) δ 12.80 (1 H), 10.69 (1 H), 8.26 (1 H), 7.51 (5 H), 7.19 (2 H), 4.62 (2 H), 4.37 (2 H), 3.94 (2 H), 2.96 (3 H), 1.11 (3 H); 1 C NMR (DMSO-d6) δ 172.5, 169.6, 161.7, 153.5, 136.9, 136.3, 133.0, 131.2, 131.0, 129.5, 128.1, 1 19.1, 61.2, 53.4, 52.5, 35.9, 22.3, 14.3; MS (ESI+) for
C23H23Cl2N3O6S m/z 540.0 (M+H)+; MS (ESI-) for C23H23Cl2N3O6S m/z 538.0 (M-H)'; HRMS (FAB) calcd for C23H23Cl2N3O6S+H, 540.0762, found 540.0775; Anal. Calcd for C23H23Cl2N3O6S • 0.34 H2O: C, 50.54; H, 4.37; N, 7.69. Found: C, 50.53; H, 4.48; N, 7.59. % Water (KF): 1.13. Example 17.
[R-(R*,S*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-5,5-dimethyl-3-thiazolidinecarboxylic acid 3-(l , 1- dimethylethyl) ester (Scheme A, A-7: where RA_, and RA.2 are the same and equal to CH3, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000051_0001
Example 17 was prepared as described in Scheme A from L-penicillamine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1747, 1666, 1606, 1562, 1537, 1516, 1432, 1413, 1324, 1268, 1259, 1213, 1195, 1161, 1142 cm' '; 'H NMR (CDC13) δ 7.56 (2 H), 7.34 (4 H), 7.21 (2 H), 6.44 (1 H), 4.94 (1 H), 4.60 (2 H), 4.08 (1 H), 3.70 (3 H), 3.10 (2 H), 1.53 (3 H), 1.42 (9 H), 1.25 (3 H); 13C NMR (CDC13) δ 171.4, 162.3, 136.3, 135.8, 132.6, 132.4, 131.0, 130.2, 130.0, 128.2, 120.5, 120.3, 120.2, 72.7, 63.9, 60.4, 52.9, 52.3, 48.3, 38.0, 30.3, 28.1, 23.9, 21.0, 14.2; MS (ESI+) for C28H33Cl2N3O6S m/z 630.7 (M+Na)+; Anal. Calcd for C28H33Cl2N3O6S • 0.13 H2O: C, 54.87; H, 5.47; N, 6.86. Found: C, 54.54; H, 5.55; N, 6.54. % Water (KF): 0.38.
Example 18. [S-(R*,R*)]^-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]ρhenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[(9H-fluoren-l-yl)methyl] ester
(Scheme A, A-7: where RA„, and RA.2 are the same and equal to H, R3 is 9-fluorenylmethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000051_0002
Example 18 was prepared as described in Scheme A from D-cysteine using 9- fluorenylmethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3280, 1750, 1692, 1671, 1604, 1560, 1538, 1515, 1441, 1430, 1422, 1346, 1320, 1222, 1118 cm -'; Η NMR (DMSO-d6) δ 8.59 (1 H), 7.87 (2 H), 7.49 (12 H), 4.65 (3 H), 4.26 (4 H), 3.52 (3 H), 2.96 (3 H); 13C NMR (DMSO-d6) δ 171.4, 161.8, 143.5, 140.6, 137.0, 136.3, 132.5, 131.2, 131.1, 129.5, 128.1, 127.6, 127.1, 125.2, 125.1, 120.0, 119.2, 70.6, 70.0, 63.8, 63.2, 53.3, 53.1, 46.4, 36.2, 25.4; MS (ESI+) for C36H31Cl2N3O6S m/z 703.9 (M+H)+; Anal. Calcd for C36H31Cl2N3O6S • 0.1 H2O: C, 61.23; H, 4.45; N, 5.95. Found: C, 61.18; H, 4.56; N, 5.89. % Water (KF): 0.22.
Example 19.
[S-(R*,R*)]^-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
[(9H-fluoren-l-yl)methyl] ester (Scheme A, A-8: where RA_, and RA_2 are the same and equal to H, R3 is 9-fluorenylmethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, 5)).PNU-
Figure imgf000052_0001
Example 19 was prepared from example 18 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1672, 1606, 1561, 1533, 1517, 1431, 1413, 1347, 1324, 1269, 1218, 1195, 1116, 760, 742 cm "1; Η NMR (DMSO-d6) δ 10.71 (1 H), 8.32 (1 H), 7.87 (2 H), 7.47 (13 H), 7.16 (2 H), 4.62 (2 H), 4.15 (5 H), 2.90 (4 H); 13C NMR (DMSO-d6) δ 172.4, 169.2, 161.8, 143.6, 140.6, 137.0, 136.3, 133.0, 131.3, 131.1, 129.7, 129.6, 128.9, 128.2, 127.7, 127.1, 126.8, 125.2, 121.3, 120.1, 120.0, 119.2, 53.4, 48.4,
46.4, 36.4, 29.5, 20.0; MS (ESI+) for C35H29Cl2N3O6S m/z 690.1 (M+H)+; Anal. Calcd for C35H29Cl2N3O6S • 0.4 H2O: C, 60.25; H, 4.30; N, 6.02. Found: C, 59.88; H, 4.47; N, 5.75. % Water (KF): 1.02.
Example 20. [S-(R*,R*)]^r-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-phenylmethyl ester (Scheme A. A-7: where RA_, and RA.2 are the same and equal to H, R3 is phenylmethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000053_0001
Example 20 was prepared as described in Scheme A from D-cysteine using benzyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1748, 1694, 1690, 1673, 1610, 1561, 1542, 1517, 1441, 1430, 1408, 1355, 1324, 1269, 1217 cm "'; Η NMR (CDC13) δ 7.50 (2 H), 7.33 (9 H), 7.09 (2 H), 6.75 (1 H), 5.19 (2 H), 4.78 (3 H), 4.38 (3 H), 3.73 (3 H), 3.20 (3 H); 13C NMR (DMSO-d6) δ 171.4, 162.3, 136.3, 135.9, 135.7, 132.5, 132.4, 131.0, 130.0, 128.7, 128.4, 128.2, 128.1, 120.4, 68.2, 63.3, 53.2, 52.5, 37.2; MS (ESI+) for C29H27Cl2N3O6S m/z 637.8 (M+Na)+; MS (ESI-) for C29H27Cl2N3O6S m/z 613.8 (M-H)"; Anal. Calcd for C29H27Cl2N3O6S • 0.1 H2O: C, 56.39; H, 4.43; N, 6.80. Found: C, 56.31; H, 4.67; N, 6.71. % Water (KF): 0.19. Example 21.
[S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- phenylmethyl ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is phenylmethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino phenyl and stereochemistry is (S, S)).
Figure imgf000053_0002
Example 21 was prepared from example 20 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3290, 3034, 1666, 1606, 1562, 1537, 1516, 1431, 1413, 1351, 1326, 1270, 1215, 1195, 799 cm"1; 'H NMR (DMSO-d6) δ 12.85 (1 H), 10.65 (1 H), 7.39 (10 H), 7.18 (2 H), 4.98 (2 H), 4.65 (2 H), 4.55 (1 H), 4.33 (1 H), 3.06 (1 H), 2.83 (2 H); 13C NMR (CD3OD) δ 172.6, 163.7, 154.4, 136.8, 136.2, 136.1, 131.9, 130.9, 129.6, 128.1, 127.9, 127.8, 127.7, 127.6, 120.0, 67.5, 66.7, 53.4, 36.5; MS (ESI-) for C28H25Cl2N3O6S m/z 599.7 (M-H)"; MS (FAB) m/z (rel. intensity) 602 (MH+, 99), 678 (37), 604 (74), 603 (33), 602 ( 99), 560 (32), 558 (48), 468 (35), 466 (51), 371 (50), 91 (73); HRMS (FAB) calcd for C28H25Cl2N3O6S+H, 602.0919, found 602.0913; Anal. Calcd for C28H25Cl2N3O6S • 0.23 H2O: C, 55.45: H, 4.23; N, 6.93. Found: C, 55.53; H, 4.46; N, 6.88. % Water (KF): 0.67.
Example 22. [S-(R*,R*)]^-[[[l-[[ -[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(tricyclo[3.3.1.13' ' ]dec-l-yl) ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 1 -adamantyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000054_0001
Example 22 was prepared as described in Scheme A from D-cysteine using 1 -adamantyl fluoroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3284, 3271, 1747, 1690, 1684, 1666, 1557, 1532, 1436, 1412, 1355, 1298, 1194, 1053, 799 cm"1; Η NMR (DMSO-d6) δ 10.67 (1 H), 8.41 (1 H), 7.53 (5 H), 7.17 (2 H), 4.51 (3 H), 4.23 (1 H), 3.63 (3 H), 3.22 (1 H), 3.04 (1 H), 2.90 (1 H), 2.75 (1 H), 2.01 (9 H), 1.56 (6 H); 13C NMR (DMSO-d6) δ 172.1, 162.3, 152.7, 137.6, 136.9, 133.2, 131.8, 131.6, 130.0, 128.7, 119.8, 53.8, 52.4, 36.7, 36.1, 30.6; MS (ESI+) for C32H35Cl2N3O6S m/z 659.7 (M+H)+; MS (ESI-) for C32H35Cl2N3O6S m/z 657.7 (M-H)"; MS (FAB) m/z (rel. intensity) 660 (MH+, 8), 662 (5), 660 (8), 618 (6), 616 (8), 480 (5), 173 (7), 136 (11), 135 (99), 123 (14), 93 (8); Anal. Calcd for C32H35Cl2N3O6S • 0.04 H2O: C, 58.12; H, 5.35; N, 6.35. Found: C, 58.19; H, 5.62; N, 6.25. % Water (KF): 0.10. Example 23.
[S-(R*,R*)H-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
(tricyclo[3.3.1.F' ']dec-l-yι) ester (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is 1 -adamantyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000055_0001
Example 23 was prepared from example 22 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 1667, 1606, 1562, 1537, 1516, 1431, 1412, 1353, 1326. 1299, 1274, 1220, 1194, 1049 cm"1; Η NMR (DMSO-d6) δ 12.70 (1 H), 10.67 (1 H), 8.21 (1 H), 7.58 (5 H), 7.17 (2 H), 4.51 (3 H), 4.22 (1 H), 3.20 (1 H), 3.04 (1 H), 2.88 (1 H), 2.76 (1 H), 2.07 (9 H), 1.12 (6 H); 13C NMR (DMSO-d5) δ 173.1, 162.3, 152.7, 137.5, 136.9, 133.8, 131.8, 131.6, 130.1, 128.7, 119.7, 80.0, 53.8, 36.8, 36.1, 30.6; MS (ESI+) for C3,H33Cl2N3O6S m/z 645.8 (M+H)÷; HRMS (FAB) calcd for
C3IH33Cl2N3O6S+H, 646.1545, found 646.1564; Anal. Calcd for C31H33Cl2N3O6S • 0.29 H2O: C, 57.13; H, 5.19; N, 6.45. Found: C, 56.82; H, 5.21; N, 6.32. % Water (KF): 0.80.
Example 24. [S-(R*,R*)]^l-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(4-morpholinyl)ethyl] ester (Scheme A, A-7: where RA_, and RA.2 are the same and equal to H, R3 is 2-(4- moφholinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000056_0001
Example 24 was prepared as described in Scheme A from D-cysteine using 4-(2- hydroxyethyl)morpholine to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1705, 1679, 1605, 1536, 1515, 1431, 1414, 1344, 1323, 1269, 1216, 1194, 1183, 1 1 17 cm"1 H NMR (300 MHz, CDC13) δ 7.82 (1 H), 7.56 (2 H), 7.31 (3 H), 7.12
(2 H), 6.95 (1 H), 4.65 (3 H), 4.39 (3 H), 3.74 (3 H), 3.69 (3 H), 3.34 (1 H), 3.18 (3 H), 2.763 (5 H); I3C NMR (75 MHz, CDCI3) δ 171.5, 169.8, 162.9, 154.4, 136.8, 136.1,
132.1, 130.6, 129.7, 127.9, 120.2, 66.3, 62.7, 57.0, 53.4, 53.2, 52.4, 36.7, 29.5; MS (ESI-) for C28H32Cl2N4O7S m/z 636.8 (M-H)"; HRMS (FAB) calcd for C28H32CL2N4O7S +H, 639.1447, found 639.1419. Anal. Calcd for C28H32Cl2N4O7S: C, 52.58; H, 5.04; N, 8.76. Found: C, 52.47; H, 5.17; N, 8.69.
Example 25. [S-(R*,R*)]4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- [2-(4-morpholinyl)ethyl] ester
(Scheme A, A-8: where RA., and RA_2 are the same and equal to H, R3 is 2-(4- morpholinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000057_0001
Example 25 was prepared from example 24 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3278, 1667, 1606, 1562, 1541, 1515, 1431, 1413, 1351, 1326, 1270, 1195, 1134, 1118, 799 cm"1; 'H NMR (300 MHz, DMSO-d6) δ 10.64 (1 H), 8.25 (1 H), 7.50 (5 H), 7.16 (2 H), 4.60 (2 H), 4.44 (1 H), 4.27 (1 H), 4.06 (2 H), 3.51 (4 H), 3.43 (2 H), 3.29 (4 H), 2.42 (4 H); 13C NMR (75 MHz, DMSO-d6) δ 173.0, 172.4, 169.8, 162.3, 137.5, 136.8, 133.5, 131.7, 130.1, 128.6, 119.7, 66.6, 63.3, 57.0, 53.7, 36.7, 21.5; MS (FAB) m/z (rel. intensity) 625 (MH+, 55), 629 (9), 628 (14), 627 (39), 626 (21), 625 (55), 308 (7), 141 (19), 114 (99), 113 (24), 100 (7); HRMS (FAB) calcd for C27H30CL2N4O7S +H, 625.1290, found 625.1309.
Example 26. [S-(R*,S*)]^r-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, R)).
Figure imgf000057_0002
Example 26 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 3293, 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1260, 1216, 1195, 1162, 799 cm"'; 'H NMR (CDC13) δ 7.55 (2 H), 7.37 (4 H), 7.14 (2 H), 4.89 (1 H), 4.66 (2 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.24 (3 H), 1.44 (9 H); 13C NMR (CDC13) δ 171.2, 169.8, 162.3, 136.3, 135.8, 132.4, 132.3, 131.0, 130.2, 130.1, 129.9, 128.2, 128.1, 127.9, 120.5, 120.2, 120.1, 82.2, 53.2, 52.5, 37.3, 31.0, 28.4, 28.2; MS (ESI+) for C25H29Cl2N3O6S m/z 603.9 (M+Na)+; MS (ESI-) for C26H29Cl2N3O6S m/z 580.0 (M-H)"; HRMS (FAB) calcd for C26H29Cl2N3O6S+H, 582.1232, found 582.1231. Anal. Calcd for C26H29Cl2N3O6S • 0.26 H2O: C, 53.18; H, 5.07; N, 7.16. Found: C, 52.78; H, 5.14; N, 6.91. % Water (KF): 0.66.
Example 27.
[S-(R*,S*)]^τ-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
(1,1-dimethylethyl) ester (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, R)).
Figure imgf000058_0001
Example 27 was prepared from example 26 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3286, 1665, 1606, 1562, 1538, 1516, 1432, 1413, 1394, 1326, 1259, 1216, 1195, 1161, 799 cm 1; Η NMR (DMSO-d6) δ 12.70 (1 H), 10.63 (1 H), 8.13 (1 H), 7.51 (5 H), 7.20 (2 H), 4.45 (4 H), 2.96 (3 H), 1.23 (9 H); 13C NMR (DMSO-d6) δ 173.1, 170.5, 162.3, 153.2, 137.5, 136.9, 131.8, 131.6, 130.0, 128.7, 119.7, 80.4, 62.2, 54.0, 49.8, 36.5, 28.3, 21.5; MS (ESI+) for C25H27Cl2N3O6S m/z 567.9 (M+H)+; MS (ESI-) for C25H27Cl2N3O6S m/z 565.9 (M-H)"; HRMS (EI) calcd for C25H27Cl2N3O6S 567.0997, found 568.1096. Anal. Calcd for C25H27Cl2N3O6S • 0.34 H2O: C, 52.82; H, 4.79; N, 7.39. Found: C, 52.17; H, 4.90; N, 7.25. % Water (KF): 1.07.
Example 28. [S-(R*,R*)]^l-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-5,5-dimethyl-3-thiazolidinecarboxylic acid 3-( , 1- dimethylethyl) ester (Scheme A, A-7: where RA_, and RA.2 are the same and equal to CH3, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000059_0001
Example 28 was prepared as described in Scheme A from D-penicillamine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1744, 1707, 1688, 1678, 1657, 1606, 1562, 1541, 1516, 1431, 1414, 1326, 1253, 1161, 1140 cm" '; Η NMR (CDC13) δ 7.58 (2 H), 7.36 (3 H), 7.14 (2 H), 6.55 (1 H), 4.87 (1 H), 4.56 (2 H), 4.10 (1 H), 3.72 (3 H), 3.08 (2 H), 1.53 (3 H), 1.44 (9 H), 1.40 (3 H); 13C NMR (CDC13) δ 171.6, 162.3, 153.6, 136.4, 135.8, 132.6, 132.4, 131.0, 130.1, 129.9, 129.8, 128.2, 120.7, 120.5, 120.3, 81.7, 73.0, 52.8, 52.6, 52.4, 48.4, 39.8, 39.5, 37.6, 30.3, 28.3, 28.0, 23.5; MS (ESI-) for C28H33Cl2N3O6S m/z 607.9 (M-H)"; MS (FAB) m/z (rel. intensity) 610 (MH+, 6), 512 (26), 510 (44), 117 (30), 115 (1 6), 99 (16), 87 (16), 59 (99), 57 (27), 57 (20), 41 (23); HRMS (FAB) calcd for C28H33Cl2N3O6S+H, 610.1545, found 610.1501;
Anal. Calcd for C28H33Cl2N3O6S • 0.07 H2O: C, 54.97; H, 5.46; N, 6.87. Found: C, 54.92; H, 5.54; N, 7.11. % Water (KF): 0.21.
Example 29. [S-(R*,R*)]^r-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-5,5-dimethyl-3- thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to CH3, R3 is t-butyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000060_0001
Example 29 was prepared from example 28 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1739, 1666, 1606, 1562, 1535, 1516, 1432, 1413, 1394, 1325, 1270, 1260, 1194, 1160, 799 cm"1; 'H NMR (DMSO-d6) δ 12.62 (1 H), 10.62 (1 H), 8.18 (1 H), 7.51 (5 H), 7.19 (2 H), 4.50 (3 H), 4.24 (1 H), 2.91 (2 H), 1.33 (12 H), 1.04 (3 H); 13C NMR (DMSO-d6) δ 172.8, 168.7, 161.9, 153.2, 137.2, 136.5, 133.1, 131.4, 131.3, 129.6, 128.3, 119.5, 80.0, 70.9, 53.7, 48.5, 37.0, 30.7, 28.1, 27.9, 24.6; MS (ESI+) for C27H31Cl2N3O6S m/z 595.9 (M+H)+; MS (ESI-) for C27H31Cl2N3OδS m/z 593.8 (M-H)"; MS (FAB) m/z (rel. intensity) 596 (MH+, 19), 672 (17), 596 (19), 499 (15), 498 ( 60), 497 (26), 496 (99), 494 (35), 173 (20), 116 (27), 57 (48); Anal. Calcd for C27H3!Cl2N3O6S • 0.27 H2O: C, 53.93; H, 5.29; N, 6.99. Found: C, 53.73; H, 5.39; N, 7.10. % Water (KF): 0.80.
Example 30. [S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-5,5-dimethyl-3-thiazolidinecarboxylic acid 3-ethyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to CH3, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000060_0002
Example 30 was prepared as described in Scheme A from D-penicillamine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3292, 1748, 1666, 1606, 1562, 1538, 1516, 1445, 1431, 1414, 1341, 1325, 1271, 1212, 1194 cm" '; 'H NMR (CDC13) δ 7.57 (2 H), 7.37 (4 H), 7.1 1 (2 H), 6.49 (1 H), 4.86 (1 H), 4.59 (2 H), 4.14 (3 H), 3.75 (3 H), 3.09 (2 H), 1.60 (3 H), 1.54 (3 H), 1.23 (3 H); 13C NMR (CDC13) δ 171.6, 162.3, 154.5, 136.3, 135.8, 132.6, 132.4, 131.1, 130.2, 130.1, 129.8, 128.2, 120.5, 120.4, 72.7, 62.5, 52.7, 52.5, 37.3, 30.2, 23.7, 14.6, 14.1; MS (ESI+) for C26H29Cl2N3O6S m/z 581.9 (M+H)+; MS (ESI-) for C26H29Cl2N3O6S m/z 579.8 (M-H)"; HRMS (EI) calcd for C26H29Cl2N3O6S 581.1154, found 581.1132; Anal. Calcd for C26H29Cl2N3O6S • 0.16 H2O: C, 53.35; H, 5.05; N, 7.18. Found: C, 53.74; H, 5.12; N, 7.12. % Water (KF): 0.49.
Example 31. [S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-5,5-dimethyl-3- thiazolidinecarboxylic acid 3-ethyl ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to CH3, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000061_0001
Example 31 was prepared from example 30 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3287, 3070, 1666, 1606, 1562, 1538, 1516, 1431, 1414, 1342, 1328, 1271, 1213, 1194, 799 cm 1; Η NMR (DMSO-d6) δ 12.58 (1 H), 10.63 (1 H), 8.22 (1 H), 7.51 (5 H), 7.20 (2 H), 4.51 (3 H), 3.95 (3 H), 3.04 (1 H), 2.86 (1 H), 1.35 (3 H), 1.16 (6 H); ,3C NMR (DMSO-d6) δ 223.3, 184.1, 183.9, 172.8, 168.4, 161.7, 136.9, 136.3, 133.1, 131.2, 131.0, 129.4, 128.1, 119.2, 70.6, 61.1, 53.6, 53.4, 48.6, 36.2, 30.1, 25.4, 24.3, 21.0, 14.1; MS (ESI+) for C25H27Cl2N3O6S m/z 568.0 (M+H)+; MS (ESI-) for C25H27Cl2N3O6S m/z 565.9 (M-H)"; MS (FAB) m/z (rel. intensity) 568 (MH+, 86), 644 (18), 571 (19), 570 (61), 569 (30), 568 (86), 335 (16), 188 (99), 173 (19), 141 (53), 116
(23); HRMS (FAB) calcd for C25H27Cl2N3O6S+H, 568.1075, found 568.1096; Anal. Calcd for C25H27Cl2N3O6S • 0.4 H2O: C, 52.16; H, 4.87; N, 7.30. Found: C, 52.46; H, 4.90; N, 7.15. % Water (KF): 1.25.
Example 32.
[S-(R*,R*)]^-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-,
R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000062_0001
Example 32 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (liq.) 1745, 1702, 1565, 1511, 1467, 1439, 1368, 1299, 1241, 1197, 1177, 1162, 1017, 778, 768 cm"'; Η NMR (CDC13) δ 7.36 (2 H), 7.25 (1 H), 7.06 (2 H), 6.94 (2 H), 5.23 (2 H), 4.75 (3 H), 4.12 (1 H), 3.72 (3 H), 3.37 (1 H), 3.14 (3 H), 1.45 (9 H); 13C NMR (CDC13) δ 171.5, 157.9, 136.9, 132.0, 130.3, 128.4, 128.2, 115.0, 81.9, 65.1, 62.8, 53.2, 52.3, 49.2, 36.9, 28.1, 27.9; MS (ESI+) for C26H30C12N2O6S m/z 568.9 (M+H)+; MS (ESI-) for C26H30C12N2O6S m/z 566.7 (M-H)"; Anal. Calcd for C26H30C12N2O6S • 0.09 H2O: C, 54.68; H, 5.33; N, 4.91. Found: C, 54.62; H, 5.41; N, 4.73. % Water (KF): 0.28.
Example 33.
[S-(R*,R*)H-[[[l-Carboxy-2-[ -[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- (1,1 -dimethylethyl) ester
(Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)). -el
Figure imgf000063_0001
Example 33 was prepared from example 32 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1734, 1704, 1676, 1612, 1565, 1511, 1439, 1393, 1300, 1241, 1 196, 1178, 1162, 777, 769 cm"1; 'H NMR (DMSO-d6) δ 8.24 (1 H), 7.50 (3 H), 7.13 (2 H), 6.93 (2 H), 5.16 (2 H), 4.52 (3 H), 4.21 (1 H), 2.91 (4 H), 1.31 (9 H); 13C NMR (DMSO-d6) δ 172.7, 169.7, 157.1, 152.6, 135.9, 131.7, 131.5. 130.2, 129.8, 128.7, 114.2, 79.8, 64.8, 61.6, 53.2, 49.2, 36.0, 34.8, 27.8, 21.0; MS (ESI+) for C25H28Cl2N2O6S m/z 554.9 (M+H)+; MS (ESI-) for C25H28Cl2N2O6S m/z 552.8 (M-H)";
Anal. Calcd for C25H28Cl2N2O6S • 0.15 H2O: C, 53.79; H, 5.11; N, 5.02. Found: C, 54.17; H, 5.17; N, 5.00. % Water (KF): 0.50.
Example 34. [S-(R*,R*)]^-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000063_0002
Example was prepared as described in Scheme A from D-cysteine using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 3282, 1742, 1705, 1692, 1664, 1562, 1509, 1436, 1352, 1343, 1236, 1196, 1175, 1015, 786 cm"1; Η NMR (CDC13) δ 7.37 (2 H), 7.25 (1 H), 7.05 (2 H), 6.94 (2 H), 6.74 (1 H), 5.23 (2 H), 4.77 (3 H), 4.34 (1 H), 4.18 (2 H), 3.74 (3 H), 3.37 (1 H), 3.13 (3 H), 1.31 (3 H); 13C NMR (CDC13) δ 171.6, 171.4, 158.0, 137.0, 132.1, 130.5, 130.4, 128.5, 128.2, 115.0, 65.2, 63.6, 63.2, 62.7, 53.6, 53.2, 52.4, 36.9, 14.5; MS (ESI+) for C24H26Cl2N2O6S m/z 540.9 (M+H)+; HRMS (El) calcd for C24H26Cl2N2O6S 540.0889, found 540.0878; Anal. Calcd for C24H26Cl2N2O6S • 0.26 H2O: C, 52.79; H, 4.89; N, 5.13. Found: C, 52.41; H, 4.82; N, 4.96. % Water (KF): 0.85.
Example 35.
[S-(R*,R*)]^r-[[[l-carboxy-2-[4-[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- ethyl ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000064_0001
Example 35 was prepared from example 34 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1709, 1675, 1612, 1565, 1511, 1439, 1416, 1346,
1300, 1241, 1196, 1179, 1115, 1018, 768 cm"1; 'H NMR (CDC13) δ 7.34 (2 H), 7.23 (1 H), 7.12 (2 H), 6.94 (2 H), 6.85 (1 H), 5.22 (2 H), 4.77 (4 H), 4.34 (1 H), 4.16 (2 H), 3.33 (4 H), 1.26 (3 H); 13C NMR (CDC13) δ 174.0, 170.2, 158.1, 155.1, 137.0, 132.0, 130.5, 128.5, 128.1, 115.0, 65.2, 63.9, 63.0, 62.9, 53.3, 36.4, 21.9, 14.5; MS (ESI+) for C23H24Cl2N2O6S m/z 527.0 (M+H)+; MS (ESI-) for C23H24Cl2N2O5S m/z 524.9 (M-H)"; HRMS (EI) calcd for C23H24Cl2N2O6S 526.0732, found 526.0726; Anal. Calcd for C23H24Cl2N2O6S • 0.20 H2O: C, 52.02; H, 4.63; N, 5.27. Found: C, 52.12; H, 4.73; N, 5.34. % Water (KF): 0.69.
Example 36.
[S-<R*,R*)]-4-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(4-morpholinyl)ethyl] ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-(4- morpholinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000065_0001
Example 36 was prepared as described in Scheme A from D-cysteine using 4-(2- hydroxyethyl)morpholine to form the requisite carbamate. Physical data as follows: mp 138-140°C; IR (mull) 3286, 1743, 1705, 1660, 1559, 1513, 1435, 1428, 1302, 1245, 1226,
1215, 1176, 1015, 764 cm "'; H NMR (300 MHz, DMSO-d6) δ 8.43 (1 H), 7.48 (3 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.59 (2 H), 4.48 (1 H), 4.26 (1 H), 4.07 (2 H), 3.63 (3 H), 3.51 (4 H), 3.23 (1 H), 3.01 (1 H), 2.84 (1 H), 2.71 (1 H), 2.41 (6 H); 13C NMR (75 MHz, DMSO-d6) δ 172.2, 157.7, 153.9, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 114.8, 66.6, 65.4, 63.4, 57.0, 53.9, 53.8, 52.4, 36.4; MS (ESI+) for C28H33Cl2N3O7S m/z 625.8
(M+H)+; Anal. Calcd for C28H33Cl2N3O7S: C, 53.67; H, 5.31; N, 6.71. Found: C, 53.69; H, 5.27; N, 6.69.
Example 37. [S-(R*,R*)]- -[[[l-Carboxy-2-[ -[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
[2-(4-morpholinyl)ethyl] ester (Scheme A, A-8: where RA and RA.2 are the same and equal to H, R3 is 2-(4- morpholinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000066_0001
Example 37 was prepared from example 36 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1710, 1610, 1585, 1565, 1511, 1439, 1408, 1351,
1301, 1240, 1196, 1179, 1116, 1017, 767 cm "1; ΪH NMR (300 MHz, DMSO-d6) δ 8.27 (1 H), 7.55 (2 H), 7.45 (1 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.59 (2 H), 4.40 (1 H), 4.27 (1 H), 4.04 (2 H), 3.52 (4 H), 3.21 (1 H), 2.86 (3 H), 2.44 (6 H), 13C NMR (75 MHz, DMSO-d6) δ 173.2, 172.5, 157.6, 136.5, 132.2, 132.0, 130.8, 130.4, 129.2, 114.7, 66.5, 65.3, 63.2, 57.0, 53.9, 53.7, 36.5, 21.5; MS (ESI+) for C27H3ICl2N3O7S m/z 611.9 (M+H)+; Anal. Calcd for C27H31Cl2N3O7S • 1.0 C2H4O2 * 0.63 H2O • 0.28 HCl: C, 50.13; H, 5.31; N, 6.03; Cl, 11.59. Found: C, 49.80; H, 5.30; N, 6.05; Cl, 11.20. % Water (KF): 1.58.
Example 38. [S-(R*,R*)]-4-[[[l-[4-[(2,6-Dichloroρhenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[(2-pyridinyl)methyl] ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-pyridinylmethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000066_0002
Example 38 was prepared as described in Scheme A from D-cysteine using 2- pyridinemethanol to form the requisite carbamate. Physical data as follows: mp 123- 125°C; IR (mull) 3334, 1728, 1709, 1668, 1531, 1511. 1441, 1405. 1345. 1294, 1286, 1236, 1228, 1015, 762 cm "'; 'H NMR (300 MHz, DMSO-d6) δ 8.57 (2 H), 7.79 (1 H), 7.54 (2 H), 7.42 (1 H), 7.27 (2 H), 7.12 (2 H), 6.92 (2 H), 5.13 (4 H), 4.69 (2 H), 4.49 (1 H), 4.34 (1 H), 3.59 (3 H), 3.24 (1 H), 2.89 (3 H); 13C NMR (75 MHz, DMSO-d6 δ 172.2, 169.9, 157.7, 156.5, 153.6, 137.3, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 123.2, 121.0, 1 14.8, 67.7, 65.3, 62.0, 54.0. 52.4, 50.3, 36.3. 35.3; HRMS (EI) calcd for C28H27Cl2N3O6S 603.0997. found 603.0992; Anal. Calcd for C28H27Cl2N3O6S: C. 55.63; H, 4.50; N. 6.95. Found: C. 55.56; H, 4.59; N, 6.93.
Example 39. [S-(R*,R*)]^-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(l-pyrrolidinyl)ethyl] ester (Scheme A, A-7: where RA., and RA_2 are the same and equal to H. R3 is 2-(l- pyrrolidinyl)ethyl, Y is CO2-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000067_0001
Example 39 was prepared as described in Scheme A from D-cysteine using l-(2- hydroxyethyl)pyrrolidine to form the requisite carbamate. Physical data as follows: mp 130-132°C; IR (mull) 1745. 1702. 1661, 1556, 1513, 1435, 1426, 1303. 1245, 1226, 1214,
1 176, 1017, 825, 765 cm "'; Η NMR (300 MHz, DMSO-d6) δ 8.42 (1 H). 7.48 (3 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.59 (2 H), 4.48 (1 H), 4.27 (1 H), 3.99 (2 H), 3.63 (3 H), 3.24 (1 H), 2.68 (9 H), 1.62 (4 H); nC NMR (75 MHz. DMSO-d6) δ 172.2, 170.0. 157.7, 136.5, 132.2. 132.0, 130.8. 130.1. 129.2. 1 14.8, 65.3. 65.1, 54.4. 53.9. 52.42. 36.35, 23.6; MS (ESI+) for C28H33Cl2N3O6S m/z 609.8 (M+H)~; Anal. Calcd for C28H33Cl2N3O6S: C, 55.08; H. 5.45; N, 6.88. Found: C, 54.72; H, 5.58; N, 6.60.
Example 40.
[R-(R*,S*)]^l-[[[l-[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-,
R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (R, S)).
Figure imgf000068_0001
Example 40 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1746, 1702, 1611. 1565, 1511, 1439, 1299, 1241, 1197, 1177, 1162, 1118, 1016, 777, 768 cm"1; Η NMR (CDC13) δ 7.39 (2 H), 7.25 (1 H), 6.93 (2 H), 6.93 (2 H), 5.24 (2 H), 4.72 (3 H), 4.20 (1 H). 3.74 (3 H), 3.35 (1 H), 3.12 (3 H), 1.44 (9 H); 13C NMR (CDC13) δ 171.7, 170.0, 169.5, 158.3, 137.3, 132.4, 130.7, 130.6, 128.8, 128.5, 115.2, 115.1, 82.4. 65.5, 53.5, 52.6. 50.3. 37.3, 28.4; MS (ESI+) for C26H30C12N,O6S m/z 554.9 (M+HV"; MS (ESI-) for C26H30C12N2O6S m/z 552.8 (M-H)"; Anal. Calcd for C26H30C12N2O6S • 0.1 H2O: C, 54.65; H. 5.33; N, 4.90. Found: C, 54.59; H. 5.30; N, 4.88. % Water (KF): 0.33.
Example 41. [R-(R*,S*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3- (1,1-dimethylethyl) ester
(Scheme A. A-8: where RA_, and RA.2 are the same and equal to H, R3 is t-butyl, Y is CO2-, R5 is 4-[(2.6-dichlorophenyl)methoxy]phenyl and stereochemistry is (R, S)).
Figure imgf000069_0001
Example 41 was prepared from example 40 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1737, 1705, 1679, 1612, 1565, 1512, 1439, 1300,
1241, 1196, 1 178, 1 163, 1 1 17, 777, 769 cm'1; 'H NMR (DMSO-d6) δ 8.07 (1 H), 7.54
(2 H), 7.44 (1 H), 7.16 (2 H), 6.93 (2 H), 5.16 (2 H), 4.56 (1 H), 4.39 (3 H), 3.56 (1 H),
2.84 (3 H), 1.23 (9 H);
13C NMR (DMSO-d6) δ 172.7, 169.9, 157.0, 152.6, 135.9, 131.6, 131.4, 130.1, 129.9, 129.8, 128.7, 114.1, 79.8, 66.9, 64.7, 61.7, 53.5, 49.3, 35.6, 34.8, 27.9, 27.6; MS (ESI+) for C25H28Cl2N2O6S m/z 554.9 (M+H)+; MS (ESI-) for C25H28Cl2N2O6S m/z 552.8 (M-H)";
Anal. Calcd for C25H28Cl2N2O6S • 0.27 H2O: C, 53.59; H, 5.13; N, 5.00. Found: C, 53.97;
H, 5.14; N, 4.96. % Water (KF): 0.86.
Example 42. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(ethylsulfonyl)^-thiazolidinyl]carbonyl]-
L-phenylalanine methyl ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H. R3 is ethyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000069_0002
Example 42 was prepared as described in Scheme A from D-cysteine using ethanesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1743, 1666, 1605, 1561, 1535. 1515. 1432. 1413, 1328, 1269. 1219. 1 195, 1 146. 799, 782 cm "'; Η NMR (CDC1,) δ 7.58 (2 H), 7.46 (1 H), 7.32 (3 H), 7.17 (2 H), 7.07 (1 H), 4.85 (1 H), 4.73 (2 H), 4.28 (1 H), 3.76 (3 H), 3.54 (1 H), 3.26 (1 H), 3.05 (4 H), 1.40 (3 H); 13C NMR (CDCl3) δ 171.3, 168.2, 162.4, 136.4, 135.8. 132.4, 132.3, 131.0, 130.1. 128.2. 120.6, 64.9, 53.2, 52.6, 51.5, 45.8, 37.1, 34.2, 31.0, 29.3, 7.7; MS (ESI+) for C23H25Cl2N3O6S2 m/z 573.9 (M+H)+; MS (ESI-) for C23H25Cl2N3O6S2 m/z 571.7 (M-H)"; HRMS (FAB) calcd for C23H25Cl2N3O6S2+H, 574.0640, found 574.0634; Anal. Calcd for C23H25Cl2N3O6S2 • 0.1 H2O: C, 47.97; H, 4.40; N, 7.30. Found: C. 48.36; H, 4.59; N, 6.80.
Example 43. 4—[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(ethylsulfonyl)- -thiazolidinyl]carbonyl]-
L-phenylalanine (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R, is ethyl. Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000070_0001
Example 43 was prepared from example 42 by the procedure described in preparation 6.. Physical data as follows: IR (mull) 1734, 1664. 1605, 1562, 1536, 1516, 1432, 1414, 1330, 1272. 1234, 1195, 1146, 799, 781 cm 1; Η NMR (DMSO-d6) δ 12.91 (1 H), 10.65 (1 H), 8.15 (1 H), 7.51 (5 H), 7.17 (2 H), 4.77 (2 H), 4.43 (1 H), 4.29 (1 H). 3.94 (6 H),
1.20 (3 H); 13C NMR (DMSO-d6) δ 172.5. 168.9, 161.9, 137.1, 136.5. 133.2. 131.4, 131.3, 129.8, 128.3, 119.3, 63.7. 53.6, 51.4, 45.3. 36.1, 34.7; MS (ESI+) for C22H23Cl2N3O6S2 m/z 559.9 (M+H)+; MS (ESI-) for C22H23Cl2N,O6S2 m/z 557.8 (M-H)"; HRMS (FAB) calcd for C22H23Cl2N3O6S2+H, 560.0483, found 560.0488; Anal. Calcd for C22H23Cl:N3O6S2 • 0.72 H2O: C. 46.08: H. 4.30; N, 7.33. Found: C. 46.42; H. 4.37; N, 7.01. % Water (KF): 2.26. Example 44. 4-[(2,6-DichIorobenzoyl)amino]-N-[[(4S)-3-[[5-(trifluoromethyl)-2- pyridinyl]sulfonyl]^-thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-(5- triflouromethylpyridyl), Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000071_0001
Example 44 was prepared as described in Scheme A from D-cysteine using 2-(5- triflouromethylpyridyl)sulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1745, 1668, 1603, 1535, 1515, 1432, 1413, 1327, 1219, 1179, 1142, 1108, 1073, 1016, 616 cm "'; 'H NMR (CDC13) δ 8.76 (1 H), 8.17 (2 H), 7.90 (1 H), 7.51 (2 H), 7.32 (4 H), 7.17 (2 H), 5.18 (1 H), 4.96 (1 H), 4.66 (1 H), 4.31 (1 H), 3.78 (3 H), 3.52 (1 H), 3.15 (3 H); 13C NMR (CDC13) δ 171.3. 168.4. 162.2, 147.2, 136.2, 136.0, 132.4, 131.0, 130.3. 128.2. 123.0, 120.4, 120.3, 65.7. 53.6. 52.5, 51.4, 37.3, 34.0; MS (ESI+) for C27H23Cl2F3N4O6S2 m/z 690.8 (M+H)+; MS (ESI+) for C27H23Cl2F3N4O6S2 m/z 712.9 (M+Na)+; Anal. Calcd for C27H23Cl2F3N4O6S2 • 0.2 H2O: C, 46.68; H, 3.39; N, 8.06. Found: C, 46.60; H, 3.52; N, 7.92. % Water (KF): 0.47. Example 45.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[5-(trifluoromethyl)-2- pyridinyl] sulfonyl]^!— thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA., and RA_2 are the same and equal to H, R3 is 2-(5- triflouromethylpyridyl), Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000072_0001
Example 45 was prepared from example 44 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1740. 1666, 1602, 1562, 1533, 1517, 1432. 1354, 1327, 1 179, 1 143, 1 108, 1074, 1016. 613 cm"'; Η NMR (DMSO-d6) δ 10.63 (1 H), 9.24 (1 H), 8.54 (1 H), 8.46 (1 H), 8.18 (1 H). 7.50 (5 H), 7.17 (2 H), 5.00 (1 H), 4.74 (1 H), 4.42 (2 H), 3.04 (2 H), 2.90 (1 H). 2.78 (1 H); l3C NMR (DMSO-d6) δ 172.8, 168.9, 162.3, 159.0. 147.8, 137.5, 137.4, 136.9, 133.5, 131.8, 131.7, 130.2, 128.7, 123.8. 1 19.7, 64.7, 53.9. 52.3, 36.7, 35.1 ; MS (ESI+) for C26H21Cl2F3N4O6S2 m/z 676.5 (M+H)+; MS (ESI-) for C26H21Cl2F3N4O6S2 m/z 674.5 (M-H)'; Anal. Calcd for C26H2ICl2F3N4O6S2 • 0.33: C, 45.69; H, 3.20; N, 8.20. Found: C, 45.81 ; H, 3.38; N, 8.13. % Water (KF): 0.88.
Example 46. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(phenylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and R 2 are the same and equal to H. R3 is phenyl, Y is SO2, R, is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000072_0002
Example 46 was prepared as described in Scheme A from D-cysteine using benzenesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1744. 1668, 1604, 1531, 1515. 1432, 1413, 1355, 1324. 1268. 1220. 1 195. 1167, 1090. 730 cm "'; Η NMR (CDC1,) δ 7.84 (2 H), 7.65 (5 H), 7.45 (1 H), 7.30 (6 H), 4.90 (1 H). 4.63 (2 H), 4.37 (1 H), 3.75 (3 H). 3.32 (1 H), 3.15 (2 H), 2.53 (1 H); 13C NMR (CDCl3) δ 171.2, 168.2, 162.4. 136.4, 136.3. 134.1. 132.4, 131.0, 130.2, 129.6. 128.2, 128.1, 127.9, 120.6. 65.3, 53.3, 52.6, 51.8. 37.4. 33.3: MS (ESI+) for C27H25Cl2N3O6S2 m/z 621.8 (M+H)+; MS (ESI-) for C27H25Cl2N3O6S2 m/z 619.8 (M-H)"; Anal. Calcd for C27H25Cl2N3O6S2 • 0.2 H2O: C, 51.84; H, 4.18; N, 6.72. Found: C, 51.72; H, 4.18; N. 6.52. % Water (KF): 0.48.
Example 47. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(phenylsulfonyl)-4- thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA_, and RA_2 are the same and equal to H. R3 is phenyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000073_0001
Example 47 was prepared from example 46 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1735, 1666. 1605. 1562, 1533, 1516, 1432, 1414,
1352, 1328. 1 195. 1180, 1 167, 1090, 731 cm 1; Η NMR (CDC13) δ 8.11 (1 H). 7.82 (2 H), 7.66 (3 H), 7.56 (2 H), 7.23 (6 H), 4.91 (1 H), 4.66 (1 H), 4.60 (1 H), 4.35 (1 H), 3.30 (1 H), 3.19 (2 H), 2.59 (1 H); 13C NMR (DMSO-d6) δ 172.2, 168.2, 161.7, 137.0, 136.9, 136.3, 133.6, 133.0, 131.2, 131.1, 129.6, 129.3, 128.1, 127.6, 1 19.2, 63.9, 53.4, 51.5, 48.4, 36.0, 33.8; MS (ESI+) for C26H23Cl2N3O6S2 m/z 607.9 (M+H)+; MS (FAB) m/z (rel. intensity) 608 (MH+, 85), 610 (67), 608 (85), 466 (30), 371 ( 41), 228 (38), 193 (38), 149 (30), 129 (31), 118 (99), 63 (35); HRMS (FAB) calcd for C26H23Cl2N3O6S2+H, 608.0483, found 608.0491 : Anal. Calcd for C26H23Cl2N3O6S2 0.27 H2O: C, 50.91; H, 3.87; N. 6.85. Found: C, 50.68; H, 4.05; N, 6.65. % Water (KF): 0.79. Example 48.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[5-(dimethylamino)-l- naphthalenyl]sulfonyl]-4—thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and RΛ.2 are the same and equal to H. R3 is 5-dimethylamino- 1-naphthyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000074_0001
Example 48 was prepared as described in Scheme A from D-cysteine using 5- dimethylamino- 1 -napthalenesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1744, 1684, 1605, 1562, 1533, 1515. 1431. 1412, 1350, 1324, 1231, 1202, 1163, 1 145. 798 cm "'; Η NMR (CDC13) δ 8.64 (1 H), 8.34 (2 H), 7.53 (5 H), 7.29 (4 H), 6.87 (3 H), 4.93 (1 H), 4.75 (1 H), 4.64 (1 H), 4.31 (1 H), 3.69 (3 H), 3.47 (1 H), 2.84 (8 H), 2.46 (1 H); 13C NMR (CDC13) δ 171.2, 167.7, 162.5, 136.3, 135.9, 132.4, 132.3, 131.9, 131.5. 131.0, 130.1, 129.7, 129.2, 128.2, 124.4, 120.4, 65.1, 53.3, 52.5, 50.1, 45.9, 37.1, 33.3; MS (ESI+) for C33H32Cl2N4O6S2 m/z 736.8 (M+NaV"; Anal. Calcd for C33H32Cl2N4O6S2 • 0.17 H2O: C. 55.15; H, 4.54: N, 7.79. Found: C, 55.20; H, 4.73; N, 7.49. % Water (KF): 0.43.
Example 49.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[5-(dimethylamino)-l- naphthalenyl]sulfonyl]-4—thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H. R, is 5-dimethylamino- 1-naphthyl, Y is SO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000075_0001
Example 49 was prepared from example 48 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1666. 1605. 1587, 1577, 1562, 1532, 1516, 1431, 1412, 1395, 1325, 1163, 1 145, 798, 631 cm "'; Η NMR (DMSO-d6) δ 10.60 (1 H), 8.54 (1 H), 8.28 (2 H), 7.54 (8 H), 7.25 (1 H), 6.93 (2 H), 4.95 (1 H), 4.84 (1 H), 4.39 (1 H), 4.17 (1 H), 2.95 (2 H), 2.80 (7 H), 2.54 (1 H); 13C NMR (DMSO-d6) δ 167.2, 161.7, 151.4, 136.6. 136.3, 133.6, 133.1, 131.1, 130.8. 130.3, 129.5, 129.3, 129.0, 128.8, 128.1, 123.6, 118.9, 118.3, 115.3, 63.6, 54.2, 50.3, 44.9. 36.7, 33.9, 21.0; MS (ESI+) for C32H30C12N4O6S2 m/z 700.8 (M+H)+; HRMS (FAB) calcd for C32H30C12N4O6S2+H, 701.1062, found 701.1039
Example 50. O-[(2,6-Dichlorophenyl)methyl]-N-[[(4S)-3-{methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-tyrosine methyl ester (Scheme A. A-7: where RA_, and RΛ.2 are the same and equal to H, R3 is methyl, Y is SO2, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000075_0002
Example 50 was prepared as described in Scheme A from D-cysteine using methanesulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (mull) 1742. 1680, 161 1, 1564, 1510, 1439, 1345. 1299, 1240, 1 179, 1 158, 1016, 976, 779. 768 cm'1; 'H NMR (CDC13) δ 7.36 (2 H), 7.24 (1 H), 7.08 (3 H), 6.97 (2 H), 5.25 (2 H), 4.77 (3 H), 4.29 (1 H), 3.74 (3 H). 3.43 (1 H). 3.53 (1 H), 3.10 (2 H). 2.93 (3 H); 13C NMR (CDC.,) δ 171.4. 168.0, 158.2, 137.0. 132.1, 130.3. 128.5, 127.9, 115.3. 65.2, 65.0, 59.4, 53.5, 53.3. 52.5. 51.9. 42.2, 37.3, 36.9, 34.2: MS (ESI+) for C22H24Cl2N2O6S2 m/z 546.8 (M+H)*; MS (ESI+) for C22H24Cl2N2O6S2 m/z 568.8 (M+H)*; HRMS (EI) calcd for C22H24Cl2N2O6S2 546.0453, found 546.0448; Anal. Calcd for C22H24Cl2N2O6S2 • 0.07 H2O: C, 48.15; H, 4.43; N. 5.10. Found: C, 48.17; H, 4.51 ; N, 5.02. % Water (KF): 0.24.
Example 51. O-[(2,6-Dichlorophenyl)methyl]-N-[[(4S)-3-<methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-tyrosine (Scheme A, A-8: where R , and RA.2 are the same and equal to H. R3 is methyl, Y is SO2, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000076_0001
Example 51 was prepared from example 50 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1737, 1675, 161 1, 1565, 151 1. 1439, 1345, 1300,
1241, 1197, 1 179, 1 157, 1016, 778. 769 cm"1; 'H NMR (CDC1,) δ 7.34 (2 H), 7.16 (5 H), 6.99 (2 H), 5.23 (2 H). 4.85 (1 H), 4.68 (2 H), 4.27 (1 H), 3.51 (1 H), 3.32 (1 H), 3.15 (2 H), 2.93 (3 H); πC NMR (CDC13) δ 174.8, 168.7, 158.3. 137.0, 132.1, 130.5, 130.4, 128.5, 127.6, 1 15.4, 1 15.2. 65.2, 64.9, 53.1, 52.0, 37.1. 36.4, 34.3; MS (ESI+) for C2IH22Cl2N2O6S2 m/z 532.8 (M+H)*; MS (ESI-) for C2,H22Cl2N2O6S2 m/z 530.7 (M-H)"; HRMS (FAB) calcd for C21H22Cl2N2O6S2+H, 533.0374, found 533.0386; Anal. Calcd for C21H22Cl2N2O6S2 • 0.06 H2O: C, 47.19; H, 4.17; N, 5.24. Found: C, 47.58; H, 4.35; N, 5.10. % Water (KF): 0.20.
Example 52. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[( 1.1 -dimethy lethy l)amino]carbonyl] thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is t-butyl, Y is CONH-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000077_0001
Example 52 was prepared from example 6 by the procedure described in preparation 6. Physical properties as follows: IR (mull) 3289. 1728, 1664, 1607, 1580. 1561, 1536, 1432, 1414, 1394, 1326, 1270, 1242, 1213, 1 195 cm'1; Η NMR (300 MHz. CD3OD) δ
7.47 (2 H), 7.24 (3 H), 7.04 (2 H), 4.63 (2 H), 4.37 (1 H), 4.17 (1 H), 3.09 (4 H), 1.22 (9 H); 13C NMR (75 MHz, CDC13) δ 176.9, 174.8, 167.2, 159.9, 140.5, 140.0, 136.4,
136.1, 134.6, 133.8, 131.8, 124.5, 66.6, 57.1, 55.3, 53.0, 40.1, 37.1, 32.9; MS (ESI+) for C25H28Cl2N4O5S m/z 566.9 (M+H)+, 588.9 M+Na)+; MS (ESI+) for C25H28Cl2N4O5S m/z 566.9 (M+H)+; HRMS (FAB) calcd for C25H28CL2N4O5S +H1 567.1235, found 567.1253.
Example 53. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[(diethylamino)carbonyl]^r- thiazolidinyl]carbonyl]-L-phenylalanine (Scheme A, A-8: where RA., and RΛ.2 are the same and equal to H, R3 is ethyl, Y is CON(CH2CH3)-, R5 is 4-[(2,6-dichlorobenzoyl)amino] phenyl and stereochemistry is (S, s».
Figure imgf000077_0002
Example 53 was prepared from example 7 by the procedure described in preparation 6. Physical properties as follows: IR (mull) 3269, 1734, 1663, 1607. 1562. 1535. 1515, 1431, 1415, 1348. 1325. 1269, 1213, 1195, 799 cm'1; Η NMR (300 MHz, CD3OD) δ 7.57 (2 H), 7.35 (3 H). 7.09 (2 H), 5.09 (1 H), 4.76 (1 H), 4.38 (2 H), 3.31 (3 H), 3.13 (5 H), 1.05 (6 H); 13C NMR (75 MHz, CD3OD) δ 176.6. 173.9, 167.1, 166.3, 140.7, 140.1, 136.1, 134.6, 133.8. 131.8, 124.1, 68.5, 57.4, 56.6, 45.9. 40.4, 36.6, 16.8; MS (ESI+) for C25H28Cl2N4O5S m/z 567.1 (M+H)+; Anal. Calcd for C25H28Cl2N4O5S: C, 52.91 ; H, 4.97; N, 9.87. Found: C, 52.60; H, 5.13; N, 9.47.
Example 54. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[methyl[2-(2- pyridinyl)ethyl]amino]carbonyl]-4-thiazolidinyl]carbonyl]-L-phenylalanine methyl ester (Scheme A. A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-(2-pyridyl)ethyl, Y is CON(CH3)-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000078_0001
Example 54 was prepared as described in Scheme A from D-cysteine using 2-(2- methylaminoethyl)pyridine to form the requisite urea. Physical data as follows: mp 80- 90°C (dec); IR (mull) 1743, 1665, 1606, 1561. 1538. 1514, 1489, 1432, 1413, 1395, 1323, 1268. 1216. 1 195, 799 cm "': Η NMR (300 MHz. DMSO-d6) δ 8.44 (1 H), 8.34 (1 H), 7.66 (1 H), 7.51 (5 H), 7.19 (4 H), 4.72 (1 H), 4.48 (1 H). 4.40 (1 H), 4.20 (1 H), 3.58 (4 H), 3.42 (1 H), 3.89 (10 H); 13C NMR (75 MHz. DMSO-d6) δ 172.1, 170.3. 162.3, 161.8, 159.4. 149.4. 137.6. 137.0, 136.8, 133.3. 131.8. 131.7. 130.0, 128.7, 123.8, 122.0, 1 19.8, 64.58. 53.8. 52.7. 52.5, 49.7, 36.5, 36.2, 35.7. 33.4; MS (ESI+) for C30H31C12N5O5S m/z 643.9(M+H)-; Anal. Calcd for C30H3IC12N5O,S: C. 55.90; H, 4.85; N, 10.86. Found: C, 55.52; H. 5.09; N. 10.64. Example 55.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-[[methyl[2-{2- pyridinyl)ethyl]amino]carbonyl]— 4-thiazolidinyl]carbonyl]-L-phenylalanine
(Scheme A, A-8: where RA_, and RA_2 are the same and equal to H, R3 is 2-(2-pyridyl)ethyl,
Y is CON(CH3)-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S,
S)).
Figure imgf000079_0001
Example 55 was prepared from example 54 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1682, 1656, 1606, 1561, 1540, 1513, 1432, 1413,
1398, 1323, 1268, 1242, 1 195. 799, 780 cm "'; Η NMR (300 MHz, DMSO-d6) δ 10.66
(1 H), 8.45 (1 H), 8.09 (1 H), 7.66 (1 H), 7.51 (5 H), 7.20 (4 H), 4.72 (1 H), 4.40 (2 H), 4.23 (1 H), 3.61 (1 H), 3.40 (1 H), 3.04 (7 H), 2.79 (3 H); MS (ESI+) for C29H29Cl2N5O5S m/z 629.9 (M+H)+; Anal. Calcd for C29H29Cl2N5O5S • 0.61 H2O: C. 54.29; H. 4.75; N,
10.92. Found: C, 54.29; H, 5.00; N, 10.32. % Water (KF): 1.72.
Example 56. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4S)-3-(4-morpholinylcarbonyl)— 4- thiazolidinyl]carbonyl]-L-phenylalanine methyl ester
(Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 and Y together form
CO-morpholino, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S,
S)).
Figure imgf000080_0001
Example 56 was prepared as described in Scheme A from D-cysteine using morpholine to form the requisite urea. Physical data as follows: mp 223-225°C; ^H NMR (300 MHz, DMSO-d6) δ 10.66 (1 H), 8.25 (1 H), 7.51 (5 H), 7.16 (2 H), 4.81 (1 H), 4.60 (1 H), 4.50 (1 H), 4.28 (1 H), 3.64 (3 H), 3.53 (4 H), 3.09 (8 H); 13C NMR (75 MHz, DMSO-d6) 172.1. 170.3, 162.3, 161.4, 137.6. 136.8, 133.3, 131.8. 131.7, 130.0, 128.7, 119.8, 66.2, 64.3, 53.8, 52.8, 52.5, 46.8, 36.1, 33.7; HRMS (FAB) calcd for C26H28CL2N4O6S+H, 595.1185. found 595.1 189: Anal. Calcd for C26H28Cl2N4O6S: C, 52.44; H, 4.74; N. 9.41. Found: C. 52.42; H, 4.96; N, 9.23.
Example 57. N-[[(4S)-3-[[Bis(2-hydroxyethyl)amino]carbonyl]^l-thiazolidin>l]carbonyl]^l— [(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R3 is 2-hydroxyethyl and Y is CON(CH2CH2OH). R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000080_0002
Example 57 was prepared as described in Scheme A from D-cysteine using diethanolamine to form the requisite urea. Physical data as follows: mp 105-107°C; IR (mull) 3284. 1743, 1662. 1608, 1561, 1539. 1516, 1432, 1414, 1355, 1326, 1270, 1217,
1 196, 799 cm '; Η NMR (300 MHz. DMSO-dή) δ 10.69 (1 H), 8.28 (1 H), 7.56 (4 H), 7.47 (1 H), 7.16 (2 H). 4.87 (3 H), 4.66 (1 H), 4.47 (1 H), 4.25 (1 H), 3.63 (3 H), 3.47 (6 H), 3.02 (6 H); MS (ESI+) for C26H30C12N4O7S m/z 612.9 (M+H)*; Anal. Calcd for C26H30C12N4O7S • 0.47 H2O: C, 50.21 ; H, 5.01; N, 9.01. Found: C, 50.02; H. 5.00; N, 8.93. % Water (KF): 1.36. Example 58.
N-[[(4S)-3-[[Bis(2-hydroxyethyl)amino]carbonyl]^l-thiazolidinyl]carbonyl]-4-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R, is 2-hydroxyethyl and Y is CON(CH2CH2OH), R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000081_0001
Example 58 was prepared from example 57 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3281 , 3196, 1724, 1660, 1608, 1580, 1561 , 1542,
1515, 1431, 1415, 1354, 1328, 1271, 1 196 cm "'; 'H NMR (300 MHz, DMSO-d6) δ 10.65 (1 H), 8.13 (1 H), 7.55 (4 H), 7.47 (1 H), 7.16 (2 H), 4.85 (2 H), 4.66 (1 H), 4.40 (1 H), 4.27 (1 H), 3.48 (6 H), 3.01 (6 H); MS (ESI+) for C25H28Cl2N4O7S m/z 598.9 (M+H)+; Anal. Calcd for C25H28Cl2N4O7S • 1.04 H2O: C, 58.58; H, 4.90; N, 9.06. Found: C, 48.88; H, 5.05; N, 8.79. % Water (KF): 3.02.
Example 59. [S-(R*,R*)]- -[[[l-[[4-[(2,6-dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-δ-oxo-3-thiazolidinepentanoic acid 3-methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H. R3 is CH2CH2CH2CO2CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl. and stereochemistry is (S,S)).
Figure imgf000082_0001
Example 59 was prepared as described in Scheme A from D-cysteine using methyl glutaryl chloride to form the requisite amide. Physical data as follows: IR (mull) 3266, 1741, 1734, 1685, 1678, 1630, 1610. 1560, 1545, 1441, 1435, 1414, 1327. 1268, 1227 cm" 1 ; Η NMR (DMSO-d6) δ 10.65 (1 H). 8.43 (1 H), 7.50 (5 H), 7.15 (2 H), 4.72 (2 H), 4.44 (2 H), 3.63 (3 H), 3.56 (3 H), 3.10 (4 H). 2.15 (4 H), 1.70 (2 H); 1 C NMR (CDC13) δ 171.6, 170.6, 170.1, 169.9, 169.6, 161.9, 137.2, 136.5, 132.9, 131.3, 129.7, 128.3, 119.4, 61.4, 53.7, 53.5, 52.0, 51.3, 48.7, 36.4, 35.8, 35.1, 33.1, 32.8, 32.5, 25.4, 19.8; MS (ESI+) for C27H29N3O7SCl2 m/z 610.0 (M+HV" ; MS (ESI-) for C27H29N3O7SCl, m/z 608.0 (M-H)"; Anal. Calcd for C27H29Cl2N3O7S: C, 53.12; H, 4.79; N, 6.88. Found: C. 52.81 ; H, 4.90; N, 6.88
Example 60. [S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-δ-oxo-3-thiazolidinepentanoic acid (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is CH2CH2CH2CO2H, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl. and stereochemistry is (S,S)).
Figure imgf000082_0002
Example 60 was prepared from example 59 by the procedure described in preparation 12. Physical data as follows: IR (mull) 3271. 3193. 3124, 1725. 1661, 1607. 1561. 1539, 1516, 1432, 1414, 1327, 1271, 1195, 799 cm "'; 'H NMR (DMSO-d6) δ 12.40 (1 H), 10.63 (1 H), 8.31 (1 H). 7.50 (5 H), 7.16 (2 H), 4.75 (2 H), 4.34 (2 H), 2.95 (4 H), 2.15 (4 H), 1.66 (2 H); 13C NMR (CD3CN) δ 175.0, 172.7, 172.6. 171.0. 163.5, 137.8, 137.0. 134.4, 132.7, 132.3, 131.1, 130.9, 129.1. 120.7. 63.2, 54.5. 49.9, 37.2, 34.1, 33.3, 20.7; MS (ESI+) for C25H25Cl2N3O7S m/z 582.0 (M+H)+; MS (ESI-) for C25H25Cl2N3O7S m/z 579.9 (M-H)"; Anal. Calcd for C25H25Cl2N3O7S • H2O: C. 50.01 ; H, 4.53; N, 7.00. Found: C, 49.61; H, 4.38; N, 6.61.
Example 61. N-[[(4S)-3-Acetyl-4-thiazolidinyl]carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L- phenylalanine methyl ester (Scheme A, A-7: where R 1 and RA.2 are the same and equal to H. R3 is CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000083_0001
Example 61 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3260, 3067, 1748, 1686. 1623, 1608, 1561. 1542, 1515, 1445, 1429, 1419, 1324, 1267, 1221 cm "1; 'H NMR (DMSO-d6) δ 8.44 (1 H), 7.52 (5 H), 7.17 (2 H), 4.78 (2 H), 4.37 (2 H), 3.63 (3 H), 3.06 (4 H), 1.94 (3 H); πC NMR (DMF-d7) δ 172.4, 170.6, 138.4, 137.5, 133.8, 132.3, 131.9, 130.6, 128.9, 120.0, 70.9, 63.6, 62.4, 54.7, 52.3, 50.2, 49.8, 49.2, 37.2, 36.6, 22.7; MS (ESI+) for C23H23Cl2N,O5S m/z 523.9 (M+H)+; MS (ESI+) for C23H23Cl2N3O5S m/z 545.8 (M+Na)*; HRMS (FAB) calcd for C23H23Cl2N3O5S+H, 524.0814, found 524.0812; Anal. Calcd for C23H23Cl2N3O5S • 0.1 H2O: C, 52.46; H. 4.45; N, 7.98. Found: C, 52.85; H, 4.42; N, 8.00. % Water (KF): 0.24. Example 62. N-[[(4S)-3-Acetyl-4-thiazolidinyl]carbonyl]— -[(2,6-dichlorobenzoyl)amino]-L- phenylalanine (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H. R, is CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S.S)).
Figure imgf000084_0001
Example 62 was prepared from example 61 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3070, 1747, 1682, 1663, 1625. 1608, 1580, 1561, 1548, 1514, 1443, 1431, 1416, 1278, 1220 cm '; 'H NMR (DMSO-d6) δ 12.48 (1 H), 10.63 (1 H), 8.29 (1 H), 7.50 (5 H), 4.73 (2 H), 4.34 (2 H), 2.97 (4 H), 1.93 (3 H); 13C NMR (DMSO-d6) δ 172.4, 169.6, 169.2, 168.5, 168.0, 161.7, 136.9, 136.3, 133.2, 133.0, 131.2, 129.6, 128.1, 1 19.2, 62.2, 61.0, 53.5, 53.3, 49.3, 48.4, 36.3, 35.7, 35.0, 33.1, 22.4, 20.9; MS (ESI-) for C22H2,Cl2N3O5S m/z 507.9 (M-H)"; Anal. Calcd for
C22H21Cl2N3O5S • 0.1 H2O: C, 51.57; H. 4.18; N, 8.20. Found: C. 51.49: H, 4.36; N, 8.07. % Water (KF): 0.40.
Example 63. [S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-5,5-dimethyl-δ-oxo-3- thiazolidinebutanoic acid (Scheme A, A-8: where RA., and RA.2 are the same and equal to CH3, R, is CH2CH2CO2H, Y is CO. R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S,S)).
Figure imgf000085_0001
Example 63 was prepared as described in Scheme A from D-penicillamine using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3264, 3198, 3071, 1721 , 1660, 1608, 1562, 1541, 1516, 1432, 1415, 1327, 1270, 1195, 799 cm"1; Η NMR (DMSO-d6) δ 10.62 (1 H), 8.15 (1 H). 7.52 (5 H), 7.18 (2 H), 4.72 (2 H), 4.43 (3 H), 2.91 (4 H), 2.17 (2 H), 1.36 (3 H), 1.07 (3 H); 13C NMR (DMSO-d6) δ 173.5, 172.6, 170.2, 169.7, 168.4, 168.1, 161.7, 136.9, 136.3, 133.3, 131.1, 129.6, 129.4, 128.1, 119.2, 70.6, 53.8, 53.5, 51.6, 48.4, 47.7, 35.9, 30.7. 30.5, 28.9, 28.6, 24.1 ; MS (ESI+) for C26H27Cl2N3O7S m/z 596.0 (M+H)+; MS (ESI+) for C26H27Cl2N3O7S m/z 617.9 (M+Na)+. MS (ESI-) for C26H27Cl2N3O7S m/z 593.8 (M-H)"; MS (FAB) m/z (rel. intensity) 596 (MH+, 20), 598 (15), 596 (20), 331 (1 1), 193 ( 13), 141 (15), 139 (99), 1 16 (16), 107 (13), 105 (50), 89 (25); HRMS (FAB) calcd for C26H27Cl2N3O7S+H, 596.1025, found 596.1036.
Example 64. [S-<R*,R*)]^H[[l-Carboxy-2-[4-[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-γ-oxo — 3-thiazolidinebutanoic acid (Scheme A, A-8: where RA., and RA_2 are the same and equal to H, R3 is CH2CH2CO2H, Y is CO, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry is (S,S)).
Figure imgf000085_0002
Example 64 was prepared as described in Scheme A from D-cysteine using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3073, 3031, 1725, 1640, 1612. 1585. 1565, 1535, 1511, 1439, 1300, 1241. 1 196, 1179, 768 cm"'; Η NMR (DMSO-d6) δ 8.26 (1 H), 7.53 (2 H), 7.44 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.75 (2 H), 4.40 (2 H), 4.20 (1 H), 2.81 (4 H), 2.32 (2 H). 2.07 (1 H); 13C NMR (DMSO-d6) δ 173.8, 172.6, 170.0, 169.3, 157.1, 136.0, 131.5, 130.4, 130.0, 129.8, 128.7, 1 14.2, 64.8, 61.5, 53.6, 48.5, 36.1. 35.5, 35.0, 33.1, 28.9, 28.6. 21.0; MS (ESI+) for C24H24Cl2N2O7S m/z 554.8 (M+H)*; MS (ESI-) for C24H24Cl2N2O7S m/z 552.7 (M-H)"; HRMS (FAB) calcd for C24H24Cl2N2O7S+H, 555.0759, found 555.0750.
Example 65. N-[[(4S)-3-Acetyl^ -thiazolidinyl]carbonyl]-O-[(2,6-dichlorophenyl)methyl]-L- tyrosine methyl ester
(Scheme A, A-7: where RA., and RΛ.2 are the same and equal to H, R3 is CH3, Y is CO, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry is (S,S)).
Figure imgf000086_0001
Example 65 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1744. 1657, 1612, 1585, 1564, 1511, 1438, 1405, 1352, 1299, 1240, 1 197, 1179, 1016, 768 cm"1; 'H NMR (CDC13) δ 7.36 (2 H), 7.24 (1 H), 6.97 (5 H), 5.24 (2 H), 5.04 (1 H), 4.78 (1 H), 4.50 (2 H), 3.74 (3 H), 3.45 (1 H), 3.17 (3 H), 2.02 (3 H); 13C NMR (CDC13) δ 172.7, 171.6, 171.4, 169.8, 168.9, 168.7, 157.8, 136.9, 131.9, 130.3, 129.9, 128.6, 128.4, 1 14.9, 65.1, 61.6, 56.0, 53.6, 53.3, 49.6, 36.7, 31.7, 22.5; MS (ESI+) for C23H24Cl2N2O5S m/z 532.9 (M+Na)+; MS (Ei ; m/z (rel. intensity) 510 (M+, 1), 338 (42), 337 (12), 336 (63), 267 (12 ), 265 (18), 163 (10), 161 (63), 159 (99), 130 (9), 88 (43); Anal. Calcd for C23H24C12N2O5S»0.19 H2O: C, 53.66; H, 4.77; N, 5.44. Found: C. 53.81; H, 4.75; N, 5.33. % Water (KF): 0.66. Example 66. N-[[(4S)-3-Acetyl-4— thiazolidinyl]carbonyl]-O-[(2,6-dichlorophenyI)methyl]-L- tyrosine (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is CH3, Y is CO, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry is (S,S)).
Figure imgf000087_0001
Example 66 was prepared from example 65 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1730, 1646, 1612, 1585, 1565, 151 1, 1439, 1414, 1299, 1240, 1 196, 1179, 1016, 779, 768 cm"1; Η NMR (DMSO-d6) δ 8.26 (1 H), 7.54 (2 H), 7.44 (1 H), 7.13 (2 H), 6.92 (2 H), 5.16 (2 H), 4.72 (2 H), 4.31 (2 H), 2.91 (5 H), 1.92 (3 H); 13C NMR (DMSO-d6) δ 172.6. 169.2, 168.0, 157.1, 136.0, 131.7, 131.5, 130.3, 128.7, 1 14.2, 64.8, 62.2, 61.0, 53.7, 49.4, 48.5, 36.1, 35.5, 35.1, 33.2, 22.4, 21.0; MS (ESI+) for C22H22Cl2N2O5S m/z 496.9 (M+H)+; MS (ESI-) for C22H22Cl2N2O5S m/z 494.8 (M-H)'; MS (FAB) m/z (rel. intensity) 497 (MH+, 99), 617 (29), 573 (12), 539 (25), 500 ( 11), 499 (78), 498 (38), 497 (99), 496 (1 1), 225 (62), 130 (14); HRMS (FAB) calcd for C22H22Cl2N2O5S+H, 497.0705, found 497.0713; Anal. Calcd for C22H22Cl2N2O5S • 0.41 H2O: C. 52.35; H, 4.56; N, 5.55. Found: C, 52.65; H, 4.51 ; N, 5.50. % Water (KF): 1.46. Example 67.
[R-(R*,S*)HH[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-γ-oxo-3-thiazolidinebutanoic acid (Scheme A, A-8: where RA_, and RA.2 are the same and equal to H, R3 is CH-,CH-,CO2H, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
Figure imgf000088_0001
Example 67 was prepared as described in Scheme A from L-cysteine using methyl succinyl chloride to form the requisite amide. Physical data as follows: 'H NMR (CD3CN) δ 8.86 (1 H), 7.55 (2 H), 7.42 (3 H), 7.24 (2 H), 7.1 1 (1 H), 4.90 (1 H), 4.65 (2 H), 4.33 (1 H), 3.14 (3 H), 2.47 (6 H), 1.80 (1 H); 13C NMR (CD3CN) δ 174.7, 172.6, 172.3, 170.7, 163.4. 137.7, 137.0, 134.4, 132.7, 132.2, 130.9, 129.1, 63.2, 60.9, 54.4, 49.7, 37.1, 36.7, 32.7, 30.6, 30.0, 29.5, 21.1, 14.4; MS (FAB) m/z (rel. intensity) 568 (MH+, 99), 646 (1 1), 644 (16), 572 (13), 571 ( 12), 570 (73), 569 (38), 568 (99), 567 (15), 216 (22), 88 (27); Anal. Calcd for C24H23Cl2N3O7S • 0.5 H2O: C, 49.92; H, 4.19; N, 7.23. Found: C, 50.01; H, 4.54; N, 7.05.
Example 68. [R-(R*,S*)H-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-δ-oxo-3-thiazolidinepentanoic acid
(Scheme A, A-8: where RA., and RA_2 are the same and equal to H, R3 is CH2CH2CH2CO2H, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
Figure imgf000088_0002
Example 67 was prepared as described in Scheme A from L-cysteine using methyl glutaryl chloride to form the requisite amide. Physical data as follows: 'H NMR (CD3CN) δ 8.85 (1 H), 7.55 (2 H), 7.44 (3 H), 7.17 (3 H), 4.86 (1 H), 4.64 (2 H), 4.34 (1 H), 3.64 (1 H), 3.13 (3 H), 2.27 (4 H), 1.79 (4 H).; 1 C NMR (CD3CN) δ 175.0, 172.9. 172.7, 170.6, 163.4, 137.7. 137.0, 134.2, 132.7, 132.2, 131.0. 129.1, 120.7, 68.2, 63.1, 54.2. 49.8. 37.1, 36.9, 34.0, 33.2, 32.6, 26.2, 20.6; MS (FAB) m/z (rel. intensity) 582 (MH+. 99), 585 (12), 584 (68), 583 (35), 582 ( 99), 581 (1 1), 88 (23), 69 (8), 57 (9), 55 (1 1), 43 (1 1); Anal. Calcd for C25H25Cl2N3O7S • 0.2 H2O: C, 51.24: H, 4.37; N, 7.17. Found: C, 51.25; H, 4.68; N, 6.92.
Example 69. N-[[(4R)-3-Acetyl-4-thiazolidinyl]carbonyl]^l— [(2,6-dichlorobenzoyl)amino]-L- phenylalanine methyl ester (Scheme A, A-7: where RA., and RA.2 are the same and equal to H, R, is CH3, Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
Figure imgf000089_0001
Example 69 was prepared as described in Scheme A from L-cysteine using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3268, 1743. 1662, 1607, 1561, 1538, 1515, 1431, 1413, 1354. 1324. 1270, 1217, 1195, 799 cm'1; 'H NMR (CDC13) δ 7.56 (3 H), 7.31 (4 H), 7.14 (2 H), 4.92 (2 H), 4.49 (1 H), 4.29 (1 H), 3.77 (3 H), 3.54 (1 H), 3.26 (1 H), 3.00 (2 H), 2.1 1 (3 H); 13C NMR (CDC13) δ 171.5. 170.3, 168.9, 152.5, 135.9, 135.7, 132.9, 132.3, 131.0, 130.1. 129.9, 128.2, 128.0, 127.9, 120.4, 63.9, 61.4, 53.1, 52.5, 49.7, 37.0, 31.2, 22.6; MS (ESI+) for C23H23Cl2N3O5S m/z 523.8 (M+H)+.
Example 70. N-[[(4R)-3-Acetyl-4—thiazolidinyl]carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L- phenylalanine (Scheme A, A-8: where RA., and RA.2 are the same and equal to H. R3 is CH„ Y is CO, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
Figure imgf000090_0001
Examρle70 was prepared from example 69 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 3068, 1727, 1661, 1607, 1561, 1540, 1516, 1444, 1431, 1414, 1327, 1271, 1218, 1195 cm'1; Η NMR (DMSO-d6) δ 12.78 (1 H), 10.67 (1 H), 8.27 (1 H), 7.49 (4 H), 7.19 (2 H), 4.75 (2 H), 4.45 (3 H), 3.01 (3 H), 1.96 (3 H); 13C NMR (DMSO-d6) δ 172.6, 172.3, 169.4, 168.6, 168.2, 161.7, 136.9. 136.3, 133.3, 132.8, 131.1, 129.6, 128.1, 1 19.1, 62.2, 60.9, 53.4, 49.3, 48.7, 35.9, 35.1, 32.7, 22.4; MS (ESI+) for C22H2]Cl2N3O5S m/z 509.8 (M+H)+; MS (ESI-) for C22H21Cl2N3O5S m/z 507.8 (M-H)"; HRMS (FAB) calcd for C22H21Cl2N3O5S+H, 510.0657, found 510.0667;
Example 71. 4— [(2,6-Dichlorobenzoyl)amino]-N-[[(4R)-4-thiazolidinyl]carbonyl]-L-phenylalanine monohydrochloride salt (Scheme A, A-10: where RA., and RA.2 are the same and equal to H, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry is (R,S)).
Figure imgf000090_0002
Example 71 was prepared as described in Scheme A from L-cysteine. Physical data as follows: IR (mull) 3249, 3190, 3036, 1729. 1662. 1605. 1578, 1562, 1541, 1516, 1432, 1414, 1328, 1271, 1 195 cm"1; Η NMR (DMSO-d6) δ 10.71 (1 H), 8.83 (1 H). 7.56 (5 H), 7.24 (2 H), 4.50 (1 H), 4.25 (1 H), 4.21 (2 H), 3.62 (1 H), 3.01 (4 H); l3C NMR (DMSO- d6) δ 172.0, 166.8, 161.8, 137.7, 132.7, 131.3, 131.0. 129.5, 128.1, 119.4, 72.0, 70.4, 62.3, 53.8, 49.0, 35.7. 33.4; MS (ESI+) for C20H19C12N,O4S m/z 468.1 (M+H)*; Scheme B
"* «..■. B-1
OH
H2N
B-2
RB-3 RB-4
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
Figure imgf000091_0004
where RB.,, RB.2, RB.3, and RB^ are defined as R, and in addition RB.3 and RB.4 may be attached to the same carbon atom and form a cyclic ring of 5-8 atoms of the formula:
Figure imgf000092_0001
together with the carbon atom to which they are attached; RB.5 is defined as OH or O-(C,^ alkyl)
Scheme B describes a general method for the preparation of thiazolidine-4- carboxylic acid derivatives of general structure B-6. B-7 and B-8 which are disubstituted at the 2 position (i.e., RB.3 and RB^, are not equal to H). Within this class of structures, the nitrogen is derivatized immediately after forming the heterocyclic ring. Accordingly, a commercially available or readily prepared sulfur-containing amino acid of structure B-1 (which is the same structure as A-1) is condensed with a commercially available or readily prepared ketone to afford the thiazolidine-4-carboxylic acid of general formula B-3 (preparation 15) (for a general discussion of the condensation of aldehydes and ketones with cysteine or similar sulfur containing amino acids see: Coppola, G.M.; Schuster, H.F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids; John Wiley: New York, 1987; Chapter 6, 171.). The amine group may be reacted with a variety of electrophilic reagents such as sulfonyl chlorides, carbonates, chloroformates. isocyanates, phosgene (or a suitable equivalent) and an amine. acid chlorides, and carboxylic acid anhydrides as described in Scheme A for the reaction of A-6. Preparation 16 is provided as a specific example of the synthesis of a compound of general structure B-4.
Condensation of B-4 with amino acid derivative B-5 under standard peptide synthesis conditions provides the compound of general structure B-6 (preparation 17). Mild base hydrolysis of the methyl ester of general structure B-6 (where RB.5 is OCH3) may be effected as described and exemplified in Scheme A (preparation 6 or 13) to afford compounds of the general structure B-7. Alternatively, in those cases where RB.5 is O-t- Bu, mild acidolysis can also provide compounds of the general structure B-7 (by the procedure described in preparation 4 of Scheme A). In the case of t-butoxycarbonyl derivatised analogs of general structure B-7 (i.e. where R3 is t-butyl and Y is CO:), mild acidolysis affords compounds of general structure B-8 (by the procedure described in preparation 4 of Scheme A).
Preparation 15. (Scheme B. B-3: where RB., and RB.2 are the same and equal to H, RB.3 and RB_4 are the same and equal to CH,, and stereochemistry is (R)).
Figure imgf000093_0001
A suspension of L-cysteine hydrochloride monohydrate (Scheme B. B-1: where RB., and RB.2 are the same and equal to H and stereochemistry is (R)) (20 g, 0.11 mol) in acetone (Scheme B, B-2: where RB.3 and RBJt are equal to CH3) (800 mL) was heated to reflux for 8 h. Cooling to room temperature resulted in precipitation of a solid which was collected by filtration, washed with acetone and dried in vacuo to afford the title compound (17.46 g) as a white solid: mp 165-167°C; (Lit. 165-168°C: Sheehan, J.C.; Yang, D-D.H. J. Am. Chem. Soc. 1951, 80, 1158) 'H NMR (D2O) δ 4.75 (1 H), 3.59 (1 H), 3.44 (1 H), 1.73 (3 H), 1.71 (3 H); MS (ESI-) for C6H,,NO2S m/z 159.9 (M-H)".
Preparation 16. (Scheme B, B-4: where RB., and RB.2 are the same and equal to H. RB„3 and RBJt are the same and equal to CH-„ Y is CO2, R3 is t-butyl and stereochemistry is (R)).
Figure imgf000093_0002
To a solution of B-3 (Scheme B where RB., and RB.2 are the same and equal to H, RB.3 and RBj, are the same and equal to CH3, and stereochemistry is (R)) (17.46 g, 0.11 mol) in acetonitrile (250 mL) at ambient temperature was added di-t-butyl dicarbonate (25.64 g, 0.1 17 mol) followed by N.N-diisopropylethylamine (16.9 mL. 0.097 mol). The reaction mixture was stirred for 2 davs and volatiles remove in vacuo. The residue was slurried in diethyl ether and filtered through a pad of celite. The filtrate was washed with 0.1 N HCl, water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization of the clear oil from hexane provided the title compound (3.85 g) as a white solid: mp 125- 126°C; (Lit. 1 14°C: Woodward, R.B.; Heusler, K.; Gosteli, J.; Naegeli. P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen. H. J. Am. Chem. Soc. 1966, 88, 852) Η NMR (CDC13) δ 8.70 (1 H), 4.89 (1 H), 3.27 (2 H), 1.81 (6 H); MS (ESI-) for CπH19NO4S m/z 260.1 (M-H)".
Preparation 17 and Example 72. [R-<R*,S*)]^-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxo-ethyl]amino]carbonyl]-2.2-dimethyl-3-thiazolidinecarboxylic acid 3-(l ,1- dimethylethyl)ester (Scheme B, B-6: where RB., and RB_2 are the same and equal to H, RB.3 and RB^, are the same and equal to CH3, Y is CO2, R3 is t-butyl, RB.5 is OCH3, R5 is 4-[(2.6- dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000094_0001
To a cooled (0-5°C) suspension of B-4 (Scheme B where RB_, and RB.2 are the same and equal to H, RB.3 and RB^, are the same and equal to CH3, Y is CO2, R3 is t-butyl and stereochemistry is (R)) (1.0 g, 3.83 mmol) and HOBt (638 mg, 4.17 mmol) in CH2C12 (20 mL) was added a solution of EDC (799 mg, 4.17 mmol) in CH2C12 (20 mL). After 30 min at 0-5°C, B-5 (Scheme B where RB.5 is OCH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (1.93 g, 4.77 mmol) was added followed by 4- methylmorpholine (520 μL, 4.77 mmol). The reaction mixture was gradually warmed to room temperature, stirred an additional 18 h and diluted with CH2CL. The organic layer was separated and washed with 0.1 N HCl. sat. aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue using CH2Cl2/acetone (3%) as eluant afforded the title compound (2.05 g) as a white solid: IR (mull) 1746, 1666, 1606, 1562, 1537, 1515, 1432, 1413, 1347, 1325, 1259, 1214, 1195, 1 169, 799 cm"1; Η NMR (CDC13) δ 7.54 (2 H), 7.32 (4 H), 7.20 (2 H), 6.90 (1 H), 4.78 (2 H), 3.74 (3 H), 3.17 (4 H), 1.74 (3 H), 1.43 (9 H); l3C NMR (CDC13) δ 171.6, 136.7, 136.2, 135.9, 132.7, 132.4, 132.3, 131.0, 130.6, 130.4, 130.0, 129.9, 128.2, 127.9, 120.5, 120.2, 120.1, 67.3, 53.4, 52.4, 42.8, 37.3, 36.9, 34.9. 30.9, 28.3; MS (ESI+) for C28H33Cl2N3O6S m/z 610 (M+H)+; MS (ESI-) for C28H33Cl2N3O6S m/z 607.9 (M-H)'; Anal. Calcd for C28H33Cl2N3O6S • 0.13 H2O: C, 54.88; H. 5.47; N, 6.86. Found: C, 54.66; H, 5.57; N, 6.73. % Water (KF): 0.37.
Example 73. [R-(R*,S*)]^t-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2-dimethyl-3- thiazolidinecarboxylic acid 3-(l,l-dimethylethyl)ester
(Scheme B, B-7: where RB_, and RB.2 are the same and equal to H, RB.3 and RB^ are the same and equal to CH3, Y is CO2, R3 is t-butyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000095_0001
Example 73 was prepared from example 72 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1738, 1665, 1606. 1562. 1535, 1516, 1432, 1413, 1347, 1259, 1213, 1 194. 1167, 799, 777 cm'1; 'H NMR (CD3CN) δ 8.89 (1 H), 7.54 (2 H), 7.41 (3 H). 7.25 (2 H). 4.66 (2 H), 3.15 (4 H), 1.72 (3 H). 1.70 (3 H), 1.35 (9 H); 13C NMR (CD3CN) δ 177.3. 171.8, 163.4, 137.9, 137.1, 133.9. 132.7, 132.3. 131.3, 129.1, 120.7, 81.2. 79.3, 68.0. 54.5. 37.4. 28.4; MS (ESI-) for C H„Cl:N,O6S m/z 593.9 (M-H)'; Anal. Calcd for C27H31Cl2N3O6S • 0.5 H2O: C, 53.56; H, 5.33; N, 6.94. Found: C, 53.77; H, 5.39; N, 6.70.
Example 74. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(4R)-2,2-dimethyl^Φ-thiazolidinyl]carbonyl]-L- phenylalanine
(Scheme B, B-8: where RB., and RB.2 are the same and equal to H, RB.3 and RB^, are the same and equal to CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000096_0001
Example 74 was prepared from example 73 by the procedure described in preparation 4. Physical data as follows: IR (mull) 3244, 3192, 3049, 1726, 1664, 1605, 1578, 1562, 1541, 1516, 1432, 1414, 1327, 1195, 799 cm'1; 'H NMR (DMSO-d6) δ 13.00 (1 H), 10.69 (1 H), 7.52 (6 H), 7.24 (2 H), 4.52 (2 H), 3.12 (2 H), 2.93 (1 H), 1.62 (9 H); l3C NMR (CD3OD) δ 166.9, 136.8, 136.0. 133.5. 131.8, 130.9, 129.5, 129.4, 127.9, 120.4, 120.2, 120.1, 60.8, 54.3, 54.0, 36.2. 36.0. 25.1; MS (ESI+) for C22H23Cl2N3O4S m/z 496.2 (M+H)÷; MS (ESI-) for C22H23Cl2N3O4S m/z 494.2 (M-H)'; Anal. Calcd for C22H23Cl2N3O4S • HCl • 0.50 H2O: C, 48.76; H. 4.65; N, 7.75. Found: C, 48.56; H. 4.72; N, 7.49. Example 75.
[S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxo-ethyl]amino]carbonyl]-2.2-dimethyl-3-thiazolidinecarboxylic acid 3-(l,l- dimethylethyl)ester (Scheme B, B-6: where RB., and RB.2 are the same and equal to H, RB_3 and RB.4 are the same and equal to CH3, Y is CO2, R3 is t-butyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000097_0001
Example 75 was prepared as described in Scheme B from D-cysteine and acetone using di- t-butyl dicarbonate to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1686. 1666, 1605, 1537, 1515, 1432, 1413, 1349, 1325, 1259, 1213, 1206. 1 195, 1169 cm"'; Η NMR (CDC13) δ 7.56 (2 H), 7.32 (3 H), 7.16 (2 H), 6.92 (1 H), 4.83 (2 H), 3.73 (3 H), 3.20 (4 H), 1.78 (6 H), 1.45 (9 H); l3C NMR (CDC13) δ 171.6, 170.0. 136.2, 132.6, 132.4. 131.0. 130.9, 130.1, 129.9, 128.2, 120.5, 120.4, 67.3, 53.3, 52.5, 52.4. 37.4, 28.4; MS (ESI+) for C28H33Cl2N3O6S m/z 610.0 (M+H)+; MS (ESI-) for C28H33Cl2N3O6S m/z 607.9 (M-H)"; Anal. Calcd for C28H33Cl2N3O6S: C, 55.08; H, 5.45; N, 6.88; Cl, 11.61; S, 5.25. Found: C, 54.87; H, 5.47; N, 6.78
Example 76. [S-(R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2-dimethyl-3- thiazolidinecarboxylic acid 3-(l,l-dimethylethyl) ester (Scheme B, B-7: where RB., and RB.2 are the same and equal to H, RB.3 and RB-, are the same and equal to CH3, Y is CO2, R3 is t-butyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000097_0002
Example 76 was prepared from example 75 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3280, 1739, 1665, 1606, 1562. 1535, 1516, 1432, 1413, 1348, 1272, 1259. 1 195. 1 167, 799 cm"'; 'H NMR (CD,CN) δ 8.83 (1 H), 7.55 (2 H), 7.43 (3 H), 7.22 (2 H), 6.83 (1 H), 4.68 (2 H), 3.07 (5 H), 1.73 (6 H), 1.40 (9 H); l3C NMR (CD3CN) δ 172.6. 163.3, 137.9, 133.4, 133.3, 132.7, 132.1, 131.1, 130.2, 130.1, 129.1, 128.1, 128.0, 120.6, 119.5. 54.1, 37.4, 29.4, 28.5, 27.6; MS (ESI+) for C27H31Cl2N3O6S m/z 595.9 (M+H)+; MS (ESI-) for C27H31Cl2N3O6S m/z 593.7 (M-H)'; MS (FAB) m/z (rel. intensity) 596 (MH+, 16), 598 (12), 596 (16), 500 (16), 499 ( 19), 498 (71), 497 (32), 496 (99), 173 (16), 1 16 (19), 57 (51); HRMS (FAB) calcd for C27H31Cl2N3O6S+H, 596.1389. found 596.1364; Anal. Calcd for C27H3,Cl2N3O6S • 0.5 H2O: C, 53.56; H, 5.33; N, 6.94. Found: C, 53.86; H, 5.35; N, 6.90.
Example 77.
[S-{R*,R*)]-3-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]ρhenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl] -l-thia-4-azaspiro[4.4]nonane-4—carboxylic acid 4-ethyl ester (Scheme B, B-6: where RB., and RB.2 are the same and equal to H, RB.3 and RB^, together form a carbocyclic ring of 5 atoms, Y is CO2, R3 is ethyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000098_0001
Example 77 was prepared as described in Scheme B from D-cysteine and cyclopentanone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1760, 1739, 1694, 1656. 1607, 1560, 1543, 1517, 1445. 1429, 141 1, 1334, 1273, 1253, 1116 cm"'; Η NMR (CDC1,) δ 7.56 (2 H), 7.44 (1 H). 7.34 (3 H), 7.11 (2 H), 6.70 (1 H), 4.84 (2 H), 4.14 (2 H), 3.74 (3 H), 3.12 (4 H). 2.67 (1 H). 2.51 (1 H), 1.73 (6 H), 1.25 (3 H); '3C NMR (CDCl3) δ 171.4, 170.7, 162.3. 136.3. 135.8, 132.5, 132.4, 131.0, 130.1, 128.2. 120.2. 66.4. 62.1. 53.1. 52.5, 37.3, 32.3. 31.9. 25.1. 24.6, 14.5, 14.1 ; MS (ESI+) for C28H3lCl2N3O6S m/z 630.0 (M+Na)*; HRMS (EI) calcd for C28H3,Cl2N3O6S 607.1310, found 607.1315; Anal. Calcd for C28H3ICl2N3O6S • 0.75 H2O: C, 54.06; H, 5.27; N, 6.90. Found: C, 53.98; H, 5.16; N. 6.72.
Example 78. [S-(R* ,R*)]-3-[ [[ 1 -Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-l-thia-4— azaspiro[4.4]nonane-4- carboxylic acid 4-ethyl ester (Scheme B, B-7: where RB_, and RB_2 are the same and equal to H, RB.3 and RB.4 together form a carbocyclic ring of 5 atoms, Y is CO2, R3 is ethyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000099_0001
Example 78 was prepared from example 77 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 1664, 1606, 1562, 1537, 1515, 1445, 1432,
1413. 1335, 1273, 1239. 1 195, 1 116, 799 cm '; 'H NMR (CDC13) δ 8.08 (1 H), 7.62 (2 H), 7.24 (3 H), 7.14 (2 H), 6.72 (1 H), 4.85 (2 H), 4.13 (2 H), 3.21 (4 H), 2.53 (2 H), 1.75 (6 H), 1.22 (3 H); 13C NMR (CDC13) δ 175.2, 171.2, 162.6, 136.7, 135.7, 132.3, 132.0, 130.7, 130.2, 127.9, 120.2, 66.3, 62.2, 53.2, 37.3, 36.6, 32.3, 25.2, 24.6, 20.5. 14.5; MS (ESI+) for C27H29Cl2N3O6S m/z 593.8 (M+H)+; MS (ESI-) for C27H29Cl2N3O6S m/z 591.8 (M-H)'; HRMS (FAB) calcd for C27H29Cl2N3O6S+H, 594.1232, found 594.1226; Anal. Calcd for C27H29Cl2N3O6S • 0.37 H2O: C. 53.95; H, 4.99; N, 6.99. Found: C. 54.28; H, 5.10: N, 7.03. % Water (KF): 1.10.
Example 79. [S-(R*,R*)]-3-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]ρhenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-l-thia-4-azaspiro[4.5]decane-4—carboxylic acid 4-ethyl ester (Scheme B, B-6: where RB., and RB.2 are the same and equal to H, RB.3 and RB^, together form a carbocyclic ring of 6 atoms, Y is CO2, R3 is ethyl, R, is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S. S)).
Figure imgf000100_0001
Example 79 was prepared as described in Scheme B from D-cysteine and cyclohexanone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1745, 1704, 1683, 1668, 1607, 1561, 1538, 1514, 1431, 1413, 1327, 1269, 1213, 1 196, 1117 cm '; Η NMR (CDC13) δ 7.57 (2 H), 7.46 (1 H), 7.33 (3 H), 7.1 1 (2 H), 6.72 (1 H), 4.88 (2 H), 4.14 (2 H), 3.74 (3 H), 3.13 (4 H), 2.51 (1 H), 1.69 (8 H), 1.22 (5 H); 13C NMR (CDCl3) δ 171.4, 170.7, 168.1, 162.3, 136.3, 135.7, 132.4, 131.0, 128.2, 120.3, 66.9, 62.8, 62.0, 55.1, 53.1, 52.5, 42.0, 39.9, 37.3, 36.9. 31.1, 29.6, 27.6, 27.1, 26.0, 25.3, 24.7, 23.1, 14.5; MS (ESI-) for C29H33Cl2N3O6S m/z 621.9 (M)'; HRMS (FAB) calcd for C29H33Cl2N3O6S+H, 622.1545. found 622.1536.
Example 80.
[S-{R*,R*)]-3-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-l-thia-4-azaspiro[4.5]decane- - carboxylic acid 4-ethyl ester (Scheme B, B-7: where RB., and RB.2 are the same and equal to H, RB.3 and RB together form a carbocyclic ring of 6 atoms, Y is CO2, R3 is ethyl. R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000100_0002
Example 80 was prepared from example 79 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3276, 1710, 1664, 1606. 1562. 1537, 1515, 1432, 1413, 1329, 1272. 1256. 1 195, 1 1 17, 800 cm"'; 'H NMR (CDC13) δ 8.07 (1 H), 7.62 (2 H), 7.24 (3 H), 7.14 (2 H), 6.75 (1 H), 4.88 (2 H), 4.12 (3 H), 3.14 (4 H), 2.74 (1 H), 2.50 (1 H), 1.69 (6 H), 1.19 (5 H); '3C NMR (CDCl3) δ 175.4, 175.1. 171.3, 162.6, 136.7, 135.7, 132.3, 132.0, 130.7, 130.3, 130.1, 128.0, 120.2, 66.8, 62.1, 53.2, 42.0, 36.9, 30.5, 27.0, 26.0, 25.3, 25.0, 24.6, 20.5, 14.4, 3.7; MS (ESI+) for C28H31Cl2N3O6S m/z 608.1 (M+H)+; MS (ESI-) for C28H31Cl2N3O6S m/z 605.9 (M-H)"; HRMS (EI) calcd for C28H31Cl2N3O6S 607.1310, found 607.1309; Anal. Calcd for C28H3,Cl2N3O6S • 0.3 H2O: C, 54.78; H, 5.19; N, 685. Found: C. 54.56; H. 5.24; N, 6.90. % Water (KF): 0.87.
Example 81.
[S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-2,2,5.5-tetramethyl-3-thiazolidinecarboxylic acid 3-ethyl ester
(Scheme B, B-6: where RB.„ RB.2, RB.3 and RB^, are the same and equal to CH3, Y is CO2, R3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000101_0001
Example 81 was prepared as described in Scheme B from D-penicillamine and acetone using ethyl chloroformate to form the requisite carbamate. Physical data as follows: IR (mull) 1748, 1666, 1606, 1562, 1538. 1516, 1432, 1413, 1327, 1275. 1233. 1215, 1195, 1080. 799 cm '; Η NMR (CDC13) δ 7.55 (2 H), 7.33 (4 H), 7.09 (3 H), 6.59 (1 H), 4.91 (1 H), 4.47 (1 H), 4.16 (2 H), 3.75 (3 H), 3.13 (2 H), 1.92 (3 H), 1.75 (3 H), 1.67 (3 H), 1.60 (3 H), 1.21 (3 H); , C NMR (CDCLJ δ 171.5, 170.0, 162.2. 136.1, 135.7. 132.5, 132.3. 131.9. 130.9, 130.7, 129.7. 128.1. 120.3. 120.1, 120.0, 61.6. 61.4. 52.9. 52.4, 52.2, 49.3, 37.4, 37.3, 34.1, 31.4, 30.8, 29.5, 24.9; MS (ESI-) for C28H33Cl2N3O6S m/z 607.9 (M- H)"; HRMS (EI) calcd for C28H33Cl2N3O6S 609.1467. found 609.1461; Anal. Calcd for C28H33Cl2N3O6S • 0.19 H2O: C, 54.77; H, 5.48; N. 6.84. Found: C, 55.00; H, 5.48; N, 6.78. % Water (KF): 0.56.
Example 82.
[S-(R* ,R* )M-[[[ 1 -Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2,5,5-tetramethyl-3- thiazolidinecarboxylic acid 3-ethyl ester
(Scheme B, B-7: where RB.„ RB.2, RB.3 and RB.4 are the same and equal to CH3, Y is CO2,
R3 is t-butyl, R, is 4-[(2.6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S. S)).
Figure imgf000102_0001
Example 82 was prepared from example 81 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3275, 1750, 1735. 1678, 1666, 1609, 1562, 1543,
1516, 1432. 1413, 1333, 1276, 1195, 1077 cm 1; 'H NMR (DMSO-d6) δ 12.48 (1 H), 10.63 (1 H), 8.36 (1 H), 7.53 (5 H), 7.19 (2 H), 4.49 (2 H), 3.96 (2 H), 3.03 (1 H), 2.79 (1 H), 1.78 (6 H), 1.48 (3 H), 1.15 (3 H), 0.90 (3 H); πC NMR (DMSO-d6) δ 172.9, 168.7, 161.7, 152.3, 137.0. 136.3, 132.9, 131.2, 131.1, 129.5, 128.1, 1 19.2, 74.7, 71.3, 60.5, 53.5, 49.0, 48.4, 38.3, 36.7, 33.5, 31.8, 28.1, 24.7, 21.0, 14.0; MS (ESI+) for C27H3,Cl2N3O6S m/z
595.8 (M+H)*; MS (ESI-) for C27H3,Cl2N3O6S m/z 593.8 (M-H)'; HRMS (FAB) calcd for C27H31Cl2N3O6S+H, 596.1389, found 596.1362: Anal. Calcd for C27H3,Cl2N3O6S • 0.56 H2O: C, 53.46; H. 5.34; N, 6.93. Found: C, 53.73; H, 5.35; N, 6.73. % Water (KF): 1.67.
Example 83. N-[[(4S)-3-Acetyl-2.2-dimethyl- -thiazolidinyl]carbonyl]^l-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme B, B-6: where RB., and RB.2 are the same and equal to H, RB_3 and RB^, are the same and equal to CH3, Y is CO, R3 is methyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000103_0001
Example 83 was prepared as described in Scheme B from D-cysteine and acetone using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1745, 1682, 1662, 1628, 1610, 1579. 1561, 1541, 1515, 1431, 1412, 1326, 1270, 1240, 1211 cm' '; 'H NMR (CDC J δ 7.55 (3 H), 7.32 (3 H), 7.19 (1 H), 7.1 1 (1 H), 6.66 (1 H), 4.89 (1 H), 4.60 (1 H), 3.78 (3 H), 3.24 (4 H), 2.04 (3 H), 1.87 (3 H), 1.79 (3 H); 13C NMR (DMSO- d6) δ 171.6, 171.5, 169.9, 169.4, 167.9, 161.8, 137.1, 136.3. 132.8. 132.6, 131.1, 129.5, 128.1, 119.2, 72.6, 66.5, 53.7, 53.3, 52.0, 51.9, 35.8, 31.7, 29.0, 26.9, 24.7, 24.5; MS (ESI+) for C25H27Cl2N3O5S m/z 551.9 (M+H)+; HRMS (EI) calcd for C25H27Cl2N3O5S 551.1049, found 551.1053; MS (EI j m/z (rel. intensity) 551 (M+, 7), 351 (46), 349 (68), 278 (16), 186 (14 ), 175 (63), 173 (98), 158 (23), 1 16 (99). 100 (20), 99 (69).
Example 84.
N-[[(4S)-3-Acetyl-2,2-dimethyl-4-thiazolidinyl]carbonyl]-4-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine (Scheme B, B-7: where RB., and RB.2 are the same and equal to H, RB_3 and RB^, are the same and equal to CH3, Y is CO. R3 is methyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000103_0002
Example 84 was prepared from example 83 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3279, 1723, 1661, 1608, 1562, 1542, 1516, 1432, 1413. 1349. 1329. 1270, 1238, 1207, 1 195 cm'1; 'H NMR (DMSO-d6) δ 12.47 (1 H), 10.62 (1 H), 7.51 (5 H), 7.18 (2 H), 4.80 (1 H), 4.67 (1 H), 4.47 (1 H), 2.98 (3 H), 1.68 (9 H); 13C NMR (DMSO-d6) δ 184.2, 172.6, 171.9, 169.8, 169.2, 167.8, 136.9, 136.3. 133.1, 131.2, 131.0. 129.5, 128.1, 119.2, 72.6, 66.6, 53.7. 53.3, 36.2, 31.7, 29.0, 27.0, 24.8, 24.6, 21.0; MS (ESI+) for C24H25Cl2N3O5S m/z 538.0 (M+H)+; MS (ESI-) for C24H25Cl2N3O5S m/z 535.9 (M-H)'; HRMS (FAB) calcd for C24H25Cl2N3O5S+H, 538.0970, found 538.0961. Example 85.
[S-<R*,R*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2-dimethyl-γ-oxo-3- thiazolidinebutanoic acid (Scheme B, B-7: where RB., and RB_2 are the same and equal to H, RB.3 and RB^, are the same and equal to CH3, Y is CO, R3 is CH2CH2CO2H, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000104_0001
Example 85 was prepared as described in Scheme B from D-cysteine and acetone using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3264. 3125. 3071, 1724, 1658, 1607, 1562, 1537. 1517, 1432, 1414, 1326, 1241. 1195, 1181 cm'1; 'H NMR (DMSO-d6) δ 12.31 (1 H), 10.65 (1 H), 8.20 (1 H), 7.50 (5 H), 7.19 (2 H), 5.81 (1 H), 4.50 (1 H), 3.02 (3 H), 2.30 (3 H). 1.71 (6 H); 13C NMR (DMSO-d6) δ 174.1. 172.8. 169.4. 161.9, 137.1, 136.5. 133.2. 131.4, 131.3, 129.7, 128.3, 1 19.3. 73.1, 65.7. 53.5. 36.3, 32.0, 30.5, 29.1, 29.0. 27.1 ; MS (ESI+) for C26H27Cl2N3O7S m/z 595.9 (M+HV"; MS (ESI-) for C26H27Cl2N3O-S m/z 593.8 (M-H)'; Anal. Calcd for C,6H,-Cl2N3O7S • 0.51 H2O: C, 51.55; H, 4.66; N, 6.94. Found: C, 51.71 ; H, 4.85; N, 6.93. % Water (KF): 1.53.
Example 86. [S-(R*,R*)]^-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-2,2,5,5-tetramethyl-γ-oxo-3-thiazolidinebutanoic acid methyl ester (Scheme B, B-6: where RB.,, RB„2, RB_3 and R^ are the same and equal to CH3, Y is CO, R3 is CH2CH2CO2CH3. R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000105_0001
Example 86 was prepared as described in Scheme B from D-penicillamine and acetone using methyl succinyl chloride to form the requisite amide. Physical data as follows: IR (mull) 3287, 1741 , 1660. 1608, 1562, 1540, 1516, 1432, 1413, 1323, 1267, 1241, 1225,
1196, 1168 cm '; Η NMR (CDC13) δ 7.55 (2 H), 7.29 (3 H), 7.13 (2 H), 6.94 (1 H), 4.95 (1 H), 4.39 (1 H), 3.74 (3 H), 3.67 (3 H), 3.27 (1 H), 3.10 (1 H), 2.80 (1 H), 2.57 (3 H), 2.18 (1 H), 1.95 (3 H), 1.77 (3 H), 1.72 (3 H), 1.68 (3 H) 1.63 (3 H); ,3C NMR (CDC13) δ 173.3, 171.6, 170.3, 169.9, 162.4, 136.3, 132.5, 132.4, 131.0. 130.2, 129.8, 128.2, 120.8, 120.7, 120.5, 73.8, 53.1, 52.6, 51.8, 49.9, 40.0, 37.4, 33.9. 31.6, 31.4, 29.4, 29.1, 24.3; MS (ESI+) for C30H35C12N3O7S m/z 652.1 (M+H)T; Anal. Calcd for C30H35C12N3O7S • 0.31 H2O: C, 54.75; H, 5.45: N. 6.38. Found: C, 55.04; H. 5.50; N. 6.69. % Water (KF): 0.84.
Example 87. N-[[(4S)-3-Acetyl-2.2.5,5-tetramethyl-4-thiazolidinyl]carbonyl]-^-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Scheme B. B-6: where RB.,, RB.2, RB.3 and RBJ| are the same and equal to CH„ Y is CO, R3 is methyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S, S)).
Figure imgf000106_0001
Example 87 was prepared as described in Scheme B from D-penicillamine and acetone using acetyl chloride to form the requisite amide. Physical data as follows: IR (mull) 1741. 1692. 1676. 1629, 1606, 1563. 1538, 1516, 1431, 1410, 1352. 1320, 1276, 1251, 1223 cm"1; Η NMR (DMSO-d6) δ 10.70 (1 H), 8.57 (1 H), 7.56 (4 H). 7.22 (2 H), 4.63 (1 H), 4.49 (1 H), 3.65 (3 H), 3.30 (1 H), 3.12 (1 H), 2.84 (1 H), 1.92 (3 H), 1.82 (3 H), 1.78 (3 H), 1.51 (3 H), 0.80 (3 H); πC NMR (DMSO-d6) δ l84.2, 171.9. 168.9, 168.1, 161.8, 137.1, 136.3, 132.4, 131.3, 131.2, 131.0, 129.4, 128.1, 119.3, 75.9, 72.8, 53.5, 52.0, 49.2, 48.4, 36.0, 33.5, 31.9, 27.6, 24.9, 24.5; MS (ESI+) for C27H31Cl2N3O5S m/z 580.1 (M+H)+; MS (ESI-) for C27H3ICl2N3O5S m/z 577.9 (M-H)"; Anal. Calcd for C27H31Cl2N3O5S • 0.12 H2O: C, 55.66; H, 5.40; N, 7.21. Found: C, 55.68; H, 5.39; N, 7.16. % Water (KF): 0.36.
Example 88.
[R-(R*,S*)]-4-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2,2,5,5-tetramethyl-δ-oxo-3- thiazolidinepentanoic acid
(Scheme B. B-6: where RB.„ RB.2, RB.3 and RB^, are the same and equal to CH3, Y is CO, R3 is CH2CH2CH2CO2H, R5 is 4-[(2.6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000107_0001
Example 88 was prepared as described in Scheme B from D-penicillamine and acetone using methyl glutaryl chloride to form the requisite amide. Physical data as follows: Η NMR (DMSO-d6) δ 10.65 (1 H), 8.45 (1 H), 7.53 (5 H), 7.22 (2 H), 4.51 (1 H), 3.11 (3 H), 2.77 (1 H), 2.21 (4 H), 1.89 (3 H), 1.82 (3 H), 1.1 1 (2 H), 1.48 (3 H), 0.77 (3 H); 13C NMR (DMSO-d6) δ 184.2, 174.2, 173.1, 170.1, 168.7, 161.7, 137.0, 136.3. 133.1, 131.3, 131.1, 129.4, 128.1, 1 19.2, 74.9, 73.0, 53.8. 49.3, 36.1, 34.8, 33.5, 32.7, 31.9, 27.7, 24.5, 20.0; MS (ESI+) for C29H33Cl2N3O7S m/z 638.0 (M+H)+; MS (ESI-) for C29H33Cl2N3O7S m/z 635.9 (M-H)'; HRMS (FAB) calcd for C29H33Cl N3O7S+H, 638.1494, found 638.1481 ; Anal. Calcd for C29H33Cl2N3O7S • 0.75 H2O: C, 53.42; H, 5.33; N, 6.44. Found: C, 53.20; H, 5.26; N, 6.45.
Scheme C
Figure imgf000108_0001
Rink-amide-MBHA resin
Figure imgf000108_0002
Figure imgf000108_0003
Figure imgf000108_0004
Scheme C (continued)
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000109_0003
Where: R^.,, R^, and Rc_3 are defined independently as R,. R^ is defined as R2.
Scheme C describes a method for the preparation of examples of the formula C-10. Commercially available Rink Amide MBHA resin is deprotected under standard solid- phase peptide synthesis conditions (Atherton. E.; Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) to afford the amine of formula C-2. Acylation with a commercially available or readily prepared amino acid residue of general C-3 affords the resin bound derivative of formula C-4. Removal of the Fmoc group under standard conditions provides amine of general structure C-5 which is acylated with a commercially available or readily prepared thiazolidine-4-carboxylic acid of general formula C-6 to afford the resin bound intermediate C-7. Standard Fmoc deprotection affords the resin bound amine of general formula C-8 which may be reacted with a variety of electrophilic reagents as described in Scheme A to afford resin bound amides, ureas, sulfonamides and carbamates of general structure C-9. Preparation 18 details an example of the reaction of a mixed carbonate to afford a carbamate of general structure C-9 (where Y is equal to CO2). Standard acidolysis affords the amide of general structure C-10.
Preparation 18 and Example 89.
[S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-amino-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(4— morpholinyl)ethyl] ester (Scheme C, C-10: where R^.,, R^, R^-.-, and R^ are the same and equal to proton, R3 is 2- (4-morpholinyl)ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
To a mixture of Rink Amide MBHA resin (Scheme C, C-l) (Nova Biochem., 1.2 g, ca. 0.59 mmol) in methylene chloride (20 mL) was added a solution of piperidine in DMF (30%, 20 mL). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 min. The resin was filtered and washed with DMF. The resin was suspended in a solution of piperidine in DMF (30%, 40 ml) and mixed for 40 min. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to afford resin C-2, which was diluted with DMF (40 mL). To this mixture was added Fmoc-Tyr(2,6-Cl2-Bn) (Scheme C, C-3: where R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) (Advanced Chemtech, 1.32 g, 2.35 mmol), HOBt (0.36 g, 2.35 mmol), PyBOP (1.20 g, 2.35) and DIEA (1.03 mL, 5.90 mmol). The reaction was mixed for 4 h and the resin filtered and washed with DMF, methylene chloride, MeOH and methylene chloride to afford the intermediate resin-bound amino acid derivative C-4 (Scheme C, where R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) which was used without characterization.
To a mixture of resin C-4 described above in methylene chloride (20 mL) was added a solution of piperidine in DMF (30%, 20 mL). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 min. The resin was filtered and washed with DMF. The resin was suspended in a solution of piperidine in DMF (30%, 40 ml) and mixed for 40 min. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to afford the resin of structure C-5 (Scheme C, where R5 is 4-[(2,6-dichlorophenyl)methoxy]ρhenyl and stereochemistry is (S)) , which was diluted with DMF (40 mL). To this mixture was added Fmoc-D-thiazolidine-4- carboxylic acid (Scheme C, C-6: where R^..,, R,^, R^ and R,^ are the same and equal to proton and stereochemistry is (S)) (Advanced Chemtech, 832 mg, 2.35 mmol), HOBt (0.36 g, 2.35 mmol), PyBOP (1.20 g, 2.35) and DIEA (1.03 mL, 5.90 mmol). The reaction was mixed for 4 h and the resin filtered and washed with DMF, methylene chloride, MeOH and methylene chloride to afford the intermediate resin-bound derivative C-7 (Scheme C, where Re.,, Rc.2, R^ and R^are the same and equal to proton, R5 is 4- [(2, 6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) which was used without characterization.
To a mixture of resin C-7 described above in methylene chloride (20 mL) was added a solution of piperidine in DMF (30%, 20 mL). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 min. The resin was filtered and washed with DMF. The resin was suspended in a solution of piperidine in DMF (30%, 40 ml) and mixed for 40 min. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to provide the intermediate of structure C-8 (Scheme C, where R^.,, R^, Rc. and R^ are the same and equal to proton, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) , which was diluted with methylene chloride (10 mL). To this mixture was added a solution of the mixed carbonate prepared from 4-(2-hydroxyethyl)morpholine (2.14 mL, 17.7 mmol) and N,N- disuccinimidyl carbonate (4.53 g, 17.7 mmol) as described in preparation 8 in methylene chloride (20 mL) followed by triethylamine (0.33 mL, 2.36 mmol). The reaction was mixed for 24 h and the resin filtered and washed extensively with DMF, methylene chloride, MeOH, and anhydrous ethyl ether. The resin was dried in vacuo to afford the resin-bound carbamate C-9 (Scheme C, where R^.,, R^, Rc.j and R^ are the same and equal to proton, R3 is 2-(4-morpholinyl)ethyl, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
Resin C-9 was swelled with a minimum of methylene chloride (ca. 2 mL) and suspended with 95 % aqueous TFA (20 mL). The mixture was mixed by magnetic stirring for lh and filtered. The resin was washed with additional TFA (2 X 5 mL), followed by methylene chloride and methanol. The combined filtrates were evaporated in vacuo, and partioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography using methylene chloride/methanol (1 to 3%) as eluant to afford the title compound (215 mg) as an amorphous powder: IR (mull) 3288, 1676, 1657, 161 1, 1564, 151 1, 1439, 1424, 1346, 1302, 1237, 1179, 1116, 1021, 767 cm'1; 'H NMR (CDC13, 300 MHz) δ 7.24 (5 H), 6.93 (2 H), 5.20 (2 H), 4.63 (3 H), 4.34 (1 H), 4.22 (2 H), 3.63 (4 H), 3.11 (4 H), 2.50 (6 H); 13C NMR (CDC13, 75 MHz) δ 173.4, 170.1, 157.9, 154.5, 136.9, 132.0, 130.4, 129.1, 128.4, 115.1, 66.8, 65.2, 63.4, 57.1, 54.0, 53.7, 53.5, 49.4. 35.2; MS (EI ) m/z (rel. intensity) 610 (M+, 1), 323 (13), 321 (20), 161 (34), 159 (53), 1 14 (31), 1 13 (98), 100 (99), 88 (13), 70 (8), 56 (11); MS (FAB) m/z (rel. intensity) 611 (MH\ 71), 614 (18), 613 (49), 612 (27), 61 1 (71), 123 (60), 1 14 (99), 113 (76), 112 (19), 107 (22), 100 (28); HRMS (FAB) calcd for C27H32Cl2N4O6S +H, 61 1.1498, found 611.1494. Anal. Calcd for C27H32Cl2N4O6S: C, 53.03; H, 5.27; N, 9.16. Found: C, 52.74; H, 5.17; N, 9.01.
Example 90. [S-(R*,R*)]-4-[[[l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-amino-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester (Scheme C, C-10: where R^.,, R^, R^-, and R^ are the same and equal to proton, R3 is ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
Figure imgf000113_0001
Example 90 was prepared as described in Scheme C. Physical data as follows: IR (mull)
3369, 3308, 3192, 1713, 1667, 1650, 1629, 1539, 1513, 1441, 1344, 1290, 1240, 1016,
768 cm"'; 'H NMR (CDC13, 300 MHz) δ 7.33 (3 H), 7.16 (2 H), 6.95 (2 H), 5.25 (2 H),
4.48 (4 H), 4.20 (2 H), 3.03 (4 H), 1.26 (3 H); ,3C NMR (CDC13, 75 MHz) δ 173.6, 170.5,
157.8, 154.7, 136.8, 313.9, 130.4, 130.2, 129.0, 128.4, 114.9, 67.9, 65.1, 63.1, 62.5, 53.8,
36.5, 14.3; MS (El ) m/z (rel. intensity) 525 (M+, 1), 323 (44), 322 (13), 321 (68), 267 (9),
265 (14), 163 (12), 161 (65), 160 (35), 159 (99), 88 (30); MS (FAB) m/z (rel. intensity)
526 (MH+, 58), 528 (40), 527 (19), 526 (58), 321 (27), 188 (29), 161 (37), 160 (99), 159
(48), 107 (26), 88 (39); HRMS (FAB) calcd for C23H25Cl2N3O5S +H, 526.0970, found
526.0942. Anal. Calcd for C23H25Cl2N3O5S: C, 52.47; H, 4.79; N, 7.98. Found: C, 52.34;
H, 4.81; N, 7.90.
Scheme D
Figure imgf000114_0001
H2NOf-Bu D-2
Figure imgf000114_0002
Figure imgf000114_0003
Figure imgf000114_0004
Figure imgf000114_0005
Figure imgf000114_0006
RD.„ RD.2, and RD.3 are defined independently as R,. RD^ is defined as R2.
Scheme D describes a method for the preparation of examples of general formula D-9. Commercially available or readily prepared N-α-Fmoc protected amino acids of general structure D-1 are coupled with O(tert-butyl)hydroxylamine (D-2) under standard coupling conditions as previously referenced to afford the t-butyl hydroxamate of general structure D-3. Standard Fmoc deprotection affords the intermediate amine of formula D-4. Coupling of this amine with a commercially available or readily prepared N-α-Fmoc- thiazolidine-4-carboxylic acid of general structure D-5 affords the pseudodipeptide intermediate of general structure D-6. Standard Fmoc deprotection affords the intermediate amine of general structure D-7 which may be reacted under the variety of conditions described in Scheme A to afford amides, carbamates, sulfonamides and ureas of general structure D-8. Preparation 22 provides a specific example of the reaction of an amine of general structure D-7 with a carbonate to afford a carbamate of general structure D-8. Mild acidolysis affords the hydroxamate of general structure D-9. Preparation 19.
(Scheme D, D-3: where R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S)).
Figure imgf000115_0001
To a cooled (0-5 °C) solution of Fmoc-Tyr(2,6-Cl2-Bn) (Scheme D, D-1 : where R5 is 4- [(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) (Advanced Chemtech, 6.0 g, 10.7 mmol), HOBt (1.63 g, 10.7 mmol), 0-(tert-butyl)hydroxylamine hydrochloride (Scheme D, D-2) (1.61 g, 12.80 mmol) in methylene chloride (30 mL) was added PyBOP (6.66 g, 12.80 mmol) followed by DIEA (6.51 mL, 37.35 mmol). The mixture was stirred at 0-5 °C for 1 hour, gradually allowed to warm to room temperature and stirred an additional 2 h. The mixture was diluted with methylene chloride and 0.25 N HCl, the organic layer separated and washed with saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography using methylene chloride/methanol (0-2.5%>) as eluant to afford the title compound (5.87 g) as an amorphous powder: 'H NMR (CDC13, 300 MHz) δ 8.08 (1 H), 7.76 (2 H), 7.54 (2 H), 7.29 (9 H), 6.95 (2 H), 5.43 (1 H), 5.30 (2 H), 4.28 (4 H), 3.06 (2 H), 1.19 (9 H); '3C NMR (CDC13, 75 MHz) δ 169.7, 157.8, 156.3, 143.6. 141.2, 136.8, 132.0, 130.4, 128.9, 128.4, 127.7, 127.0, 125.0, 119.9, 1 15.0, 82.3, 67.1, 65.1, 54.0, 46.9, 37.6, 26.0; MS (ESI+) for C35H34Cl2N2O5 m/z 632.9 (M+H)÷. MS (ESI+) for C35H34Cl2N2O5 m/z 654.9 (M+Na)+.
Preparation 20. (Scheme D. D-6: where RD.„ RD.2, RD.3 and RD^, are the same and equal to proton. R5 is 4- [(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000116_0001
To a solution of D-3 (Scheme D, where R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) (5.87 g, 9.28 mmol) in anhydrous DMF (94 mL) was added diethylamine (9.40 mL. 90.84 mmol) at ambient temperature. The solution was stirred for 90 min and volatiles were removed in vacuo to afford the intermediate amine D-4 (Scheme D, where R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) as an oil which was used without further purification.
To a cooled (0-5 °C) solution of Fmoc-D-thiazolidine-4-carboxylic acid (Scheme D, D-5: where RD.,, RD.2, RD_3 and RD^, are the same and equal to proton and stereochemistry is (S)) (Advanced Chemtech. 3.93 g, 11.10 mmol) and HO At (1.51 g, 11.10 mmol) in methylene chloride/DMF (4:1. 30 mL) was added EDC (2.12 g, 11.10 mmol). The reaction mixture was allowed to stir for 15 min and a solution of the amine (D-4 described above) in methylene chloride/DMF (4:1. 30 mL) was added followed by DIEA (1.61 mL, 9.28 mmol). After 1 h at 0-5 °C, an additional equivalent of DIEA (1.61 mL, 9.28 mmol) was added and the mixture allowed to warm to room temperature. After stirring overnight, volatiles were removed in vacuo and the residue partitioned between ethyl acetate and 0.25 N aqueous HCl. The organic layer was separated and washed with water, saturated aqueous NaHCO3, brine, dried (Na-,SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography using CH2Cl2/acetone (3%>) containing isopropanol (0.1 %) as eluant to afford the title compound (2.4 g) as an amorphous solid: Η NMR (300 MHz, CDC13) δ 7.77 (2 H), 7.55 (2 H), 7.32 (7 H), 7.12 (2 H), 6.92 (2 H), 6.70 (1 H), 5.19 (3 H), 4.55 (5 H), 4.26 (2 H), 3.30 (1 H), 3.11 (3 H), 1.14 (9 H); l3C NMR (75 MHz, CDC13) δ 170.0, 168.8, 158.0, 143.4, 141.3, 137.0, 132.1, 130.4, 128.5, 127.9. 127.2, 124.9, 120.1, 115.3, 82.5, 68.4, 65.3, 52.8, 47.1, 36.5, 26.2. MS (ESI+) for C39H39Cl2N3O6S m/z 747.9 (M+H)+; MS (ESI+) for C39H39Cl2N3O6S m/z 769.8 (M+Na)+; MS (ESI-) for C39H39Cl2N3O6S m/z 745.7 (M-H)".
Preparation 21. (Scheme D, D-7: where RD_,, RD_2, RD-3 and R,^, are the same and equal to proton, R5 is 4- [(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)).
Figure imgf000117_0001
To a solution of D-6 (Scheme D, where RD.,, RD.2, RD.3 and RDA are the same and equal to proton, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S)) (500 mg, 0.67 mmol) in anhydrous DMF (7 mL) was added diethylamine (0.70 mL, 6.55 mmol) at ambient temperature. The solution was stirred for 90 min and volatiles were removed in vacuo. The residue was washed with ethyl ether/hexane (3:2) to afford the title compound (352 mg) as an amorphous solid which was used without further purification: Η NMR (300 MHz, DMSO-d<5) δ 10.61 (1 H), 8.27 (1 H), 7.54 (2 H), 7.44 (1 H), 7.15 (2 H), 6.94 (2 H), 5.15 (2 H), 4.50 (1 H), 4.03 (2 H), 3.75 (1 H). 3.19 (1 H), 2.82 (3 H), 2.57 (1 H), 1.06 (9 H); MS (ESI+) for C24H29Cl2N3O4S m/z 526.1 (M+H)+; MS (ESI-) for C24H29Cl2N3O4S m/z 524.1 (M-H)'.
Preparation 22. (Scheme D, D-8: where RD.„ RD.2, RD.3 and RD.4 are the same and equal to proton, R3 is 2- (4-morpholinyl)ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
Figure imgf000118_0001
To a solution of 4-(2-hydroxyethyl)morpholine ( 1.22 mL, 10.05 mmol) in CH3CN
(55 mL) at ambient temperature was added N,N-disuccinimidyl carbonate (2.49 g, 10.05 mmol) and triethylamine (4.20 mL, 30.15 mmol). The solution was stirred at room temperature for 4 h and concentrated in vacuo to give a viscous oil. The oil was dissolved in a minimal amount of methylene chloride (15 mL) and added to a solution of D-7 (Scheme D, where RD_,, RD.2, RD_3 and RD.4 are the same and equal to proton, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (S, S) (350 mg, 0.67 mmol), triethylamine (0.10 m, 0.74 mmol) and DMAP (1 mg) in CH2C12 (4 mL). The reaction mixture was stirred overnight and diluted with CH2C12 (15 mL). Propylamine (8.6 mL, 100.5 mmol) was slowly added (exothermic) and the solution stirred vigorously for 15 min, then diluted with water. The organic layer was separated and washed with 0.1 M HCl, saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate/acetone (3:1) as eluant afforded the title compound (251 mg) as an white powder: IR (mull) 3264, 1709, 1661, 1564, 1531, 1512, 1439, 1419, 1345, 1301, 1241, 1181, 1118, 1016, 767 cm'1; 'H NMR (300 MHz, CDC13) δ 8.48 (1 H), 7.36 (2 H), 7.24 (1 H), 7.17 (2 H), 6.96 (2H), 5.23 (2 H), 4.60 (3 H), 4.31 (3 H), 3.71 (4 H), 3.33 (4 H ), 2.59 (6 H), 1.15 (9 H); 13C NMR (75 MHz, CDC13) δ 168.9, 158.0, 137.0, 132.1, 130.5, 128.7, 128.5, 115.3, 82.5, 66.8, 65.3, 63.4, 57.2, 53.7, 52.9, 36.4, 30.6, 29.3, 26.2, 19.1, 13.7; MS (ESI+) for C31H40C12N4O7S m/z 682.9 (M+Hf. MS (ESI+) for C3,H40C12N4O7S m/z 705.0 (M+Na)+; Anal. Calcd for C31H40C12N4O7S • 0.35 H2O: C, 53.97; H, 5.95; N, 7.95. Found: C. 54.22; H, 6.11; N, 7.95. % Water (KF): 0.91.
Preparation 23 and Example 91. (Scheme D, D-9: where RD_,, RD.2, RD.3 and RD.4 are the same and equal to proton, R3 is 2- (4-morpholinyl)ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
Figure imgf000119_0001
Hydroxamate D-8 (Scheme D, where RD.,, RD.2, RD.3 and RD.4 are the same and equal to proton, R3 is 2-(4-morpholinyl)ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, 5)) (150 mg, 0.22 mmol) was dissolved in anhydrous TFA (12 mL) at ambient temperature and gradually warmed to 40 °C. After 5 h at 40 °C, volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/methanol (5%) as eluant afforded the title compound (51 mg) as an amorphous solid: IR (mull) 3273, 3229, 1708, 1652, 1564, 1546, 1511, 1439, 1422, 1346, 1236, 1180, 1114, 1022, 768 cm "'; 'H NMR (300 MHz, DMSO- dtf) δ 10.70 (1 H), 8.93 (1 H), 8.32 (1 H), 7.54 (2 H), 7.45 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.56 (2 H), 4.36 (1 H), 4.25 (1 H), 4.06 (2 H), 3.51 (4 H), 3.15 (1 H), 2.76 (3 H), 2.36 (4 H); 13C NMR (75 MHz, DMSO-dtf) δ 169.8, 167.9, 157.6, 136.5, 132.2, 132.0, 130.8, 130.5, 129.2, 114.7, 66.7, 65.3, 63.3, 59.1, 57.1, 53.8, 52.1, 37.8, 31.3, 30.1; MS (ESI+) for C27H32Cl2N4O7S m/z 627.0 (M+H)+; MS (ESI-) for C27H32Cl2N4O7S m/z 624.9 (M-H)'; Anal. Calcd for C27H32Cl2N4O7S • 0.46 H2O: C, 51.00; H, 5.22; N, 8.81. Found: C, 51.34; H, 5.23; N, 8.67. % Water (KF): 1.31.
Example 92. (Scheme D, D-9: where RD_,, RD.2, RD.3 and R^ are the same and equal to proton, R3 is ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S).
Figure imgf000120_0001
Example 92 was prepared as described in Scheme D from Fmoc-Tyr(2,6-Cl2-Bn) using ethyl chloroformate to provide the requisite carbamate. Physical properties as follows: IR (mull) 3278, 1654, 1612, 1585, 1564, 1547, 1511, 1439, 1347, 1237, 1195, 1179, 1022, 782, 769 cm"'; Η NMR (300 MHz , CDC13) δ 7.39 (3 H), 7.17 (2 H), 6.94 (2 H), 5.24 (2 H), 4.53 (4 H), 4.18 (2 H), 3.15 (2 H), 2.87 (2 H), 1.28 (3 H); 13C NMR (75 MHz , CD3OD) δ 172.7, 170.1, 159.4, 156.2, 138.1, 133.7, 132.1, 131.6, 130.8, 129.8, 115.9, 66.3. 64.4, 63.6, 38.6, 36.8, 35.1, 15.0; HRMS (FAB) calcd for C23H25CL2N3O6S +H, 542.0919, found 542.0921; Anal. Calcd for C23H25Cl2N3O6S: C, 50.93; H, 4.64; N, 7.75. Found: C, 50.79; H, 4.79; N, 7.52.
Example 93. (Scheme D, D-9: where RD.,, RD.2, RD_3 and RD.4 are the same and equal to proton, R3 is 2- (l-piperidinyl)ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, Y is CO2 and stereochemistry is (S, S)).
Figure imgf000120_0002
Example 93 was prepared as described in Scheme D from Fmoc-Tyr(2,6-Cl2-Bn) using 1- (2-hydroxyethyl)piperidine to provide the requisite carbamate. Physical properties as follows: IR (mull) 3276, 1707, 1653, 1611, 1584, 1564, 1511, 1439, 1237, 1195, 1179, 1 144, 11 13, 1093, 1021 cm ''; Η NMR (300 MHz, DMSO-dtf) δ 7.54 (2 H), 7.44 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.58 (2 H), 4.36 (1 H), 4.25 (1 H), 4.00 (3 H), 2.76 (3 H), 2.31 (3 H), 1.62 (1 H), 1.42 (3 H), 1.26 (8 H); 13C NMR (75 MHz, DMSO-d6) δ 172.2, 168.9, 167.3, 157.0, 135.9, 131.7, 131.4, 130.2, 129.9, 128.7, 114.1, 64.7, 63.0, 54.0, 51.6, 36.2, 30.9, 25.5, 24.7, 23.8, 22.0, 21.5, 13.9; MS (ESI+) for C28H34Cl2N4O6S m/z 624.9 (M+H)+.
Scheme E
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Figure imgf000122_0004
Scheme E (continued)
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000123_0003
Preparation 24.
(Scheme E, E-2 where stereochemistry is (S)). - (2-Methoxy-2-oxoethylidene)-l- (phenylmethyl)-L-Proline 1,1-dimethylethyl ester
Figure imgf000123_0004
o a stirring solution of E-1 (Scheme E where stereochemistry is (S)) (3.62g, 12.4mmol), prepared by the method of Rapoport (J. Am. Chem. Soc. 1984, 106, 4539), in CH3CN (lOmL) was added methyl bromoacetate (1.4mL, 14.9mmol). After stirring for 70h, CH2CI2 (70mL) was added. The solution stirred for 10 minutes before PI13P (4.89g, 18.6mmol) was added, and after 2 minutes Et3N (5.2mL, 37.3mmol) was added. After stirring for 20h, the solution was washed with 1M NaH2PO4 (lOOmL), and the aqueous phase was extracted with CH2CI2 (50mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The resulting yellow oil/white solid was dissolved in CHCI3 and chromatographed on silica gel (300g, 230-400 mesh, 70mm OD column, packed CHCI3, eluted with CHCI3, 3L, then 10:90 EtOAc-CHCl3, 250mL fractions) using the flash technique. Fractions 19-23 provided the title compound (3.23g) as a pale yellow oil. iH-NMR: (300MHZ, CDCI3): δ = 7.17-7.36
(5 H), 4.75 (1 H), 4.54 (1 H), 4.20 (1 H), 3.96 (1 H), 3.61 (3 H), 3.36-3.47 (1 H), 3.08
(1 H), 2.04-2.28 (2 H), 1.41 (9 H); EI/MS (70eV) m/z (rel. intensity): 331 (M+, 17.3), 275 (11.9), 230 (95.0), 170 (26.0), 91 (base); IR (neat): 2979, 2948, 1735, 1692, 1600,
1454, 1435, 1414, 1369, 1299, 1277, 1184, 1137, 1059, 964, 843, and 789cm"1 ; HRMS: Calcd. for C19H25N1O4: 331.1783. Found: 331.1771; [α]D 25: +107° ( c = 0.939,
CH2CI2).
Preparation 25.
(Scheme E, E-3 where stereochemistry is (2R,5S)).
(2R-cis)-5-[ (l,l-dimethylethoxy)carbonyl]-l- (phenylmethyl)-2-pyrrolidineacetic acid methyl ester ( (2R,5S))
Raney-Nickel (20g of a 50%> slurry in H2O) was washed with abs. EtOH (3x25mL) and suspended in abs. EtOH (50mL), and a solution of E-2 (Scheme E, where stereochemistry is (S)) (9.34g, 28.2mmol) in abs. EtOH (50mL) was added. After stirring for 3h, the Ra-Ni was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in EtO Ac (lOOmL), 5% Pt/C (3. Og) was added, and the mixture was hydrogenated under 50 psi H2 for 12 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (300g, 230-400 mesh, 70mm OD column, packed and eluted with 15:85 EtOAc-hexanes, 270mL fractions) using the flash technique. Fractions 5-8 provided the title compound (6.55g) as a clear, colorless oil. ^-NMR: (300MHz, CDCI3): δ = 7.22-7.34 (5 H), 3.86 (1 H), 3.79 (1 H), 3.62 (3 H), 3.21-3.29 (2 H), 2.57 (1 H), 2.33 (1 H), 1.64-2.05 (4 H), 1.37 (9 H); EI/MS (70eV) m/z (rel. intensity): 232 (base), 91 (39.8); IR (nujol): 2977, 1739, 1454, 1437, 1367, 1295, 1251, 1197, 1 153, 1074, 844, 753, and
699cm-1 ; Anal: Calcd. for C19H27N1O4: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.39; H, 8.15; N, 4.11; [α]D 25: -22° (c = 1.051, CH2CI2).
Preparation 26. (Scheme E, E-4 where stereochemistry is (2R,5S)).
(2R-cis)-5-[ (l,l-dimethylethoxy)carbonyl]-l- (phenylmethyl)-2-pyrrolidineacetic acid ( (2R,5S))
Figure imgf000125_0001
To a stirring solution of E-3 (Scheme E, where stereochemistry is (2R,5S)) (2.00g, ό.OOmmol) in MeOH (60mL) was added 1M. K2CO3 (20mL). After stirring for 12h, the reaction mixture was evaporated in vacuo, the residue was dissolved in H2O (0.1L), the pH was adjusted to ca. 6 with 1M HCl, and the mixture was extracted with CHCI3 (2X0. IL). The combined extracts were washed with H2O, brine, dried (Na2SO4), and evaporated in vacuo to afford the title compound (1.89g) as a white solid. MP: 95-96°C (lit. 98-lθrC); !H-NMR: (300MHz, CDCI3): δ = 7.30-7.37 (5 H), 4.00 (1 H), 3.68 (1 H), 3.45 (1 H), 3.20 (1 H), 2.59 (1 H), 2.46 (1 H), 1.76-2.21 (4 H), 1.31 (9 H); EI/MS (70eV) m/z (rel. intensity) :218 (base), 91 (86.7); IR (nujol): 1719, 1497, 1451, 1367, 1296, 1285,
1260, 1160, 1153, 1079, 965, and 757cm-1 ; Anal: Calcd. for CisH25Nιθ4:C, 67.69; H, 7.89; N, 4.39. Found: C, 67.55; H, 7.97; N, 4.15; [α]D 25: +27° ( c = 0.795, CH2CI2).
Preparation 27. (Scheme E, E-6 where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry of the pyrrolidine ring is (2R,5S) and the amino acid is (S)).
(5R)-5-[2-[[ (lS)-l-Methoxycarbonyl-2-[4-[ (2,6- dichlorophenyI)methoxy]phenyI]ethyl]amino]-2-oxoethyI]-l- (phenylmethyl)-L- proline 1,1-dimethylethyl ester ( (IS, 5R, L))
Figure imgf000126_0001
To a stirring solution of E-4 (Scheme E, where stereochemistry is (2R,5S)) (0.48g, 1.50mm01) in CH2CI2 (lOmL) was added 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.29g, 1.50mmol), 1 -hydroxybenzotriazole hydrate (0.20g, 1.50mmol), 4-dimethylaminopyridine (0.05g, 0.45mmol), and 2,6- dichlorobenzyl-L -tyrosine methyl ester hydrochloride (Scheme E, E-5: where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (S)) (0.59g, 1.50mmol) to give a heterogeneous mixture. Upon addition of triethylamine (0.3mL) the reaction mixture became homogeneous and stirred for 12h. The reaction mixture was partitioned between CH2O2 (50mL) and IN HCl (50mL). The organic phase was washed with sat'd aq. NaHCO3, H2O, brine, dried (Na2SO4), filtered and evaporated in vacuo . The resulting yellow oil was chromatographed on silica gel (150g, 230-400 mesh, 70mm OD column, packed and eluted acetone/CH2Cl2 5:95, 40mL fractions). Fractions 36-48 furnished the title compound (0.90g) as a glass. !H-NMR: (300MHz, CDCI3): δ = 9.09 (1 H), 7.38 (2 H), 7.10-7.30 (8 H), 6.97 (2 H), 5.22 (2 H), 4.75 (1 H), 3.81 (1 H), 3.68 (3 H), 3.60 (1 H), 3.15-3.35 (3 H), 3.04 (1 H), 2.42 (1 H), 2.21 (1 H), 1.86-2.07 (4 H), 1.37 (9 H); FAB/MS m/z (rel. intensity): 655 (M+H, 46.4), 599 (11.3), 553 (23.6), 260 (18.8), 204 (91.4), 91 (base); IR (nujol):3262, 3001, 1733, 1665, 1612, 1585, 1565, 1512, 1439, 1392,
1240, 1226, 1197, 1177, 1 153. 1018, and 768 cm"1 ; Anal: Calcd. for C35H40N2O6CI2: C, 64.12; H, 6.15; N, 4.27; Cl, 10.82. Found: C, 63.75 H, 6.29; N, 4.11; Cl, 10.88; [α]D 25: +6° ( c = 0.863, CHCI3).
Preparation 28. (Scheme E, E-7 where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry of the pyrrolidine ring is (2R,5S) and the amino acid is (S)).
(5R)-5-[2-[[ (lS)-l-Carboxy-2-[4-[ (2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]-2-oxoethyl]-l- (phenylmethyl)-L- proline 1,1-dimethylethyl ester ( (IS, 5R, L))
Figure imgf000127_0001
To a stirring solution of E-6 (Scheme E, where R5 is 4-[ (2,6-dichlorophenyl)methoxy]- phenyl, and stereochemistry of the pyrrolidine ring is (2R,5S) and the amino acid is (S)) (l.OOg, 1.53mmol) in MeOH (50mL) was added 1M K2CO3 (lOmL). After stirring for 12h, the reaction mixture was evaporated in vacuo, the residue was dissolved in H2O (0.1L), the pH was adjusted to ca. 6 with 1M HCl, and the mixture was extracted with CHCI3 (2X0. IL). The combined extracts were washed with H2O, brine, dried (Na2SO4), and evaporated in vacuo to afford the title compound (0.85g) as a white solid.
MP: 80-83°C; ^-NMR: (300MHz, CDCI3): δ = 9.87 (1 H), 7.35 (2 H), 7.21-7.26 (7 H), 7.13 (2 H), 6.94 (2 H), 5.22 (2 H), 4.64 (1 H), 3.80 (1 H), 3.55 (1 H), 3.29-3.37 (3 H), 3.04 (1 H), 2.48 (1 H), 2.26 (1 H), 1.94 (1 H), 1.76 (1 H), 1.59 (1 H), 1.41 (1 H), 1.34 (9 H); FAB/MS m/z (rel. intensity): 641 (M+H, 45.8), 585 (13.0), 260 (6.1), 204 (base), 91 (96.8); IR (nujol): 1732, 1642, 1612, 1585, 1565, 1534, 151 1, 1439, 1240, 1230, 1196,
1178, 1153, 1018, 779, and 767cm'1 ; HRMS: Calcd. for C34H38Cl2N2O6: 641.2185. Found. 641.2164; [α]D 25: +5° ( c = 0.795, CHCI3).
Preparation 29 and Example 94.
(Scheme E, E-8 where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry of the pyrrolidine ring is (2R,5S) and the amino acid is (S)).
(5R)-5-[2-[[ (lS)-l-Carboxy-2-[4-[ (2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]-2-oxoethyl]-l- (phenylmethyl)-L- proline ( (IS, 5R, L))
Figure imgf000128_0001
To a solution of E-7 (Scheme E, where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry of the pyrrolidine ring is (2R,5S) and the amino acid is (S)) (0.85g, 1.32mmol) in H2θ/n-PrOH (1 : 1, 0.1L) was added HO Ac (6mL), and the solution refluxed for 5h, then stirred at RT for 12h. Evaporation in vacuo afforded the title compound (0.78g) as a white solid. MP: 198-202°C; !H-NMR: (300MHz, DMSO): δ =8.56 (1 H), 7.56-7.59 (2 H), 7.45-7.50 (1 H), 7.25-7.29 (5 H), 7.21 (2 H), 6.96 (2 H), 5.18 (2 H), 4.41 (1 H), 3.89 (1 H), 3.74 (1 H), 3.31 (1 H), 3.03-3.09 (2 H), 2.85 (1 H), 2.18-2.34 (2 H), 1.88-2.00 (1 H), 1.63-1.84 (2 H), 1.44-1.58 (1 H); FAB/MS m/z (rel. intensity): 585 (M+H, 21.6), 539 (2.1), 246 (14.5), 204 (60.9), 159 (12.6), 91 (base); IR (nujol): 3309, 3083, 3037, 3014, 1662, 1644, 1562, 1514, 1440, 1377, 1348, 1241, 1197, 1178, 1018,
998, 815, and 771cm1 ; Anal: Calcd. for C30H30N2O6C12O.38H2O: C, 60.83; H, 5.24; N, 4.73. Found: C, 60.83; H, 5.33; N, 4.69; Karl Fischer water: 0.42%.
Example 95.
(Scheme E, E-8 where R5 is 4-[ (2,6-dichlorophenyl)methoxy]phenyl, and stereochemistry of the pyrrolidine ring is (2S,5R) and the amino acid is (S)).
(5S)-5-[2-[[ (lS)-l-Carboxy-2-[4-[ (2,6-dichIorophenyl)methoxy]phenyl]ethyl]amino]- 2-oxoethyl]-l- (phenylmethyl)-D-proline ( (IS, 5S, D))
Figure imgf000129_0001
Example 95 was prepared as described in Scheme E from E-1 (Scheme E where stereochemistry is (R) prepared by the method of Rapoport (J. Am. Chem. Soc. 1984, 106,
4539). Physical data as follows: 198-204°C; H-NMR: (300MHz, DMSO): δ = 8.60 (1 H), 7.54-7.68 (3 H), 7.26-7.41 (8 H), 7.05 (2 H), 5.27 (2 H), 4.57 (1 H), 3.96 (1 H), 3.82 (1 H), 3.40 (1 H), 3.14 (2 H), 2.86-2.94 (1 H), 2.27-2.47 (2 H), 1.96-2.10 (1 H), 1.72-1.88 (1 H), 1.55-1.72 (1 H), 1.30-1.42 (1 H); FAB/MS m/z (rel. intensity): 585 (M+H, 50.5), 539 (4.5), 332 (32.1), 331 (18.1), 246 (6.2), 244 (6.0), 204 (77.2), 91 (base); IR (nujol): 3211, 3033, 3006, 1724, 1647, 1610, 1565, 1512, 1438, 1354, 1301, 1273, 1240, 1196, 1018, 871, and 767cm'1; Anal: Calcd. for C30H30N2O6CI20.43H2O:C, 60.77; H, 5.24; N, 4.72. Found: C, 60.76; H, 5.37; N, 4.59; Karl Fischer water analysis: 1.71%.
Scheme F
Figure imgf000130_0001
Figure imgf000130_0002
Where RF.3 is defined as proton or C,.6 alkyl. Scheme F describes a general method for the preparation of examples of the formula F-4, F-5, F-6, F-7, and F-8. A commercially available or readily prepared sulfur containing amino acid of structure F-1 is condensed with amino acid derivative F-2 under standard peptide synthesis conditions as described in Scheme A. Deprotection of the carbamate from F-3 provides the useful intermediate F-4. The amine group may be reacted with a variety of electrophilic reagents as described in Scheme A to provide esters of general structure F-5. Mild base hydrolysis provides acids of structure F-6. Mild hydrolysis of esters of general structure F-3 provides acid of formula F-7. In those cases in which RF.3 is equal to t-butyl, mild acidolysis of compounds of general structure F-3 afford the amino acid of general structure F-8.
Preparation 30 and Example 96. (Scheme F, F-3: where RF., and RF.2 are the same and equal to proton, RF.3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S))
Figure imgf000131_0001
To a cooled (0 °C) solution of Boc-L-thiomorpholine-3-carboxylic acid ((a) Van Der Auwera, C; Anteunis, M.J.O. Int. J. Peptide Protein Res. 1987, 29, 574: (b) Kogami, Y.; Okawa, K. Bull. Chem. Soc. Jpn. 1987, 60, 2963: (c) Larsson U.; Carlson R. ACT A Chemica. Scand. 1994, 48, 517: (d) Carson J.F.; Wong F.F. J. Org. Chem. 1964, 29, 2203.) (Scheme F, F-1: where RF_, and RF.2 are the same and equal to proton and stereochemistry is (R)) (6.7 g, 27 mmol) in CH2C12 (100 mL) was added HOBt (4.0 g, 29.7 mmol), DMAP (700 mg), EDC (5.7 g, 29.7 mmol) and triethylamine (13.5 mL, 97 mmol). The reaction mixture was stirred for 10 min, then the amino acid derivative F-2 (Scheme F, where R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, RF.3 is CH3, and stereochemistry is (S)) (10.0 g, 24.7 mmol) was added. After 20 h, volatiles were removed in vacuo and the residue partitioned between 2.5% aqueous HCl (100 mL) and H2O (100 mL). The organic layer was separated and washed saturated aqueous NaHCO3 (100 mL), dried and concentrated in vacuo. Purification of the residue by chromatography on SiO2 (500 g) using CH2C12 /ethyl acetate (10%>) as eluent afforded the title compound (12.31 g) as a solid: "H NMR (CDC13) δ 1.44 (9 H), 2.35 (1 H), 2.70 (3 H), 3.13 (2 H), 3.33 (1 H), 3.77 (3 H), 4.22 (1 H), 5.00 (1 H), 6.48 ( 1 H), 7.18 (2 H), 7.31 (3 H), 7.44 (1 H), 7.56 (2 H); 13C NMR (CDCl3) δ 171.6, 168.9, 162.5, 136.5, 135.9, 132.4, 131.0, 130.2, 128.2, 120.5, 81.7, 77.3, 53.3, 52.6, 37.0, 28.2, 26.5; IR (mull) 3296, 2924, 1744, 1685, 1668, 1605, 1536, 1515, 1432, 1412, 1321, 1294, 1260, 1244, 1213, 1195, 1161, 798 cm'1; MS (FAB) m/z (rel. intensity) 598 (M+H, 3), 596 (M+H, 5). Anal. Calcd for C27H31Cl2N3O6S : C, 54.36; H, 5.24; N, 7.04. Found: C, 54.23; H, 5.24; N, 6.86. Corrected for 0.60% H2O, found by Karl Fischer analysis.
Preparation 31 and Example 97. (Scheme F, F-4: where RF_, and RF.2 are the same and equal to proton, RF.3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S))
Figure imgf000132_0001
Acetyl chloride (1.75 mL, 24 mmol) was slowly added to MeOH (26 mL) at 0-5 °C. After 15 min, a solution of the carbamate F-3 (Scheme F, where RF., and RF.2 are the same and equal to proton, RF„3 is CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)) (2.4 g, 4.0 mmol) in methanol (8 mL) was added. After 50.5 h at 0 °C, the solvent was removed in vacuo to yield the title compound (2.11 g): 'H NMR (300 MHz, DMSO-dtf) δ 2.68 (1 H), 3.00 (6 H), 3.47 (1 H), 3.64 (3 H), 4.02 (1 H), 4,52 (1 H), 7.28 (2 H), 7.54 (5 H), 9.15 (1 H), 9.3 (1 H), 9.70 (1 H), 10.7 (1 H); IR (mull) 3191, 3031, 1742, 1664, 1604, 1577, 1561, 1540, 1516, 1432, 1414, 1326, 1271, 1210, 799 cm' '; MS (EI) m/z (rel. intensity) 495 (M+, 1). Preparation 32 and Example 98. (Scheme F, F-5: where RF_, and RF.2 are the same and equal to proton, RF.3 is CH3, R3 is CH2CH2CO2CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]ρhenyl, Y is CO-, and stereochemistry is (R, S)).
Figure imgf000133_0001
To a solution of amine F-4 (Scheme F, where RF„, and RF_2 are the same and equal to proton, RF„3 is CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)) (650 mg, 1.2 mmol) was added mo/?ø-methyl succinate (320 mg, 2.4 mmol), EDC
(460 mg, 2.4 mmol), pyridine (10 mL) and DMAP at ambient temperature. After 27 h, the mixture was diluted with 25 mL of saturated NaHCO3 was extracted with methylene chloride. The combined organic extracts were dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/ethyl acetate (3:2) as eluant followed by lyophilization afforded the title compound (600 mg) as an amorphous solid: IR (mull) 1742, 1659, 1657, 1608, 1537, 1516. 1432, 1414, 1324, 1269, 1259, 1228, 1214, 1195, 1176 cm"1; 'H NMR (300 MHz, CDC13) δ 2.63 (7 H), 3.21 (3 H), 3.68 (3 H), 3.78 (3 H), 3.90 (1 H), 4.80 (2 H), 5.50 (1 H), 6.56 (1 H), 7.29 (5 H), 7.57 (2 H); 1 C NMR (75 MHz, CDC13) δ 173.9, 172.0, 171.7, 168.5, 162.7, 136.1, 135.9, 133.3, 132.3, 131.0, 130.1, 128.2, 121.0, 120.7, 53.1, 52.5, 52.3, 52.0, 44.4, 36.7, 29.4,
27.7, 26.9, 26.4; MS (EI) m/z (rel. intensity) 609 (M+, 5). Anal. Calcd for C27H29Cl2N3O7S : C, 53.12; H, 4.79; N, 6.88. Found: C, 53.04; H, 4.81; N, 6.83. Corrected for 0.74% H2O found by Karl Fischer analysis.
Preparation 33 and Example 99. [R-(R*,S*)]- 3-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]~-γ-oxo— 4-thiomorpholinebutanoic acid (Scheme F, F-6: where RF_, and RF.2 are the same and equal to proton, RF.3 is proton, R3 is CH2CH2CO2H, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is (R, S)).
Figure imgf000134_0001
To a solution of the diester F-5 (Scheme F, where RF., and RF.2 are the same and equal to proton, RF.3 is CH3, R3 is CH2CH2CO2CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is (R, S)) (490 mg, 0.80 mmol) in THF (20 mL) and MeOH (6 mL) was added a solution of LiOH»H2O (178 mg, 4.25 mmol) in H2O (6 mL). After 22 h, the mixture was concentrated in vacuo. The residue was partially dissolved in 10% HCl (20 mL) and the resulting solid collected by filtration. The solid was washed with water and lyophilized from aqueous acetonitrile to afford the title compound (400 mg) as an amoφhous solid: IR (mull) 3267, 3193, 3058, 3034, 2924, 1725, 1658, 1607, 1562, 1537, 1516, 1432, 1414, 1326, 1195, 1178, 800 cm"1; 'H NMR (300 MHz, DMSO-d^) δ 2.62 (7 H), 3.17 (3 H), 3.95 (1 H), 4.57 (2 H), 5.26 (1 H), 7.18 (2 H), 7.55 (5 H), 8.02 (1 H), 10.64 (1 H), 12.34 ( 1 H); MS (FAB) m/z (rel. intensity) 582 (M+H, 18).
Preparation 34 and Example 100.
[R-(R*,S*)]-3-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]^- thiomorpholinecarboxylic acid 4-( 1 , 1 -dimethylethyl) ester
(Scheme F, F-7: where RF_, and RF.2 are the same and equal to proton, RF_3 is proton, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000135_0001
To a solution of ester F-3 (Scheme F, where RF_, and RF.2 are the same and equal to proton, RF.3 is CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)) (656 mg, 1.02 mmol) in MeOH (25 mL) was added K2CO3 (550 mg, 4 mmol) and H2O (13 mL). After 3 h, volatiles were partially removed and the solution diluted with 10% HCl (20 mL) causing precipitation of a solid. The product was collected by filtration, washed with H2O and dried in a vacuum oven to afford the product (610 mg): IR (mull) 1736, 1665, 1606, 1562, 1537, 1516, 1432, 1413, 1323, 1294, 1260, 1244, 1211, 1195, 1160 cm" '; Η NMR (300 MHz, DMSO-dtf) δ 1.35 (9 H), 2.45 (2 H), 2.74 (5 H), 4.00 (1 H), 4.47 (1 H), 4.70 (1 H), 7.19 (2 H), 7.52 (5 H), 7.92 (1 H), 10.60 (1 H), 12.75 (1 H); MS (FAB) m/z (rel. intensity) 582 (M+H, 12). Anal. Calcd for C25H29Cl2N3O6S : C, 53.61; H, 5.02; N, 7.21;. Found: C, 53.20; H, 5.12; N, 7.10. Corrected for 2.30% H2O found by Karl Fischer analysis.
Preparation 35. (Scheme F, F-3: where RF., and RF_2 are the same and equal to proton, RF.3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000135_0002
To a cooled (0-5 °C) solution of Boc-L-thiomoφholine-3-carboxylic acid (Scheme F, F- 1: where RF_, and RF_2 are the same and equal to proton and stereochemistry is (R)) (1.34 g, 5.4 mmol) in methylene chloride (20 mL) was added HOBt (800 mg, 5.94 mmol), DMAP (140 mg, EDC (1.14 g, 5.94 mmol) and triethylamine (2.7 mL, 19.4 mmol). After 10 min, F-2 (Scheme F where RF_, and RF.2 are the same and equal to proton, RF_3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (2.02 g, 4.94 mmol) was added, the reaction allowed to warm to ambient temperature and stirred for 24 h. Volatiles were removed in vacuo and the residue partitioned between methylene chloride and 2.5%) aqueous HCl. The organic layer was separated and washed with sat. aqueous NaHCO3, dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/ethyl acetate (5%) as eluant afforded the title compound (1.64 g): IR (mull) 1730, 1687, 1667, 1606, 1538, 1515, 1431, 1412, 1395, 1320, 1294, 1258, 1250, 1194, 1158 cm"1; 'H NMR (300 MHz, CDC13) δ 1.44 (9 H), 1.46 (9 H), 2.35 (1 H), 2.67 (3 H), 3.22 (3 H), 4.25 (1 H), 4.73 (1 H), 4.97 (1 H), 6.52 (1 H), 7.29 (5 H), 7.53 (3 H); MS (FAB) m/z (rel. intensity) 638 (M+H, 2). Anal. Calcd for C30H37C12N3O6S: C, 56.42; H, 5.84; N, 6.58. Found: C, 56.13; H, 5.98; N, 6.58.
Preparation 36 and Example 101. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(3R)-3-thiomoφholinyl]carbonyl]-L- phenylalanine monohydrochloride (Scheme F, F-8: where RF_, and RF.2 are the same and equal to proton, RF.3 is proton, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)).
Figure imgf000136_0001
To a solution of HCl saturated in ethyl ether (5 mL) at ambient temperature was added carbamate F-3 (Scheme F, where RF_, and RF_2 are the same and equal to proton, RF.3 is t- butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R, S)) (100 mg, 0.15 mmol) with vigorous stirring. After 43.5 h, the precipitate was collected by filtration and washed with ethyl ether to afford the title compound (90 mg): IR (mull) 3241 , 3189, 3033, 2731, 1725, 1661, 1605, 1578, 1562, 1542, 1515, 1432, 1414, 1328, 1195 cm-VH NMR (300 MHz, DMSO-dtf) δ 2.66 (1 H), 2.99 (6 H), 3.50 (1 H), 3.98 (1 H), 4.45 (1 H), 7.26 (1 H), 7.52 (5 H), 9.00 (2 H), 9.30 (1 H), 10.69 (1 H); MS (FAB) m/z (rel. intensity) 482 (M+H, 83), 540 (32), 539 (9), 538 (42), 486 (13), 485 (16), 484 (60), 483 (24), 482 (83), 173 (11), 102 (99). Anal. Calcd for C2IH21Cl2N3O4S • HCl: C, 48.61; H, 4.27; N, 8.10; Cl, 20.50; S, 6.18. Found: C, 48.92; H, 4.27; N, 7.79; Cl, 19.68. Corrected for 6.53%) H2O found by Karl Fischer analysis.
Example 102. 4-[(2,6-Dichlorobenzoyl)amino]-N-[[(3R)-4-[ 1 -oxo-3-( 1 H-tetrazol-5-yl)propyl]-3- thiomoφholinyl]carbonyl]-L-phenylalanine methyl ester (Scheme F, F-5: where RF_, and RF_2 are the same and equal to proton, RF.3 is CH3, R3 is 2- (5-lH-tetrazolyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is (R, S)).
Figure imgf000137_0001
Example 102 was prepared as described in Scheme F using lH-tetrazole-5-propanoic acid (Hutchinson, D.W.; Naylor, M. Nucleic Acids Res. 1985, 13, 8519) to form the requisite amide. Physical data as follows: IR (mull) 3264, 3047, 1742, 1659, 1607, 1561, 1537, 1516, 1432, 1415, 1324, 1268, 1219, 1 195, 799 cm"1; 'H NMR (300 MHz, DMSO-dtf) δ 2.26 (1 H), 2.66 (2 H), 3.02 (8 H), 3.61 (3 H), 3.87 (1 H), 4.56 (1 H), 5.25 (1 H), 7.21 (2 H), 7.50 (5 H), 8.18 (1 H), 8.45 (1 H), 8.64 (1 H); MS (FAB) m/z (rel. intensity) 620 (M+H, 61).
Example 103.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(3R)-4-[l-oxo-3-(lH-tetrazol-5-yl)propyl]-3- thiomoφholinyl]-carbonyl]-L-phenylalanine (Scheme F, F-6: where RF_, and RF_2 are the same and equal to proton, RF.3 is proton, R3 is 2-(5-lH-tetrazolyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is (R, S)).
Figure imgf000138_0001
Example 103 was prepared from example 102 by the procedure described in preparation 34. Physical data as follows: IR (mull) 3376, 3296, 3267, 3127, 1746, 1683, 1669, 1641,
1623, 1610, 1542, 1522, 1444, 1436, 1411 cm"'; MS (ESI+) for C25H25Cl2N7O5S m/z 605.8 (M+H)+; MS (FAB) m/z (rel. intensity) 606 (MW, 51), 682 (17), 608 (40), 607 (28), 606 (51), 605 (16), 254 (99), 226 (23), 175 (17), 137 (20), 102 (33); HRMS (FAB) calcd for C25H25Cl2N7O5S +H, 606.1093, found 606.1105.
Example 104.
N-[[(3R)-4-(3-Cyano-l-oxopropyl)-3-thiomoφholinyl]carbonyl]-4-[[2,6- dichlorobenzoyl)amino]-L-phenylalanine (Scheme F, F-6: where RF_, and RF.2 are the same and equal to proton, RF_3 is proton, R3 is
CH2CH2CN, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO-, and stereochemistry is
(R, S)).
Figure imgf000139_0001
Example 104 was prepared as described in Scheme F using 3-cyanopropanoic acid (readily prepared from commercially available 3-cyanopropanoic acid) to form the requisite amide. Physical data as follows: IR (mull) 2251 , 1735, 1655, 1612, 1585, 1565, 1512, 1439, 1298, 1240, 1196, 1179, 1016, 1000, 779, 768 cm"1; 'H NMR (300 MHz, CDC13) δ 2.40 (12 H), 4.88 (1 H), 5.22 (2 H), 6.72 (1 H), 6.96 (2 H), 7.23 (5 H).
Example 105. [R-(R*,S*)]-3-[[[l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]- phenyl]ethyl]amino]carbonyl]-γ-oxo^J— thiomoφholinebutanoic acid (Scheme F, F-6: where RF., and RF.2 are the same and equal to proton, RF_3 is proton, R3 is CH2CH2CO2H, R5 is 4-[(2,6-dichlorophenyl)methoxy]ρhenyl , Y is CO-, and stereochemistry is (R, S)).
Figure imgf000139_0002
Example 105 was prepared as described in Scheme F using mowo-methyl succinate to form the requisite amide. Physical data as follows: IR (mull) 3031, 1726, 1646, 1612, 1585, 1565, 1511, 1439, 1421, 1297, 1240, 1 196, 1 179, 1016, 768 cm'1; Η NMR (300 MHz, DMSO-dtf) δ 2.62 (8 H), 3.64 (3 H), 4.39 (2 H), 5.20 (2 H), 6.92 (2 H), 7.15 (2 H), 7.50 (3 H), 7.98 (2 H); 13C NMR (75 MHz, DMSO-dtf) δ 174.5, 173.2, 171.9, 168.9, 136.5, 132.3, 132.0, 130.8, 130.7, 129.2, 114.8, 65.3, 54.3, 52.5, 36.0, 29.7, 28.0, 27.0; MS (FAB) m/z (rel. intensity) 569 (M+H, 24). Anal. Calcd for C25H26Cl2N2O7S: C, 52.73; H, 4.60; N, 4.92; Cl, 12.45. Found: C, 52.51; H, 4.60; N, 4.94; Cl, 12.78. Corrected for 3.37%o H2O found by Karl Fischer analysis.
Scheme G
Figure imgf000141_0001
Figure imgf000141_0002
Figure imgf000141_0003
Figure imgf000141_0004
Where Rg., and RG_2 are defined independently as H or CH3; RG_3 is defined as H, C,.6 alkyl or C3.6 alkenyl; and g is defined as 0 or 2. Scheme G describes a general method to prepare lactam examples of general structures G-5 and G-6. Readily prepared lactams of general structure G-l may be alkylated by the reaction of an appropriate alkylating in the presence of a suitable base as described in preparation 37 to provide intermediates of general structure G-2. Mild hydrolysis provides the monoacid of general structure G-3 which may be condensed with an amino acyl intermediate of structure G-4 as described in Scheme A. Full hydrolysis of the diester of general structure G-5 affords the diacid of structure G-6.
Preparation 37. (Scheme G, G-2: where RQ., and RG_2 are CH3, R^ is CH3 and g is equal to 2).
Figure imgf000142_0001
To a cooled (0-5 °C) solution of dimethyl ester G-l (Scheme G, where RG_, and R^ are CH3, RQ.3 is H and g is equal to 2) (Thomas, E.T.; Rynbrandt, R.H; Zimmermann, D.C.; Bell, L.T.; Muchmore, C.R.; Yankee, E.W. J. Org Chem. 1989, 54, 4535) (25.7 g, 0.1 mole) and iodomethane (30 mL, 0.48 mol) in THF (200 mL) was added NaH (4.8 g, 0.12 mmol, 60%) in oil dispersion). After 22 h, the reaction was quenched by the addition of H2O (100 mL) and diluted with CH2C12 (50 mL). The organic layer was separated, dried and dried in vacuo. The crude brown oil was triturated with hexanes (200 mL) and the residue concentrated in vacuo to afford the crude product (18.44 g) which was used without further purification: Η NMR (300 MHz, CDC13) δ 2.03 (12 H), 2.64 (3 H), 3.64 (6 H).
Preparation 38. (Scheme G, G-3: whereR^ is CH3, RQ. is CH3 and g is equal to 2).
Figure imgf000142_0002
To a cooled (0-5 °C) solution of diester G-2 (Scheme G, where RQ., and R^are CH3, R^ is CH3 and g is equal to 2) (10.0 g, 36.9 mmol) in aqueous methanol (66%, 75 mL) was added LiOH»H2O (1.55 g, 36.9 mmol). After 22 h, the mixture was partially concentrated in vacuo and diluted with water. The aqueous layer was washed with methylene chloride and acidified (pH ca. 2) with 10% HCl. The aqueous layer was extracted with methylene chloride and the combined organic extracts dried and concentrated in vacuo to afford the title compound (3.63 g) as a yellow solid: IR (mull) 1735, 1630, 1442, 1429, 1418, 1405, 1330, 1308, 1287, 1255, 1217, 1185, 1122, 1016, 642 cm'1; 'H NMR (300 MHz, CDC13) δ 1.90 (6 H), 2.24 (4 H), 2.43 (2 H), 2.68 (3 H), 3.67 (3 H); 13C NMR (75 MHz, CDC13) δ 176.3, 175.5, 173.2), 64.6, 52.0, 33.1, 32.9, 29.9, 28.41, 28.38, 26.0, 24.9; MS (EI) m/z (rel. intensity) 257 (M+, 1).
Preparation 39 and Example 106. 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R^ and RQ., are both equal to CH3, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000143_0001
To a solution of acid G-3 (Scheme G, whereR^ and R^ are equal to CH3 and g is equal to 2) (1.0 g, 3.9 mmol), amine G-4 (Scheme G, where R5 is 4-[(2,6-dichlorophenyl)- methoxyjphenyl and stereochemistry is (S)) (1.82 g, 4.67 mmol), and DMAP (100 mg, 0.8 mmol) in pyridine (15 mL) was added EDC (895 mg, 4.67 mmol). After 21 h, the reaction was diluted with saturated aqueous NaHCO3 and methylene chloride. The organic layer was separated and washed with 10%> aqueous HCl, dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/ethyl acetate (20%>) as eluant followed by lyophilization from aqueous acetonitrile afforded the title compound (1.71 g) as an amoφhous solid: IR (mull) 3284, 2924, 1738, 1666, 1665, 1564, 1539, 1511, 1439, 1398, 1299, 1240, 1198, 1178, 1 1 17, 1016, 768 cm'1; 'H NMR (300 MHz, CDC13) δ 2.10 (12 H), 2.66 (3 H), 3.07 (2 H), 3.66 (3 H), 3.73 (3 H), 4.83 (1 H), 5.24 (2 H), 5.98 (1 H), 6.95 (2 H), 7.02 ( 2 H), 7.25 (1 H), 7.36 (2 H); 13C NMR (75 MHz, CDC13) δ 174.7, 174.66, 173.2, 172.0, 171.2), 158.1, 137.0), 132.1, 130.5, 130.3, 128.5, 128.3, 115.2, 65.2, 64.3, 53.3, 52.4, 51.9, 37.0, 33.2, 30.2, 30.17, 28.4, 26.0, 24.7; MS (EI) m/z (rel. intensity) 592 (M+, 4). Anal. Calcd for C29H34Cl2N2O7: C, 58.69; H, 5.77; N, 4.72; Cl, 11.95. Found: C, 58.33; H, 5.65; N, 4.76; Cl, 1 1.89.
Preparation 40 and Example 107.
2-[3-[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]-3- oxo-propyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid (Scheme G, G-6: where RQ.J is equal to CH3, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000144_0001
To a solution of diester G-5 (Scheme G, where RQ.2 and RG.3 are both equal to CH3, R5 is 4- [(2,6-dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (5) (1.0 g, 1.68 mmol), in THF (30 mL) and MeOH (9 mL) was added LiOH»H2O (370 mg, 8.8 mmol). After 22.5 h, the reaction mixture was acidified with 10%> aqueous HCl (30 mL) causing precipitation of a solid. The solid was collected by filtration and lyophilized from aqueous acetonitrile to afford the title compound (0.91 g) as an amoφhous solid: IR
(mull) 3031, 2925, 1727, 1637, 1585, 1564, 1543, 1511, 1439, 1424, 1404, 1299, 1240, 1196, 1179, 768 cm 1; 'H NMR (300 MHz, DMSO-d^ δ 1.77 (12 H), 2.76 (1 H), 3.97 (1 H), 4.36 (1 H), 5.16 (2 H), 6.94 (2 H), 7.15 (2 H), 7.49 (3 H), 8.16 (1 H); 13C NMR (75 MHz, CDCl3) δ 174.6, 174.1, 173.6, 172.2, 157.6, 136.5, 132.2, 132.0, 130.7, 130.6, 129.2, 114.7, 65.3, 64.1, 54.0, 36.5, 33.7, 33.1, 30.1, 30.05, 29.8, 28.7, 25.7, 24.6; MS (FAB) m/z (rel. intensity) 565 (M+H, 99). Anal. Calcd for C27H30C12N2O7: C, 57.35; H, 5.35; N, 4.95; Cl, 12.54. Found: C, 56.93; H, 5.15; N, 5.02; Cl, 12.42. Corrected for 1.03%) H2O found by Karl Fischer analysis.
Example 108. 2-[3-[[(l S)-l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-l-(3-methyl-2-butenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R^ is CH3, R^ is l-(3-methyl-2-butenyl), R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000145_0001
Example 108 was prepared as described in Scheme G using l-bromo-3-methyl-2-butene to form the requisite N-alkyl lactam. Physical data as follows: IR (mull) 32.95, 29.52, 1740, 1678, 1662, 1564, 1538, 1512, 1439, 1414, 1300, 1279, 1240, 1199, 1178, 1017, 768 cm'1; 'H NMR (300 MHz, CDC13) δ 1.64 (3 H), 1.70 (3 H), 2.06 (12 H), 3.09 (2 H), 3.66 (3 H), 3.74 (2 H), 3.74 (3 H), 4.85 (1 H), 5.20 (1 H), 5.24 (2 H), 6.95 (2 H), 7.02 (2 H), 7.25 (1 H), 7.36 (2 H); 13C NMR (75 MHz, CDC13) δ 174.7, 173.3, 172.1, 172.0, 171.3, 158.1, 137.0, 135.1, 132.1, 130.5, 130.3, 128.5, 128.3, 119.7, 115.2, 65.2, 65.1, 53.2, 52.4, 51.9, 37.5, 37.0, 34.4, 34.2, 30.6, 29.9, 28.6, 26.6, 25.6, 25.5, 17.9; MS (FAB) m/z (rel. intensity) 647 (M+H, 24). Example 109. 2-[3-[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]-3- oxo-propyl]-l-(3-methyl-2-butenyl)-5-oxo-2-pyrrolidinepropanoic acid (Scheme G, G-6: where R^is l-(3-methyl-2-butenyl), R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000146_0001
Example 109 was prepared from example 108 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3290, 2921, 1726, 1635, 1585, 1565, 1545, 1511, 1439, 1419, 1341, 1299, 1240, 1197, 1179, 780, 768 cm '; 'H NMR (300 MHz, DMSO- d<j) δ 1.57 (3 H), 1.62 (3 H), 1.72 (6 H), 2.02 (6 H), 2.77 (1 H), 2.98 (1 H), 3.55 (2 H), 5.05 (1 H), 5.16 (2 H), 6.94 (2 H), 7.15 (2 H), 7.49 (2 H), 7.54 (2 H), 8.15 (1 H); 13C NMR (75 MHz, DMSO-dtf) δ 174.6, 174.3, 173.6, 173.56, 172.2, 157.6, 136.5, 134.0, 132.2, 132.0, 130.6, 129.2, 121.1, 121.0, 114.7, 65.2, 65.0, 54.1, 54.0, 37.1, 36.5, 34.5,
34.1, 30.0, 29.9, 28.8, 26.3, 25.84), 25.81, 18.1; MS (FAB) m/z (rel. intensity) 619 (M+H, 99).
Example 110. 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-<)xopropyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where RQ_2 and RQ.3 are equal to CH3, R5 is 4-[(2,6-dichlorobenzoyl)- aminojphenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000147_0001
Example 110 was prepared as described in Scheme G using iodomethane to form the requisite N-alkyl lactam. Physical data as follows: IR (mull) 3258, 2922, 1738, 1662, 1606, 1561, 1539, 1515, 1432, 1414, 1401, 1323, 1268, 1196, 1177, 799 cm'1; 'H NMR (300 MHz, CDC13) δ 2.01 (12 H), 2.61 (3 H), 3.09 (2 H), 3.64 (3 H), 3.75 (3 H), 4.84 (1 H), 6.15 (1 H), 7.09 (2 H), 2.31 (3 H), 7.58 (2 H), 7.99 (1 H);MS (EI) m/z (rel. intensity) 607 (M+, 4), 605 (M+, 6); Anal. Calcd for C29H33Cl2N3O7: C, 57.43; H, 5.48; N, 6.93; Cl, 11.69. Found: C, 57.18; H, 5.56; N, 6.85; Cl, 11.68. Corrected for 0.93% H2O, found by Karl Fischer analysis.
Example 111. 2-[3-[[(lS)-l-Carboxy-2-[4— [(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]-3-oxo- propyl]-l-methyl-5-oxo-2-pyrrolidinepropanoic acid (Scheme G, G-6: where R^ is CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000147_0002
Example 11 1 was prepared from example 110 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3265, 3056, 2925, 1724, 1658, 1609, 1579, 1561, 1542, 1516, 1432, 1414, 1327, 1271, 1217, 1195, 800 cm'1; Η NMR (300 MHz, DMSO- d<y) δ 1.89 (12 H), 2.49 (3 H), 2.78 (1 H), 2.99 (1 H), 4.38 (1 H), 7.18 (2 H), 7.51 (5 H), 8.17 (1 H), 10.64 (1 H); MS (FAB) m/z (rel. intensity) 580.5 (M+H, 68).
Example 112. 2-[3-[[(lS)-l-[[4-[(2,6-Dichloroρhenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where ^ is CH3, R^ is proton, R5 is 4-[(2,6-dichlorophenyl)- methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000148_0001
Example 112 was prepared as described in Scheme G. Physical data as follows: IR (mull) 3276, 3029, 1738, 1686, 1564, 1538, 151 1, 1439, 1299, 1279, 1239, 1197, 1178, 1016, 767, cm'1; Η NMR (300 MHz, CDC13) δ 1.85 (6 H), 2.24 (2 H), 2.35 (4 H), 3.03 (2 H), 3.66 (3 H), 3.74 (3 H), 4.82 (1 H), 5.24 (2 H), 6.50 (2 H), 6.95 (2 H), 7.05 (2 H), 7.27 (1 H), 7.37 (2 H); MS (EI) m/z (rel. intensity) 578 (M+, 0.2); Anal. Calcd for
C28H32Cl2N2O7: C, 58.04; H, 5.57; N, 4.83. Found: C, 57.93; H, 5.43; N, 4.97. Corrected for 1.14 %> H2O found by Karl Fischer analysis.
Example 113. 2-[3-[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]-3- oxo-propyl]-5-oxo-2-pyrrolidinepropanoic acid
(Scheme G, G-6: where RQ.-, is proton, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000149_0001
Example 113 was prepared from example 112 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3294, 3033, 1716, 1647, 1585, 1565, 1544, 1511, 1439, 1420, 1299, 1240, 1197, 1179, 768 cm'1; 'H NMR (300 MHz, DMSO-dtf) δ 1.60 (6 H), 2.12 (6 H), 2.78 (1 H), 2.99 (1 H), 4.36 (1 H), 5.19 (2 H), 6.97 (2 H), 7.17 (2 H), 7.45 (1 H), 7.58 (2 H), 7.70 (1 H), 8.22 (1 H); MS (FAB) m/z (rel. intensity) 551 (M+H, 99); Anal. Calcd for C26H28Cl2N2O7: C, 56.63; H, 5.12; Cl, 12.86; N, 5.08. Found: C, 56.28; H, 5.01; Cl, 13.08; N, 5.24. Corrected for 1.47% H2O found by Karl Fischer analysis.
Example 114. 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxo-2-pyrrolidinepropanoic acid methyl ester (Scheme G, G-5: where R^ is CH3, R,^ is proton, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000149_0002
Example 114 was prepared as described in Scheme G. Physical data as follows: Η NMR (300 MHz, CDC13) δ 1.81 (6 H), 2.27 (6 H), 3.10 (2 H), 3.63 (3 H), 3.75 (3 H), 4.89 (1 H), 6.46 (1 H), 6.58 (1 H), 7.10 (2 H), 7.26 (3 H), 7.58 (2 H), 8.14 (1 H); MS (FAB) m/z 592
(M+H)+, 568, 367, 349, 307, 278, 226, 194, 173. Example 115. 2-[3-[[(lS)-l-Carboxy-l-[4-[(2,6-dichlorobenzolyl)amino]phenyl]ethyl]amino]-3- oxopropyl]-5-oxo-2-pyrrolidinepropanoic acid (Scheme G, G-6: where R^-, is proton, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, g is equal to 2 and stereochemistry is (S)).
Figure imgf000150_0001
Example 115 was prepared from example 114 by the procedure described in preparation 40. Physical data as follows: IR (mull) 3272, 3195, 3121, 3063, 2953, 2923, 2868, 2855, 1715, 1659, 1608, 1579, 1561, 1541, 1516, 1456, 1432, 1414, 1377, 1367, 1326, 1271,
1221, 1195, 800 cm'1; 'H NMR (300 MHz, DMSO-d6 δ 1.63 (6 H), 2.13 (6 H), 2.79 (1 H), 3.00 (1 H), 4.38 (1 H), 7.19 (2 H), 7.51 (5 H), 7.64 (1 H), 8.16 (1 H), 10.58 (1 H),
12.37 (2 H); MS (FAB) m/z 564 (M+H)+, 546, 519, 335, 280, 194, 173. Anal. Calc'd for C26H27Cl2N3O7: C, 55.33; H, 4.82; Cl, 12.56; N, 7.44. Found: C, 55.10; H, 4.76; Cl, 12.56; N, 7.36. Corrected for 2.49% H2O, found by Karl Fischer analysis.
Example 116. 2-[3-[[(lS)-l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]-3-oxopropyl]-5-oxoproline (Scheme G, G-5: where R^and RG-3 are equal to proton, R5 is 4-[(2,6-dichlorophenyl)- methoxyjphenyl, g is equal to 0 and stereochemistry is (S)).
Figure imgf000151_0001
Example 115 was prepared as described in Scheme G from 2-carboxy-5-oxo-2- pyrrolidinepropanoic acid (Majer, Z.; Kajtar, M.; Tichy, M.; Blaha, K. Coll. Czech. Chem. Commun. 1982, 47, 950). Physical data as follows: IR (mull) 3302, 1736, 1671, 1612, 1585, 1564, 1535, 1511, 1439, 1298, 1240, 1 197, 1179, 1016, 768 cm"1; 'H NMR (300 MHz, CDC13) δ 2.12 (8 H), 3.02 (2 H), 3.65 (3 H), 4.81 (1 H), 5.21 (2 H), 6.94 (2 H), 7.07 (2 H), 7.22 (1 H), 7.35 (2 H), 7.86 (1 H), 8.34 (1 H); MS (FAB) m/z (rel. intensity) 537 (M+H, 99).
Example 117. 2-[3-[[( 1 S)- 1 -Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]-3- oxo-propyl]-5-oxoproline (Scheme G. G-6: where R^ is proton, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl, g is equal to 0 and stereochemistry is (S)).
Figure imgf000151_0002
Example 116 was prepared from example 115 by the procedure described in preparation
40. Physical data as follows: IR (mull) 3292, 3059, 3029, 1718, 1650, 1612, 1585, 1565, 1537, 1511, 1439, 1240, 1196, 1179, 768 cm"'; 'H NMR (300 MHz, CDC13) δ 2.11 (8 H), 2.83 (1 H), 3.20 (1 H), 4.74 (1 H), 5.24 (2 H), 6.95 (2 H), 7.15 (2 H), 7.25 (1 H), 7.36 (2 H); MS (FAB) m/z (rel. intensity) 523 (M+H, 99); Anal. Calcd for C24H24Cl2N2O7: C, 55.08; H, 4.62; N, 5.35, Cl, 13.55. Found: C, 54.68; H, 4.66; N, 5.13: Cl, 13.70. Corrected for 1.59% H2O found by Karl Fischer analysis.
Scheme H.
Figure imgf000152_0001
OH
H-2
" Cl
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000152_0004
Scheme H teaches a general method for the preparation of 6-chloroazatyrosine examples of structures H-4 and H-5, by adaption of the methodology for the preparation of protected azatyrosine reagents as described by Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012-12013 and references cited therein. Thus regioselective iodination of 2-chloro-3-pyridinol gives the chloro-iodopyridinol H-2, that is O-alkylated as exemplified by the synthesis of H-3. Palladium-catalyzed reaction of H-3 with the organozinc derived from a suitably protected β-iodoalanine, provides the protected 5- chloroazatyrosine H-4. N-deprotection of H-4 gives the aminoester H-5, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples of this invention
Preparation 41. (Scheme H: H-2) 2-Chloro-6-iodo-3-pyridinol (C5H3CHNO). To a solution of 2-chloro-3-pyridinol H-l (10.2 g, 78.7 mmol) and K2CO3 (38.9 g, 0.274 mol) in H2O (120 mL) is added I2 (24.3 g, 95.8 mmol), and the reaction mixture is stirred at rt for 4 h. The reaction mixture is quenched by the addition of aq satd Na2S2θ3"5H2θ, and its pH is lowered to pH 2 with the addition of 12 M aq HCl. The mixture is extracted with EtOAc. The combined EtOAc extracts are dried, filtered and concnetrated to a yellow solid, that is crystallized from 120:25 heptane/EtOAc (145 mL) to give, as a yellow solid, 11.2 g of the title compound: lH NMR (CD3SOCD3, 300
MHz) δ 9.87 (1H), 7.59 (1H), 7.06 (1H); 13C NMR (CD3SOCD3, 75 MHz) δ 150.68,
138.07, 134.98, 127.02, 101.18.
Preparation 42. (Scheme H: H-3)
2-ChIoro-3-[(2,6-dichlorophenyl)methoxy]-6-iodopyridine (C \ 2H7CI3INO).
To a solution of H-2 (5.11 g, 20.0 mmol), PPh3 (5.30 g, 20.0 mmol), and 2,6- dichlorobenzylalcohol (3.54 g, 20.0 mmol) in dry THF (100 mL) at 0 °C under Ar is added DEAD (3.15 mL, 20.0 mmol). The reaction mixture is kept at 0 °C for 1.5 h and at rt for 1.5 h. It is concentrated to a residue, that is purified by silica flash chromatography (17:3 hexanes/EtOAc) to give 7.61 g of the title compound: TLC (17:3 hexanes/EtOAc) Rr0.57;
lH NMR (CD3SOCD3, 300 MHz) δ 7.85 (IH), 7.62 (IH), 7.58-7.45 (3H), 5.34 (2H). Preparation 43.
(Scheme H: H-4)
(5)-2-Chloro-3-[(2,6-dichlorophenyI)methoxy]-α-[[(l,l-di»nethylethoxy)- carbonyl]amino]-6-pyridinepropanoic acid methyl ester (C21H23CI3N2O5).
To an amberized flask containing activated Zn dust (0.777 g, 1 1.89 mmol) under Ar is added sequentially Λ/-[(l,l-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester [93267-04-0] (3.91 g, 1.89 mmol), THF (11.9 mL), and dimethylacetamide (11.9 mL). The reaction mixture was purged of O2 by the bubbling of Ar through the mixture for 5 min. It is stirred at 65±5 °C for 2 h, and is cooled to rt. To this mixture is added PdCl2(PPh3)2 (0.412 g), followed immediately afterward by a degassed solution of H-3 (2.46 g, 5.94 mmol) in 1 : 1 THF/dimethylacetamide (11.8 mL). The reaction mixture is stirred at 65±5 °C for 5 h. It is cooled to 0 °C and quenched with sat'd aq NH4CI (100 mL). The reaction mixture is extracted with EtOAc. The combined extracts are washed with brine, dried, filtered and concentrated to a green-yellow oil; that is purified by silica flash chromatography to give 1.90 g of the title compound: TLC (7:3 hexanes/EtOAc) Rf
0.32; lU NMR (CDCI3, 300 MHz) δ 7.76 (IH), 7.57 (2H), 7.48 (IH), 7.29 (IH), 7.27
(IH), 5.30 (2H), 4.32 (IH), 3.60 (3H), 3.01 (IH), 2.98 (IH), 1.31 (9H).
Preparation 44. (Scheme H: H-4)
(S)-2-Chloro-3-[(2,6-dichlorophenyl)methoxy]-α-amino-6-pyridinepropanoic acid methyl ester dihydrochloride salt (C j 6H \ 5C13N2O3 -2HC1).
A solution of H-4 (1.90 g, 3.88 mmol) in 4 M HCl in dioxane (35 mL) is stirred at rt under Ar for 20 h. The reaction mixture is concentrated in vacuo. The residue is taken up in H2O (40 mL), and extracted with Et2θ. The aqueous solution is frozen and lyophilized to give 1.39 g of the title compound: !H NMR (CD3SOCD3, 300 MHz) δ 8.62 (3H), 7.81
(IH), 7.58 (2H), 7.48 (IH), 7.38 (IH), 5.32 (2H), 4.37 (IH), 3.72 (3H), 3.27 (2H).
Example 118. (Scheme A, A-5) [S-(R*,R*)]^-[[[l-[[2-Chloro-3-[(2,6-dichlorophenyl)methoxy]-6- pyridyl]methyl]-2-methoxy-2-oxoethyl] amino] carbonyl]-3-thiazolidinecarboxylic acid (1,1-dimethylethyl) ester (C30H37Cl3N3O6S).
Example 118 was prepared as described in Scheme A from D-cysteine using the product of preparation 44 as amino acid intermediate A-4. Physical properties as follows: TLC (1:1 hexanes/EtOAc) RfO.27; lR NMR (CDCI3, 300 MHz) δ 8.43 (IH), 7.74 (IH),
7.58 (2H), 7.48 (IH), 7.29 (IH), 5.29 (2H), 4.67 (IH), 4.53 (IH), 4.44 (IH), 4.23 (IH), 3.62 (3H), 3.06 (3H), 2.82 (IH), 1.27 (9H).
Example 119. (Scheme A, A-9) [S-(R* R*)]^l-[[l-Carboxy-2-[[2-Chloro-3-[(2,6-dichlorophenyl)methoxy]-6- py ridyl] ethyl] amino] carbony l]-3-thiazolidinecarboxylic acid (1 ,1-dimethylethyl) ester ^^gC^l^OgS).
Example 119 was prepared from example 118 by the procedure described in preparation 12. Physical data as follows: mp 93-95 °C; TLC (600:400:2 EtOAc/hexanes/HCO2H) Rf
0.38; *H NMR (CD3SOCD3, 300 MHz) δ 8.30 (IH), 7.74 (IH), 7.57 (2H), 7.48 (IH),
7.27 (IH), 5.29 (2H), 4.67^.36 (2H), 4.53 (IH), 4.23 (IH), 3.37-3.11 (3H), 2.97 (IH), 1.27 (9H). Scheme I.
Figure imgf000156_0001
o I-2
Figure imgf000156_0002
Figure imgf000156_0003
Figure imgf000156_0004
Figure imgf000156_0005
Figure imgf000156_0006
Scheme I teaches a general method for the preparation of azatyrosine reagents 1-3, 1-4, 1-5, 1-6 and 1-7, by adaptation of the methodology for the preparation of protected azatyrosine reagents as described by Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012-12013 and references cited therein. Thus O-protection of chloroiodopyridinol I-l (identical to H-2) is followed by reaction with the organozinc, derived from a suitably protected β-iodoalanine, to provide the protected 6-chloroazatyrosine 1-3. Reductive dehalogenation of 1-3 gives 1-4, that is 0-deprotected to give 1-5. Reagent 1-5 is O- alkylated, as exemplified by the preparation of 1-6. N-deprotection of 1-6 gives the aminoester 1-7, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples of this invention.
Preparation 45.
(Scheme 1, 1-2)
(±)-2-Chloro-3-[(2-tetrahydropyranyI)oxy]-6-iodopyridine (C j QH j j CIINO2).
To a solution of chloroiodopyridinol I-l (same as H-2, the product of preparation 41) (1.00 g, 3.91 mmol) and dihydropyran (1.0 mL, 10.6 mmol) in CH2C12 (10 mL) under Ar at rt is added pyridinium chloride (0.050 g). The reaction mixture is stirred for 72 h. It is diluted with CH2CI2, and is washed with satd aq NaHCO3 and brine. The CH2CI2 solution is dried, filtered and concentrated to an oil, that is purified by silica flash chromatography (19:1 hexanes/EtOAc) to give 1.06 g of the title product: TLC (19:1 hexanes/EtOAc) R 0.24; !H NMR (CDCI3, 300 MHz) δ 7.55 (IH), 7.17 (IH), 5.50 (IH),
3.77 (IH), 3.61 (IH), 2.07-1.57 (6H).
Preparation 46. (Scheme 1, 1-3)
(S)-2-Chloro-α-[[(l,l-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydro- pyrany!)oxy]-6-pyridinepropanoic acid methyl ester
Figure imgf000157_0001
To an amberized flask containing activated Zn dust (0.349 g, 5.51 mmol) under Ar is added THF (2 mL) and 1 ,2-dibromoethane (0.018 mL, 0.21 mmol). The suspension is brought to reflux for several minutes, cooled to approximately 30 °C, and TMSC1 (0.17 mL of a 1 M solution in THF) is added. The reaction mixture is stirred at 40±5 °C for 30 min and then is cooled to below rt. A solution of N-[(l,l-dimethylethoxy)carbonyl]-3- iodo-L-alanine methyl ester [93267-04-0] (1.81 g, 5.50 mmol) in 11:7 dimethylacetamide/THF (9.0 mL) is added, and the resulting reaction mixture is stirred at 45 °C for 5 h. The reaction mixture is cooled to below rt, and solid PdC^PPt^^ (0.192 g) is added, followed immediately by addition of a degassed solution of the iodopyridine (0.936 g, 2.76 mmol) in 1 :1 THF/dimethylacetamide (5.6 mL). This reaction mixture is stirred for 4 h at 45 °C. It is cooled to 0 °C, quenched with sat'd aq ΝH4CI, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4CI and brine.
The EtOAc solution is dried, filtered and concentrated to give a green-yellow colored foam, that upon purification by silica flash chromatography (7:3 hexanes/EtOAc) gives
0.879 g (1.85 mmol, 60%) of the title product: TLC (7:3 hexanes/EtOAc) Rf0.2X; !H
NMR (CDCI3, 300 MHz) d 7.39 (IH), 7.00 (IH), 5.46 (IH), 4.61 (IH), 4.13 (IH), 3.80 (3H), 3.62 (IH), 3.20 (IH), 2.13-1.53 (6H), 1.42 (9H).
Preparation 47. (Scheme 1, 1-4)
(5)-α-[[(l,l-Dimethylethoxy)carbonyl]ammo]-3-[(2-tetrahydropyranyl)oxy]-6- pyridinepropanoic acid methyl ester (Cj 9^3^05). A suspension of pre-reduced Pd/CaCO3 (3.5 g) and 1-3 (1.15 g, 2.77 mmol) in EtOH (40 mL) is hydrogenated (30 psi H2) for 19 h at rt. The mixture is filtered, and the filtrate is evaporated to give a yellow-colored foam, that is purified by silica flash chromatography (600:400:1 hexanes/EtOAc/z'PrOH) to give 0.367 g of the title compound: TLC (1 :1 hexanes/EtOAc) R -0.27; lU NMR (CDCI3, 300 MHz) δ 8.30 (IH), 7.29 (IH), 7.03 (IH), 5.81 (IH), 5.39 (IH), 4.65 (IH), 3.86 (IH), 3.73 (3H), 3.62 (IH), 3.21 (2H), 1.96-1.53 (6H), 1.42 (9H). Preparation 48. (Scheme 1, 1-5)
(5)-α-[[(l,l-Dimethylethoxy)carbonyl]amino]-5-hydroxy-2-pyridinepropanoic acid methyl ester (C14H20 2O5).
A solution of 1-4 (0.346 g, 0.91 mmol) and pyridinium /7-toluenesulfonate (0.031 g, 0.12 mmol) in EtOH (8 mL) is stirred at 55±5 °C for 20 h. The reaction mixture is cooled to rt, and concentrated in vacuo. The residue is taken up in EtOAc. The solution is washed with brine, and dried, filtered and concentrated to a pale yellow-colored oil that is purified by silica flash chromatography (500:500:1 hexanes/EtOAc/z'PrOH). Evaporation of the column fractions gives 0.132 g of the title compound: TLC (1:1 hexanes/EtOAc) RfO.XS;
lH NMR (CDCI3, 300 MHz) δ 8.13 (IH), 7.13 (IH), 7.03 (IH), 5.71 (IH), 4.65 (IH), 3.70 (3H), 3.20 (2H), 1.39 (9H).
Preparation 49. (Scheme 1, 1-6) (S)-5-[(2,6-Dichlorophenyl)methoxy]-α-[[(l,l-dimethylethoxy)carbonyl]amino]-2- pyridinepropanoic acid methyl ester (C21H24CI2N2O5).
To a solution of 1-5 (0.126 g, 0.43 mmol), 2,6-dichlorobenzylalcohol (0.075 g, 0.43 mmol) and PPI13 (0.113 g, 0.43 mmol) in dry THF (4 mL) at 0 °C under Ar is added
DEAD (0.068 mL). The reaction mixture is permitted to warm to rt, and is stirred for 18 h. It is concentrated, and the residue is purified by silica flash chromatography (700:300: 1 hexanes/EtOAc/z'PrOH) to give 0.149 g of the title compound: TLC (7:3 hexanes/EtOAc)
Rf0.34; lH NMR (CDCI3, 300 MHz) δ 8.31 (IH), 7.37 (2H), 7.25 (2H), 7.08 (IH), 5.81
(IH), 5.29 (2H), 4.65 (IH), 3.70 (3H), 3.24 (2H), 1.63 (1 H), 1.43 (9H).
Preparation 50. (Scheme 1, 1-7)
(5)-α-Amino-5-[(2,6-dichlorophenyl)methoxy]-2-pyridinepropanoic acid methyl ester dihydrogen chloride salt
Figure imgf000159_0001
A solution of carbamate 1-6 (0.546 g, 1.20 mmol) in 4 M HCl in dioxane (12 mL) is stirred at rt under Ar for 16 h. The reaction mixture is concentrated in vacuo. The residue is dissolved in H2O (40 mL), and this solution is extracted with Et2θ. The aqueous solution is frozen and lyophilized to give, as a light yellow-colored solid, 0.485 g of the title compound: lU NMR (CD3SOCD3, 300 MHz) δ 8.75 (3H), 8.47 (IH), 7.81 (IH),
7.57 (3H), 7.48 (IH), 5.35 (2H), 4.49 (IH), 3.67 (3H), 3.42 (2H).
Example 120. (Scheme A, A-5)
[5-(R*R*)]-4-[[[l-[[3-[(2,6-DichloroρhenyI)methoxy]-6-pyridyl]methyl]-2- methoxy-2-oxoethyI]amino]carbonyl]-3-thiazolidinecarboxylic acid (1,1- dimethylethyl) ester ^^QC^^OgS).
Example 120 was prepared as described in Scheme A from D-cysteine using the product of preparation 49 as amino acid intermediate A-4. Physical properties as follows: TLC (1 : 1 hexanes/EtOAc) Rf 0.22; ]H NMR (CDCI3, 300 MHz) δ 8.28 (2H), 7.38 (2H), 7.28 (2H), 7.09 (IH), 5.29 (2H), 4.90-4.74 (3H), 4.40 (IH), 3.67 (3H), 3.38-3.22 (3H), 1.61 (2H),
1.40 (9H).
Example 121.
(Scheme A, A-9)
[S-(R*,R*)]-4-[[[l-Carboxy-2-[3-[(2,6-dichlorophenyl)methoxy]-6- pyridyl] ethyl] amino] carbonyl]-3-thiazolidinecarboxylic acid (1,1-dimethylethyl) ester (C24H28Cl2N3O6S).
Example 121 was prepared from example 120 by the procedure described in preparation 12. Physical data as follows: mp 92-94°; TLC (500:500:3 hexanes/EtOAc/HCO2H) Rf
0.10; lH NMR (CDCI3, 300 MHz) δ 8.31 (IH), 8.26 (IH), 7.55 (2H), 7.28 (2H), 7.46 (IH), 7.21 (IH), 5.25 (2H), 4.72-4.38 (2H), 4.60 (IH), 4.23 (IH), 3.21-3.12 (2H), 3.09- 2.94 (IH), 2.74 (IH), 1.29 (9H). Scheme J.
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000161_0003
Figure imgf000161_0004
Scheme J teaches a general method for the preparation of αrα-acylamino derivatives of aza-phenylalanine. Thus bis-acylation of 2-amino-5-iodopyridine J-1 gives the imide J-2, that is reacted with the organozinc, derived from a suitably protected β-iodoalanine, to provide the protected acylamino azaphenylalanine J-3. N-deprotection of J-3 gives the aminoester J-4, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples of this invention.
Preparation 51. (Scheme J: J-2) 2-[[Bis(2,6-Dichlorobenzoyl)]amino]-5-iodopyridine (Ci H9Cl lN2θ2).
To a solution of 2-amino-5-iodopyridine J-1 (2.20 g, 10.0 mmol) and Et3N (2.12 mL,
15.0 mmol) in dry THF (100 mL) at rt under Ar, is added dropwise 2,6- dichlorobenzoylchloride (1.60 mL, 11.0 mmol) over 45 min. The reaction mixture is stirred for 15 h. It is diluted with EtOAc (300 mL), and is washed with cold aq 1 M NaOH and brine. The solution is dried, filtered and concentrated to give a yellow-colored waxy solid, that is purified by silica flash chromatography (3:1 hexanes/EtOAc) to give 2.60 g of the title compound: TLC (7:3 hexanes/EtOAc) Rf 0.60; !H NMR (CDC13, 300 MHz) δ
8.59 (IH), 8.03 (IH), 7.99 (IH), 7.44-7.26 (6H).
Preparation 52. (Scheme J: J-3)
(S)-2-[[Bis-(2,6-dichlorobenzoyl)]amino]- -[[(l,l- dimethylethoxy)carbonyl]amino]-5-pyridinepropanoic acid methyl ester
Figure imgf000162_0001
To an amberized flask containing activated Zn dust (0.865 g, 13.23 mmol) under Ar is added sequentially N-[(l , l-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester (4.36 g, 13.23 mmol), THF (13 mL) and NN-dimethylacetamide (13 mL). The reaction mixture is purged of O2 by the bubbling Ar through the mixture for 5 min, and then is warmed to 45±5 °C for 7 h. It is cooled to rt. To this mixture is added PdCl2(PPh3)2
(0.461 g) followed immediately by a degassed solution of iodide J-2 (2.60 g, 4.59 mmol) in 1 : 1 THF/NN-dimethylacetamide (18 mL). The reaction mixture is stirred at 45±5 °C under Ar for 13 h. It is cooled to 0 °C and quenched with satd aq ΝH4CI (150 mL). The mixture is extracted with EtOAc. The combined EtOAc extracts are washed with brine, dried, filtered and concentrated to a green-yellow-colored paste, that is purified by silica flash chromatography (700:300:1 hexanes/EtOAc/iPrOH) to give 1.43 g of the title compound: TLC (7:3 hexanes/EtOAc) Rf0.29; !H NMR (CDCI3, 300 MHz) δ 8.13 (IH),
7.57 (IH), 7.46 (IH), 7.26 (6H), 4.80 (IH), 4.50 (IH), 3.67 (3H), 3.05 (2H), 1.46 (9H).
Preparation 53. (Scheme J: J-4)
(S)- -Amino-2-[[bis-(2,6-dichlorobenzoyI)]amino]-5-pyridinepropanoic acid methyl ester dihydrochloride salt (C23H17CI4N3O4 HCI).
A solution of J-3 (0.69 g, 1.08 mmol) in 4 M HCl in dioxane (15 mL) is stirred under Ar for 20 h. The reaction mixture is concentrated in vacuo, diluted with H O. and extracted with Et2θ. The aqueous solution is frozen and lyophilized to give, as a pale yellow-
colored solid, 0.627 g of the title compound: !H NMR (CD3SOCD3, 300 MHz) δ 8.80
(2H), 8.27 (IH), 7.82 (I H), 7.67-7.26 (7H), 4.25 (I H). 3.52 (3H), 3.16 (2H), 3.04 (IH); MS (ESI+) m/z 541.7.
Example 122. (Scheme A, A-5)
[5-(R* R*)]-4-[[[l-[[2-[[Bis-(2,6-dichlorobenzoyl)]amino]-5-pyridyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid (1,1- dimethylethyl) ester
Figure imgf000163_0001
Example 122 was prepared as described in Scheme A from D-cysteine using the product of preparation 52 as amino acid intermediate A-4. Physical properties as follows: TLC (1 :1 hexanes/EtOAc) 7^0.22; H NMR (CDCI3, 300 MHz) δ 8.28 (2H), 7.38 (2H), 7.28 (2H),
7.09 (IH), 5.29 (2H). 4.90-4.74 (3H), 4.40 (IH), 3.67 (3H), 3.38-3.22 (3H), 1.61 (2H), 1.40 (9H).
Example 123. (Scheme A, A-9)
[S-(R*,Λ*)]^4-[[[[l-Carboxy-2-[2-[[Bis-<2,6-dichlorobenzoyl)]amino]-5- pyridyl] ] ethyl] amino] carbonyI]-3-thiazolidinecarboxy lie acid (1 ,1-dimethylethyl) ester (C3 \ H28Cl4N4O7S). Example 123 was prepared from example 122 by the procedure described in preparation 12. Physical data as follows: mp 158-160°; TLC (50:50:2 hexanes/EtOAc/HCO2H) Rf
0.18; 'H NMR (CD3SOCD3, 300 MHz) δ 8.42 (IH), 8.22 (IH). 7.75 (IH), 7.69-7.17
(5H), 7.53 (IH), 4.59 (IH), 4.40 (2H), 4.19 (IH), 3.19-3.02 (2H), 2.84 (IH), 2.56 (IH), 1.34 (9H).
Scheme K.
Figure imgf000164_0001
Figure imgf000164_0002
Scheme K teaches a general method for the preparation of oxazolidinecarboxylic acid Examples K-3 and K-4, where R3, R5 and Y are identical to the definitions of Scheme B. Thus coupling of oxazolidinecarboxylic acid K-1 and aminoester K-2 (as exemplified by the reaction of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) provides Examples K-3, that are hydrolyzed to Examples K-4 of this invention. Example 124. (Scheme K: K-3. where R3 is (phenyl)methyl, R5 is 4-[(2.6-dichlorobenzoyl)amino]phenyl, Y is CO2 and the stereochemistry is [S-(R* R*)])
[S-(R* R*)]-4-[[[l-[[4-[(2,6-DichIorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl] amino] carbonyl]-3-oxazolidinecarboxy lie acid 3-phenylmethyl ester (C29H27Cl2N3O7).
Example 124 was prepared as by coupling commercially available (5 -3,4-oxazolidinedi- carboxylic acid 3-(phenylmethyl) ester to amino acid K-2 (Scheme K, where R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl stereochemistry is (S)) under the conditions described by preparation 3. Physical properties as follows: TLC (3:2 Heptane/EtOAc) Rf= 0.17; UV (MeOH) lma 225 (e 12600, sh), 251 (17900); l3C NMR ( ,-dimethylsulfoxide) δ 188.75. 171.96, 169.86, 162.40, 162.30, 152.99, 137.59, 137.47, 136.87, 136.81, 133.23, 131.79, 131.65, 130.08, 128.80, 128.67, 128.28, 127.76, 1 19.84, 1 19.75, 79.82, 66.77, 57.85, 53.85, 52.47, 36.62 (23 lines expected; 26 lines observed); MS (FAB) m/z 602, 600, 558, 556, 531, 466. 371, 351, 349, 280, 278, 175, 173; MS (FAB) m/z 600.1312 (calcd [M+H]+ 600.1304; Anal. C, 57.75; H, 4.75; N, 6.80; Cl, 1 1.86 (calcd for 0.42% H2O: C 57.77, H 4.56, N 6.97, Cl 11.76).
Example 125. (Scheme K: K-4 where R3 is (phenyl)methyl. R; is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO2 and the stereochemistry is [S-(R*.R*)])
[S-(R* R*)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]- carbonyl]-3-oxazolidinecarboxylic acid 3-phenylmethyl ester (C28H25Cl2N3O7). Example 125 was prepared from example 124 by the procedure described in preparation 12. Physical properties as follows: TLC (950:50: 1 CH2Cl2/MeOH/HCO2H)
Figure imgf000165_0001
0.34; Η NMR ( -dimethylsulfoxide) δ 10.65 (IH). 8.31 (IH). 7.61-7.42 (5H), 7.40-7.20 (5H), 7.15 (2H), 5.19-4.85 (2H), 4.90 (IH), 4.76 (IH), 443 (IH), 4.36 (IH), 4.11 (IH), 3.65 (IH), 3.04 (IH). 2.87 (IH); MS (FAB) m/z 588. 586 544, 542, 532, 391, 337, 335, 327, 269, 267, 161. 147.133, 129, 1 17, 1 15, 103, 101. 91 ; MS (FAB) 586.1 132 (calcd 586.1147). Example 126.
(Scheme K: K-3 where R, is benzyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is
CO2 and the stereochemistry is [#-(#*. S*)])
[R-(R*yS*)]-4-[[[l-[[4-|(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-oxazolidinecarboxyIic acid 3-phenylmethyl ester
(C29H27Cl2N3O7).
Example 126 was prepared as described in Scheme K from commercially available (/?)-
3,4-oxazolidinedicarboxylic acid 3 -(phenylmethyl) ester. Physical properties as follows:
TLC (3:2 heptane/EtOAc) Rf= 0.19; UV (MeOH) λmax 225 (e 12400, sh), 252 (17700), 284 (2960. sh); 13C NMR (CDC13) δ 171.23, 169.14, 162.43, 154.26, 136.47, 135.93,
135.65, 132.37, 132.28, 130.91, 130.00, 128.62, 128.39, 128.1 1, 120.30, 79.66, 67.94,
58.38, 53.14, 52.49, 37.19 (23 lines expected; 21 lines observed); MS (FAB) m/z 602, 600,
558, 556, 466, 351, 349, 280, 278, 175, 173; MS (FAB) m/z 600.1299 (calcd for [M+H]+
600.1304); Anal. C 57.69, H 4.90, N 6.71, Cl 1 1.49 (calcd for 0.35% H2O: C 57.81, H 4.56, N 6.97, Cl 11.77).
Example 127.
(Scheme K: K-4 where R3 is benzyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is
CO2 and the stereochemistry is [R-(R*,S*)])
[R-(R * S*)]-4-[ [ [l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]-carbonyI]-3-oxazolidinecarboxylic acid
3-{phenylmethyl) ester (C28H25Cl2N3O7).
Example 127 was prepared from example 126 by the procedure described in preparation
12.
Physical properties as follows: TLC (950:50:1 CH2Cl2/MeOH/HCO2H) Rf= 0.31; Η NMR (</4-methanol) δ 7.60 (2H),7.49-7.23 (8H), 7.21 (2H), 5.23-4.97 (2H), 4.95 (IH),
4.88 (IH), 4.70 (IH), 4.36 (IH), 4.14 (IH), 3.85-3.73 (IH), 3.23 (IH), 3.00 (IH); MS
(FAB) m/z 588, 586. 544. 542, 532, 391, 371, 337, 335, 245, 177, 173. 149, 123, 105, 103,
91 ; MS (FAB) m/z 586.1 163 (calcd 586.1 147). Scheme L.
Figure imgf000167_0001
Figure imgf000167_0002
f Rs
H2N' L-3
Figure imgf000167_0003
Figure imgf000167_0004
Scheme L teaches a general method for the preparation of N-alkylaryl azetidinedi- carboxylic acid Examples L-4 and L-5, where RL_, is C,.6 alkyl, RL.2 is C6.,0aryl and R5 is defined as in Scheme B. The N-phenylethyl-2.4-azetidinedicarboxylic acid dimethyl ester stereoisomers of general structure LI were prepared as described (Hoshino. J.; Hiraoka, J.; Hata. Y.: Sawada. S.; Yamamoto. Y. J. Chem. Soc. Perkin Trans. 1 1995, 693-697) and separated by silica flash chromatography. Thus partial saponification of diester L-1 gives the half-acid L-2. that is coupled with reagent L-3 (as exemplified by the use of reagents
A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples L-4, that are then hydrolyzed to Examples L-5 of this invention.
Preparation 54. (Scheme L: L-1 where RL_, is methyl, RL.2 is phenyl and stereochemistry is [25-
[l(Λ*),2α,4β]]).
[2S-[l(R*),2α,4β]]-l-(l-Phenylethyl)-2,4-azetidinedicarboxylic acid dimethyl ester
[168647-92-5] (C,5H,9NO4).
Physical properties as follows: TLC (4:1 Hexanes/EtOAc) Rf= 0.42; BC NMR (CDC13) δ 173.61, 142.41, 128.31, 127.39, 127.35, 60.95. 60.67, 51.64, 24.96, 21.72.
Preparation 55.
(Scheme L: L-1 where RL., is methyl, RL.2 is phenyl and stereochemistry is [2R-
[l(S*),2α,4β]]).
[2R-[l(S*),2α,4β]]-l-(l-Phenylethyl)-2,4-azetidinedicarboxylic acid dimethyl ester (CI5H19NO4).
Physical properties as follows: TLC (4: 1 Hexanes/EtOAc) Rf= 0.31 ; 13C NMR (CDC13) δ
172.97, 141.21, 128.44, 128.07, 127.68, 61.54, 60.69, 51.61, 24.91, 19.55.
Preparation 56.
(Scheme L: L-1 where RL., is methyl, RL_2 is phenyl and stereochemistry is [l(>S)-c/.y]). [l(5)-c/s]-l-(l-Phenylethyl)-2,4-azetidinedicarboxyIic acid dimethyl ester [168753-32-
0] (C,5H,9NO4).
Physical properties as follows: TLC (4:1 Hexanes/EtOAc) Rf= 0.21; nC NMR (CDC13) δ
172.58, 172.08, 140.84, 128.22, 128.15, 127.65, 66.32. 60.10. 59.65, 52.06, 51.59, 24.26,
19.91. Preparation 57.
(Scheme L: L-1 where RL., is methyl, RL_2 is phenyl and stereochemistry is [2R-
[l(i?*),2α,4β]]).
[2R-[l(R*),2 ,4β]]-l-(l-Phenylethyl)-2,4-azetidinedicarboxylic acid dimethyl ester
(C15H19NO4). Physical properties as follows: TLC (8:2 hexanes/EtOAc) Rf= 0.42; l C NMR (CDC13) δ
173.61, 142.41, 128.31, 127.39, 127.35, 60.95, 60.67, 51.64, 24.96. 21.72; MS (+ESI) m/z
278.3.
Preparation 58. (Scheme L: L-1 where RL., is methyl, RL.2 is phenyl and stereochemistry is [25-
[l(5*),2α,4β]].
[2S-[l(S*),2α,4β]]-l-(l-Phenylethyl)-2,4-azetidinedicarboxylic acid dimethyl ester
(C,5H,9NO4),.
Physical properties as follows: TLC (8:2 hexanes/EtOAc) Rf= 0.31 ; 13C NMR (CDC13) δ 172.97. 141.21, 128.44, 128.07, 127.68, 61.54. 60.69, 51.61, 24.91. 19.55; MS (+ESI) m/z
278.3.
Preparation 59.
(Scheme L: L-1 where RL., is methyl, RL_2 is phenyl and stereochemistry is [X(R)-cis]).
[l(R)-cw]-l-(l-PhenylethyI)-2,4-azetidinedicarboxylic acid dimethyl ester (C15HI9NO4).
Physical properties as follows: TLC (8:2 hexanes/EtOAc) Rf= 0.21 ; l3C NMR (CDC13) δ
172.58, 172.08, 140.84, 128.22, 128.15, 127.65, 66.32, 60.10, 59.65, 52.06, 51.59, 24.26,
19.91; MS (+ESl) m/z 278.3.
Preparation 60. (Scheme L: L-2 where RL., is methyl. RL.2 is phenyl and stereochemistry is [25-
[l(/.*),2α,4β]]).
[2S-[l(R*),2α,4β]]-l-(l-Phenylethyl)-2,4-azetidinedicarboxylic acid monomethyl ester
(CI4H,7NO4).
A mixture of L-1 (Scheme L. where RL., is methyl, RL.2 is phenyl and stereochemistry is [25-[l(i?*),2α,4β]], the product of preparation 54) (7.95 g; 28.7 mmol) and LiOH (30 mmol) in 1 : 1 MeOH/H2O (240 mL) is stirred at rt for 42 h. The reaction mixture is adjusted to pH 5 with HOAc. and is concentrated. The resulting concentrate is diluted with brine and extracted repeatedly with CHC1,. The combined CHCl, extracts are dried, filtered and concentrated to give a yellow foam (6.61 g), that is purified by preparative C18 reverse phase chromatography to give the title compound as a crystalline solid: mp 112-113 °C; TLC (650:350:1 hexanes/EtOAc/HCO2H) Rf= 0.17; MS (FAB) m/z 527, 264, 248, 218, 204, 192, 186. 177, 160, 114, 105; Anal. C 64.04, H 6.57, N 5.37 (calcd C 63.87, H 6.51, N 5.32).
Preparation 61 and Example 128. (Scheme L: L-4 where RL_, is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [2S-[X(R*),2aAβ(R*)]]) [25-[l(R*),2α,4β(R*)]]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid methyl ester (C3lH3ICl2N3O6). A mixture of L-2 (Scheme L, where RL_, is methyl, RL„2 is phenyl and stereochemistry is [25-[l(J?*).2α,4β]], the product of preparation 60) (0.62 g, 2.4 mmol), L-3 (Scheme L where R5 is 4-[(2,6-dichlorobenzoyl)amino)phenyl and stereochemistry is (5)) (0.95 g, 2.4 mmole), and BOP-C1 (0.68 g; 2.7 mmol) in CH2C12(10 mL) is treated with ( -Pr)2NEt (1.7 mL, 9.8 mmol). The reaction mixture is stirred at rt under N2 for 19 h. It is diluted with half-saturated NaHCO3 and extracted with CH2C12. The CH2C12 extracts are dried, filtered and concentrated to give a beige-colored foam (1.40 g), that is purified by silica flash chromatography to give the title compound: TLC (1 :1 Hexanes/EtOAc) Rf= 0.23; l3C NMR (CDCl3) δ 173.25, 172.73, 171.63, 162.57. 141.86, 136.76, 136.01, 132.44, 132.39, 130.90, 130.00. 128.57, 128.12, 127.55, 127.08. 120.37, 63.25, 60.06, 59.17, 52.41, 52.12, 51.47, 37.65. 26.06, 21.25; MS (FAB) m/z 612.1658; Anal. C 59.66, H 5.14, N 6.64 (calcd C 60.79, H 5.10, N, 6.86).
Preparation 62 and Example 129. (Scheme L: L-5 where RL., is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [2S-[X(R*),2a,4\3(R*)]]) [25-[l(R*),2α,4β(R*)]]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]- ethyl]-amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid dilithium salt (C29H25Cl2Li2N3O6).
A mixture of L-4 (Scheme L, where RL., is methyl, RL_2 is phenyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is [2S-[X(R*),2a,4β(R*)]], the product of preparation 61) (0.684 g, 1.12 mmol) and LiOH-H2O (0.25 g, 6.0 mmol) is dissolved by warming in MeOH (10 mL). This solution is diluted with 1 :1 H2O/THF (20 mL), and the reaction mixture is stirred at rt for 22 h. The mixture is adjusted with 1 N HCl to pH 6. The solution is concentrated to give a white solid, that is purified by preparative C 18 reverse phase chromatography (MeCN/H2O gradient). Evaporation of the column fractions gives a white solid, that is dissolved in warm H2O. The solution is frozen and lyophilized to give, as a white solid, the title compound: mp 270 °C; TLC (850:150:1 CHCl3/MeOH/HCO2H) Rf= 0.21-0.36; l3C NMR (CD,OD) δ 178.05, 174.59, 174.01. 162.20. 142.33, 135.09, 134.91, 133.04, 130.54, 129.24, 128.61, 126.46, 126.41,126.17, 124.94, 1 18.33,82.70, 61.70, 60.50, 53.30, 36.23. 25.85, 18.65; MS (FAB) m/z 584.1350: Anal. C 55.17, H 5.01, N 6.63. Cl 1 1.16 (calcd for 7.52% H2O: C 54.02, H 4.75, N 6.52. Cl. 1 1.21).
Example 130. (Scheme L: L-4 where RL., is methyl, RL.2 is phenyl, R5 is 4-[(2,6- dichlorobenzoyl)- amino]phenyl and stereochemistry is [2/?-[l(5*),2α,4β(5*)]]). [2R-[l(S*),2α,4β(S*)]]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyl]-l-(l-phenylethyI)-2-azetidinecarboxyIic acid methyl ester (C31H3ICl2N3O6).
Example 130 was prepared as described in Scheme L using the product of preparation 55 as intermediate L-1. Physical properties as follows: TLC (3:2 EtOAc/Hexanes) Rf= 0.43; [α D +58 (c 0.91. MeOH); l3C NMR (CDC13) δ 173.24. 172.15. 172.05, 162.58, 140.75, 136.45, 136.01, 132.89, 132.38, 130.91, 129.60, 128.67. 128.39, 128.11, 127.97, 120.39, 63.54, 60.19, 59.54, 53.15, 52.16, 51.91, 37.86, 26.12, 18.37. MS (EI) m/z 613, 611, 598, 596, 554, 552, 527. 525, 508, 506, 450, 448, 351, 349. 218. 191, 175, 173, 160, 131, 114, 105; Anal. C 60.68, H 5.18, N 6.67, Cl 11.24 (calcd for C 60.79, H 5.10, N 6.86, Cl 11.58). Example 131.
(Scheme L: L-5 where RL„, is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [2R-[X(S*),2a,4β(S*)]]). [2R-[l(5*),2α,4β(5*)]]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)- amino]phenyl]ethyl]-amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid, dilithium salt (C29H25Cl2Li2N O6). Example 131 was prepared from Example 130 by the procedure described in preparation 62. Physical properties as follows: [α] 25 D +84 (c 0.95, MeOH); ,3C NMR (CD3OD) δ 179.18. 176.55, 174.13, 163.58, 141.88, 136.32, 136.29, 134.96, 131.90. 130.86. 129.47, 128.49. 128.07.127.87, 127.16, 1 19.74, 63.70, 63.49. 59.77, 56.27, 38.24, 26.25. 18.70; MS (FAB) m/z 598, 596, 592, 590, 552, 550, 546. 544, 161 ; Anal. C 55.20, H 5.52, N, 6.59 (calcd for 10.98% H2O: C 52.00, H 4.99, N 6.27).
Example 132. (Scheme L: L-4 where RL., is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- aminojphenyl and stereochemistry is [l(5),2α,4α(5)], a single diastereomer having a cis relative configuration but unknown absolute configuration at C-2 and C-4 of the azetidine.)
[l(5),2α,4α(S)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid 2-methyl ester (C31H31Cl2N3O6). Example 132 was prepared as described in Scheme L using the product of preparation 56 as intermediate L-1. Physical properties as follows: TLC (9:1 CHCl3/acetone) Rf= 0.29; l C NMR (CDCl3) δ 172.70, 172.29, 171.65. 162.49, 140.97, 136.71, 136.12, 132.47, 132.39, 130.81, 130.22, 128.35, 128.07, 127.82. 120.17, 66.61, 61.52, 59.99, 52.38, 52.24, 51.79. 37.73. 25.16, 20.09. Example 133.
(Scheme L: L-5 where RL_, is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [l(5),2α,4α], a single diastereomer having a cis relative configuration but unknown absolute configuration at C-2 and C-4 of the azetidine.) [l(S),2α,4α(5)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]- amino]-carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid (C29H27Cl2N3O6). Example 133 was prepared from Example 132 by the procedure described in preparation 62. Physical properties as follows: [α]25 D +20 (c 0.88, MeOH); πC NMR (CD3OD) δ 173.70. 173.05, 172.61, 163.69, 140.09. 136.93, 136.20. 133.18, 131.89. 130.89, 129.95, 128.09. 127.89.127.88, 127.65, 120.03, 66.07, 61.29. 59.86. 52.70, 36.98. 25.03. 18.81; MS (FAB) m/z 662, 660. 586, 584, 539, 482, 480, 436, 434. 204, 175, 173, 160, 133, 109, 105; Anal. C 57.90, H 5.01, N 6.93 (calcd for 4.98% H >: C 56.63, H 4.98, N 6.83).
Example 134. (Scheme L: L-4 where RL., is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [2R-[X(R*),2aAβ(S*)]]) [2R-[l(R*),2α,4β(5*)]]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyI]-l-(l-phenylethyl)-2-azetidinecarboxylic acid methyl ester (C3,H31Cl2N3O6).
Example 134 was prepared as described in Scheme L using the product of preparation 57 as intermediate L-1. Physical properties as follows: TLC (1 :1 EtOAc/Hexanes) Rf- 0.30; l3C NMR (CDC13) δ 173.78. 172.76, 172.10, 162.47, 141.81, 136.70, 135.96, 132.43, 132.38, 130.88, 129.79, 128.55. 128.10, 127.58, 127.00, 120.58, 63.32, 60.06, 59.27, 52.70, 52.50, 51.44, 37.08. 25.76, 21.52; MS (+ESI, 200: 1 MeOH/HCO2H solution) m/z 613.8, 611.8. Example 135.
(Scheme L: L-5 where RL., is methyl, RL_2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [2 ?-[l(i?*),2α,4β(5*)]])
[2R-[l(R*),2α,4β(5*)]]-4-[[[l-Carboxy-2-[4-[(2,6-dichIorobenzoyl)amino]phenyl]- ethyl]-amino]carbonylj-l-(l-phenylethyl)-2-azetidinecarboxylic acid dilithium salt (C29H25Cl2Li2N3O6).
Example 135 was prepared from Example 134 by the procedure described in preparation 62. Physical properties as follows: [α]25 D +76 (c 0.89. MeOH); 13C NMR (CD3OD) δ 179.44, 176.71, 175.90, 163.55, 143.81, 136.54, 136.26. 134.47, 131.90, 120.81, 129.70, 127.83, 127.34, 126.33, 1 19.88. 63.06, 62.11, 58.71 , 55.46, 37.17. 26.76, 20.56; MS (FAB) m/z 598, 596, 592. 590. 552, 550, 546, 544. 237. 105; Anal. C 55.12, H 5.24, N 6.59, Cl 10.56 (calcd for 6.21 % H2O: C 54.78, H 4.66, N 6.61 , Cl 11.15).
Example 136. (Scheme L: L-4 where R, ., is methyl, RL.2 is phenyl, R, is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [25-[l(5*),2α,4β(7?*)]]) [25-[l(S*),2α,4β(R*)]]-4-[[Il-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid methyl ester (C„H3lCl2N3O6)
Example 136 was prepared as described in Scheme L using the product of preparation 58 as intermediate L-1. Physical properties as follows: TLC (85:15 CHCl3/acetone) Rf= 0.54; πC NMR (CDCl3) δ 173.44, 172.62, 171.72, 162.79, 140.46, 136.69, 136.34, 133.12, 132.79, 131.29, 130.40, 129.08, 128.52, 128.45, 128.23, 120.57, 64.15, 60.51 , 60.09, 53.11, 52.59, 52.19. 37.73, 26.70, 18.75; Anal. C 60.70, H 5.39, N 6.62 (calcd C 60.79, H 5.10, N 6.86). Example 137.
(Scheme L: L-5 where RL., is methyl, RL.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [25-[l(5*),2α,4β(i?*)]])
[25-[l(5*),2α,4β(R*)]]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]- ethyl]-amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid (C29H2-Cl2N3O6). Example 137 was prepared from Example 136 by the procedure described in preparation 62. Physical properties as follows: [α]25 D +2 (c 1.00, MeOH); ,3C NMR (CD3OD) δ 172.31, 169.43, 167.37, 163.72, 161.39, 160.93, 136.98, 136.11, 134.40, 133.20, 131.84, 130.93, 129.42, 129.39, 128.60, 127.89, 120.11, 62.68, 61.41, 53.51, 36.35, 25.00, 16.17; MS (FAB) m/z 586, 584, 482, 480, 204. 175. 173, 106, 105; Anal. C 53.07. H 4.52. N 6.15, Cl 10.46 (calcd for 0.80 equiv TFA and 2.13% H2O: C 53.20, H 4.30, N 6.08, Cl 10.26).
Example 138. (Scheme L: L-4 where RL_, is methyl, R[.2 is phenyl, R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [X(R),2a,4 (S)], a single diastereomer having a cis relative configuration but unknown absolute configuration at C-2 and C-4 of the azetidine.)
[l(R),2α,4α(5)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-l-(l-phenylethyl)-2-azetidinecarboxylic acid 2-methyl ester (C„H31Cl2N3O6). Example 138 was prepared as described in Scheme L using the product of preparation 59 as intermediate L-1. Physical properties as follows: TLC Rf= 0.47 (85:15 CHCl3/acetone); , C NMR (CDC13) δ 173.42, 172.40. 171.74. 162.46, 140.80, 136.76, 136.03, 132.64. 132.35, 130.80, 129.82, 128.38, 128.04, 127.85, 127.69, 120.39, 66.11, 61.50, 59.78, 52.83, 52.42. 51.72, 37.12, 25.03, 20.20; MS (+ESI, 200:1 MeOH HCO2H solution) m/z 614.2, 612.2; Anal. C 60.66, H 5.18. N 6.80. Cl 11.42 (calcd C 60.79, H 5.10, N 6.86, Cl 1 1.58).
Example 139. (Scheme L: L-5 where RL., is methyl, RL.2 is phenyl. R5 is 4-[(2,6-dichlorobenzoyl)- amino]phenyl and stereochemistry is [X(R),2 ,4a(S)]. a single diastereomer having a cis relative configuration but unknown absolute configuration at C-2 and C-4 of the azetidine)
[l(R),2α,4α(5)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]- amino]-carbonyI]-l-(l-phenylethyl)-2-azetidinecarboxylic acid (C29H25Cl2N3O6). Example 139 was prepared from Example 138 by the procedure described in preparation 62. Physical properties as follows: [ ]25 D -30 (c 0.90. MeOH); 13C NMR (CD3OD) δ 172.71, 172.44, 171.81, 163.71, 138.03, 136.99, 136.15, 133.31, 131.89, 130.89, 129.45, 128.33, 128.29,128.02, 127.86, 120.23, 65.62, 61.51. 59.60, 53.47, 36.04, 24.91, 17.68; MS (FAB) m/z 586. 584, 371, 298. 204, 177, 175. 173. 133. 105, 100; Anal. C 55.69, H 4.49, N 6.55, Cl 1 1.81 (calcd for 0.38 equiv TFA and 2.06% H2O: C 55.80, H 4.54, N 6.56. Cl 1 1.07).
Scheme M.
Figure imgf000176_0001
O N 0 I
O— M-2
M-3
-O v O-
°\ N P -o v OH
Figure imgf000176_0002
Figure imgf000176_0003
Scheme M teaches a general method for the preparation of N-acyl azetidinedicarboxylic acid Examples M-6 and M-7, where RM., is C,.6 alkyl, M-2 ΪS C6.10aryl, and R3. R5 and Y are defined as in Scheme B. Thus removal of the A-alkylaryl substituents RM_, and RM.2 of M-l gives aminodiester M-2, that is acylated to provide M-3. Partial saponification of diester M-3 gives half-acid M-4, that is coupled with reagent M-5 (as exemplified by the use of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples M-6, that are then hydrolyzed to Examples M-7 of this invention.
Preparation 63. (Scheme M: M-2 where stereochemistry is (2R-trans)) (2R-trans)-2,4- Azetidinedicarboxylic acid dimethyl diester (C7HπNO4).
To an N2-purged solution of freshly chromatographed Preparation M-l (Scheme M where RM., is methyl, RM.2 is phenyl and stereochemistry is [2Λ-[l(i?*),2α,4β]] prepared as described by preparation 57) (656 mg, 2.37 mmol) in MeOH (20 mL) is added 20%> Pd(OH)2/C (120 mg), and this mixture is hydrogenated for 19 h under an H2 atmosphere (approximately 42 psi pressure). The mixture is filtered and concentrated to give the title compound as a colorless oil: TLC (4:1 Hexanes/EtOAc) Rf= 0.04; Η NMR (CDC13) δ 4.33 (2H), 3.77 (6H), 3.38 (IH), 2.71 (2H); MS (+ESI) m/z 174.2.
Preparation 64. (Scheme M: M-3 where R3 is ethyl, Y is CO2-, and the stereochemistry is (2R-trans)) (2R-//-α«s)-l,2,4-AzetidinetricarboxyIic acid l-ethyl-2,4-dimethyl triester (Cl0H15NO6). To a mixture of freshly prepared amine M-2 (Scheme M where stereochemistry is (2R- trans)) (14 mmol) in CH2C12 (20 mL) under N2 at 0 °C is added Et3N (3.0 mL, 22 mmol), followed by the dropwise addition of ClCO2Et (1.5 mL, 18 mmol). After 22 h the reaction is quenched with saturated NaHCO3, diluted with H2O. and extracted with EtOAc. The combined organic extracts are dried, filtered and concentrated to give 2.79 g of the carbamate, that is purified by silica flash chromatography: TLC (4:1 Hexanes/EtOAc) Rf=
0.17; [α]25 D +183 (c 0.83, MeOH); lU NMR (CDC13) δ 4.77 (2H), 4.15 (IH), 4.10 (IH), 3.80 (6H), 2.58 (2H). 1.23 (3H); I3C NMR (CD,OD) δ 173.1 1, 173.05, 157.47. 63.30, 61.00, 60.18. 53.41. 26.43, 15.27; MS (El) m/z 245. 186, 172, 142, 1 14; Anal. C 48.90, H 6.21, N 5.73 (calcd C 48.98, H 6.16, N 5.71). Preparation 65. (Scheme M: M-4 where R3 is ethyl, Y is CO2-, and the stereochemistry is (2R-trans)) (2R-/rfl«s)-l,2,4-Azetidinetricarboxylic acid l-ethyl-2-methyl diester (C9H13NO6). A mixture of M-3 (Scheme M, where R3 is ethyl, Y is CO:-. and the stereochemistry is (2R-trans)) (1.68 g, 6.85 mmol) and LiOH (7.00 mmol) in 1 : 1 MeOH/H2O) (40 mL) is stirred at rt for 45 h, and then is concentrated. The residue is dissolved in half-saturated NaHCO3, and the solution is extracted with Et2O. The Et2O solution is discarded. The aqueous solution is adjusted with concentrated HCl to pH 4. and is concentrated to a yellow solid. This solid is triturated with CHC13. The CHC1, solution is filtered and concentrated to give, as a light brown oil, the title compound: TLC (600:400: 1
Hexanes/Acetone/HCO2H)
Figure imgf000178_0001
0.21-0.45; Η NMR (CDC13) δ 4.87 (IH), 4.77-4.68 (IH), 4.64-4.50 (IH), 4.18-3.97 (2H), 3.76 (3H), 2.52-2.33 (2H), 1.26-1.13 (3H); MS (-ESI, MeOH solution) m/z 230.1. This material is used without purification.
Preparation 66 and Example 140. (Scheme M: M-6 where R3 is ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO2-, and the stereochemistry is [27?-(2α,4β(5*)])
[2R-(2α,4β(5*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyI]-l,2-azetidinedicarboxylic acid l-ethyl-2-methyl diester (C26H27Cl2N3O8). To a mixture of Preparation M-4 (1.08 g, 4.67 mmol) and HOBt+H2O (0.63 g, 4.7 mmol) in CH2C12 (10 mL) at 0 0C is added a solution of EDC (1.04 g, 5.42 mmol) in CH2C12 (15 mL). This mixture is stirred at 0°C for 30 min. It is then treated with M-5 (Scheme M where R5 is 4-[(2,6-dichlorobenzoyl)amino)phenyl and stereochemistry is (5)) (1.88 g, 4.66 mmol) and N-methylmorpholine (0.52 mL, 4.7 mmol). The resulting solution was stirred at 0°C for 2 h and at rt for 2 h. The reaction mixture is diluted with 10% KHSO4 and extracted with CH:C12. The combined CH2C12 extracts are washed with satd ΝaHCO3 and brine, and are combined, dried, filtered and concentrated to give a yellow foam (2.58 g), that is purified by flash chromatography to give, as a white solid, the title compound: mp 97-99°C; TLC (9:1 CHCl,/acetone) Rf= 0.30; [α]25 D +79 (c 1.02. MeOH); UV (MeOH) λmax 225 (€ 12200: sh). 251 (17500); 13C NMR (CD,OD) δ 171.50. 171.30, 171.08. 163.67, 156.23, 155.96, 136.92. 136.19, 133.21, 133.03, 131.87. 130.93, 129.64, 129.44, 127.92, 119.97, 61.61, 60.56, 59.82, 59.1 1, 58.41, 53.45, 51.58. 51.52. 36.57, 36.29. 24.91. 13.43 (22 lines expected: 28 lines observed); MS (FAB) m/z 580.1260 (calcd for [M+H]+, 580.1253); Anal. C 51.95, H 4.56, N 6.89, Cl 15.18 (calcd for 0.61% H2O: C 53.48. H 4.73, N 7.20, Cl 12.14).
Preparation 67 and Example 141. (Scheme M: M-7 where R3 is ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, Y is CO2-, and the stereochemistry is [2tf-(2α,4β(5*)]) [2R-(2α,4β(S*)]-4-[[[l-Carboxy-2-[4-[(2,6-dichIorobenzoyl)amino]phenyl]ethyl]- amino]-carbonyl]-l,2-azetidinedicarboxylic acid l-ethyl ester (C24H23Cl2N3O8). To a suspension of M-6 (Example 140, Scheme M where R3 is ethyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, Y is CO2-, and the stereochemistry is [2i?-(2α,4β(5*)]) (0.201 g, 0.347 mmol) in MeOH (5 mL) is added H2O (4.3 mL)andl.00 M LiOH (0.70 mL). The reaction mixture is stirred at rt for 23 h. It is concentrated in vacuo. The aqueous concentrate is diluted with H2O, and the solution is adjusted to approximately pH 12 with IN NaOH. It is extracted with Et2O, and the Et2O extract is discarded. The aqueous solution is adjusted to approximately pH 3 with IN HCl. It is extracted repeatedly with Et2O. The combined Et2O extracts were dried, filtered and concentrated to give, as a white solid, the title compound: TLC (500:500: 1 MeOH/CH2Cl2/HCO2H) Rf= 0.20; Η NMR (CD3OD) δ 7.59 (2H), 7.50-7.37 (3H), 7.23 (2H), 4.78-4.64 (2H), 4.61-4.51 (IH), 4.22- 3.89 (2H), 3.30-3.185 (IH), 3.07-2.93 (IH), 2.42-2.23 (2H), 1.21 and 1.1 1 (3H total); MS (FAB) m/z 552.0946 (calcd for [M+Hf 552.0940); Anal. C 50.48, H 4.61. N 6.64, Cl 12.95 (calcd for 1.60% H2O: C 51.35, H 4.31, N 7.49, Cl 12.63).
Scheme N.
Figure imgf000180_0001
Figure imgf000180_0002
R5
H,N N-3
Figure imgf000180_0003
Figure imgf000180_0004
Figure imgf000180_0005
Scheme N teaches a general method for the preparation of N-acyl azetidinecarboxyiic acid Examples Ν-5 where n equals 0, 1 or 2, m equals 0. 1 or 2. (m + n) equals 2. X is nitrogen and R3, R5 and Y are defined as in Scheme B, and azetidine-carboxylic acid Examples N-6 where n equals 0, 1 or 2. m equals 0, 1 or 2, (m + n) equals 2, X is nitrogen and R5 is defined as in Scheme B. Thus acylation of aminoacid N-1 gives Λ'-acylacid N-2, that is coupled with reagent N-3 (as exemplified by the use of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples N-4. Ester hydrolysis of N-4 provides Examples N-5. N-deacylation of Examples N-5 provides Examples N-6.
Preparation 68. (Scheme N: N-2 where n is 2. m is 0. X is N, Y is -CO2-, R3 is (1 ,1 -dimethyl)ethyl, and the stereochemistry is (5)).
(5)-l, 2 -Azetidinedicarboxylic acid l-( 1,1-dimethylethyl) ester (C9HI5NO4). To a mixture of (5)-(-)-2-azetidinecarboxylic acid (1 10 mg, 1.1 mmol), Boc2O (290 mg, 1.30 mmol), and DMAP (0.017 g, 0.14 mmol) in 4: 1 DMF/H2O (10 mL) is added Et3N (0.30 mL, 2.2 mmol). The reaction mixture is stirred at rt for 68 h, and then is concentrated. The concentrate is diluted with EtOAc. and the EtOAc solution is washed with cold 10%) KHSO4. The combined organic extracts are dried, filtered and concentrated to give the title compound as a colorless oil: TLC (750:250: 1 Hexanes/acetone/HCO2H)
Rf= 0.26; }H NMR (CD3OD) δ 4.97 (IH), 4.57 (IH), 3.98 (IH), 3.87 (IH), 2.57 (H), 2.13 (IH), 1.42 (9H); MS (-ESI) m/z 200.3.
Preparation 69 and Example 142. (Scheme N: N-4 where n is 2. m is 0, X is N, Y is -CO2-, R3 is (l.l-dimethyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5)). [25-(R*^*)]-2-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-l-azetidinecarboxylic acid l-(l,l-dimethyl)ethyl ester (C26H29Cl2N3O6).
To a mixture of acid N-2 (Scheme N. where n
Figure imgf000181_0001
2, m is 0, X is N, Y is -CO2-, R3 is (1,1- dimethyl)ethyl, and the stereochemistry is (5)) (1.04 g; 5.17 mmol) and HOBt-H2O (0.71 g, 5.3 mmol) in CH2C12 (10 mL) at 0 °C is added a mixture of EDC-HC1 (1.00 g, 5.22 mmol) in CH2C12 (20 mL). The reaction mixture is stirred at 0 °C for 30 min, and then N-3 (Scheme N where R5 is 4-[(2,6-dichlorobenzoyl)amino)phenyl and stereochemistry is (5)) (2.10 g, 5.20 mmol) and N-methylmorpholine (0.60 mL, 5.46 mmol) are added. The reaction mixture is stirred at 0°C for 30 min and at rt for 3 h. The reaction mixture is partitioned between 10% KHS04 and CH2C12. The aqueous phase is extracted twice more with CH2C12. The combined organic extracts are washed with saturated ΝaHCO3 and brine, and then are dried, filtered and concentrated to a yellow oil (2.54 g) that is purified by silica flash chromatography to give the title compound as a white foam: mp 106-108 °C; TLC (1 :1 Hexanes/EtOAc); Rf= 0.21; [α]25 D -38 (c 1.01, MeOH); l3C NMR (CD3OD) δ 172.37, 171.58, 163.64, 156.68, 136.98, 136.22. 133.1 1, 131.87, 130.90, 129.49, 127.91, 120.00, 80.42, 61.87, 53.31, 51.45, 36.40, 27.16. 20.08; MS (EI) m/z 551, 549, 478, 476, 451, 449, 396, 394, 351, 349, 280, 278, 175, 173; Anal. C 56.33, H 5.48, N 7.23, Cl 12.43 (calcd for 0.52% H2O: C 56.44, H 5.34, N 7.59, Cl 12.82).
Preparation 70 and Example 143. (Scheme N: N-5 where n is 2, m is 0, X is N. Y is -CO2-, R3 is (l,l-dimethyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is [25-( ?*,i?*)])
[2S-(R*vR*)]-2-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyI]amino]- carbonyl]-l-azetidinecarboxylic acid l-(l,l-dimethylethyl) ester (C25H27Cl2N3O6). A solution of N-4 (Scheme N, where n is 2, m is 0. X is N, Y is -CO2-, R3 is (1,1- dimethyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5)) (507 mg, 0.92 mmol) and LiOH (1.25 mmol) in 1 : 1 MeOH/H2O (10 mL) is stirred at rt for 18 h. The reaction mixture is diluted with cold 10%) KHSO4 and extracted with CH2C12. The organic extracts are dried, filtered and concentrated to a white foam (498 mg), that is purified by silica flash chromatography to give the title compound: TLC (750:250:1 hexanes/acetone/HCO2H)
Figure imgf000182_0001
0.12; [α]25 D -27 (c 0.94, CHC13); 1 C NMR (CD3OD) δ 210.05, 172.70, 172.27, 163.63, 156.75, 136.89, 136.22, 133.36, 131.88, 130.90, 129.56, 127.91, 119.95, 80.47, 61.93, 53.18, 36.47, 27.15, 20.09; MS (-ESI) m/z 533.8; MS (EI) m/z 435, 419, 417, 401, 399, 373, 371, 280, 278, 175, 173, 147, 145; Anal. C 55.23, H 5.25, N 7.42, Cl 12.87 (calcd for 1.10% H2O: C 55.36, H 5.14, N 7.75, Cl 13.07).
Preparation 71 and Example 144. (Scheme N: N-6 where n is 2, m is 0, X is N. R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (25), L)
N-[[(25)-2-Azetidinyl]carbonyl]-4-[(2, 6-dichlorobenzoyl)amino]-L-phenyIalanine trifluoroacetic acid salt (C20H19C12N3O6 .C2HF3O2). A solution of N-5 (Scheme N, where n is 2, m is 0. X is N, Y is -CO2-, R3 is (1,1- dimethyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is [25- (R*,R*)]) (900 mg; 1.7 mmol) in 1 : 1 TFA CH2C12 (5 mL) is stirred at rt for 1.5 h, and is concentrated. The residue is thrice diluted with CHC13 and re-concentrated. This residue is dissolved in MeOH and concentrated to a white foam, that is dissolved in 1 : 1 MeOH/H2O and then concentrated to remove most of the MeOH. The solution is frozen and lyophilized to give the product as a white powder: [α]25 D -6 (c 0.72. MeOH); I3C NMR (CD3OD) δ 172.62, 167.54. 163.78, 136.82, 136.13, 133.43, 131.84. 130.97, 129.38, 127.93, 120.15, 58.38, 54.03, 43.73, 36.27, 23.33; MS (+ESI) m/z 436.0; MS (FAB) m/z 438, 436; Anal. C 46.77. H 3.75, N 7.24, Cl 12.44 (calcd for a 1 :1 TFA salt with 1.68% H2O: C 47.21, H 3.79, N 7.51, Cl 12.67). Example 145.
(Scheme N: N-4 where n is 1. m is 1, X is N, R3 is (l,l-dimethyl)ethyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, Y is CO2- and the stereochemistry is (5)) [S]-3-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyI]-2-methoxy-2- oxoethyl]amino]-carbonyl]-l-azetidinecarboxylic acid l-(l,l-dimethyl)ethyl ester (C26H29Cl2N3O6).
Example 145 was prepared as described in Scheme N from 3 -azetidinecarboxyiic acid. Physical properties as follows: TLC (1 :1 EtOAc/hexanes) Rf= 0.22; [α]25 D +18 (c 0.92, MeOH); l3C NMR (CD3OD) δ 172.92, 171.91, 163.68, 156.55, 136.87, 136.20, 133.27, 131.89, 130.91, 129.36, 127.90. 120.04, 79.80, 53.85, 51.45. 36.43, 32.26, 27.24; MS (EI) m/z 469, 467, 451, 359, 351, 349. 280, 278, 175, 173, 57; Anal. C 56.82. H 5.39, N 7.52, Cl 12.81 (calcd for 0.06% H2O: C 56.70, H 5.31, N 7.63, Cl 12.87).
Example 146. (Scheme N: N-5 where n is 1, m is 1, X is N, R3 is (l,l-dimethyl)ethyl, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl. Y is CO2- and the stereochemistry is (5)) (-S -3-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]]- 1-azetidinecarboxylic acid l-(l,l-dimethylethyl) ester (C25H27Cl2N3O6). Example 146 was prepared from example 145 by the procedure described in preparation 70. Physical properties as follows: TLC (600:400: 1 Hexanes/Acetone/HCO2H)
Figure imgf000183_0001
0.X7; [α]25 D +33 (c 0.92, MeOH); 13C NMR (CD3OD) δ 173.05. 172.89, 163.69, 156.56, 136.78, 136.19, 133.59, 131.89. 130.91. 129.40, 127.90. 120.00. 79.78. 53.67. 51.72. 36.47, 32.31, 27.24; MS (-ESI) m/z 533.9; MS (FAB) m/z 538. 536, 438, 436. 337, 335, 280. 278, 175,
173. 57: Anal. C 55.03, H 5.21, N 7.52, Cl 12.81 (calcd for 1.22% H2O: C 55.30, H 5.15,
N 7.74. Cl 13.06).
Example 147. (Scheme N: N-6 where n is 1, m is 1, X is NH, R5 is 4-[(2,6-dichlorobenzoyl)amino]- phenyl. and the stereochemistry is (L)) V-[[3-Azetidinyl]carbonyl]-4-[(2,6-dichlorobenzoyl)amino)-L-phenylalanine, trifluoroacetic acid salt (C20H19C12N3O6 .C2HF3O2).
Example 147 was prepared from Example 146 by the procedure described in preparation 71. Physical properties as follows: [α]25 D +32 (c 0.87, MeOH); 13C NMR (CD3OD) δ
173.32. 170.57, 163.80, 136.70, 136.13, 133.76, 131.84, 130.97, 129.45, 127.93, 120.17,
54.03. 36.59, 35.32); MS (FAB) m/z 438, 436, 391, 331, 175, 173, 101, 55; Anal. C
46.85. H 4.07, N 7.33, Cl 12.39 (calcd for a 1 :1 TFA salt with 3.34% H2O: C 46.41, H
3.92, N 7.38, Cl 12.45). Example 148.
[5-(i?*,i?*)]-4-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-{2-pyridinylmethyl) ester
(Scheme A, A-7: where RA., and RA_2 are the same and equal to proton, R3 is 2- pyridinylmethyl, Y is CO,-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)).
Figure imgf000184_0001
Example 148 was prepared as described in Scheme A from D-cysteine using 2- pyridinemethanol to form the requisite carbamate. Physical data as follows: 'H NMR
(300 MHz, CDC13) δ 8.37 (1 H), 7.70 (1 H). 7.51 (2 H), 7.27 (6 H), 7.08 (2 H). 6.92 (1 H), 5.24 (2 H). 4.77 (3 H). 4.40 (1 H), 3.74 (3 H). 3.37 (1 H), 3.15 (3 H); l3C NMR (75 MHz, CDCl3) δ 171.4, 162.5, 155.2, 149.0, 137.1, 136.5. 136.0. 132.4. 130.7, 129.9, 128.0, 123.1, 120.6, 63.0. 53.4. 52.5, 36.8; MS (ESI+) for C28H,6Cl,N4O6S m/z 616.8 (M+H)+; HRMS (El) calcd for C28H26Cl2N4O6S 616.0950, found 616.0946. Anal. Calcd for C28H26Cl2N4O6S: C. 54.46; H, 4.24; N, 9.07. Found: C, 54.61 ; H, 4.32; N, 8.97.
Example 149. [5-<i?*.Λ*)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)- amino]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(2- pyridinylmethyl) ester
(Scheme A. A-8: where RA_, and RA.2 are the same and equal to proton, R3 is 2-pyridinylmethyl, Y is CO2-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)).
Figure imgf000185_0001
Example 149 was prepared from example 148 by the procedure described in preparation 6. Physical data as follows: IR (mull) 1713, 1666, 1605, 1576, 1561, 1539, 1515, 1442, 1431, 1413, 1351, 1325, 1271, 1 194, 766 cm'1; Η NMR (300 MHz, CD3OD) δ 8.80 (1 H), 8.56 (1 H), 7.99 (2 H), 7.58 (2 H), 7.45 (3 H), 7.25 (2 H), 5.43 (2 H). 4.60 (3 H), 3.30 (3 H), 2.93 (2 H); 1 C NMR (75 MHz, CD3OD) δ 172.7. 171.5, 163.7, 152.8, 151.3, 146.6, 141.9, 136.8, 136.1. 133.6, 131.8, 130.9, 129.6, 127.9, 126.1. 125.4, 120.1, 63.2, 62.8, 59.4, 53.5, 36.4, 35.1 ; MS (ESI+) for C27H24Cl2N4O6S m/z 602.9 (M+H)+; MS (FAB) m/z (rel. intensity) 603 (MH+, 59), 605 (43), 603 (59), 154 (51 ). 139 (99), 137 (46), 136 (47), 123 (67), 105 (58). 103 (61), 93 (38); HRMS (FAB) calcd for C27H24Cl2N4O6S +H,
603.0872, found 603.0876; Anal. Calcd for C27H24Cl2N O6S • 0.3 H2O: C, 53.26; H, 4.07; N, 9.20. Found: C. 52.97: H. 4.23; N, 9.04. Example 150. [S Λ*.Λ*)]-4-[[[l-[[4-[(2,6-DicWoroben∞yl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-δ-oxo-3-thiazolidinepentanoic acid (Scheme A, A-7: where RA_, and RA.2 are the same and equal to proton. R3 is (CH2)3CO2H, Y is CO-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)).
Figure imgf000186_0001
Example 150 was prepared as described in Scheme A from D-cysteine using glutaric anhydride to form the requisite amide. Physical data as follows: IR (mull) 3077, 3053, 3040, 1738, 1728, 1696, 1682, 1641, 1557, 1437, 1430, 1414, 1307, 1232, 1209 cm'1; Η NMR (300 MHz, CDC13) δ 7.56 (2 H), 7.30 (3 H), 7.08 (2 H), 4.96 (1 H), 4.62 (3 H), 3.72 (3 H), 3.28 (4 H), 2.37 (4 H), 1.90 (2 H); 13C NMR (75 MHz, CDC13) δ 179.5, 176.0, 175.6, 173.6, 167.2, 140.6, 140.0, 136.1, 134.5, 133.7, 133.4, 131.8, 124.4, 66.7, 65.9, 57.2, 56.3, 40.3, 39.3, 37.3, 36.7, 36.2, 33.5, 23.6; MS (FAB) m/z (rel. intensity) 596
(MH\ 90), 598 (63), 597 (40), 596 (90), 341 (25), 263 (25), 230 (32), 225 (31 ), 193 (31), 141 (99), 88 (36); HRMS (FAB) calcd for C26H27Cl2N3O7S +H, 596.1025, found 596.1036. Anal. Calcd for C26H27Cl2N3O7S • 0.3 H2O: C. 51.88; H, 4.62; N, 6.98. Found: C, 51.69; H, 4.69; N, 6.59. Example 151.
[5-(Λ!,',i?*)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]- phenyl]ethyl]amino]carbonyl]-δ-oxo-3-thiazolidinepentanoic acid methyl ester (Scheme A, A-8: where RA_, and RA_2 are the same and equal to proton, R3 is (CH2)3CO2CH3, Y is CO-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)).
Figure imgf000187_0001
Example 151 was prepared as described in Scheme A from D-cysteine using methyl glutaryl chloride to form the requisite amide. Physical data as follows: IR (mull) 3287, 3196, 1724. 1662. 1607, 1562, 1540, 1516, 1431. 1414, 1326, 1268, 1217, 1195, 799 cm'1; MS (FAB) m/z (rel. intensity) 596 (MH\ 72), 598 (52), 596 (72), 229 (37), 193 (37), 167 (34), 133 (44). 129 (69), 121 (48), 103 (83), 89 (99); 'H NMR (300 MHz, CD3OD) δ 7.56 (2 H), 7.43 (3 H), 7.23 (2 H), 4.53 (3 H), 3.63 (3 H). 2.96 (4 H), 2.45 (3 H), 2.24 (2 H), 1.93 (2 H); nC NMR (75 MHz, CDC13) δ 174.0, 172.1. 169.9, 162.9, 162.8, 136.1, 132.2, 130.6, 130.0. 127.9, 120.3, 62.9, 54.5, 51.6, 49.8. 36.8, 33.5, 33.0, 32.7, 29.6, 19.6; HRMS (FAB) calcd for C26H27Cl2N3O7S +H, 596.1025, found 596.1047. MS (FAB) m/z (rel. intensity) 596 (MH\ 72), 598 (52), 596 (72), 229 (37), 193 (37), 167 (34), 133 (44), 129 (69), 121 (48), 103 (83), 89 (99).
Example 152. [5-(Λ*,i?*)]^l-[[[l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]ρhenyl]ethyl]amino]- carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(l-piperidinyl)ethyl] ester (Scheme A, A-8: where RA., and RA.2 are the same and equal to proton, R3 is 2-(l- piperidinyl)ethyl, Y is CO,-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (5, 5)).
Figure imgf000187_0002
Example 152 was prepared from example 5 by the procedure described in preparation 6. Physical data as follows: IR (mull) 3254, 2654. 171 1. 1565. 1547, 1512, 1438, 1344. 1300, 1240, 1196, 1179, 1 1 19, 1014, 767 cm '; 'H NMR (300 MHz. CD3OD) δ 7.45 (2 H), 7.36 (1 H), 7.19 (2 H), 6.97 (2 H), 5.26 (2 H), 4.50 (5 H), 3.60 (11 H), 1.83 (6 H); MS (ESI+) for C38H33Cl2N3O6S m/z 610.0 (M+HV"; Anal. Calcd for C28H33Cl,N3O6S -1.5 H2O • HCl: C, 49.90; H, 5.53; N. 6.24; Cl, 15.78. Found: C, 49.86; H, 5.43; N, 6.29; Cl, 15.65. % Water (KF): 3.99.
Example 153. [5-(Λ*, ?*)]-4-[[[l-Carboxy-2-[4-[(2,6-dichlorophenyl)methoxy]phenyl]ethyl]amino]- carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-3-thiazolidinecarboxamide (Scheme A, A-8: where RA., and RA.2 are the same and equal to proton, R3 is 2-(2-pyridyl)- ethyl, Y is COΝ(CH3)-, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (5, 5)).
Figure imgf000188_0001
Example 153 was prepared as described in Scheme A using 2-(2-methylaminoethyl)- pyridine to form the requisite urea and hydrolysis according to the procedure described in preparation 6. Physical data as follows: mp 80°C (softens), 125°C; IR (mull) 1661, 1611, 1585, 1565, 1511, 1489, 1439, 1394, 1300, 1240. 1196, 1179, 1017. 779, 768 cm'1; Η NMR (300 MHz, CD3OD) δ 8.44 (1 H), 7.75 (1 H), 7.35 (5 H), 7.12 (2 H), 6.93 (2 H), 5.22 (2 H), 4.83 (1 H), 4.65 (1 H), 4.32 (2 H), 3.77 (1 H), 3.45 (1 H), 3.20 (1 H), 3.00 (5 H), 2.84 (3 H); l3C NMR (75 MHz. CD3OD) δ 173.0, 170.8, 162.4. 158.4, 157.9, 147.9, 138.0, 136.6, 132.2. 130.6, 130.1, 129.3, 128.3, 124.2, 122.0, 1 14.5. 64.8, 64.7, 53.3, 52.5, 49.7, 35.7, 34.8, 32.8; MS (ESI+) for C29H30C12N4O5S m/z 6X7.0 (M+H)÷; Anal. Calcd for C29H30C12N4O5S: C, 56.40; H. 4.90; N, 9.07. Found: C, 56.31; H. 5.07; N, 8.98. Preparation 72 and Example 154.
[5-(Λ*, ?*)]^-[[[l-[[4-[(2.6-Dichlorobenzoyl)amino]phenyl]methyl]-2-[(4-pyridinyl)- methoxy]-2-oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000189_0001
To a solution of Example 12 (Scheme A, A-8: where RA., and RA.2 are the same and equal to H, R3 is ethyl, Y is CO2, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)) (400 mg, 0.74 mmol) in dimethylformamide (4 mL) was added tetramethylguanidine (204 μL, 1.63 mmol) followed by 4-picolyl chloride (138 mg, 0.81 mmol). The solution was heated to 65 °C for 3 h and volatiles removed in vacuo. Purification of the residue by flash chromatography using methylene chloride/methanol (2%) as eluant afforded the title compound (320 mg) as an amoφhous solid: IR (mull) 3275, 1748, 1677, 1608, 1561, 1539, 1515. 1431, 1415, 1344, 1325, 1271, 1222, 1194, 799 cm 1: Η NMR (300 MHz, CDC13) δ 8.87 (1 H), 8.48 (2 H), 7.50 (2 H), 7.25 (3 H), 7.10 (2 H), 6.93 (2 H), 5.08 (2 H), 4.79 (2 H), 4.61 (1 H), 4.28 (1 H), 4.13 (2 H), 3.16 (4 H), 1.21 (3 H); ,3C NMR (75 MHz, CDC13) δ 174.6, 170.7, 170.6, 162.6, 149.2. 144.5, 136.9, 136.0. 132.3, 131.7, 130.7, 129.8, 128.0. 122.5, 120.3, 65.0, 63.0, 62.7, 53.3, 37.3, 20.9, 14.5; MS (ESI+) for C29H28Cl2N4O6S m/z 630.8 (M+HV"; Anal. Calcd for C29H28Cl2N4O6S: C, 55.15; H, 4.47; N, 8.87. Found: C, 54.85; H, 4.58; N, 8.74. Anal. Calcd for C29H28Cl2N4O6S: C, 55.15; H. 4.47; N, 8.87; Cl, 1 1.23; S, 5.08. Found: C, 54.85: H, 4.58; N, 8.74.
Preparation 73 and Example 155. [5-(/?*./?*)]-3-[[[l-Carboxy-2-[4-[(2,6- lichlorophenyl)methoxy]phenyl]ethyl]amino]- carbonyl]-8-methyl-l-thia-4,8-diazaspiro[4.5]decane^)~carboxylic acid 4-ethyl ester (Scheme B, B-7: where RB., and RB.2 are the same and equal to H, RB.3 and R together form a cyclic ring of 6 atoms of the formula -CH,CH,N(CH3)CH,CH,-, Y is CO,, R3 is ethyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (5. 5)).
Figure imgf000190_0001
t-Butyl ester B-6 (Scheme B where RB., and RB.2 are the same and equal to H, RB.3 and RB. 4 together form a cyclic ring of 6 atoms of the formula -CH,CH,N(CH3)CH2CH2-, Y is CO2, R3 is ethyl, RB.5 is O-t-butyl, R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (5, 5), prepared according to Scheme B from 1 -methyl-4-piperidone and D-cysteine) (681 mg, 1.02 mmol) was dissolved in a solution of HCl in dioxane (4 M, 28 mL) at ambient temperature. After 18 h, volatiles were removed in vacuo to afford a residue (650 mg) which was lyophilized from water. Further purification of a portion of this product (200 mg) was effected by chromatography on a Biotage Flash 40™ system using a 40 g KP-C18-HS (35-70 μm) silica gel cartridge using aqueous acetonitrile (40%) as eluant to afford the title compound (94 mg) as an amoφhous powder: IR (mull) 1696, 1611, 1585, 1565, 1511, 1439, 1404, 1335, 1303, 1271, 1239, 1 196, 1178, 1017, 769 cm ' '; 'H NMR (DMSO-d(5, 300 MHz) δ 8.25 (1 H), 7.54 (2 H), 7.43 (1 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.84 (1 H), 4.41 (1 H), 4.00 (2 H), 3.07 (4 H), 2.73 (4 H), 2.53 (3 H), 1.96 (1 H), 1.69 (1 H), 1.1 1 (3 H); 13C NMR (CDC13, 75 MHz) δ 173.9, 169.2, 157.7, 153.2, 136.9, 132.1, 130.7, 130.5, 129.3, 128.5, 114.7, 73.2, 66.7, 65.2, 62.8, 54.0, 43.5, 36.5, 14.6; MS (ESI+) for C28H33Cl2N3O6S m/z 610.0 (M+H)+; MS (ESI-) for C28H33Cl2N3O6S m/z 607.9 (M-H)"; HRMS (FAB) calcd for C28H33Cl2N3O6S+H, 610.1545, found 610.1561. Anal. Calcd for C28H33Cl,N3O6S • 0.6 HCl • H2O: C, 51.70; H, 5.52; N, 6.46; Cl, 14.17. Found: C, 51.28; H, 5.49; N, 6.50; Cl, 14.57. % Water (KF): 2.72.
Example 156.
[5-(Λ*,Λ*)]^l-[[[l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-(3-tetrahydrofuranyl) ester (Scheme A, A-7: where RA_, and RA„2 are the same and equal to proton. R3 is 3- tetrahydrofuranyl, Y is CO,-, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5, 5)).
Figure imgf000191_0001
Example 156 was prepared as described in Scheme A from D-cysteine using 3- hydroxytetrahydrofuran to form the requisite carbamate. Physical properties as follows: mp 125-126.5°C. IR (mull) 3311, 1750. 1744, 1708, 1661, 1549, 1515, 1439, 1408, 1307, 1243. 1227, 1212, 1173, 1019 cm'1; 'H NMR (300 MHz, CD3OD) δ 7.38 (3 H), 7.14 (2 H), 7.96 (2 H), 5.20 (1 H), 5.25 (2 H), 4.61 (4 H), 3.79 (4 H), 3.74 (3 H), 3.19 (2 H), 2.84 (2 H), 2.29 (2 H); 13C NMR ( 75 MHz, CDC13, spectra complicated via the presence of diastereomers) 6171.7, 171.6, 158.1, 137.0, 132.1, 130.5, 130.4, 130.3, 128.5. 128.2,
1 15.1, 77.2, 77.2, 73.2, 67.0, 65.2, 63.1, 63.0, 53.3, 52.5. 52.4, 36.9, 32.9; MS (ESI+) for C,6H2gCl,N,O7S m/z 582.8 (M+H)+; Anal. Calcd for C26H28Cl2N2O7S: C, 53.52; H, 4.84; N, 4.80. Found: C, 53.34; H, 4.87; N, 4.86.
Example 157. [S-(R*,R*)]-2-[[[l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-hexahydro- γ-oxo- 1 H-azepine- 1 - butanoic acid
Figure imgf000191_0002
Example 157 was prepared as described for the preparation of Example 167. Physical properties as follows: IR (mull) 1781. 1709. 1651. 1625, 1612, 1550. 1537. 1515, 1444, 1431. 1418. 1398, 1331, 1 193, 798 cm'1; 'H NMR (300 MHz, DMSO-dtf) δ 1.45 (8 H), 2.30 (4 H). 2.90 (3 H), 3.80 (1 H), 4.50 (2 H), 7.16 (2 H), 7.50 (5 H), 7.94 (1 H), 10.62 (1 H), 7.71 (1 H); MS (FAB) m/z (rel. intensity) 578 (M+H. 43), 581 (9), 580 (29), 579 ( 19), 578 (43), 577 ( 10), 227 ( 11 ), 226 (99), 198 ( 18), 173 (9), 98 (46).
Preparation 74 and Example 158. (Scheme N, N-6: where n is 2, m is 0, X is N, R< is 4-[(2,6- dichlorobenzoyl)amino]phenyl and stereochemistry is 2S-(R*,R*))
[2S-(R*^?*)]-2-[[[l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyI]azetidine (C21H21Cl2N3O4).
A solution of the product of example 142 (Scheme N: N-4 where n is 2, m is 0, X is N, Y is -CO,-, R3 is (Ll-dimethyl)ethyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (5)) (512 mg; 0.93 mmol) in 1 : 1 TFA CH,C1, ( 10 mL) is stirred at rt for 1 h. The reaction mixture is concentrated under reduced pressure. The residue is taken up in a mixture of CH,Cl, and satd aqueous NaHCO,. The aqueous phase I extracted twice additionally with CH2C12. The combined CH2C12 portions are dried, filtered and concentrated to give a yellow oil (440 mg), that is purified by silica flash chromatography (95 :5 CH2Cl2/MeOH) to afford the title compound (324 mg) as a white foam: mp 113- 1150C; TLC (95:5 CH2Cl,/MeOH) Rf= 0.10; [α]25 D -34 (c 0.96, MeOH); UV (MeOH) λmax 224 (sh, ε 12100), 251 (17700), 284 (sh, 2880); IR (mineral oil mull) 3260, 1744, 1664, 1606, 1561, 1537, 1515, 1431, 1414, 1323, 1270, 1223, 1195, 799, 782 cm-'; Η NMR (CD3OD) δ 7.61 (2H), 7.50-7.38 (3H), 7.25 (2H), 4.86 (IH), 4.75 (IH), 4.21 (IH), 3.73 (3H), 3.61 (2H), 3.39-3.28 (IH), 3.23 (IH), 3.05 (IH), 2.63-2.50 (IH), 2.21-2.08 (IH); MS (+ESI) m/z 450.0; MS (EI) m/z 451, 449. 396, 394, 351, 349, 278, 211, 175, 173, 96, 70, 56; Anal. C 55.68, H 4.79, N 8.96, Cl 15.43 (calcd for +1.08% H2O: C 55.41, H 4.77, N 9.23, Cl 15.58).
Example 159. 0-[(2,6-Dichlorophenyl)methyl]-Λ^-[[(4S)-3-(methylsulfonyl)-4- thiazolidinyl]carbonyl]-L-tyrosinamide (Scheme C, C-10: where R^., R^, Rc.3 and R^ are the same and equal to proton, R3 is methyl . Y is SO,-. R5 is 4-[(2,6-dichlorophenyl)methoxy]phenyl and stereochemistry is (5, 5)).
Figure imgf000193_0001
Example 159 was prepared as described in Scheme C using methanesulfonyl chloride to form the requisite sulfonamide. Physical properties as follows: mp 228-230°C; Η NMR (300 MHz, DMSO-d6) δ 8.03 (1 H), 7.54 (2 H), 7.44 (2 H), 7.14 (3 H), 6.92 (2 H), 5.16 (2 H), 4.69 (2 H), 4.41 (1 H), 4.31 (1 H), 3.21 (1 H), 3.01 (3 H), 2.87 (3 H); l3C NMR (75 MHz, DMSO-dtf) δ 172.9, 169.1, 157.5. 136.5, 132.3, 132.0, 130.8, 130.6. 129.2, 114.6, 65.3, 64.4, 54.3, 52.0, 37.3, 35.0; MS (ESI-) for C21H23Cl2N3O5S, m/z 530.2 (M-H)'; Anal. Calcd for C,,H23Cl2N3O5S2: C, 47.37; H. 4.35; N, 7.89. Found: C. 47.43; H, 4.46; N, 7.81. Example 160.
[S-(R*,R*)]-3-[[[l-[[4-[(2,6-Dichlorophenyl)methoxy]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl] -l-thia-4-azaspiro[4.4]nonane-4-carboxylic acid 4—ethyl ester (Scheme B, B-6: where RB., and RB.2 are the same and equal to H, RB.3 and RBJt together form a carbocyclic ring of 5 atoms, RB_5 is OCH3, Y is CO2, R3 is ethyl, R5 is 4-[(2,6- dichlorophenyl)methoxy]phenyl and stereochemistry is (5, 5)).
Figure imgf000193_0002
Example 160 was prepared as described in Scheme B. Physical properties as follows: IR (mull) 1746, 1705, 1681, 1510, 1439. 1399, 1336, 1301, 1276, 1241 , 1203, 1 178, 1110, 1017, 769 cm'1; 'H NMR (CDC13) δ 7.36 (2 H), 7.25 (1 H), 7.03 (2 H), 6.93 (2 H), 6.64 (1 H), 5.22 (2 H), 4.85 (2 H), 4.15 (2 H), 3.73 (3 H), 3.15 (4 H), 2.69 (1 H), 2.48 (1 H), 1.76 (6 H), 1.23 (3 H); 13C NMR (CDC13) δ 171.5, 170.7, 158.0, 152.5, 137.0, 132.0, 130.5, 130.3, 128.5, 128.2, 1 15.0. 66.4, 65.2, 61.9, 53.1, 52.4, 37.1. 32.3, 25.1. 24.6, 14.5; MS (ESI+) for C28H32Cl,N,O6S m/z 594.9 (M+H)+. MS (ESI-) for C,8H3,Cl,N,O6S m/z 592.8 (M-H)'; Anal. Calcd for C28H32Cl,N,O6S • 0.10 H,O: C, 56.30: H, 5.43; N, 4.69. Found: C, 56.20; H, 5.24; N, 4.69. % Water (KF): 0.31.
Example 161.
[S-<R*,R*)]-3-[[[l-Carboxy-2-[4-[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-l-thia-4-azaspiro[4.4]nonane— 4- carboxylic acid 4-ethyl ester (Scheme B, B-7: where RB_, and RB_2 are the same and equal to H, RB_3 and RB^, together form a carbocyclic ring of 5 atoms, Y is CO2, R3 is ethyl, R5 is 4-[(2,6-dichlorophenyl)- methoxy]phenyl and stereochemistry is (5, 5)).
Figure imgf000194_0001
Example 161 was prepared from example 160 by the procedure described in preparation 6. Physical properties as follows: IR (mull) 1737, 1708, 1675, 1612, 1511, 1439, 1402, 1338, 1301, 1241, 1 197, 1179, 1115, 1018, 769 cm '; 'H NMR (DMSO-d6) δ 8.07 (1 H), 7.54 (2 H), 7.45 (1 H), 7.12 (2 H), 6.94 (2 H), 5.15 (2 H), 4.63 (1 H), 4.33 (1 H), 3.91 (2 H), 3.05 (2 H), 2.79 (1 H), 2.60 (1 H), 1.60 (6 H), 1.07 (3 H); ,3C NMR (DMSO-d6) δ 172.7, 169.4, 157.1, 155.7, 135.9, 131.6, 131.4, 130.3. 129.6, 128.7, 114.1, 83.9, 64.7, 60.5, 53.1, 38.0, 36.2, 31.8, 24.2, 24.1, 14.1 ; MS (ESI+) for C27H30C1,N2O6S m/z 580.8 (M+H)+; MS (ESI-) for C27H30C12N2O6S m/z 578.8 (M-H)'; HRMS (El) calcd for C27H30C1,N,O6S 580.1202, found 580.1172; Anal. Calcd for C27H30C12N,O6S ' 0.19 H2O: C, 55.44; H, 5.24; N, 4.79. Found: C, 55.24; H, 5.32; N, 4.79. % Water (KF): 0.59.
Preparation 75.
Figure imgf000194_0002
The aminoester product of preparation 75 is useful as a synthetic intermediate (for example, reagent A-4 of Scheme A). To a cold (0-5°C) solution of anhydrous methanolic HCl was added 100 g of L-4- nitrophenylalanine (Advanced ChemTech) portionwise over 15 min. The mechanically stirred mixture was heated to gentle reflux for 48 h. The mixture was allowed to cool and then filtered through a sintered glass filter funnel, washing the collected solids with hot MeOH until only insoluble residues remained. The filtrate was concentrated in vacuo to afford the methyl ester (120 g) as waxy off white solid which was used without further purification.
To a suspension of methyl ester described above (87 g, 0.33 mole) in CH2C1, (1500 mL) at ambient temperature was added di-t-butyldicarbonate (109 g, 0.50 mole) followed by the dropwise addition of Et3N (51 mL. 0.37 mole). After 15 min additional Et3N (40 mL, 0.29 mol) was added to maintain a slightly basic mixture (ca. pH 8). The reaction mixture was stirred 18 h and additional CH,C1, (1400 mL) and Et3N (15 mL, 0.1 1 mol) were added. After an additional 2 h the reaction mixture was quenched by the slow addition of MeOH (100 mL), stirred for 1 h and then partitioned between CH2C12 and cold 10% aqueous KHSO4. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue using hexane and a gradient of a 1 :1 mixture of EtOAc/CH,Cl2 (25-33%) afforded the Boc-methyl ester (69 g) as a white solid. Physical properties as follows: Η NMR (300 MHz; CDC13) δ 8.16 (2H), 7.31 (2H), 5.04 (IH). 4.63 (IH), 3.73 (3H), 3.18 (2H), 1.41 (9H); MS (ES+) for C15H20N2O6 m/z 325.2 (M+H)\
Palladium on carbon (10% w/w, 1.25 g) was added to a Parr hydrogenation flask under a N, atmosphere and carefully wetted with 100 mL of MeOH/THF (1 :1). A solution of the Boc-methyl ester described above (25 g, 77 mmol) in 400 mL of MeOH/THF (1 : 1) was added and the mixture shaken on a hydrogenation apparatus under a hydrogen atmosphere (20 psi) for 1 h at ambient temperature. The reaction mixture was filtered through a pad of Celite and the solids washed several times with MeOH. The combined filtrates were concentrated in vacuo to afford the 4-aminophenylalanyl derivative (22.7 g) which was used without further purification. Physical properties as follows: 'H NMR (300 MHz, CDC13) δ 6.89 (2H), 6.61 (2H). 4.96 (IH), 4.50 (IH), 3.69 (3H). 2.95 (2H), 1.41 (9H); MS (ES+) for C15H,,N,O4 m/z 295.2 (M+H)*. A cold (0-5°C) solution of 2,6-dichlorobenzoyl chloride (1 1.1 mL, 77.5 mmol) in 125 mL of THF was treated dropwise with a solution of the 4-aminophenylalanyl derivative described above (22.7 g, 77.1 mmol) and Et3N (16 mL, 115 mmol) in 125 mL of THF. The reaction mixture was allowed to warm to temperature and stir an additional 18 h. The mixture was diluted with EtOAc (2 L) and then washed with IN HCl, H,O, IN NaOH and brine. The organic extract was dried (Na,SO4), filtered, and concentrated in vacuo to give the crude product as a pale yellow solid. This material was recrystallized from acetone/hexanes (ca. 1 :1) to afford the amide (30.8 g) as a crystalline solid. Physical properties as follows: mp 192.2-193.1°C; IR (mull) 3305, 1747, 1736, 1690, 1665, 1609, 1548. 1512. 1433, 1414, 1325, 1277, 1219, 1 171. 781 cm '; 'H NMR (300 MHz; CDC13) δ 7.57 (2H), 7.34 (4H), 7.14 (2H), 4.98 (IH), 4.60 (IH), 3.74 (3H), 3.1 1 (2H), 1.42 (9H); MS (ES+) for C22H24Cl2N2O5 m/z 467.0 (M+H)+.
To 650 mL of anhydrous 4M HCl in dioxane at ambient temperature was added the amide described above (30.6 g, 65.5 mmol) portionwise and the resulting mixture was stirred until all the solids had dissolved (ca. X h). Volatiles were removed in vacuo to give a light yellow solid which was partitioned between water (500 mL) and ether (1 L). The water layer was separated and concentrated in vacuo to approximately 200 mL. The aqueous solution was then frozen and lyophilized to afford the aminoester product (25.6 g) as a light yellow solid. Physical properties as follows: [α]25 D = +5 (c X, MeOH); IR (mull) 3244, 3186. 3112, 1747, 1660, 1604, 1562, 1539, 1516, 1431, 1416, 1327, 1273, 1243,
799 cm '; 'H NMR (300 MHz; CD3OD) δ 7.69 (2H), 7.45 (3H), 7.29 (2H), 4.34 (IH), 3.83 (3H), 3.21 (2H); ,3C NMR (300 MHz; CD3OD) δ 169.0, 163.9, 137.8, 136.08, 131.8, 131.0. 130.3, 129.7, 127.9, 120.6, 53.8. 52.3, 35.4; MS (ES+) for C17HI6Cl,N2O3 m/z 367.1 (M+H)\ Preparation 76.
H,N, ,CH, ■ HCl
Figure imgf000196_0001
The aminoester product of preparation 75 is useful as a synthetic intermediate (for example, reagent A-4 of Scheme A).
To a cold (0-5°C) solution of anhydrous methanolic HCl (200 mL) was added 25 g of N- α-t-Boc-0-2,6-dichlorobenzyl-L-tyrosine (Sigma) portionwise over 15 min. After 30 minutes at 0-5°C, the mixture was heated to 50°C for 2 h. The solution was cooled to room temperature and the volatiles removed in vacuo. The solid was suspended in ethyl ether and collected by filtration to afford the title compound (21.4 g) which was used without further purification. Physical properties as follows: [ ]25 D = +16(c 1.00, ethanol); Η ΝMR (300 MHz. CD3OD) δ 7.44 (2 H), 7.35 (1 H), 7.21 (2 H), 7.02 (2 H), 5.28 (2 H), 4.29 (1 H), 3.81 (3 H), 3.18 (2 H); MS (ESI+) for C,7H17Cl,ΝO3 m/z 354.1 (M+H)+; Anal. Calcd for C,7H17Cl2NO3 « HCl: C, 52.26: H, 4.64; N, 3.59. Found: C, 52.17; H, 4.74; N, 3.61.
Example 162 2-[[[(lS)-l-[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-l-piperidinecarboxylic acid l-[(l,l-dimethyl)ethyl] ester
Figure imgf000197_0001
Example 162: HCl gas was bubbled through a solution of Λ/-(tert-butoxycarbonyl)-4-(2,6- dichlorobenzoylamino)-L-phenylalanine (2.5 lg, 5.53 mmol) in MeOH (20 mL) for 10 minutes. The solution was stirred for additional 2 hours at room temperature. The solvent was removed in vacuo and the excess HCl was removed by the addition of Et2θ (3 x 15 mL) and evaporation under reduced pressure. The resultant gum was dissolved in THF (10 mL) and N-tert-butoxycarbonyl-pipecolinic acid (1.28 gm. 5.59 mmol), BOP-reagent (2.69 gm, 6.09 mmol) and DIEA (2.9 mL. 16.6 mmol) were added and the reaction mixture was stirred overnight. EtOAc (25 mL) was added and the mixture was extracted with IN HCl (20 mL). The organic phase was washed with saturated LiCl (20 mL) then saturated NaHCOo (30 mL). The organic layer was dried over
Figure imgf000198_0001
filtered and evaporated. Chromatography of the residue (silica gel, Hexanes -> 50%> EtOAc/Hexanes gradient elution) provided Example 162 as a solid (1.45 gm, 45 %): ESMS (m/z) 578, 580
(MH+).
Example 163 2-[[[( S)- 1 -[[4-[(2,6-Dichlorobenzoyl)amino]phenyl]methyl]-2-methoxy-2- oxoethyl]amino]carbonyl]-γ-oxo-l-piperidinebutanoic acid
Figure imgf000198_0002
HCl gas was bubbled through a MeOH (20 mL) solution of Example 162 (1.27 gm, 2.20 mmol) for 10 min. Stirring was continued overnight at room temperature. The solvent was removed in vacuo and the excess HCl was removed by washing with Et2θ (3 x 10 mL) on a vacuum filter. The HCl salt was completely dried under high vacuum to provide Compound 1 (1.09 gm, 97 %) as a solid: ESMS (m/z) 478, 480 (MH+).
Example 163: Compound 1 (147 mg, 0.285 mmol) was dissolved in DMF (5 mL) containing DIEA (150 μL, 0.88 mmol). To this solution was added succinic anhydride (59 mg, 0.59 mmol) and the mixture was stirred at 50°C for 5 hr under dry nitrogen. The solvent was evaporated and the residue was purified by column chromatography (silica gel, Hexanes -> EtOAc gradient elution) to provide Example 163 as a solid (164 mg):
ESMS (m/z) 578, 580 (MH+). Examples 164-166
The following mono methyl esters were prepared in a similar manner as Example 163
Figure imgf000199_0001
ex# R3 MS
(m z)
164 ^ 646
HOOC' (MH+)
165 620
HOOC (MH+)
166 HOOC " 574
\^
([M-H]")
Example 167 2-[[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-γ- oxo-1-piperidinebutanoic acid
Figure imgf000199_0002
Example 163 (154 mg, 0.266 mmol) was treated with LiOH (26 mg, 1.07 mmol) in
H2O (5 mL) for 3 hours. The product was then precipitated by the addition of 3 N HCl. The product was collected by vacuum filtration and washed with cold H2O (2 x 3 mL). Drying under high vacuum provided Example 167 as a solid (109 mg): ESMS (m/z) 562 ([M-H]').
Example 168-170
The following compounds were prepared in a similar manner as 167.
Figure imgf000200_0001
(m/z)
168 630
HOTXT ° ([M-H]')
169 604
HOOC^ ° ([M-H]')
170 HOOC V*" 560 ([M-H]")
Preparation 77
Figure imgf000200_0002
Merrifield resin Intermediate -1
RB=& ^CH2-
® =po» met Intermediate-1 : Attachment of N-tert-butoxycarbonyl-[4-(2,6,-dichlorobenzoylamino)]- L-phenylalanine to Merrifield resin was done using Horiki's method (Horiki et al., Chem. Lett. 1978(2) 165-168). In a 250 mL round bottom flask fitted with a drying tube, Merrifield resin (Biorad, 10.0 g, 13.5 mmol/g) and anhydrous potassium fluoride (Aldrich, 1.57g, 27.0 mmol) were added to a solution of N-tert-butoxycarbonyl-[4-(2,6,- dichlorobenzoylamino)]-L-phenylalanine (Bachem California, 6.13 g, 13.5 mmol) in dry DMF (100 mL). The reaction mixture was stirred at 80°C in an oil bath for 24 hr. The cooled resin was then filtered and washed thoroughly with DMF (2 x 250 mL), 50%) aqueous DMF (3 x 250 mL), methanol (3 x 250 mL), dichloromethane (3 x 250 mL), and finally methanol (3 x 250 mL). The resin was then dried under reduced pressure to constant weight to give Intermediate-1. Incorporation of N-tert-butoxycarbonyl-[4-(2,6,- dichlorobenzoylamino)]-L-phenylalanine onto the resin was estimated to be 0.045 mmol/g from the increase in resin mass.
Example 171 jV-[[2-(l,3-Benzodioxol-5-yl)-l-methyl-5-oxo-3-pyrrolidinyl]carbonyl]-4-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine
Figure imgf000201_0001
Example 171 : The Intermediate-1 (0.15 g, 0.1065 mmol/g) was pretreated with CH2CI2 (2x 3 mL). The swollen resin was then deprotected with 50%) TFA/CH2CI2 (3mL, 30min). The resin was rinsed in the following order: CH2CI2 (2 x 3 mL), CH3OH (2 x 3 mL), CH9CI-) (2 x 3 mL). The resin was swollen with DMF (2 x 3 mL). 2-(3.4- methylenedioxyphenyl)- 1 -methyl-5-oxo-3 -pyrrolidine carboxylic acid (84 mg, 0.32 mmol) in DMF (1.0 mL) was activated with 0.5 M HBTU/HOBT in DMF (0.7 mL) and DIEA (0.139 mL, 0.799 mmol), and then added to the swollen resin. The mixture was vortexed for 2 hr at room temperature. The resin was filtered and washed in the following order: DMF(2 x 3 mL), CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C12 (2 x 3 mL), respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight. The resin was placed in the polypropylene column and pretreated with 3 mL of THF. Then to the preswollen resin 1.6 mL of THF, 0.48 mL of CH3OH, and 0.160 mL of 2N LiOH were added. The mixture was vortexed for 15 min and filtered to a clean and preweighed test tube. The resin was next washed with 2mL of THF/5%) CH3OH (2x) and the combined filtrates were evaporated. The resulting gum was dissolved in 1 mL of water. The solution was then acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with water (5mL, 2x) and dried in vacuo to furnish 15.4 mg of Example 171 as a solid. ESMS (m z): 596, ([M-H]').
Preparation 78
Figure imgf000202_0001
Xι=
Figure imgf000203_0001
Intermediate-2F: The resin bound N-tert-butoxycarbonyl-[4-(2,6- dichlorobenzoylamino)]-L-phenylalanine (Intermediate-1), (250 mg, 0.1125 mmol/g) was placed in a 8.0 mL, polypropylene filter column fitted with a 2-way polypropylene stopcock. The resin was pretreated with CH2CI2 (2 x 3 mL). The swollen resin was then deprotected with 50% TFA CH2CI2 (3-4 mL, 30min) with shaking. The resin was rinsed in the following order: CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C12 (2 x 3 mL).
The resin was swollen with DMF (2 x 3 mL). N-Tert-butoxycarbonyl-nipecotic acid (103 mg, 0.45 mmol) in DMF (1.0 mL) was activated with 0.5 M HBTU/HOBT in DMF (0.910 mL) and DIEA (0.195 mL), then added to the swollen resin. The mixture was vortexed for 2 hr at room temperature. The resin was washed in the following order: DMF (2 x 3 mL), CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C12 (2 x 3 mL) and dried (Intermediate-
2F). If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained.
The intermediate resins Intermediate-2D, 2E, 2G, 2H, 21, 2J & 2K were each produced following this procedure.
Example 172 5-[[(2S)-2-[[[(lS)-l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]- 1 -piperidinyl]carbonyl]-3- pyridinecarboxylic acid
Figure imgf000204_0001
Example 172
Example 172: Resin bound Intermediate-2D (2.0 g, 1.3 mmol/g) was pretreated with CH2C1 (2 x 20 mL). The swollen resin was then deprotected with 50% TFA CH C19 (20 mL, 30min). The resin was rinsed in the following order: CH2CI2 (2 x 20 mL), CH3OH (2 x 20 mL), CH2C12 (2 x 20 mL). The resin was swollen with DMF (2 x 20 mL). 3,5-
Pyridine dicarboxylic acid (652 mg, 3.9 mmol) in 20 mL of DMF was activated with 0.5 M HBTU/HOBT in DMF (8.0 mL) and DIEA (1.7 mL, 9.75 mmol), then added to the swollen resin. The mixture was vortexed for 2 hr at room temperature. The resin was filtered and washed in the following order: DMF(2 x 20 mL), CH2C12 (2 x 20 mL), CH3OH (2 x 20 mL), CH2C1 (2 x 20 mL), respectively. If a Kaiser test (Kaiser et al.,
Anal. Biochem. 1970. 34, 594-598) on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight (2.2 g). The resin was treated with 25 mL of liquid HF by stirring for 60 min at 0°C in an HF-reaction apparatus (Peninsula Laboratories Inc., Belmont, CA). The HF was rapidly evaporated off by vacuum aspiration at 0°C. Then
100 mL of dry ethyl ether was added. The resin and the resulting precipitates were filtered off and washed three times with 50 mL of ethyl ether, and dried in vacuo. The mixture was then treated with 25 mL of IN NaOH (4x). and the combined solutions were lyophilized. The crude product was purified by HPLC using a C-18 column and a linear acetonitrile/0.1 % HCl gradient. The gradient was run from 60%) solvent A (0.1 %> HCl) to 80%> solvent B (80% acetonitrile in 0.1 % HCl) in 20 min. Lyophilization furnished 20 mg (2.5%) of Example 172. ESMS (m/z): 612 ([M-H]").
Examples 173-267
X
Figure imgf000205_0001
Method- A (Example 173) 4-[(2,6-Dichlorobenzoyl)amino]-JV-[[l -(3-methoxy- 1 -oxopropyl)-3-piperidinyl]carbonyl]-
L-phenylalanine
Figure imgf000205_0002
Example 173
The Intermediate-2F (0.25 g, 0.1 125 mmol/g) was pretreated with CH2C12 (2 x 3 mL).
The swollen resin was then deprotected with 50%> TFA/CH2CI9 (3mL. 30min). The resin was rinsed in the following order: CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C12 (2 x 3 mL). The resin was swollen with DMF (2 x 3 mL). 3-methoxypropionic acid (53 mg, 045 mmol) in DMF (1.0 mL) was activated with 0.5 M HBTU/HOBT in DMF (0.910 mL) and DIEA (0.195 mL), then added to the swollen resin . The mixture was vortexed for 2 hr at room temperature. The resin was filtered and washed in the following order: DMF (2 x 3 mL), CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C12 (2 x 3 mL), respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight. The resin was placed in the polypropylene column and pretreated with THF (3 mL). Then THF (3.5 mL), CH3OH (1.0 mL) and 2N LiOH (0.175 mL) were added. The mixture was vortexed for 15 min and filtered to a clean and preweighed test tube. The resin was next washed with THF/5%> CH3OH (2mL) and the combined filtrates were evaporated. The resulting gum was dissolved in H2O (1 mL). The solution was then acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with water (2 x 5 mL) and dried in vacuo to furnish 38.3 mg of Example 173 as a solid: ESMS (m z) 548
([M-H]').
Method B (Example 174): 3-[[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-γ- oxo-1-piperidinebutanoic acid
Figure imgf000206_0001
Exampl 17 ό The Intermediate-2F (0.25g, 0.1125 mmol/g) was pretreated with CH2C12 (2 x 3 mL). The swollen resin was then deprotected with 50%) TFA/CH2O2 (3mL. 30min). The resin was rinsed in the following order: CH2CI2 (2 x 3 mL), CH3OH (2 x 3 mL). CH2CI2
(2 x 3 mL). The resin was then swollen with DMF (3mL). Succinic anhydride (45 mg, 0.45 mmol) dissolved in DMF (4 mL) was added to the swollen resin and stirred at 50°C for 2hr. The resin was filtered and washed in the following order: DMF (2 x 3 mL),
CH2C12 (2 x 3 mL), CH3OH (2 x 3 mL), CH2C1 (2 x 3 mL), respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight. The resin was placed in the polypropylene column and pretreated with THF (3 mL). Then to the swollen resin THF (3.5 mL), CH3OH (1.0 mL) and 2N LiOH (0.175 mL) were added. The mixture was vortexed for 15 min and filtered to a clean and preweighed test tube. The resin was next washed with THF/5%> CH3OH (2 x 2 mL) and the combined filtrates were evaporated. The resulting gum was dissolved in H2O (1 mL).
The solution was then acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with H2O (2 x 5 mL) and dried in vacuo to furnish 30.5 mg of Example 174 as a
solid: ESMS (m/z) 562 ([M-H]").
Method C (Example 175):
N-[[l-[[(4-Carboxyphenyl)amino]carbonyl]-4-piperidinyl]carbonyl]-4-[(2,6- dichlorobenzoyl)amino]-L-phenylalanine
Figure imgf000207_0001
Example 175
The Intermediate-2G (0.25g, 0.1125 mmol/g) was pretreated with CH2C12 (2 x 3 mL). The swollen resin was then deprotected with 50% TFA CH2CI2 (3mL, 30min). The resin was rinsed in the following order: CH2CI2 (2 x 3 mL), CH3OH (2 x 3 mL), CH2CI2
(2 x 3 mL). The resin was then swollen with DMF (3mL). Ethyl 4-isocyanatobenzoate (22 mg, 0.108 mmol) dissolved in DMF (3 mL) and DIEA (47 μL 0.27 mmol) were added to the swollen resin. This reaction mixture was vortexed for 6-8 hr at room temperature. The resin was filtered and washed in the following order: DMF (2 x 3 mL), CH2CI2 (2 x
3 mL), CH3OH (2 x 3 mL), CH CI2 (2 x 3 mL), respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant. The resin was placed in the polypropylene column and pretreated with THF (3 mL). Then to the swollen resin THF (3.5 mL), CH3OH (1.0 mL) and 2N LiOH (0.175 mL) were added respectively. The mixture was vortexed for 15 min and filtered to a clean and preweighed test tube. The resin was next washed with THF/5%> CH3OH (2mL) and the combined filtrates were evaporated. The resulting gum was dissolved in H2O (1 mL). The solution was then acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with H2O (2 x
5 mL) and dried in vacuo to furnish 18 mg of Example 175 as a solid: ESMS (m/z) 625, ([M-H]').
Examples 176-266
The following compounds were prepared in a similar manner as described above.
Figure imgf000208_0001
ex# Method Q MS
(m z)
Figure imgf000208_0002
Figure imgf000209_0001
92 A 560
0
1 0 V. [M-H]") 93 A 560
0
1 0 I [M-H]') 94 B 0 HOOC^^ CM0 562 [M-H]") 95 B
. ,___^ 0 CH 630
HOOC c [M-H]') 96 B
HOOC ° CH° 604 [M-H]')
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Example 267
5-[[[(lS)-l-Carboxy-2-[4-[(2,6-dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]- tetrahydro-γ-oxo-1 ,4-thiazepine-4(5H)-butanoic acid
Figure imgf000214_0001
Figure imgf000214_0002
The Intermediate-1 (0.3g, 0.195mmol/g) was pretreated with CΗ2C12 (2x 3 mL). The swollen resin was then deprotected with 50%> TFA CH2C12 (3mL, 30 min). The resin was rinsed in the following order: CH2C12 (2x 3 mL), CH,OH (2x 3mL), CH2Cl2(2x 3mL). The resin was swollen with DMF (2x 3mL). N-Tert-butoxycarbonyl-l,4-thiazoline-5- carboxylic acid (204 mg, 0.78 mmol) in DMF (2.0 mL) was activated with 0.5 M HBTU/HOBT in DMF ( 1.6 mL) and DIEA (0.340 mL. 1.95 mmol), then added to the swollen resin. The mixture was vortexed for 2 hr at room temperature. The resin was filtered and washed in the following order: DMF (2x 3 mL), CH2C12 (2x 3mL), CH3OH (2x 3mL), CH2Cl2(2x 3mL), respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resin (intermediate-3. 0.2 g, 0.13mmol/g) was pretreated with CH2C12 (2x 3 mL). The swollen resin was then deprotected with 50%> TFA/CH,C12 (3mL. 30 min). The resin was rinsed in the following order: CH2C12 (2x 3mL), CH3OH (2x 3mL), CH2C12 (2x 3mL). The resin was then swollen with DMF (3mL). Succinic anhydride (78 mg, 0.78 mmol) dissolved in DMF (4mL) was added to the swollen resin and stirred at 50°C for 2hr. Then the resin was filtered and washed in the following order: DMF (2x 3mL), CH2C12 (2x 3mL), CH3OH (2x 3mL), CH2C12 (2x 3mL) respectively. If a Kaiser test on a small quantity of the resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight. The resin was placed in the polypropylene column and pretreated with THF (3 mL). Then THF (3.9 mL), CH.OH (1.2 mL) and 2N LiOH (0.195 mL) were added to the swollen resin. The mixture was vortexed for 15 min and filtered to a clean and preweighed test tube. The resin was next washed with THF/5% CH3OH (2x 2mL) and the combined filtrates were evaporated. The resulting gum was dissolved in H2O (1 mL). The solution was then acidified with IN HCl to pH 2.0. The precipitate was centrifuged. washed with H2O (2 x 5mL) and dried in vacuo to furnish 80 mg of Example 267 as a solid: ESMS (m/z)
594([M-H]").
Scheme O
Figure imgf000216_0001
Wang resin
Figure imgf000216_0002
Figure imgf000216_0003
Figure imgf000216_0004
Figure imgf000216_0005
Scheme O (continued)
Figure imgf000217_0001
Figure imgf000217_0002
Figure imgf000217_0003
Where: RQ., is defined as R12; Ro_2 is defined as C,.6 alkyl or C7.I7 arylalkyl; Ro.3, and RQ.5, are defined independently as R,. Ro.6 is defined as R2. Y, and Y2 are defined independently as Y. Scheme O describes a method for the preparation of examples of the formula O-9 and O-12. Commercially available Wang resin (O-l) is acylated with commercially available N-α-Fmoc-Phe(NO2)-OH (O-2) under standard conditions to afford the resin of formula O-3. Reduction of the aromatic nitro group (Meyer et al, Mol. Diversity 1995, /, 13-20) affords the resin bound aniline (O-4) which may be reacted with a variety of electrophilic reagents to afford resin bound amides (O-5 where Y, is C(=O)), ureas (O-5 where Y, is C(=O)NH), sulfonamides (O-5 where Y, is SO2), and carbamates (O-5 where Y, is C(=O)O). Removal of the Fmoc group under standard conditions provides amine of general structure O-6 which is acylated using standard solid-phase peptide synthesis conditions (Atherton, E.; Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) with a commercially available or readily prepared thiazolidine-4-carboxylic acid of general formula O-7 to afford the resin bound intermediate O-8. Mild cleavage under standard conditions (Atherton, E.; Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) affords the acid of general structure O-9. In those cases where RQ.2 is a 9-fluorenylmethyl group, standard Fmoc group removal affords the amine of general structure O-10, which may be reacted with a variety of electrophilic reagents as described in Scheme A to afford resin bound amides, ureas, sulfonamides and carbamates of general structure O-ll. Mild cleavage under standard conditions affords the acid of general structure O-12.
Preparation 79 and Example 268.
(41S)-4-[[[(15)-l-Carboxy-2-[4-[(benzoyl)amino]phenyl]ethyl]amino]carbonyl]-3- thiazolidinecarboxylic acid 3 -ethyl ester
Figure imgf000219_0001
To a mixture of Wang resin (1%> DVB, Advanced Chemtech, 2.75 g, 2.20 mmol based on manufacture's loading of 0.8 mmol/g resin) in DMF (12 mL) was added N-α- Fmoc-Phe(ΝO2)-OH, O-2 (Advanced Chemtech, 1.90 g, 4.40 mmol) at room temperature. After mixing for 10 min (by passing a slow stream of nitrogen through the mixture) pyridine (587 μL, 7.26 mmol) and 2,6-dichlorobenzoyl chloride (630 μL, 4.40 mmol) were added. The mixture was agitated overnight via nitrogen bubbling, filtered, washed with DMF, methylene chloride and methanol and dried in vacuo. In order to cap any unreacted hydroxymethyl groups, the resin was suspended in dichloroethane (5 mL) and to this mixture was added benzoyl chloride (0.75 mL) and pyridine (0.75 mL). The mixture was agitated for 2 h, filtered, washed with DMF, methylene chloride, methanol, methylene chloride and methanol, and dried in vacuo to afford the resin O-3 (3.30 g). IR (diamond anvil) 1733, 1606 (resin), 1520 (resin), 1494 (resin), 1452 (resin), 1347, 1247, 1174, 1029 cm To the prewashed (2 X 20 mL DMF) resin O-3 (1.0 g, ca. 0.6 mmol based on an adjusted loading of 0.6 mmol/g) was added SnCl2 » 2 H2O (6 mL of a 2M solution in DMF, 12 mmol). The viscous suspension was agitated for 4 hours by nitrogen bubbling, filtered and washed with DMF (2 X 20 mL). The resin was resuspended with SnCl2 » 2 H2O (6 mL of a 2M solution in DMF, 12 mmol), agitated overnight via nitrogen bubbling, filtered, washed extensively with DMF, water, 2-propanol, methylene chloride and methanol and dried in vacuo to afford the resin O-4. Examination of the FTIR spectra of a small sample of resin O-4 failed to exhibit an absoφtion at 1347 cm"1.
To a mixture of prewashed (2 X 20 mL CH2C12) resin O-4 (0.30 g, ca. 0.18 mmol based on an adjusted loading of 0.6 mmol/g) in 1 ,2-dichloroethane (3 mL) was added benzoyl chloride (174 μL, 1.50 mmol) and DIEA (313 μL, 1.80 mmol). The mixture was agitated overnight via nitrogen bubbling, filtered, washed with methylene chloride, DMF, methanol, and methylene chloride and dried in vacuo to afford resin O-5. To a mixture of resin O-5 in methylene chloride (5 mL) was added a solution of piperidine in DMF (30%>, 5 mL). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 min. The resin was filtered, washed with DMF and resuspended in a solution of piperidine in DMF (30%), 10 ml). After gentle mixing for 40 min, the resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride and diluted with DMF (40 mL). To this mixture was added N-ethoxycarbonyl-D-thiazolidine-4-carboxylic acid (O-7, 0.15 g, 0.72 mmol), HOBt (0.11 g, 0.72 mmol), PyBOP (0.37 g, 0.72 mmol) and DIEA (313 μL, 1.80 mmol). The reaction was mixed for 4 h at which point the qualitative Kaiser test was negative. The resin was filtered and washed with DMF, methylene chloride and MeOH and dried in vacuo to afford resin O-8. After swelling with a minimum of methylene chloride (ca. 0.5 mL), the resin O-8 was suspended with 95 %> aqueous TFA (5 mL). The mixture was mixed by magnetic stirring for lh, filtered and washed with TFA (2 X 3 mL) and methylene chloride. The combined filtrates were evaporated in vacuo to afford a residue that was purified by flash chromatography using methylene chloride/methanol (2%>) containing glacial acetic acid (0.1 %>) as eluant to afford the title compound (80 mg). Lyophilization from glacial acetic acid afforded an amorphous powder: IR (drift) 331 1, 3298, 1670, 1601, 1579, 1531, 1487, 1412, 1380, 1345, 1324, 1265, 1205, 1190, 709 cm'1; "H ΝMR (300 MHz, DMSO-cfc) δ 10.39 (1 H), 8.39 (1 H), 8.14 (2 H), 7.86 (2 H), 7.74 (3 H), 7.36 (2 H), 4.83 (2 H), 4.59 (1 H), 4.48 (1 H), 4.22 (2 H), 3.48 (2 H), 3.26 (1 H), 3.06 (2 H), 1.35 (3 H); l3C ΝMR (75 MHz, DMSO- dό) δ 173.4, 169.8, 165.8, 154.0, 138.0, 135.4, 133.3, 131.9, 129.8, 128.8, 128.0, 120.4, 61.8, 54.2, 48.8, 36.7, 14.8; MS (ESI+) for C23H25Ν3O6S m/z 472.0 (M+H)+; MS (ESI-) for C23H25N3O6S m/z 470.1 (M-H)"; MS (FAB) m/z (rel. intensity) 472 (MH\ 99), 472 (99), 371 (31), 160 (31), 81 (31), 71 (45), 69 (46), 57 (71), 55 (58), 43 (47), 41 (42); HRMS (FAB) calcd for C23H25N3O6S +H, 472.1542, found 472.1563; Anal. Calcd for
C23H25N3O6S • 1.5 H2O: C, 55.41; H, 5.66; N, 8.43. Found: C, 55.47; H, 5.21; N, 8.00.
Example 269. (45)-4-[[[(15)-l-Carboxy-2-[4-[(acetyl)amino]phenyl]ethyl]amino]carbonyl]-3- thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000221_0001
The title compound was prepared as described in Scheme O using acetyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3311, 1709, 1667, 1602, 1536, 1517, 1412, 1378, 1344, 1321, 1266, 1218, 1185, 1116, 769 cm"1; 'H NMR (300 MHz, DMSO-fltø δ 9.79 (1 H), 8.15 (1 H), 7.37 (2 H), 7.02 (2 H), 4.54 (2 H), 4.31 (1 H), 4.19 (1 H), 3.95 (2 H), 3.12 (1 H), 2.93 (1 H), 2.75 (2 H), 1.82 (3 H), 1.09 (3 H); ,3C NMR (75 MHz, DMSO-cfø δ 173.2, 169.8, 168.5, 154.0, 138.2, 132.4, 129.8, 119.1, 62.1, 61.7, 53.9, 36.7, 24.4, 21.5, 14.8; MS (ESI+) for C18H23N3O6S m/z 410.0 (M+H)+; MS (ESI-) for C18H23N3O6S m/z 408.0 (M-H)"; MS (FAB) m/z (rel. intensity) 410 (MH+, 99), 486 (20), 411 (22), 410 (99), 409 (9), 205 (22), 188 (9), 177 (9), 160 (35), 148 (9), 88 (14); HRMS (FAB) calcd for C18H23N3O6S +H, 410.1385, found 410.1379. Anal. Calcd for CI8H23N3O6S • 0.3 H2O: C, 52.11; H, 5.73; N, 10.13. Found: C, 51.73; H, 5.73; N, 9.82.
Example 270. (4S)-4-[[[(15)-l-Carboxy-2-[4-[(3-phenylpropanoyl)amino]phenyl]ethyl]amino]carbonyl]-
3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000221_0002
The title compound was prepared as described in Scheme O using hydrocinnamoyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3311, 2978, 2930, 1665, 1601, 1534, 1517, 1413, 1379, 1344, 1252, 1216, 1187, 1115, 700 cm"1; Η NMR (300 MHz, CDCl3/CD3OD (10%)) δ 7.34 (2 H), 7.21 (5 H), 7.02 (2 H), 4.67 (3 H), 4.30 (1 H), 4.09 (2 H), 3.11 (4 H), 2.97 (2 H), 2.58 (2 H), 1.19 (3 H); 13C NMR (75 MHz, CDCl3) δ 172.7, 171.3, 170.0, 154.8, 140.7, 137.0, 131.6, 129.7, 128.4, 128.2, 126.2, 119.9, 63.0, 62.6, 53.1, 38.9, 36.7, 31.5, 29.6, 14.2; MS (ESI+) for C25H29N3O6S m/z 500.2 (M+H)+; MS (ESI-) for C25H29N3O6S m/z 498.3 (M-H)"; Anal. Calcd for C25H29N3O6S: C, 60.10; H, 5.85; N, 8.41. Found: C, 59.85; H, 6.07; N, 8.09.
Example 271.
(4S)-4- [[[( XS)-X -Carboxy-2- [4-[(3 -pyridinylcarbony l)amino]pheny 1] ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000222_0001
The title compound was prepared as described in Scheme O using nicotinoyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3301, 3061, 2983, 2935, 1709, 1675, 1603, 1535, 1517, 1415, 1380, 1345, 1326, 1204, 1 140 cm 1; 'H NMR (300 MHz, DMSO- tf) δ 12.74 (1 H), 10.42 (1 H), 9.11 (1 H), 8.76 (1 H), 8.29 (2 H), 7.67 (2 H), 7.55 (1 H), 7.19 (2 H), 4.62 (2 H), 4.44 (1 H), 4.29 (1 H), 4.05 (2 H), 3.24 (1 H), 3.04 (1 H), 2.88 (2 H), 1.15 (3 H); l3C NMR (75 MHz, DMSO-<fø) δ 173.1, 170.0, 164.3, 154.0, 152.4, 149.0, 137.7, 135.9, 133.5, 131.1, 129.8, 123.9, 120.5, 62.4, 61.8, 53.8, 36.7, 14.8; MS (ESI+) for C22H24N4O6S m/z 473.3 (M+H)+; MS (ESI-) for
C22H24N4O6S m/z 471.3 (M-H)"; HRMS (FAB) calcd for C22H24N4O6S +H, 473.1494, found 473.1509.
Example 272. (4<S)-4-[[[(15 -l-Carboxy-2-[4-[(4-methoxybenzoyl)amino]phenyl]ethyl]amino]carbonyl]-
3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000222_0002
The title compound was prepared as described in Scheme O using -anisoyl chloride to form the requisite amide. Physical data as follows: IR (drift) 1709, 1667, 1604, 1532, 1514, 1439, 1412, 1379, 1343, 1323, 1255, 1221, 1178, 1027, 763 cm"1; 'H NMR (300 MHz, CDCl3/CD3OD (10%)) δ 7.79 (2 H), 7.47 (2 H), 7.05 (2 H), 6.87 (2 H), 4.68 (2 H), 4.58 (1 H), 4.28 (1 H), 4.07 (2 H), 3.79 (3 H), 3.66 (2 H), 3.04 (4 H), 1.17 (3 H); 13C NMR (75 MHz, CDC13) δ 177.9, 174.0, 170.1, 166.3, 158.8, 141.1, 135.8, 133.7, 133.0, 130.8, 124.6, 117.7, 66.9, 66.6, 59.3, 40.7, 33.5, 24.5, 18.2; MS (ESI+) for
C24H27N3O7S m/z 502.0 (M+H)+; MS (ESI-) for C24H27N3O7S m/z 500.1 (M-H)"; MS (FAB) m/z (rel. intensity) 502 (MH+, 52), 503 (17), 502 (52), 297 (12), 240 (12), 160 (21), 135 (99), 88 (12), 73 (20), 69 (13), 57 (12); HRMS (FAB) calcd for C24H27N3O7S +H, 502.1648, found 502.1657. Anal. Calcd for C24H27N3O7S • 0.3 H2O: C, 56.86; H, 5.49; N, 8.29. Found: C, 56.65; H, 5.34; N, 7.92.
Example 273. (45)-4-[[[(15)-l-Carboxy-2-[4-[(4-methylbenzoyl)amino]phenyl]ethyl]amino]carbonyl]-3- thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000223_0001
The title compound was prepared as described in Scheme O using /?-tolouyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3310, 2981 , 2929, 1671, 1608, 1599, 1531, 1517, 1413, 1379, 1344, 1324, 1265, 1210, 1188 cm"1; Η NMR (300 MHz, DMSO-βtø) δ 10.10 (1 H), 8.24 (1 H), 7.85 (2 H), 7.67 (2 H), 7.33 (2 H), 7.17 (2 H), 4.62 (2 H), 4.41 (1 H), 3.28 (2 H), 4.02 (2 H), 3.23 (1 H), 3.04 (1 H), 2.87 (2 H), 2.38 (3 H), 1.15 (3 H); 13C NMR (75 MHz, DMSO-< ) δ 173.2, 169.8, 165.6, 154.0, 141.9, 138.1, 133.1, 132.5, 129.7, 129.7, 128.1, 120.4, 62.4, 61.8, 54.0, 36.7, 21.4, 14.8; MS (ESI+) for C24H27N3O6S m/z 486.2 (M+H)+; HRMS (FAB) calcd for C24H27N3O6S +H, 486.1699, found 486.1713; Anal. Calcd for C24H27N3O6S • 0.3 H2O: C, 58.71; H, 5.67; N, 8.56. Found: C, 58.37; H, 5.67; N, 8.35. Example 274.
(45)-4-[[[(15)-l-Carboxy-2-[4-[[2-(trifluoromethyl)benzoyl]amino]phenyl]ethyl]amino]- carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000224_0001
The title compound was prepared as described in Scheme O using (2- trifluoromethyl)benzoyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3295, 1709, 1663, 1603, 1533, 1518, 1414, 1380, 1344, 1316, 1269, 1176, 1132, 1108, 769 cm'1; 'H NMR (300 MHz, DMSO-ctø) δ 10.48 (1 H), 8.23 (1 H), 7.77 (2 H), 7.58 (2 H), 7.17 (2 H), 4.64 (2 H), 4.44 (1 H), 4.29 (1 H), 3.99 (2 H), 3.24 (1 H), 3.05 (2 H), 1.09 (3 H); 13C NMR (75 MHz, DMSO-fø δ 173.2, 169.2, 165.8, 154.1, 137.8, 136.7, 133.0, 130.4, 129.9, 128.9, 126.7, 126.4, 126.0, 119.8, 62.2, 61.8, 54.0, 37.1, 14.7; MS (ESI+) for C24H25F3N3O6S m/z 540.0 (M+H)+; MS (ESI-) for C24H25F3N3O6S m/z 538.1 (M- H)-; HRMS (FAB) calcd for C24H24F3N3O6S +H, 540.1416, found 540.1423 ; Anal. Calcd for C24H24F3N3O6S • 0.5 H2O: C, 51.49; H, 4.70; N, 7.83. Found: C, 51.42; H, 4.42; N, 7.45.
Example 275. (45)-4-[[[(15)-l-Carboxy-2-[4-[(2,4,6-trichlorobenzoyl)amino]phenyl]ethyl]amino]- carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000224_0002
The title compound was prepared as described in Scheme O using 2,4,6- trichlorobenzoyl chloride to form the requisite amide. Physical data as follows: IR (drift) 3286, 2926, 1709, 1664, 1604, 1578, 1542, 1517, 1413, 1379, 1345, 1325, 1269, 1218, 1187 cm"1; 'H NMR (300 MHz, CDCl3/CD3OD (10%)) δ 7.58 (2 H), 7.41 (2 H), 7.20 (2 H), 4.84 (2 H), 4.69 (1 H), 4.41 (1 H), 4.19 (2 H), 3.27 (4 H), 1.26 (3 H); ,3C NMR (75 MHz, DMSO-βtø) δ 173.0, 169.8, 161.5, 154.0, 137.2, 135.9, 135.1, 133.9, 132.6, 130.1, 128.5, 119.6, 62.2, 61.7, 54.0, 36.7, 14.8; MS (FAB) m/z (rel. intensity) 574 (MH+, 95), 576 (96), 574 (95), 160 (99), 91 (79), 88 (40), 69 (64), 57 (59), 55 (59), 43 (56), 41 (39); HRMS (FAB) calcd for C23H22Cl3N3O6S +H, 574.0373, found 574.0364. Anal. Calcd for C23H22Cl3N3O6S: C, 48.06; H, 3.86; N, 7.31; Cl, 18.50. Found: C, 48.52; H, 4.13; N, 7.08.
Example 276.
(45)-4-[[[(15)-l-Carboxy-2-[4-[[(2,5-dichlorophenyl)sulfonyl]amino] phenyl]ethyl]- amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000225_0001
The title compound was prepared as described in Scheme O using 2,5- dichlorobenzene sulfonyl chloride to form the requisite sulfonamide. Physical data as follows: IR (drift) 1709, 1676, 1531, 1512, 1450, 1428, 1409, 1378, 1344, 1221, 1167, 1143, 1113, 1101, 1041 cm 1; "H NMR (300 MHz, DMSO-^) δ 8.36 (1 H), 7.90 (3 H), 7.20 (2 H), 7.12 (2 H), 4.70 (2 H), 4.47 (1 H), 4.34 (1 H), 4.10 (2 H), 3.19 (4 H), 1.27 (3 H); 13C NMR (75 MHz, DMSO-cfø) δ 173.0, 169.8, 153.9, 138.7, 135.5, 134.8, 134.1, 132.6, 131.0, 130.5, 130.0, 120.0, 62.4, 61.7, 53.5, 36.3, 14.8; MS (FAB) m/z (rel. intensity) 576 (MH+, 99), 652 (27), 578 (83), 577 (31), 576 (99), 160 (98), 106 (47), 88 (40), 81 (32), 69 (31), 57 (28); HRMS (FAB) calcd for C22H23Cl2N3O7S2+H, 576.0433, found 576.0400. Anal. Calcd for C22H23Cl2N3O7S2 • 0.1 H2O: C, 45.70; H, 4.04; N, 7.27. Found: C, 45.94; H, 4.04; N, 6.87.
Example 277. (4S)-4-[[[(lS)-l-Carboxy-2-[4-[[[(2,6-dichlorophenyl)amino]carbonyl] amino]phenyl]- ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000226_0001
The title compound was prepared as described in Scheme O using 2,6- dichlorophenyl isocyanate to form the requisite urea. Physical data as follows: IR (drift) 3284, 3277, 1709, 1655, 1600, 1569, 1544, 1452, 1431, 1415, 1347, 1238, 1217, 1195, 771 cm'1; Η NMR (300 MHz, DMSO-fltø) δ 9.09 (1 H), 8.41 (1 H), 8.09 (1 H), 7.52 (2 H), 7.31 (3 H), 7.08 (2 H), 4.62 (2 H), 4.35 (1 H), 4.28 (1 H), 3.27 (1 H), 3.02 (1 H), 2.85 (2 H), 1.10 (3 H); 13C NMR (75 MHz, DMSO-cfø) δ 173.6, 169.8, 154.0, 152.8, 138.7, 134.4, 133.9, 131.3, 130.0, 128.8, 128.7, 118.1, 62.4, 61.8, 54.3, 36.7, 14.8; HRMS (FAB) calcd for C23H24Cl2N4O6S +H, 555.0872, found 555.0877. Anal. Calcd for C23H24Cl2N4O6S • 2 H2O: C, 46.71 ; H, 4.77; N, 9.47. Found: C, 47.08; H, 4.53; N, 9.06.
Scheme P
^ OH P-1
Wang resin
Figure imgf000227_0001
Figure imgf000227_0002
Figure imgf000227_0003
Scheme P (continued)
Figure imgf000228_0001
Figure imgf000228_0002
Where: RP_, is defined as R12; RP.2 is defined as C,.6 alkyl or C7.,7 arylalkyl; RP.3, Rp_ 4, and Rp.5, are defined independently as R,. RP.6 is defined as R2.
Scheme P describes a method for the preparation of examples of the formula P-9 and P-12. Commercially available Wang resin (P-1) is acylated with commercially available Λr- -Boc-Phe(I)-OH (P-2) under standard conditions to afford the resin of formula P-3. Carbonylation of the resin bound aryl iodide with carbon monoxide and an amine in the presence of a source of palladium(O) affords the resin bound amide of general formula P-5 (for a general review of carbonylation chemistry, see: Colquhoun, H.M.; Thompson, D.J.; Twigg, M.V. Carbonylation Plenum Press: New York, 1991). Mild cleavage under standard conditions affords the amino acid of general structure P-5 which is esterified under mild acid catalysis to afford the amino ester of general structure P-6. Condensation with a commercially available or readily prepared thiazolidine-4-carboxylic acid of general formula P-7 under conditions described in Scheme A affords the pseudodipeptide of general structure P-8. Mild base hydrolysis of the ester of general structure P-8 affords the acid of general structure P-9. In the case where RP.2is a 9- fluorenylmethyl group, standard Fmoc group removal (Atherton, E.; Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) affords the amine of general structure P-10, which may be reacted with a variety of electrophilic reagents as described in Scheme A to afford amides, ureas, sulfonamides and carbamates of general structure P-11. Mild base hydrolysis of the ester in general structure P-11 affords the acid of general structure P-12.
Preparation 80 and Example 278. (45)-4-[[[(15)-l-Carboxy-2-[4-[[(2,4,6-trichlorophenyl)amino]carbonyl] phenyl]ethyl]- amino]carbonyl]-3-thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000230_0001
To a cooled (0-50C) mixture of Wang polystyrene resin P-1 (Advanced Chemtech, 2.0 g, ca. 1.5 mmol), JV-Boc-4-iodo-L-phenylalanine P-2 (Bachem, 4.00 g, 10 mmol), and PPh3 (1.30 g, 5.0 mmol) in THF (20 mL) was added diethyl azodicarboxylate (0.80 mL, 5.0 mmol) in 4 approximately equal portions at 5 min intervals. When the orange color had discharged, the mixture was warmed to ambient temperature and stirred for 5 h. The mixture was diluted with THF (30 mL) and filtered. The resin was washed with DMF, THF and MeOH and dried in vacuo to afford the esterified resin P-3 (2.68 g) as a colorless powder: 13C NMR (100 MHz, CD2C12, 4 mm MAS probe) δ 171.86, 155.33, 137.85, 136.40, 131.87, 128.00, 92.74, 80.09, 54.05, 38.05, 28.51.
N2 was bubbled through a mixture of N-Boc-4-iodo-L-phenylalanine functionalized Wang resin P-3 (500 mg, ca. 0.3 mmol), PPh3 (0.21 g, 0.8 mmol), 2,4,6-trichloroaniline (0.98 g, 5.0 mmol) and DIEA (3.48 mL, 20 mmol) in ΝMP (20 mL) for 10 min. Pd2dba3 (0.18 g, 0.2 mmol) was added and the reaction mixture was placed under a CO atmosphere and heated (bath temp. 70 °C) for 18 h. Upon cooling to ambient temperature, the mixture was diluted with 3%> (w/v) sodium diethyldithiocarbamate in 95:5 ΝMP:DIEA (10 mL). After an additional 10 min, the mixture was filtered and the resin washed with NMP, THF and MeOH and dried in vacuo to afford the functionalized resin P-4 as a colorless powder. Resin P-4 was swollen with methylene chloride (0.5 mL) and diluted with 95:5
TFA:H2O (10 mL). After 90 min the mixture was filtered and the resin washed with TFA (3 x 5 mL) and CH2C12. The combined filtrates were concentrated in vacuo and the residue lyophilized from glacial acetic acid to provide the amino acid P-5 (152 mg) as a powder which was used without purification. Physical data as follows: MS (FAB) m/z (rel. intensity) 387 (M+H, 42), 427 (26), 426 (80), 389 (46), 387 (42), 366 (33), 279 (99), 177 (54), 146 (18), 119 (26), 23 (26); HRMS (FAB) calcd for C16H13Cl3N2O3+H, 387.0070, found 387.0084. The amino acid P-5 was dissolved in methanolic HCl (20 mL) and stirred at room temperature for 18 h. Concentration in vacuo afforded the methyl ester P-6 which was used without purification. Physical data as follows: MS (ES+) for CI7H15Cl3N2O3 m/z 400.9 (M+H)+. To a cooled (0-5 °C) solution of N-ethoxycarbonyl-D-thiazolidine-4-carboxylic acid P-7 (82 mg, 0.4 mmol) and HOAt (54 mg, 0.4 mmol) in CH2C12/DMF (1:1, 4 mL) was added EDC (76 mg, 0.4 mmol). After stirring for 10 min, the solution was added to the amino ester P-6 described above at 0-5 °C followed by DIEA (208 μL, 1.2 mmol). After an additional 30 min at 0-5 °C, the solution was allowed to warm to room temperature and stirred an additional hour. Volatiles were removed in vacuo and the residue partitioned between ethyl acetate and 0.1 Ν aqueous HCl. The organic layer was separated, washed with 0.1 Ν aqueous HCl, saturated aqueous ΝaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using CH2Cl2/ethyl acetate/hexanes (1 :1 :2) containing 2-propanol (0.1 %>) as eluant afforded the ester P-8 as a powder: 'H NMR (300 MHz, CDC13) δ 7.99 (1 H), 7.87 (2 H), 7.40 (2 H), 7.24 (2 H), 4.92 (1 H), 4.70 (2 H), 4.34 (1 H), 4.10 (2 H), 3.74 (3 H), 3.20 (4 H), 1.25 (3 H); 13C NMR (75 MHz, CDC13) δ 171.2, 169.7, 165.4, 154.9, 140.6, 134.3, 133.4, 132.2, 131.3, 129.7, 128.4, 127.9, 63.1, 62.7, 60.4, 53.0, 52.6, 37.6, 21.0, 14.5; MS (ESI+) for C24H24Cl3N3O6S m/z 589.9 (M+H)÷; MS (ESI-) for C24H24Cl3N3O6S m/z 588.0 (M-H)".
To a cooled (0-5 °C ) solution of the ester P-8 (72 mg, 0.12 mmol) in THF (5 mL) and water (0.5 mL) was added an 0.1 N aqueous solution of NaOH (1.3 mL, 0.13 mmol) via a syringe pump over 1 h. After an additional 45 min at 0-5°C, the reaction mixture was diluted with ethyl acetate and acidified with 0.25 N HCl to a pH of ca. 3. The organic layer was separated, washed with water and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride and methanol (0-5%>) as eluant provided a solid which was crystallized from ethyl acetate/CH2Cl2/hexanes to afford the title compound (45 mg) as colorless solid: IR (drift) 1743, 1726, 1709, 1691, 1675, 1663, 1553, 1521, 1490, 1428, 1415, 1379, 1345, 1290, 1189 cm-'; Η NMR (300 MHz, DMSO- d6) δ 10.27 (1 H), 8.35 (1 H), 7.92 (, 2 H), 7.81 (2 H), 7.37 (2 H), 4.62 (2 H), 4.53 (1 H), 4.29 (2 H), 4.00 (2 H), 3.11 (3 H), 2.77 (1 H), 1.12 (3 H); 13C NMR (75 MHz, DMSO- tf) δ 172.9, 170.0, 165.4, 154.0, 142.5, 135.5, 133.9, 133.0, 131.6, 129.8, 128.7, 128.0, 62.0, 61.7, 53.4, 37.0, 14.8; MS (FAB) m/z (rel. intensity) 574 (MH+, 80), 576 (80), 574 (80), 379 (99), 160 (82), 91 (95), 81 (72), 69 (93), 57 (86), 55 (86), 43 (90); HRMS (FAB) calcd for C23H22Cl3N3O6S +H, 574.0373, found 574.0358.
Scheme Q
Figure imgf000233_0001
Figure imgf000233_0002
Figure imgf000233_0003
RQ-1 β~ Y~RQ-2 c r0^ Q-4 Z °
Figure imgf000233_0004
RQ-1 rVγNHrV
Z ° R 5 Q"7
Figure imgf000233_0005
Rq., and RQ.2 are defined independently as R,. RQ.3 is defined as C,.6 alkyl or C7.17 arylalkyl. RQ.4 is defined as oxygen or N-Rπ. RQ.5 is defined as a suitable protecting group for a nitrogen (such as Boc or Fmoc) or oxygen (such as t-butyldimethylsilyl) (Greene, T.W.; Wuts, P.G.M.. Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991).
Scheme Q describes a general method for the preparation of examples of the formula Q-7. A commercially available or readily prepared sulfur containing amino acid of structure Q-l is condensed with a suitably protected aldehyde to afford the thiazolidine-4-carboxylic acid of general formula Q-2. Standard deprotection (Greene, T.W.; Wuts, P.G.M.. Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991) affords intermediate Q-3 which is readily cyclized to the bicycle Q-4 using 1 , 1 '-carbonyldiimidazole or phosgene or a suitable equivalent. For the preparation of bicycles of general structure Q-4 in which Z is CH2, see as examples: (a) Aszodi, J.; Bonnet, A.; Teutsch, G. Tetrahedron 1990, 46, 1579. (b) Baldwin, J.E.; Lee, V.; Schofield, C.J. Heterocycles 1992, 34, 903. (c) Genin, M.J.; Johnson, R.L. J. Am. Chem. Soc. 1992, 114, 8778. (d) Siddiqui, M.A.; Preville, P.; Tarazi, M.; Warder, S.E.; Eby, P.; Gorseth, E.; Puumala, K.; DiMaio. J. Tetrahedron Lett. 1997, 38, 8807. (e)Subasinghe, M.L.; Bontems, R.J.; Mclntee, E.; Mishra, R.K.; Johnson, R.L. J. Med. Chem. 1993, 36, 2356. Removal of the ester protecting group affords the acid of general structure Q-5 which is condensed with amino acyl derivative Q-6 under standard peptide synthesis conditions to provide Q-7 (for a review of procedures of peptide synthesis see: Bodansky, M.; Bodansky, A. The Practice of Peptide Synthesis; Springer- Verlag: Berlin, 1984). Mild base hydrolysis of the ester of general structure Q-7 provides acid Q-8.
Preparation 81.
(Scheme Q, Q-2: where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, RQ.4 is NH, RQ_5 is Boc and stereochemistry is (S)).
Figure imgf000234_0001
To a suspension of D-cysteine 1.5 hydrate hydrochloride (Q-l, Scheme Q where RQ., and RQ., are equal to hydrogen, RQ_3 is hydrogen and stereochemistry is (S)) (5 g, 27.1 mmol) in absolute ethyl alcohol (50 mL) was added triethylorthoformate (13.5 mL, 81.2 mmol) at ambient temperature. A stream of anhydrous HCl gas was bubbled through the solution for 30 min. The stream of anhydrous HCl gas was maintained as the mixture heated to 70°C for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with diethyl ether to afford D-cysteine ethyl ester (4.43 g) as a white solid which was used without further purification. Physical data as follows: Η NMR (300 MHz, D2O) δ 4.36 (1 H), 4.27 (2 H), 3.12 (2 H), 1.25 (3 H); MS (ESI+) for C5H,,NO2S m/z 150.0 (M+H)+.
To a solution of D-cysteine ethyl ester (1.89 g, 10.2 mmol) in H2O (46 mL) was added potassium acetate (1.22 g, 12.4 mmol) and t-butyl N-(2-oxoethyl)carbamate (Aldrich, 2.38 g, 12.0 mmol based on 80%> purity as determined by 'H ΝMR) in ethyl alcohol (46 mL) at ambient temperature. After 8 h, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography using methylene chloride/methanol (1%>) as eluant to afford the title compound (1.9 g) as an oil: Η ΝMR (300 MHz, CDC13) δ 5.01 (1 H), 4.75 (1 H), 4.26 (2 H), 3.93 (1 H), 3.37 (2 H), 3.12 (1 H), 2.91 (1 H), 147 (9 H), 1.32 (3 H); MS (ESI+) for C12H22Ν2O4S m/z 291.1 (M+H)+. MS (ESI-) for C12H22N2O4S m/z 288.9 (M-H)".
Preparation 82. (Scheme Q, Q-3: where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, RQ.4 is NH, and stereochemistry is (S)).
Figure imgf000235_0001
To a cooled (10-15°C) solution of Q-2 (Scheme Q where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, RQ.4 is NH, RQ.5 is Boc and stereochemistry is (S)) (1.9 g) in dioxane (38 mL) was added dropwise anhydrous 4 M HCl in dioxane (156 mL). The solution was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo and azeotroped three times with methanol which afforded the title compound (1.72 g) as a tacky yellow solid: Η NMR (300 MHz, CDC13) δ 8.57 (2 H), 5.80 (1 H), 5.25 (1 H), 4.39 (2 H), 4.17 (1 H), 3.79 (4 H), 1.37 (3 H); MS (ESI+) for C7H14N2O2S m/z 191.1 (M+H)+. MS (ESI-) for C7H,4N2O2S • 2HC1 m/z 261.0 (M-H)".
Preparation 83. (Scheme Q, Q-4: where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, Z is NH, and stereochemistry is (S)).
Figure imgf000236_0001
To a cooled (0-5°C) solution of Q-3 (Scheme Q where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, RQ.4 is NH, and stereochemistry is (S)) (X .72 g, 6.54 mmol) in THF (650 mL) was added triethylamine (2.83 mL, 20.3 mmol) and l,l'-carbonyldiimidazole (1.11 g, 6.87 mmol). After 3 d at ambient temperature, the mixture was recooled (0-5°C), treated with additional l,l '-carbonyldiimidazole (530 mg, 3.27 mmol) and allowed to warm to ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and 0.25 N HCl. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The diastereomeric mixture was separated by chiral chromatography [5 x 25 cm (R,R) Whelk-O I, 50 mL/min 40%> Isopropanol/heptane, 210 nm,]. Further purification of each isolated diastereomer by flash chromatography using methylene chloride/ethyl acetate (25%>) as eluant afforded the diastereomers (255 mg, 464 mg) as oils. Physical data for the faster eluting diastereomer (analytical column conditions 0.46 x 25 cm (R,R) Whelk-O I, 0.5 mL/min 40% IPA heptane, 210 nm) as follows: Η NMR (300 MHz, CDC13) δ 5.51 (1 H), 5.15 (1 H), 4.32 (2 H), 3.96 (1 H), 3.86 (1 H), 3.53 (1 H), 3.26 (1 H), 3.13 (1 H), 1.34 (3 H); MS (ESI+) for C8H,2N2O3S m/z 217.1 (M+H)+. MS (ESI+) for CgH12N2O3S m/z 239.0 (M+Na)+. MS (ESI-) for C8H,2N2O3S m/z 215.1 (M-H)".).
Preparation 84. (Scheme Q, Q-5: where RQ., and RQ., are equal to hydrogen, and Z is NH).
Figure imgf000237_0001
To a cooled (0-5 °C) solution of the faster eluting diastereomer of general structure
Q-4 (Scheme Q where RQ., and RQ., are equal to hydrogen, RQ_3 is ethyl, Z is NH, and stereochemistry is (S)) (100 mg, 0.46 mmol) in THF (13 mL) and H2O (1.5 mL) was added via syringe pump over 1 h 0.1 N NaOH (9.7 mL, 0.97 mmol). The reaction mixture was stirred for 2 h at 0°C, acidified with 1.0 N HCl (0.97 mL) and concentrated in vacuo. The resulting residue was dried over P2O5 in a vacuum desiccator to afford the title compound (87 mg) as a glassy solid which was used without further purification: MS (ESI+) for C6H8N2O3S m/z 189.0 (M+H)+. MS (ESI+) for C6H8N2O3S m/z 211.0 (M+Na)+. MS (ESI-) for C6H8N2O3S m/z 187.0 (M-H)".
Preparation 85.
(Scheme Q, Q-7: where RQ., and RQ., are equal to hydrogen, Z is NH, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S)).
Figure imgf000238_0001
To a cooled (0-5°C) suspension of Q-5 (Scheme Q where RQ., and RQ., are equal to hydrogen, and Z is NH) (87 mg, 0.46 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriaol- 1 -yl)-/V,N,N ,N -tetramethyluronium hexafluorophosphate (HATU) (175 mg, 0.46 mmol), Q-6 (Scheme Q where R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry is (S)) (204 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.38 mmol). After 7 h, the reaction mixture was diluted with methylene chloride, washed with 0.1 Ν HCl and brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/ethyl acetate (25%>) as eluant afforded the title compound (89 mg) as a white solid: 'H ΝMR (300
MHz, CDC13) δ 7.57 (2 H), 7.31 (3 H), 7.13 (2 H), 4.97 (1 H), 4.82 (1 H), 4.47 (1 H), 3.80 (4 H), 3.55 (1 H), 3.46 (1 H), 3.34 (1 H), 3.08 (2 H); MS (ESI+) for C23H22Cl2Ν4O5S m/z 537.0 (M+H)+. MS (ESI+) for C23H22Cl2N4O5S m/z 558.9 (M+Na)+.
Preparation 86 and Example 279.
4-[(2,6-Dichlorobenzoyl)amino]-N-[[(7aS')-hexahydro-5-oxoimidazo[5,l-6]thiazol-3-yl]- carbony 1] -L-phenylalanine (Scheme Q, Q-8: where RQ., and RQ., are equal to hydrogen, Z is ΝH, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S)).
Figure imgf000238_0002
To a cooled (0-5°C) solution of Q-7 (Scheme Q where RQ., and RQ., are equal to hydrogen, Z is NH, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S ) (88 mg, 0.16 mmol) in THF (5 mL) and H2O (0.5 mL) was added via syringe pump over 1 h 0.1 N NaOH (3.4 mL, 0.34 mmol). After 2 h, the reaction mixture was partitioned between ethyl acetate and 0.1 N HCl (7 mL) and diluted with H2O (20 mL). The organic layer was separated, washed with H2O, dried (MgSO4), filtered and concentrated in vacuo. The resulting white solid was lyophilized from glacial acetic acid to afford the title compound (22 mg) as white solid: IR (drift) 2924, 1726, 1720, 1663, 1657, 1608, 1515, 1456, 1431, 1402, 1398, 1243, 1194, 797, 780 cm"1: Η NMR (300 MHz, CD3OD) δ 8.05 (1 H), 7.61 (2 H), 7.46 (3 H), 7.25 (2 H), 4.93 (2 H), 4.74 (2 H), 4.47 (1 H), 3.77 (1 H), 3.39 (2 H), 3.25 (1 H), 3.04 (2 H); 13C NMR (75 MHz, CD3OD) δ 171.8, 165.2, 164.7, 138.2, 137.7, 135.1, 133.4, 132.4, 130.9, 129.4, 121.7, 66.3, 64.4, 54.5, 44.9, 37.4, 33.9; HRMS (FAB) calcd for C22H20CL2N4O5S +H, 523.0610, found 523.0629. MS (ESI+) for C22H20C12N4O5S m/z 523.0 (M+H)+. MS (ESI-) for C22H20C12N4O5S m/z 521.1 (M-H)'.
Example 280. 4-[(2,6-Dichlorobenzoyl)amino]-Λ-[[(7ai?)-hexahydro-5-oxoimidazo[5,l- ?]thiazol-3-yl]- carbonyl]-L-phenylalanine (Scheme Q, Q-8: where RQ., and RQ., are equal to hydrogen, Z is NH, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S)).
Figure imgf000239_0001
Example 280 was prepared as described in Scheme Q from the slower eluting diastereomer of general structure Q-4 (Scheme Q where RQ., and RQ., are equal to hydrogen, RQ.3 is ethyl, and Z is NH). Physical data as follows: IR (drift) 3251 , 3079, 1730, 1662, 1611, 1549, 1516, 1482, 1431, 1333, 1306, 1269, 1229, 1196, 792 cm"1; Η NMR (300 MHz, CD3OD) δ 7.59 (2 H), 7.44 (3 H), 7.24 (2 H), 4.65 (1 H), 3.81 (1 H), 3.44 (1 H), 3.23 (2 H), 3.08 (2 H); 13C NMR (75 MHz, CD3OD) δ 175.3, 172.22, 164.6, 155.3, 139.7, 139.1, 136.1, 134.1, 133.9, 132.3, 131.8,130.9, 122.0, 68.4, 64.6, 45,6, 44.0, 36.3; HRMS (FAB) calcd for C22H20C12N4O5S +H, 523.0610, found 523.0629. MS (ESI+) for C22H20C12N4O5S m/z 523.0 (M+H)+. MS (ESI-) for C22H20C12N4O5S m/z 521.0 (M-H)". Anal. Calcd for C22H20C12N4O5S ' 0.13 H2O: C, 50.26; H, 3.88; N, 10.66. Found: C, 50.72; H, 3.96; N, 10.13. % Water (KF): 045.
Example 281.
4-[(2,6-Dichlorobenzoyl)amino]-N-[(tetrahydro-5-oxo-5H-thiazolo[3,2-c]oxazol-3-yl)- carbonyl]-L-phenylalanine (less polar diastereomer) (Scheme Q, Q-8: where RQ., and RQ., are equal to hydrogen, Z is O, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S)).
Figure imgf000240_0001
Example 281 was prepared as described in Scheme Q using commercially available (t-butyldimethylsilyloxy)acetaldehyde to form the requisite thiazolidine-4-caroxylic acid. Physical data as follows: IR (drift) 3293, 3194, 1754, 1667, 1603, 1533, 1517, 1431, 1411, 1392, 1324, 1266, 1206, 798, 781 cm"1; 'H NMR (300 MHz, DMSO- tf) δ 8.44 (1 H), 7.53 (5 H), 7.21 (2 H), 5.00 (1 H), 4.84 (1 H), 4.65 (1 H), 4.42 (2 H), 3.08 (2 H), 2.91 (1 H); 13C NMR (75 MHz, CD3OD) δ 169.4, 163.8, 160.6, 136.7, 136.2, 133.9, 131.9, 130.9, 129.5, 127.9, 120.4, 68.1, 64.4, 63.2, 53.4, 36.1, 33.7; MS (ESI+) for C22H,9Cl2N3O6S m/z 524.0 (M+H)+. MS (ESI-) for C22H,9Cl2N3O6S m/z 522.0 (M-H)". Anal. Calcd for C22H,9Cl2N3O6S • 0.31 H2O: C, 49.86; H, 3.73; N, 7.93. Found: C, 49.61; H, 3.82; N, 7.54. % Water (KF): 1.06.
Example 282. 4-[(2,6-Dichlorobenzoyl)amino]-N-[(tetrahydro-5-oxo-5H-thiazolo[3,2-c]oxazol-3-yl)- carbonyl]-L-phenylalanine (more polar diastereomer) (Scheme Q, Q-8: where RQ., and RQ., are equal to hydrogen, Z is O, R5 is 4-[(2,6- dichlorobenzoyl)amino]phenyl, and stereochemistry of the C-terminal amino acid is (S)).
Figure imgf000241_0001
Example 282 (diastereomer of Example 281) was prepared as described in Scheme
Q. Physical data as follows: IR (drift) 3296, 1753, 1666, 1603, 1579, 1535, 1517, 1431, 1411, 1390, 1324, 1267, 1207, 798, 781 cm"1; Η ΝMR (300 MHz, DMSO-cfø) δ 8.57 (1 H), 7.54 (5 H), 7.20 (2 H), 5.23 (1 H), 4.86 (1 H), 4.66 (1 H), 4.45 (2 H), 3.22 (1 H), 3.09 (1 H), 2.93 (m, 2 H); 13C ΝMR (75 MHz, CD3OD) δ 172.8, 169.7, 163.8, 160.6, 136.8, 136.2, 133.7, 131.9, 130.9, 129.5, 127.9, 120.2, 68.1, 64.9, 63.1, 53.6, 37.5, 36.2, 34.2; MS (ESI+) for C22H,9Cl2N3O6S m/z 523.9 (M+H)+. MS (ESI-) for C22H,9Cl2N3O6S m/z 521.9 (M-H)'; HRMS (EI) calcd for C22H,9CL2N3O6S 523.0372, found 523.0366. Anal. Calcd for C22H19Cl2N3O6S • 0.35 H2O: C, 49.79; H, 3.74; N, 7.92. Found: C, 50.14; H, 4.08; N, 8.13. % Water (KF): 1.19.
Example 283. (4S)-4-[[[(lS l-Carboxy-2-[4-[(2,6- dichlorobenzoyl)amino]phenyl]ethyl]amino]carbonyl]-2-(4-pyridinyl)-3- thiazolidinecarboxylic acid 3-ethyl ester
Figure imgf000242_0001
Example 283 was prepared as described in Scheme B using D-cysteine and 4- pyridinecarboxaldehyde to from the requisite thiazolidine carboxylic acid. Physical data as follows: IR (drift) 3055, 2981, 2928, 1679, 1604, 1535, 1515, 1450, 1431, 1406, 1378, 1331, 1194, 797, 778 cm"1; lH NMR (300 MHz, CD3OD) δ 8.68 (2 H), 8.28 (2 H), 7.55 (2 H), 7.42 (4 H), 7.25 (2 H), 6.28 (1 H), 4.70 (1 H), 4.09 (2 H), 3.46 (1 H), 3.16 (1 H), 2.94 (1 H), 2.73 (1 H), 1.17 (3 H); 13C NMR (75 MHz, CD3OD) δ 190.2, 171.1, 162.1, 153.8, 141.4, 135.3, 134.6, 131.9, 130.3, 129.4, 128.2, 126.4, 122.4, 118.5, 61.0, 51.7, 35.5, 26.6, 11.7; MS (FAB) m/z (rel. intensity) 617 (MH+, 99), 621 (35), 620 (72), 619 (99), 618 (91), 617 (99), 371 (22), 179 (23), 173 (28), 124 (27), 57 (24); HRMS (FAB) calcd for C28H26Cl2N4O6S +H, 617.1028, found 617.1019. Anal. Calcd for C28H26Cl2N4O6S • 0.9 HCl • 1.1 H2O: C, 50.19; H, 4.38; N, 8.36; Cl, 15.34. Found: C, 49.79; H, 4.49; N, 8.11; Cl, 15.05. % Water (KF): 2.96. Example 284.
4-[[[(15 -2-Amino-l-[4-[(2,6-dichlorophenyl)methoxy]phenyl]methyl]-2- oxoethyl]amino]-carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(l-pyrrolidinyl)ethyl] ester
Figure imgf000243_0001
Example 284 was prepared as described in Scheme C. Physical data as follows: IR (drift) 1709, 1675, 1511, 1458, 1435, 1421, 1390, 1380, 1354, 1299, 1240, 119 5, 1179, 1114, 765 cm -1; 'H NMR (300 MHz, CD3OD) δ 8.40 (1 H), 7.41 (3 H), 7.22 (2 H), 6.99 (2 H), 5.29 (2 H), 4.46 (6 H), 3.77 (2 H), 3.50 (2 H), 3.19 (4 H), 2.89 (1 H), 2.04 (1 H), 2.12 (4 H); 13C NMR (75 MHz, CD3OD) δ 174.5, 171.6, 171.1, 157.9, 153.3, 136.6, 132.2, 130.6, 130.0, 129.7, 128.3, 114.5, 64.9, 63.2, 62.1, 60.9, 54.4, 53.6, 50.0, 49.0, 37.0, 36.5, 35.2, 22.6; MS (ESI+) for C27H32Cl2N4O5S m/z 595.1 (M+H)+. HRMS (FAB) calcd for C27H32Cl2N4O5S +H, 595.1548, found 595.1531.
Example 285.
(4S)-4-[[[(XS)-X-Caιboxy-2-[4-[(2,6- dichlorophenyl)methoxy]phenyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid 3-
(3-tetrahydrofuranyl) ester
Figure imgf000243_0002
Example 285 was prepared as described in Scheme A. Physical data as follows: 'H NMR (300 MHz, CD3OD) δ 7.41 (3 H), 7.18 (2 H), 6.98 (2 H), 5.28 (2 H), 5.15 (1 H) 4.69 (2 H), 4.44 (1 H), 3.82 (4 H); 1 C NMR (75 MHz, DMSO-<fø) δ 172.8, 157.9, 136.7, 132.2, 130.6, 130.1, 129.5, 128.3, 1 14.5, 76.8, 72.7, 66.5, 64.9, 62.4, 53.5, 36.3, 34.9, 32.4; MS (FAB) m/z (rel. intensity) 569 (MH\ 75), 571 (51), 570 (29), 569 (75), 322 (22), 161 (20), 159 (30), 89 (25), 73 (31), 71 (99), 43 (41); HRMS (FAB) calcd for C25H26CL2N2O7S +H, 569.0916, found 569.0939. Anal. Calcd for C25H26Cl2N2O7S: C, 52.73; H, 4.60; N, 4.92;. Found: C, 52.41; H, 4.80; N, 4.62.
Example 286. (45)-4-[[[(15)-2-Amino-l-[[4-[(2,6-dichlorophenyl)methoxy]phenyl]methyl]-2-oxoethyl]- amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(l-piperidinyl)ethyl] ester
Figure imgf000244_0001
Example 286 was prepared as described in Scheme C. Physical data as follows: Η NMR (300 MHz, CD3OD) δ 7.43 (3 H), 7.22 (2 H), 6.98 (2 H), 5.28 (2 H), 4.66 (2 H), 4.59 (1 H), 4.47 (1 H), 4.47 (2 H), 3.05 (10 H), 1.78 (4 H), 1.62 (2 H); l3C NMR (75 MHz, CD3OD) δ 175.9, 172.9, 159.3, 138.1, 133.6, 132.0, 131.4, 131.1, 129.7, 120.1, 115.9, 66.3, 64.6, 63.7, 62.3, 61.9, 57.8, 55.8, 55.1, 51.3, 50.3, 38.5, 37.8, 36.6, 25.0, 23.5; MS (ESI+) for C28H34Cl2N4:O5S m/z 609.0 (M+H)+. Example 287.
(45)-4-[[[(15)-2-Amino-l-[[4-[(2,6-dichlorophenyl)methoxy]phenyl]methyl]-2-oxoethyl]- amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(4-methyl-l-piperazinyl)ethyl] ester
Figure imgf000245_0001
Example 287 was prepared as described in Scheme C. Physical data as follows: 'H NMR (300 MHz, CD3OD) δ 741 (3 H), 7.21 (2 H), 6.98 (2 H), 5.28 (2 H), 4.67 (1 H), 4.58 (1 H), 4.46 (1 H), 4.23 (2 H), 3.20 (2 H), 2.71 (13 H), 2.50 (3 H); MS (ESI+) for C28H35Cl2N5O5S m/z 624.0 (M+H)+; Anal. Calcd for C28H35Cl2N5O5S • 0.5 C2H4O2 • 0.5 H2O: C, 49.82; H, 5.54; N, 10.02. Found: C, 49.82; H, 5.77; N, 9.65.
Example 288. (45)-4-[[[(15)-2-Amino-l-[[4-[(2,6-dichlorobenzoyl)amino]phenyl]methyl]-2-oxoethyl]- amino]carbonyl]-3-thiazolidinecarboxylic acid 3-[2-(4-morpholinyl)ethyl] ester
Figure imgf000245_0002
Example 288 was prepared as described in Scheme C. Physical data as follows: IR (drift) 1671, 1603, 1536, 1518, 1430, 1415, 1361, 1349, 1324, 1269, 1194, 1134, 1118, 1104, 799 cm"1; Η NMR (300 MHz, CD3OD) δ 7.62 (1 H), 7.46 (3 H), 7.31 (2 H), 4.68 (3 H), 4.41 (3 H), 3.95 (4 H), 3.48 (5 H), 3.22 (3 H), 2.90 (2 H); 13C NMR (75 MHz, CD3OD) δ 175.8, 173.1, 165.3, 154.7, 138.2, 137.6, 135.2, 133.3, 132.4, 130.9, 129.4, 121.7, 121.5, 65.0, 64.8, 63.7, 60.6, 57.4, 55.8, 53.6, 51.4, 50.4, 38.6, 38.1, 36.6, 35.0; MS (ESI+) for C27H3ICl2N5O6S m/z 623.9 (M+H)+; HRMS (FAB) calcd for C27H3,Cl2N5O6S+H 624.1450, found 624.1452.
Scheme R.
Figure imgf000247_0001
Scheme R Scheme R teaches a general method for the preparation of Examples corresponding to structures R-4 and R-5, where 1 is nitrogen. Thus reaction of the amide -l (obtained from the imide J-2), with the organozinc derived from a suitable protected β-iodoalanine, provides the acylamino azaphenylalanine R-2. N-deprotection of R-2 gives the aminoester R-3, that is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of Examples R-4 and R-5 of this invention.
Preparation 87
(Scheme R: R-l where R<; is Ν, R7 is H, R8 is -ΝHC(O)-, and R, is 2,6-dichloro) 2,6-Dichloro-N-(5-iodo-2-pyridinyl)benzamide (C12H7Cl2IN2O). A mixture of J-2 and NH2NH2-H2O in MeOH is refluxed for 6 h under Ar. The reaction mixture is cooled, and the MeOH is removed in vacuo. The residue is partitioned between H2O and EtOAc. The EtOAc extracts are dried, filtered and concentrated to give a brown-colored solid, that is purified by silica flash chromatography (99:1 toluene/EtOAc) to provide Preparation 87: TLC (98:2 toluene/EtOAc) Rf= 0.43; Η NMR (CDC13, 300 MHz) δ 10.23 (IH), 8.26 (IH), 7.99 (IH), 7.57 (IH), 741-7.31 (3H); 13C NMR (CDC13, 75 MHz) δ 163.40, 153.22, 150.95, 147.16, 135.83, 132.72, 131.90, 130.34, 128.65, 128.50, 117.09, 86.55; MS (ESI) 393, 391.
Preparation 88 (Scheme R: R-2 where R6 is N, R7 is H, R8 is -NHC(O)-, R, is 2,6-dichloro and the stereochemistry is S) (S)-6-[(2,6-Dichlorobenzoyl)amino]-α-[[(l,l-dimethyIethoxy)carbonyl]amino]-3- pyridinepropanoic acid methyl ester (C21H23Cl2N3O5). To an amberized flask containing activated Zn dust (0.0.802 g, 12.27 mmol) under Ar is added dry THF (6 mL) and 1,2- dibromoethane (0.045 mL). This suspension is brought briefly to a gentle reflux, and then is cooled to rt. A solution of TMSC1 (1 M in THF, 0.39 mL) is added. The reaction mixture is stirred at 45 ± 5 °C for 30 min. and then is cooled to rt. To this mixture is added a degassed solution of N-[( 1,1 -dimethyl ethoxy)carbonyl]-3-iodo-L-alanine methyl ester (4.04 g, 12.27 mmol) in 2:1 NN-dimethylacetamide/THF (18 mL). The reaction mixture is stirred at 45 ± 5 °C for 5 h, and then is cooled to 0 °C. To this mixture is added PdCl2(PPh3)2 (0.428 g) followed immediately by a degassed solution of Preparation 87 in 1 :1 NN-dimethylacetamide/THF (19 mL). This reaction mixture is stirred at 45 ± 5 °C for 44 h. It is cooled to 0 °C, and is quenched with cold aqueous satd ΝH4C1. This mixture is extracted with EtOAc. The combined EtOAc extracts are washed with aqueous satd NH4C1 and brine. The EtOAc extracts are dried, filtered and concentrated to provide a green- brown colored oil, that is purified by silica flash chromatography (steps of 750:250:1, 700:300:1 and 650:350: 1 heptane/EtOAc/iPrOH) to provide Preparation 88: TLC Rf= 0.28 (7:3 hexanes/EtOAc).
Preparation 89 (Scheme R: R-3 where R« is N, R7 is H, R8 is -NHC(O)-, , is 2,6-dichloro and the stereochemistry is S)
(S)-α-Amino-6-[(2,6-dichlorobenzoyl)amino]-3-pyridinepropanoic acid methyl ester dihydrochloride salt (C16H15CI2N3O3-2HCI, R-3). A solution of Preparation 88 (0.812 g, 1.73 mmol) in 4 M HCl in dioxane (20 mL) is stirred under Ar at rt for 20 h. The reaction mixture is concentrated in vacuo, and the residue is taken up in H2O (60 mL). This aqueous mixture is extracted with Et2O (3 60 mL), and the Et2O extracts are discarded. The aqueous solution is frozen and lyophilized to provide Preparation 89: IR (diffuse reflectance) 3021, 2995, 2953, 2893, 2884, 2866, 2853, 2844, 2341, 2015, 1916, 1749, 1646, 1569, 1252 cm"1; MS (EI) 367 (M+), 282, 280, 262, 175, 173, 147, 145, 109, 107, 88. Preparation 90 & Example 289 [5-(i?* i?*)]- -[[[l-[[2-[(2,6-Dichlorobenzoyl)amino]-5-pyridinyl]methyl]-2- methoxy-2-oxoethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid ethyl ester
(C23H24Cl2N4O6S)
(Scheme R: R-4 where R, is H, R2 is H, R3 is -Et, X is S, (Y) is -C(O)O, m is 2, n is 0, o is
1 , R^ is N, R7 is H, R8 is -NHC(O)-, R, is 2,6-dichloro and the stereochemistry is [S-
(R* R*)])
Figure imgf000250_0001
To a mixture of the N-acylthiazolidinecarboxylic acid (0.292 g, 1.42 mmol), HOAt (0.193 g, 1.42 mmol) in 4:1 CH2C12/DMF (5.25 mL) at 0 °C is added EDC (0.272 g, 1.42 mmol). This reaction mixture is stirred at 0 °C for 20 min. Solid Preparation 89 (0.568 g, 1.29 mmol) and ΝMM (0.316 mL, 3.27 mmol) are added. The resulting reaction mixture is stirred at 0 °C for 4 h, and then is kept at 4°C for 40 h. The mixture is concentrated in vacuo, and the residue is taken up in CH2C12. The CH2C12 mixture is extracted with H2O, aq satd ΝaHCO3, and H2O. The combined aqueous washes are back-extracted with CH2C12. The combined CH2C12 extracts are dried, filtered and concentrated to a pale yellow-colored foam, that is purified by silica flash chromatgraphy (600:400:1 EtOAc/heptane/iPrOH) to give Preparation 90 (Example 289): IR (diffuse reflectance) 3275, 1742, 1697, 1665, 1586, 1559, 1532, 1476, 1427, 1398, 1382, 1351, 1344, 1311, 1284, 1279, 1242, 1223, 1196, 1100, 1023, 802, 787, 770, 697 cm'1; MS (EI) 554 (M+), 495, 422, 395, 352, 315, 293, 280, 172, 160, 144, 116, 107, 88, 60.
Example 290
[5'-(/?*i?*)]^l-[[[l-Carboxy-2-[2-[(2,6-dichlorobenzoyl)amino]-5- pyridinyl]ethyl]amino]carbonyl]-3-thiazolidinecarboxylic acid ethyl ester
(C22H22Cl2N4O6S, Example 290)
(Scheme R: R-4 where R, is H, R2 is H, R3 is -Et, X is S, (Y) is -C(O)O, m is 2, n is 0, o is
1, Rf, is N, R7 is H, R8 is -NHC(O)-, Rg is 2,6-dichloro and the stereochemistry is [S-
(R* R*)])
Figure imgf000251_0001
To a solution of Preparation 289 (0.400 g, 0.72 mmol) in 6:1 THF/H2O (25.6 mL) at 0 °C under Ar is added slowly over 4 h (via syringe pump) an aqueous solution of
NaOH (1 M, 7.92 mL). The reaction mixture is stirred an additional 1.5 h. The reaction mixture is partitioned between aqueous HCl and EtOAc. The aqueous solution is separated, and is extracted further with EtOAc. The combined EtOAc extracts are dried, filtered and concentrated to a beige-colored foam. This foam is taken up in 1 : 1 MeCN/H2O. This solution is frozen and lyophilized to give Example 290 as a beige- colored solid: mp 142-144 °C; IR (diffuse reflectance) 3169, 3094, 3031, 2980, 2964, 2935, 1735, 1691, 1591, 1556, 1531, 1480, 1431, 1400, 1379, 1344, 1308, 1288, 1266, 1216, 1194, 1148, 799, 782, 772 cm"1; Anal. C 48.72, H 4.29, Cl 12.26, N 9.95, S 5.62 (calcd C 48.81, H 4.10, Cl 13.10, N 10.35, S 5.92). Biological Assays
Jurkat-Endothelial Cell Adhesion Assay:
The following assay established the activity of the present compounds in inhibiting β, -mediated cell adhesion in a representative in vitro system. This assay measures the adhesive interactions of a T-cell line, Jurkat, known to express the 4β, integrin, to endothelial monolayers in the presence of test compounds. The test compounds were added in increasing concentrations to T-cells and then the T- cell compound mixture was added to IL-1 stimulated endothelial cell monolayers. The plates were incubated, washed and the percentage of attached cells was quantitated. The present assay directly demonstrates the cell adhesion inhibitory activity and adhesion modulatory activity of the compounds.
Human umbilical vein endothelial cells were purchased from Clonetics (San Diego, CA.) at passage number 2. The cells were grown on 0.5%> porcine skin gelatin pre-coated flasks (Sigma, St. Louis MO.) in EGM-UV media (Clonetics, San Diego, CA) supplemented with 10%> fetal bovine serum. Cells are refed every 2-3 days reaching confluence by day 4 to 6. The cells are monitored for factor VIII antigen and results show that at passage 12, the cells are positive for this antigen. The endothelial cells are not used following passage 6.
The T-cell line Jurkat was obtained from American Type Tissue Culture Collection (Rockville, MD) and the cells were cultured in RPMI containing 10 % fetal calf serum. The cells were washed twice in Hank's Balanced Salt Solution (HBSS) and resuspended in Dulbecco's Minimal Eagle's Media (DMEM) containing 2.5 mg/ml Human Serum Albumin (HSA). Jurkat cells (lxlO6 cells/ml) were stained with 10 ng/ml BCECF-AM (Molecular Probes, Eugene. OR)) in HBSS without phenol red. The cells were loaded with BCECF for 60 minutes in the dark at 370C, washed 2 times, and resuspended in DMEM-HSA solution.
Confluent endothelial monolayers, grown in 96-well tissue culture plates, were stimulated for 4 hr. at 37 °C with 0.1 ng/ml (-50 U/ml) recombinant IL-1 (Amgen, Thousand Oaks, CA). Following this incubation, the monolayers were washed twice with HBSS and 0.1 ml of DMEM-HSA solution was added. Jurkat cells (5 x 105 cells) were combined with the appropriate concentration of the test compound and 0.1 ml of the Jurkat cell-compound mixture was added to the endothelial cell monolayers. Generally, 100, 20, 5 and 1.25 μM compound concentrations were tested. These concentrations are adjusted downward for analogs found or thought to be more potent. The plates were placed on ice for 5 minutes to allow for Jurkat cell settling and the plates were incubated at 37 °C for 20 minutes. Following this incubation, the monolayers were washed twice with PBS containing 1 mM calcium chloride and 1 mM magnesium chloride and the plates were read using a Millipore Cytofluor 2300 (Marlboro, MA.). Fluorescence in each well was measured as Arbitrary Fluorescence Units and percent adhesion in the absence of compound was adjusted to 100%) and the % adhesion in the presence of compound was calculated. Monolayers were also fixed in 3%> paraformaldehyde and evaluated microscopically to verify the adhesion. This procedure is a modification of a previously published method (Cardarelli et al., J. Biol. Chem. 269:18668-18673 (1994)).
Jurkat-CS-1 assay
The CS-1 derived peptide, CLHPGEILDVPST, and the scrambled control peptide, CLHGPIELVSDPT, were synthesized on a Beckman 990 synthesizer using t-Boc methodology. The peptides were immobilized onto microtiter plates using the heterobifunctional crosslinker 3-(2-pyridyldithio)propionic acid N- hydroxysuccinimide ester (SPDP) as reported by Pierschbacher et al., Proc. Natl. Acad. USA, 80:1224-1227 (1983). Microtiter plates were coated with 20 μg/ml HSA for 2 hr. at room temperature, washed once with PBS and derivatized with 10 μg/ml SPDP for 1 hr. After washing, 100 μl of a 100 μg/ml cysteine containing peptide solution which had been recently dissolved was added to the wells and allowed to crosslink to the plates overnight at 4 °C. Unbound peptide was removed from plates by washing with PBS. To block non-reacted sites, the plates are coated with 100 μl of a 2.5 mg/ml BSA solution in PBS for 1 hr. at 37 °C. 100 μl of Jurkat cells (2.5 x 106 cells/ml) in DMEM plus BSA (2.5 mg/ml) was mixed with an appropriate concentration of the compound to be tested and the mixture was added to peptide coated dishes and incubated for 1 hr. at 37 °C. Generally 100, 20, 5 and 1.25 μM concentrations of the compound were tested. The concentrations of the compound were adjusted downward for compounds thought or found to be more potent.
Following this incubation the plates were washed once with PBS and the attached cells were fixed with 3%> paraformaldehyde in PBS and stained with 0.5%> toluidine blue in 3.7%> formaldehyde. The cells were stained overnight at room temperature and the optical density at 590 nm of toluidine blue stained cells was determined using a vertical pathway spectrophotometer to quantitate attachment (VMAX Kinetic Microplate Reader, Molecular Devices, Menlo Park, CA). This procedure is a modification of a previously published method (Cardarelli et al, J. Biol. Chem., 269:18668-18673 (1994) and Cardarelli et al, Proc. Natl. Acad. Sci. USA, 83:2647-2651 (1986)). The preferred compounds are those which have low IC50 values in the
Jurkat EC assay or the Jurkat-CS-1 assay described above or which have at least moderate activity in both assays. All of the compounds of the present invention have an activity of less than 50 μM in the Jurkat CS-1 assay or less than 500 μM in the Jurkat EC assay. Compounds with activity in the Jurkat CS-1 assay preferably have IC50 values of less than 1 μM, more preferably less than 0.5 μM, most preferably less than or equal to 0.08 μM. Compounds with activity in the Jurkat EC assay preferably have IC50 values of less than 10 μM, more preferably less than 5 μM, most preferably less than or equal to 0.8 μM.
In the Jurkat EC Assay, IC50 value ranges (μM) are depicted by A, B, and C and in the Jurkat CS-1 Assay, IC50 value ranges are depicted by D, E, and F. These ranges are as follows: In vitro data:
EC: A > 1 μM; 1 μM > B > 0.25 μM; C < 0.25 μM CS-1 D > 0.75 μM; 0.75 μM > E > 0.05 μM; F < 0.05 μM.
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Biological Activity in Dextran Pleurisy Model
Certain compounds of the present invention were tested in a Dextran® pleurisy model. Rationale for Developing an c^β, Integrin Antagonist to Treat Inflammatory Diseases
VLA-4. a member of the βl integrin family of adhesion molecules, is thought to play a critical role in several types of inflammatory disease processes by promoting leukocyte adhesion to vascular cell adhesion molecule (VCAM-1) and the CS-1 domain of fibronectin in extracellular tissue matrix (Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S. Hemler M. Lobb RR. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4-fibronectin binding site. Cell; 60: 577-584. 1990, Humphries MJ. Akiyama SK. Komoriya A, Olden K. Yamada KM. Identification of an alternatively-spliced site in human plasma fibronectin that mediates cell type-specific adhesion. J Cell Biol; 103: 2637-2647. 1986, Wayner EA, Garcia-Pardo
A, Humphries MJ. McDonald JA, Carter WG. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol; 109: 1321-1330, 1989, Guan J-L, Hynes RO. Lvmphoid cells recognize an alternatively-spliced segment of fibronectin via the integrin c^β, . Cell; 60: 53-61, 1990) Of the cell types expressing VLA-4, the major emphasis has been on eosinophils, lymphocytes, and monocytes. Validation of the role of VLA-4 has relied predominantly on the use of anti-VLA-4 antibodies which have been shown to suppress delayed-type hypersensitivity responses (Issekutz TB. Dual inhibition of VLA-4 and
LFA-1 maximally inhibits cutaneous delayed-tvpe hypersensitivity-induced inflammation. Am J Pathol; 143: 1286-1293, 1993, Scheynius A. Camp RL, Pure E. Reduced contact sensitivity reactions in mice treated with monoclonal antibodies to leukocyte function- associated molecule- 1 and intercellular adhesion molecule- 1. J Immunol; 150: 655-663, 1993, Ferguson TA, Kupper TS. Antigen-independent processes in antigen-specific immunity. J Immunol; 150: 1 172-1182, 1993, Chisholm PL, Williams CA, Lobb RR. Monoclonal antibodies to the integrin α-4 subunit inhibit the murine contact hypersensitivity response. Eur J Immunol; 23: 682-688. 1993. Elices MJ, Tamraz S, Tollefson V, Vollger LW. The integrin VLA-4 mediates leukocyte recruitment to skin inflammatory sites in vivo. Clin Exp Rheumatol; 1 1 (Suppl 8) S77-80), 1993, experimental allergic encephalomyelitis (Yednock TA, Cannon C, Fritz LC, Sanchez- Madrid F, Steinman LM, Karin N. Prevention of experimental autoimmune encephalomyelitis bv antibodies against ocβ, integrin. Nature; 356: 63-66. 1992, Canella
B, Raine CS. The VCAM-1 /VLA-4 pathway is involved in chronic lesion expression in multiple sclerosis (MS). J Neuropathol Exp Neurol; 52: 31 1. 1993), HIV-induced encephalitis (Sasseville VG, Newman W, Brodie SJ. Hesterberg P, Pauley D. Ringler DJ. Monocvte adhesion to endothelium in simian immunodeficiency virus-induced AIDS encephalitis is mediated bv vascular cell adhesion molecule- l/α,β,_ integrin reactions. Am J Pathol; 144: 27-40, 1994). pulmonary inflammation and airway hyperreactvity in asthma (Abraham WM, Sielczak MW. Ahmed A, Cortes A. Lauredo IT. Kim J. Pepinsky, B. et al. α, -integrins mediate antigen-induced late bronchial responses and prolonged airway hvperresponsiveness in sheep. J Clin Invest; 93: 776-787, 1994. Pretolani M. Ruffle C, Roberto LapaeSilva J, Joseph D. Lobb RR. Vargaftig BB. Antibody to very late activation antigen 4 prevents antigen-induced bronchial hvperreactivity and cellular infiltration in the guinea-pig airways. J Exp Med; 180: 795-805. 1994), experimental models of autoimmune-mediated diabetes (Yang X-D. Karin N, Tisch R, Steinman L, McDevitt HO. Inhibition of insulitis and prevention of diabetes in non-obese diabetic mice bv blocking L-selectin and very late antigen 4 adhesion receptors. Proc Natl Acad Sci USA; 90: 10494-10498, 1993, Burkly LC, Jakubowski A, Hattori M. Protection against adoptive transfer of autoimmune diabetes medicated through very late antigen-4 integrin. Diabetes; 43: 529-534, 1994), and experimental colitis (Podolsky DK, Lobb R, King N. Benjamin CD, Pepinsky B, Sehgal P, et al. Attentuation of colitis in the cotton-top Tamarin bv anti- 4 integrin monoclonal antibody. J Clin Invest; 92: 372-380, 1993). Since eosinophils represent a major component of the inflammatory cell influx in asthmatic lung tissue we developed a simple acute inflammatory model of VLA-4 integrin-dependent eosinophil infiltration which could be used to identify VLA-4 antagonists; such compounds would be of potential value in the treatment of asthma as well as other diseases in which VLA-4 played a role. Materials and Methods Animals, housing and viral testing:
C57BL/6 mice (Jackson, Bar Harbor. ME; ), 6-8 weeks old, weighing 20-25g were used throughout. All mice were acclimated for at least 7-14 days after arrival and maintained under controlled temperature (20-22°C) and a 12 hr daily light cycle (6.00 A.M. - 6.00 P.M.). Mice were housed in laminar flow racks and checked biweekly for viral infections (mouse hepatitis virus, minute virus of mice, rodent orphan parvovirus. Sendai) with kits obtained from Oreganon Teknika (Durham. NC) using established enzyme-linked immunoabsorbent assays. Mice testing positive for any of the above were omitted from the study. All mice were fed standard laboratory chow (Upjohn Lab Rodent Irradiated Mouse Chow. #501 1-3, PMI Feeds. St. Louis. MO) and acidified drinking water (pH 5.0) ad libitum. Induction of Inflammation by Intrapleural Injection of Dextran:
Intrapleural injections were made using a 27G needle cut to 3-4 mm and blunted by filing. Injections were made by inserting the needle between the mid-intercostal ribs on the right side of the thoracic cavity.
Dextran (MW 5-40x10^, St Louis, MO.) was injected as a 10%> solution in saline in a volume of 100 μl/mouse. Care was taken to avoid bleeding at the site of injection at which the intercostal muscles were cut to facilitate smooth insertion of the needle. Quantitation of Pleural Inflammatory Leukocyte Responses: Pleural leukocytes were collected as follows: 4h post-induction, pleural inflammatory exudate was removed by washing with 2 x 1.0 ml Ca++/Mg++ free HBSS
(Gibco, Grand Island, NY) containing 45 mg EDTA 100 ml HBSS, 4°C. Total leukocyte counts were made by hemocytometer following erythrocyte lysis in 2%> acetic acid in PBS buffer; exudate leukocyte pellets were resuspended in serum for cytospin preparations and stained (Diff Quik, Baxter Healthcare, McGraw Park, IL) for differential leukocyte counts (neutrophils. eosinophils, and mononuclear leukocytes).
The pleural cavities of mice receiving either no intrapleural injection, or saline were washed and the cells counted in the same way to estimate baseline or saline-induced pleural leukocyte counts respectively. Administration of compounds:
All drugs were dissolved in PBS and the pH adjusted to 7.5 with NaOH. Each compound was administered intravenously through the retroorbital sinus at hourly intervals (0-3h) starting from time "0" as indicated. Mice were carefully monitored for side effects; none were noted for the series of compounds reported herein. The following compounds were tested for their inhibitory effects on dextran- induced leukocyte infiltration: Examples 3, 8. 9, 10. 12. 16. 37, 62, 66, 67, 99, 100, 111, 1 13, 115, 127. 131 , 141. 184, 185, 192, PBS (saline) was administered iv. as a control. Inhibition of eosinophil infiltration, which was suppressed by anti-alpha-4 Mab (PS/2, 50%>), was used as a readout of VLA-4 antagonist activity of the compounds tested. Data for neutrophils are also reported. Results: Dextran pleural leukocyte response. The total pleural leukocyte counts were 255x104(+/- 16 SEM) cells in the normal pleural cavity; of the normal pleural leukocyte population, all cells were mononuclear (a similar response was observed following intrapleural saline injection). Four hours after intrapleural injection of dextran total pleural leukocyte counts increased to 719xl04(+/-67 SEM) and comprised 36.8x104(+/-4.1 SEM) eosinophils, 292x104(+/-25 SEM) neutrophils and 391xl04(+/-48 SEM) mononuclear leukocytes.
% inhibition of Eosinophil infiltration A>40; B: 20-39; C < 19
Example Dose Eos
3 50 x 2 iv A
8 100 x 1 po C
9 50 x 2 iv A
10 100 x 1 po B
12 50 x 2 iv A
16 50 x 2 iv A
37 50 x 2 iv A
62 50 x 2 iv B
66 50 x 2 iv A
67 50 x 2 iv A
99 50 x 2 iv A
100 50 x 2 iv B
111 50 x 2 iv C
1 13 50 x 2 iv C Example Dose Eos
115 50 x 2 iv B
127 50 x 2 iv B
131 50 x 2 iv C
141 50 x 2 iv A
185 50 x 2 iv B
184 50x2iv B
192 50 x 2 iv B

Claims

CLAIMS What is claimed is: 1. A compound of the formula:
Figure imgf000267_0001
wherein
R, may occur one to four times and each occurrence is independently hydrogen or C,.6 alkyl;
R2 is hydrogen, pyridyl, C,.6 alkyl, (C,_6 alkyl)-CO2-R,,, or -CO2-R,,; in addition, R, and R: may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000267_0002
together with the carbon atom to which they are attached:
R3 is hydrogen, phenyl. C,.6 alkyl, C3^ alkenyl, C7.,7 arylalkyl , (C,.6 alkyl)-CO2- R,„ (C2.6 alkenyl)-CO2-R„, (C,.6 alkyI)-CO-C,.6 alkyl, (C,.6 alkyl)-O-C,.6 alkyl, (C,.6 alkyl)- OH, (C,.6 alkyl)-CN, adamantyl or one of the following:
Figure imgf000268_0001
yl)2 in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000268_0002
R4 is -O-R„, NH2, NHOH, -O-(C7.)0 arylalkyl), or is of the formula
— θ-CH2-
R5 is a formula of the following:
Figure imgf000268_0003
R6is N or CH;
R7 is hydrogen or halogen; Rg is -NH-Y,-, -OCH2- or -CONH-;
Rg may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl;
R10 is C,^ alkyl, or (C,^ alkyl)-OH, or hydrogen;
Ru is hydrogen or C,^ alkyl;
R12 is C,^ alkyl or the following formula:
Figure imgf000269_0001
R13 is N or CH;
W is (CM alkyl);
X is S, O, or CH2;
Y and Y, are independently -CO-, -C(=O)O-, -SO2-, or -C(=O)N(R10)-;
Z is O, CH2, or N-R„; / is 1, 2, or 3; m is 1 or 2; n is 0 or 1 ; o is 0 or 1 ; is 0 or 1; q is 0 or 1 ; and r is O, 1, 2 or 3; with the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl; (3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is
CH2), W is equal to CH2; and
(4) the compound is not
Figure imgf000270_0001
2. The compound according to claim 1, wherein
Rj is a formula of the following:
Figure imgf000270_0002
wherein R7 is hydrogen or Cl.
3. The compound according to claim 2, wherein
R2 is hydrogen or C,^ alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000270_0003
together with the carbon atom to which they are attached;
m is 2; and p s 0.
4. The compound according to claim 3, wherein
R, is hydrogen or C,.3 alkyl;
R2 is hydrogen or C alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000271_0001
together with the carbon atom to which they are attached;
R3 is hydrogen, C,.6 alkyl, C7.17 arylalkyl, (ClJf> alkyl)-OH, (Cw alkyl)-CO2-R„, (C,. 6 alkyl)-CN, adamantyl, phenyl, or one of the following:
(Ci-6
Figure imgf000271_0002
-(Ci.6 aI yD—
Figure imgf000271_0003
R4 is -O-R„ , NH2, NHOH, or is of the formula
-θ-CH2-
R,, is hydrogen or CH3; and X is S or O.
5. The compound according to claim 3, wherein
R, is hydrogen; R2 is hydrogen;
R3 is(C2^ alkenyl)-CO2-R„, (Cw alkyl)-O-C,.3 alkyl, (C,^ alkyl)-CO2R„, or one of the following:
Figure imgf000272_0001
- HN-
-Nθ2
Cθ2-Rι J1 Cθ2-Rn
R4 is O-R„; Re is CH; Rn is hydrogen; R7 is hydrogen;
X is S;
Y is -CO-; and / is 1.
6. The compound according to claim 3, wherein
R, is hydrogen;
R2 is hydrogen; R3 is CM alkyl, (Cw alkyl)-CO2-Rn, (CM alkenyl)-CO2-R„, (Cw alkyl)-CO-CM alkyl, (Cw alkyl)-O-C,.3 alkyl, (CM alkyl)-CN, or one of the following:
(Ci-β
Figure imgf000273_0001
Figure imgf000273_0002
Figure imgf000273_0003
Figure imgf000273_0004
R4 is OH;
Rf, is CH;
R,, is hydrogen;
R7 is hydrogen;
X is CH2; and
Y is -CO- or -C(=O)NH-.
7. The compound according to claim 2, wherein
W is (C,.j alkyl);
X is CH2;
Y is -C(=O)O-;
R, is hydrogen;
R2 is hydrogen, (C,.3 alkyl)-CO2-R, „ or -CO2-R„;
R3 is hydrogen, C7.10 arylalkyl, C,.6 alkyl, or (C,^ alkyl)-CO2-R,,;
R4 is OH;
R6 is CH;
Rn is hydrogen;
R7 is hydrogen;
/ is 1 or 3; and M is O.
8. The compound according to claim 2, wherein
W is C,.3 alkyl;
X is CH2; R, is hydrogen;
R2 is (C alkyl)-CO2-Rn, or CO2-Rn;
R3 is hydrogen, C,.3 alkyl, or C2.7 alkenyl;
R4 is OH,
Re is CH; R-i i is hydrogen;
R7 is hydrogen;
/ is 1; is 1;
H is 1; o is 0; and p is 1.
9. The compound according to claim 1, wherein said compound is
Figure imgf000274_0001
10. The compound according to claim 4, wherein
R, is hydrogen; R2 is hydrogen;
R3 is Cw alkyl, (C^ alkyl)-CO2Rn, (CM alkenyl)-CO2R„, (C,^ alkyl)-O-C,.3 alkyl, or one of the following:
.^ -co2-Rι " ^ ^
OH -Q
Figure imgf000275_0001
R4 is O-R„; R« is CH;
R,, is hydrogen or C,^ alkyl; R7 is hydrogen;
X is S;
Y is -C(=O)O-; and / is 1.
11. The compound according to claim 1 , wherein
R, is hydrogen or C,.3 alkyl;
R2 is hydrogen or CM alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms, or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000275_0002
together with the carbon atom to which they are attached;
R3 is hydrogen, C,4 alkyl, C7.,7 arylalkyl, (Cw alkyl)-OH. (Cw alkyl)-CO2-R„, (C,. 6 alkyl)-CN, adamantyl, phenyl, or one of the following:
Figure imgf000276_0001
R4 is -O-R„ , NH2, NHOH, or is of the formula
Figure imgf000276_0002
Rn is hydrogen or C alkyl; and X is S or O.
12. A compound of the formula:
Figure imgf000276_0003
wherein
R, may occur one to four times and each occurrence is independently hydrogen or Cw alkyl; R2 is hydrogen, pyridyl, C,^ alkyl, (C,^ alkyl)-CO2-Ru, or -CO2-Rπ; in addition, R, and R, may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000277_0001
together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, C,^ alkyl, C^ alkenyl, C7.,7 arylalkyl , (C,^ alkyl)-CO2-
R,„ (CM alkenyl)-CO2-R,„ (Cw alkyl)-CO-Cw alkyl, (C,.6 alkyl)-O-Cw alkyl, (Cw alkyl)- OH, (C,^ alkyl)-CN, adamantyl or one of the following:
-(Cι.6 aD yl)-N Z — N Z
-(Ci-β ak O- 3 *tft
Figure imgf000277_0002
Figure imgf000277_0003
in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000277_0004
R4 is -O-R„, NH2, NHOH, -O-(C7.,0 arylalkyl), or is of the formula
-o-CH2-jr
R5 is a formula of the following:
Figure imgf000278_0001
R^ is N or CH; R7 is hydrogen or halogen;
R8 is -NH-Y,-, -OCH2- or -CONH-;
R9 may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl;
R,0 is C,^ alkyl, or (Cw alkyl)-OH, or hydrogen; Rn is hydrogen or C,^ alkyl;
R,2 is C alkyl or the following formula:
Figure imgf000278_0002
W is (C,.6 alkyl);
X is S, O, or CH2;
Y and Y, are independently -CO-, -C(=O)O-, -SO2-, or -C(=O)N(R,0)-;
Z is O, CH2, or N-R„;
/ is 1, 2, or 3; m is 1 or 2; n is O or 1; o is 0 or 1 ; p is 0 or 1; q is 0 or 1 ; and r is O, 1, 2 or 3; with the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; (4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and/or an IC50 value of less than 50μM in a Jurkat EC assay; and (5) the compound is not
Figure imgf000279_0001
13. A pharmaceutical composition comprising: a therapeutically effective amount of the compound as set forth in any one of the preceding claims; and a pharmaceutically acceptable carrier or diluent.
14. A method for treating or preventing α4β, adhesion mediated conditions in a human which comprises administering to a patient an effective amount of the compound according to any one of claims 1. 2. 3. 4, 5, 6, 7, 8, 9, 10, 11, or 12.
15. The method according to claim 14, wherein said condition is selected from the group consisting of rheumatoid arthritis, asthma, allergy conditions, allograft rejection, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions, inflammatory bowel diseases, atherosclerosis, and ulcerative colitis.
16. The method according to claim 15, wherein said condition is asthma.
17. A compound of the formula:
Figure imgf000280_0001
wherein
R, may occur one to four times and each occurrence is independently hydrogen or Ci4) alkyl;
R2 is hydrogen, pyridyl, C,^ alkyl, (C,^ alkyl)-CO2-Rπ, or -CO2-R,,; in addition, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000280_0002
together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, C,^ alkyl, C3^ alkenyl, C7.,7 arylalkyl , (C,^ alkyl)-CO2-
R„, (CM alkenyl)-CO2-Rπ, (Cw alkyl)-CO-CM alkyl, (Cw alkyl)-O-C,.6 alkyl, (Cw alkyl)- OH, (Cw alkyl)-CN, adamantyl or one of the following:
Figure imgf000281_0001
in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000281_0002
R4 is -O-R,„ NH2, NHOH, -O-(C7.10 arylalkyl), or is of the formula
-θ-CH2-
R5 is a formula of the following:
Figure imgf000281_0003
R6is N or CH;
R7 is hydrogen or halogen; R8 is -NHCO-;
R, may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl;
R,0 is C alkyl, or (C,^ alkyl)-OH, or hydrogen; R,, is hydrogen or C,^ alkyl;
R12 is C,^ alkyl or the following formula:
Figure imgf000282_0001
R13 is N or CH;
W is (Cβ alkyl); X is S, O, or CH2;
Y is -CO-, -C(=O)O-, or -C(=O)N(RI0)-;
Z is O, CH2, or N-R,,;
/ is 1, 2, or 3; is 1 or 2; w is O or l; o is 0 or 1 ; p is 0 or 1 ; q is 0 or 1 ; and r is O, 1, 2 or 3; with the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl; and
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2.
18. The compound according to claim 17, wherein
R5 is a formula of the following:
Figure imgf000283_0001
wherein R7 is hydrogen or Cl.
19. The compound according to claim 18, wherein
R2 is hydrogen or C,^ alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000283_0002
together with the carbon atom to which they are attached; n is 0; m is 2; and p is .
20. The compound according to claim 19, wherein
R, is hydrogen or C,.3 alkyl;
R, is hydrogen or CM alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same atom and form a ring of 5-8 atoms of the formula: -2*2-
Figure imgf000284_0001
together with the carbon atom to which they are attached;
R3 is hydrogen, Cw alkyl, C7.17 arylalkyl, (Cw alkyl)-OH, (Cw alky -COj-R,,, (C,. 6 alkyl)-CN, adamantyl, phenyl, or one of the following:
Figure imgf000284_0002
R4 is -O-R,, , NH„ NHOH, or is of the formula
Figure imgf000284_0003
R,, is hydrogen or CH3; and X is S or O.
21. The compound according to claim 19, wherein
R, is hydrogen;
R2 is hydrogen;
R3 is (C2^ alkenyl)-CO2-R,„ (CM alkyl)-O-C,.3 alkyl, (C^ alkyl)-CO2R,„ or one of the following:
Figure imgf000285_0001
R4 is O-R„;
Re is CH;
Rπ is hydrogen;
R7 is hydrogen;
X is S;
Y is -CO-; and
/ is 1.
22. The compound according to claim 19, wherein
R, is hydrogen;
R2 is hydrogen;
R3 is Cw alkyl, (Cw alkyl)-CO2-Rn, (C^ alkenyl)-C02-Rπ, (Cw alkyl)-CO-CM alkyl, (CM alkyl)-O-C,.3 alkyl, (C,.6 alkyl)-CN, or one of the following:
Figure imgf000285_0002
R4 is OH; Rf, is CH; Rπ is hydrogen; R7 is hydrogen;
X is CH2; and Y is -CO- or -C(=O)NH-.
23. The compound according to claim 18, wherein
W is (C,.3 alkyl);
X is CH2; Y is C(=O)O-;
R, is hydrogen;
R2 is hydrogen, (C,.3 alkyl)-CO2-R„, or -CO2-R,,;
R3 is hydrogen, C7.10 arylalkyl, C,^ alkyl, or (C,^ alkyl)-CO2-Rn;
R4 is OH; R« is CH;
Ru is hydrogen;
R7 is hydrogen;
/ is 1 or 3; and n is 0.
24. The compound according to claim 18, wherein
W is C,.3 alkyl; X is CH2; R, is hydrogen;
R2 is (C alkyl)-CO2-Ru, or CO2-R„; R3 is hydrogen. C,.3 alkyl, or C2.7 alkenyl; R4 is OH, Rt is CH; Rπ is hydrogen; R7 is hydrogen; / is 1; m is 1; n is 1; o is 0; and is 1.
25. The compound according to claim 17, wherein said compound is
Figure imgf000287_0001
26. The compound according to claim 20, wherein
R, is hydrogen;
R2 is hydrogen;
R3 is ClJ6 alkyl, (Cw alkyl)-CO2R, „ (CM alkenyl)-CO2R,„ (C,.6 alkyl)-O-C,.3 alkyl, or one of the following:
Figure imgf000287_0002
R4 is O-R„; R6 is CH;
R,, is hydrogen or C,^ alkyl; R7 is hydrogen;
X is S; Y is -C(=O)O-; and / is 1.
27. The compound according to claim 17, wherein
R, is hydrogen or C,.3 alkyl;
R2 is hydrogen or CM alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms, or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000288_0001
together with the carbon atom to which they are attached;
R3 is hydrogen, C^ alkyl, C7.,7 arylalkyl, (Cw alkyl)-OH, (Cw alkyl)-CO2-Ru, (C,. 6 alkyl)-CN. adamantyl, phenyl, or one of the following:
Figure imgf000288_0002
Figure imgf000288_0003
R4 is -O-R„ , NH2, NHOH, or is of the formula Rπ is hydrogen or C,^ alkyl; and X is S or O.
28. A compound of the formula:
Figure imgf000289_0001
wherein
R, may occur one to four times and each occurrence is independently hydrogen or Cw alkyl;
R2 is hydrogen, pyridyl, C,^ alkyl, (CM alkyl)-CO2-R,„ or -CO2-R„; in addition, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000289_0002
together with the carbon atom to which they are attached;
R3 is hydrogen, phenyl, C,^ alkyl, C3^ alkenyl, C7.,7 arylalkyl , (C,.6 alkyl)-CO2- R,„ (CM alkenyl)-CO2-R,„ (Cw alkyl)-CO-Cw alkyl, (C,.6 alkyl)-O-Cw alkyl, (Cw alkyl)- OH, (C,^ alkyl)-CN, adamantyl or one of the following: -(C i -6 -(Ci-6 aIkyI)-N Z
Figure imgf000290_0001
Figure imgf000290_0002
Figure imgf000290_0003
in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000290_0004
R4 is -O-R,„ NH2, NHOH, -O-(C7.,0 arylalkyl), or is of the formula
Figure imgf000290_0005
R5 is a formula of the following:
Figure imgf000290_0006
R^ is N or CH;
R7 is hydrogen or halogen; R8 is -NHCO-;
Ro may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl; R,0 is Cw alkyl, or (C,^ alkyl)-OH, or hydrogen;
Rπ is hydrogen or C,^ alkyl; RI2 is C,^ alkyl or the following formula:
Figure imgf000291_0001
R13 is N or CH; W is (Cw alkyl);
X is S, O, or CH2;
Y is -CO-, -C(=O)O-, or -C(=O)N(R10)-;
Z is O, CH2, or N-R„;
/ is 1, 2, or 3; m is 1 or 2; n is 0 or 1 ; o is 0 or 1 ; p is 0 or 1 ; q is 0 or 1 ; and r is 0, 1, 2 or 3; with the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; and
(4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and/or an IC50 value of less than 50μM in a Jurkat EC assay.
Figure imgf000292_0001
wherein
R, may occur one to four times and each occurrence is independently hydrogen or Cw alkyl;
R2 is hydrogen, pyridyl, C,^ alkyl, (C,^ alkyl)-CO2-Rn, or -CO2-R,,; in addition, R, and R2 may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000292_0002
together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, C,^ alkyl, C3^ alkenyl, C7.I7 arylalkyl , (C,.6 alkyl)-CO2-
R,„ (CM alkenyl)-CO2-R„, (C,^ alkyl)-CO-C,^ alkyl, (CM alkyl)-O-Cw alkyl, (Cw alkyl)- OH, (C,^ alkyl)-CN, adamantyl or one of the following:
Figure imgf000293_0001
kyI)2
in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000293_0002
R4 is -O-R,„ NH2, NHOH, -O-(C7.10 arylalkyl), or is of the formula
-θ-CH2-|i-
R5 is a formula of the following:
Figure imgf000293_0003
I^is N or CH;
R7 is hydrogen or halogen; R8 is -OCH2-;
R, may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl;
R10 is C,^ alkyl, or (C,^ alkyl)-OH, or hydrogen; Rπ is hydrogen or C,^ alkyl;
R12 is C,^ alkyl or the following formula:
Figure imgf000294_0001
R13 is N or CH;
W is (CM alkyl); X is S, O, or CH2;
Y is -CO-, -C(=O)O-, or -C(=O)N(RI0)-;
Z is O, CH2, or N-R„;
/ is 1, 2, or 3; m is 1 or 2; w is O or l ; o is 0 or 1 ; p is 0 or 1 ; q is 0 or 1 ; and r is O, 1, 2 or 3; with the provisos that
(1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; (4) when R3 is phenyl, C,^ alkyl, C7.17 arylalkyl, (C,.6 alkyl)-CO2-R,„
(C,^ alkyl)-O-C,.6 alkyl, or (C,^ alkyl)OH, o is 0; and (5) the compound is not
Figure imgf000295_0001
30. The compound according to claim 29, wherein
R5 is a formula of the following:
Figure imgf000295_0002
wherein R7 is hydrogen or Cl.
31. The compound according to claim 30, wherein
R2 is hydrogen or C,^ alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000295_0003
together with the carbon atom to which they are attached; n is 0; m is 2; and p is 0.
32. The compound according to claim 31 , wherein
R, is hydrogen or C,.3 alkyl;
R2 is hydrogen or C alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000296_0001
together with the carbon atom to which they are attached; R3 is hydrogen, C,^ alkyl, C7.17 arylalkyl, (C^ alkyl)-OH, (C,^ alkyl)-CO2-R„, (C,.
6 alkyl)-CN, adamantyl, phenyl, or one of the following:
Figure imgf000296_0002
-(Ci-6 alkyl)— N -N r~\ Z
Figure imgf000296_0003
R4 is -O-R„ , NH2, NHOH, or is of the formula
-θ-CH2-^
Rπ is hydrogen or CH3; and X is S or O.
33. The compound according to claim 31 , wherein
R, is hydrogen; R2 is hydrogen;
R3 is(CM alkenyl)-CO2-R,„ (CI-6 alkyl)-O-C,.3 alkyl, (CM alkyl)-CO2R,„ or one of the following:
Figure imgf000297_0001
R4 is O-R„;
R^ is CH;
Rπ is hydrogen;
R7 is hydrogen;
X is S;
Y is -CO-; and
/ is 1.
34. The compound according to claim 31 , wherein
R, is hydrogen;
R2 is hydrogen;
R3 is C^ alkyl, (C1-6 alkyl)-CO2-R„, (CM alkenyl)-CO2-Rπ, (Cw alkyl)-CO-CM alkyl, (Cw alkyl)-O-C,.3 alkyl, (C1-6 alkyl)-CN, or one of the following:
Figure imgf000298_0001
R, is OH; s is CH;
R„ is hydrogen;
R7 is hydrogen;
X is CH2; and
Y is -CO- or -C(=O)NH-
35. The compound according to claim 30, wherein
W is (C,.3 alkyl);
X is CH2;
Y is -C(=O)O-;
R, is hydrogen;
R2 is hydrogen, (C,.3 alkyl)-CO2-Ru, or -CO2-R,,;
R3 is hydrogen, C7.10 arylalkyl, C,^ alkyl, or CiJb alkyl)-CO2-Rn;
R4 is OH;
Rs is CH;
Rπ is hydrogen;
R7 is hydrogen;
/ is 1 or 3; and n is O.
36. The compound according to claim 30, wherein
W is C,.3 alkyl;
X is CH2; R, is hydrogen;
R2 is (CM alkyl)-CO2-R,„ or CO2-R„;
R3 is hydrogen, C,.3 alkyl, or C2-7 alkenyl;
R4 is OH,
Rs is CH; Rn is hydrogen;
R7 is hydrogen;
/ is 1; m is 1; rt is 1; o is 0; and is 1.
37. The compound according to claim 29, wherein said compound is
Figure imgf000299_0001
38. The compound according to claim 32, wherein
R, is hydrogen; R2 is hydrogen;
R3 is Cs alkyl, (CM alky -COA,, (CM alkenyl)-CO2Rπ, (CM alkyl)-O-C,.3 alkyl, or one of the following:
Figure imgf000300_0001
R4 is O-R„; s is CH;
R,, is hydrogen or C,^ alkyl;
R7 is hydrogen;
X is S;
Y is -C(=O)O-; and
/ is 1.
39. The compound according to claim 29, wherein
R, is hydrogen or C,.3 alkyl;
R2 is hydrogen or CM alkyl; in addition, R, and R2 may be attached to the same carbon atom and may form a carbocyclic ring of 5-8 atoms, or be attached to the same atom and form a ring of 5-8 atoms of the formula:
Figure imgf000300_0002
together with the carbon atom to which they are attached;
R3 is hydrogen, CM alkyl, C7.I7 arylalkyl, (Cw alkyl)-OH, (CM alkyl)-CO2-Rπ, (C,^ alkyl)-CN, adamantyl, phenyl, or one of the following: (Cι_6 a]kyl) (Co-6 alkyl)— N Z
Figure imgf000301_0001
Figure imgf000301_0002
Figure imgf000301_0003
Figure imgf000301_0004
Figure imgf000301_0005
R, is -O-R,, , NH2, NHOH, or is of the formula
-0-CH2-
N
Rn is hydrogen or C,_s alkyl; and X is S or O.
40. A compound of the formula:
Figure imgf000301_0006
wherein
R, may occur one to four times and each occurrence is independently hydrogen or C1-6 alkyl;
R2 is hydrogen, pyridyl, C,^ alkyl, (C,^ alkyl)-CO2-R,,, or -CO2-Rπ; in addition, R, and R, may be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they may be attached to the same carbon atom and form a ring of 5-8 atoms of the formula:
Figure imgf000302_0001
together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, C,^ alkyl, C3^ alkenyl, C7.17 arylalkyl , (C,_s alkyl)-CO2-
R,„ (CM alkenyl)-CO2-Rn, (Cw alkyl)-CO-CM alkyl, (CM alkyl)-0-Cw alkyl, (CM alkyl)- OH, (C,_s alkyl)-CN, adamantyl or one of the following:
Figure imgf000302_0002
kyI)2
in addition, R2 and R3-(Y)0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached:
Figure imgf000302_0003
R4 is -O-R,„ NH2, NHOH, -O-(C7.,0 arylalkyl), or is of the formula
Figure imgf000302_0004
Rj is a formula of the following:
Figure imgf000303_0001
Rsis N or CH; R7 is hydrogen or halogen; Rg is -OCH2-;
Ro may occur one to three times and is a halogen, C,^ alkoxy, C,^ alkyl or trifluoromethyl;
R10 is C,^ alkyl, or (C,^ alkyl)-OH, or hydrogen;
Rπ is hydrogen or C1-6 alkyl;
R12 is C,^ alkyl or the following formula:
Figure imgf000303_0002
R13 is N or CH; W is (C alkyl); X is S, O, or CH2;
Y is -CO-, -C(=0)O-, or -C(=O)N(R,o)-; Z is O, CH2, orN-R„; / is 1, 2, or 3; is 1 or 2; n is 0 or 1 ; o is 0 or 1 ; p is 0 or 1 ; q is 0 or 1 ; and r is 0, 1, 2 or 3; with the provisos that (1) when Y is -C(=O)O-, R3 cannot be hydrogen;
(2) when R4 is equal to O-(C4 alkyl), C4 alkyl is not equal to tert-butyl;
(3) in those pyrrolidine structures (/ is 1 ; m is 2; n is 0; o is 0; p is 1 ; X is CH2), W is equal to CH2; (4) the compound has an IC50 value of less than 5μM in a Jurkat CS-1 assay and or an ICJ0 value of less than 50μM in a Jurkat EC assay;
(5) when R3 is phenyl, C,^ alkyl, C7.17 arylalkyl, (C,^ alkyl)-CO2-R,„ (CM alkyl)-O-Cw alkyl, or (C,_s alkyl)OH, o is 0; and
(6) the compound is not
Figure imgf000304_0001
PCT/US1999/014233 1998-06-23 1999-06-23 INHIBITORS OF α4β1 MEDIATED CELL ADHESION WO1999067230A1 (en)

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US09/720,088 US6685617B1 (en) 1998-06-23 1999-06-23 Inhibitors of α4β1 mediated cell adhesion
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MXPA00012765A MXPA00012765A (en) 1998-06-23 1999-06-23 INHIBITORS OF alpha4.
AU47116/99A AU764553B2 (en) 1998-06-23 1999-06-23 Inhibitors of alpha 4 beta 1 mediated cell adhesion
KR1020007014696A KR20010083065A (en) 1998-06-23 1999-06-23 Inhibitors of α4β1 mediated cell adhesion
CA002342778A CA2342778A1 (en) 1998-06-23 1999-06-23 Inhibitors of .alpha.4.beta.1 mediated cell adhesion
NZ509010A NZ509010A (en) 1998-06-23 1999-06-23 4 to 7 Membered heterocyclic ring systems containing either nitrogen and optionally sulphur useful as inhibitors of alpha-4, beta-1 mediated cell adhesion
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US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6407066B1 (en) 1999-01-26 2002-06-18 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
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US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
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US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7081460B2 (en) 2001-04-09 2006-07-25 Ortho-Mcneil Pharmaceutical, Inc. Quinazoline and quinazoline-like compounds for the treatment of integrin-mediated disorders
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GEP20063956B (en) * 1999-08-13 2006-11-10 Biogen Idec Inc Cell adhesion inhibitors
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (en) * 1995-01-23 1996-08-01 Biogen, Inc. Cell adhesion inhibitors
US5688913A (en) * 1993-12-06 1997-11-18 Cytel Corporation CS-1 peptidomimetics, compositions and methods of using the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688913A (en) * 1993-12-06 1997-11-18 Cytel Corporation CS-1 peptidomimetics, compositions and methods of using the same
WO1996022966A1 (en) * 1995-01-23 1996-08-01 Biogen, Inc. Cell adhesion inhibitors

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US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
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US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
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