EP1019046A1 - Protease inhibitors - Google Patents

Protease inhibitors

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Publication number
EP1019046A1
EP1019046A1 EP98920926A EP98920926A EP1019046A1 EP 1019046 A1 EP1019046 A1 EP 1019046A1 EP 98920926 A EP98920926 A EP 98920926A EP 98920926 A EP98920926 A EP 98920926A EP 1019046 A1 EP1019046 A1 EP 1019046A1
Authority
EP
European Patent Office
Prior art keywords
ylcarbonyl
thiazol
hydrazide
leucinyl
naphthyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98920926A
Other languages
German (de)
French (fr)
Other versions
EP1019046A4 (en
Inventor
Stacie Marie Halbert
Evelyne Michaud
Scott Kevin Thompson
Daniel Frank Veber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
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Publication of EP1019046A1 publication Critical patent/EP1019046A1/en
Publication of EP1019046A4 publication Critical patent/EP1019046A4/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention relates in general to heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K.
  • Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxy apatite are incorporated.
  • Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem.
  • cystatin an endogenous cysteine protease inhibitor
  • cystatin an endogenous cysteine protease inhibitor
  • Other studies such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem., 1994, 56, 118, and Everts, et al, J. Cell. Physiol, 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1106, Inaoka, et al,
  • cathepsin K which has also been called cathepsin O
  • cathepsin O a cysteine protease
  • the abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix.
  • selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. Palmer, et al., J. Med.
  • Chem., 1995, 38, 3193 disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain.
  • Other classes of compounds such as aldehydes, nitriles, a-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases.
  • the synthesis of azatides (polyacylhydrazides) as peptide mimetics has recently been disclosed by Han and Janda, J. Am. Chem. Soc. 1996, 118, 2539.
  • N-phenyl-N'-(2-phenyloxazol-4-ylcarbonyl)hydrazide as well as its N-(2,4-dinitrophenyl) derivative, have been described in Afridi, A., et al., J. Chem. Soc, Perkin Trans. 1, 1976, 3, 315-20.
  • Benko, A.,et al., Justus LiebigsAnn. Chem., 1968, 717, 148-53 describes the preparation of N-(4-ethoxycarbonylthiazol-2-yl)-N'-[2-(4- pyridinyl)thiazol-4-ylcarbonyl]hydrazide.
  • cysteine protease inhibitors have been identified.
  • these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance.
  • An object of the present invention is to provide heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • this invention provides intermediates useful in the preparation of the compounds of Formula I.
  • this invention provides methods of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • proteases particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of Formula I:
  • L is C 2 -6alkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6alkyl, CH(R 4 )NR 5 R 6 , CH(R 4 )Ar, CH(R 4 )OAr', or NR 4 R 7 ;
  • Ar is phenyl or naphthyl, optionally independently substituted by one or more of Ph-Co-6 a lkyl, Het-Co-6alkyl, C ⁇ galkyl, Ci.galkoxy, Ph-C()-6 a lk° ⁇ y-- Het-Co-galkoxy,
  • Cj.galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring. Ph may be optionally substituted with one or more of Cj.galkyl, Ci.galkoxy, OH, (CH2) ⁇ _ 6 NR 8 R 9 , O(CH 2 )i-6NR 8 R 9 , CO 2 R ⁇ or halogen.
  • Ar' is phenyl or naphthyl, optionally independently substituted by one or more of Het-C()-6alkyl, Ci.galkyl, Cj.galkoxy, Ph-C ⁇ -galkoxy, Het-Co-galkoxy, OH, (CH2)I-6 NR8R9 > O(CH2)i-6N 8 R 9 , or halogen.
  • Ph may be optionally substituted with one or more of C ⁇ galkyl, C galkoxy, OH, (CH2) ⁇ _6NR 8 R 9 , 0(CH 2 )i-6NR 8 R 9 , CO2R', or halogen.
  • Two Cj-galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar' ring.
  • Het is a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph-C()-6 a lkyl, Het-C ⁇ -6 alkyl, Cj.galkyl, Cj. 6 ⁇ ° ⁇ ' Ph-C 0 . 6 alkoxy, Het-C 0 -6alkoxy, OH, (CH 2 ) ⁇ _6 NR R 9 , 0(CH 2 ) ⁇ _6NR 8 R9, CO2R'.
  • Two C ⁇ _6alkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring.
  • Ph may be optionally substituted with one or more of C ⁇ _ 6 alkyl, C galkoxy, OH, (CH 2 )i-6NR 8 R 9 , 0(CH 2 ) ⁇ _6NR 8 R 9 , CO 2 R', or halogen.
  • such heterocycles are selected from the group consisting of the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pryidazinyl, pyrimidinyl, triazinyl, tetrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isothiazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl,
  • W is C(O) or SO 2 ;
  • R ⁇ R 1 , R 2 , R 5 , R 8 , R 9 , R 10 , and R 12 are independently H, C galkyl, C 2 . galkenyl, Ar-Crj- ⁇ alkyl, or Het-C ⁇ _6alkyl;
  • R 3 is C 3 . 6 alkyl, Ar, Het, CH(R! ⁇ Ar, CH(R 1 -t)OAr, NR 1 ⁇ R 12 ,
  • R 4 , R - 11 , and R 15 are independently H, C j _ 6 alky 1, C 2 -6 a lkenyl, C 3 _6cycloalkyl-
  • R 7 is Cj.galkyl, C ⁇ galkenyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C()-6alkyl, or Het- CQ-6 a lkyl;
  • R 4 and R 7 may be combined to form a 3-7 membered monocyclic or 7-10- membered bicyclic carbocyclic or heterocyclic ring, optionally independently substituted with 1-4 of C ⁇ alkyl, Ar-Co-e-alkyl, Het-Co-6 a lkyl, Ci .galkoxy, Ar-Cr ⁇ galkoxy, Het-C Q . 6 alkoxy, OH, (CH 2 )i-6NR 8 R 9 , or 0(CH 2 )i-6NR 8 R 9 ;
  • R 6 and R 13 are R 14 , R 14 C(0), R 14 C(S), R 14 OC(0), or R 14 OC(O)NR 9 CH(R 15 )(CO); and
  • R 14 is C2_6 a lkenyl, Ar-Co_6alkyl, or Het-C Q -6alkyl.
  • R 3 is:
  • Rl6 is H or C- galkyl, preferably H or Me;
  • R*7 is Ci.galkyl, C2-6 a lkenyl, and C3.
  • jcycloalkyl-Ci.galkyl preferably n- propyl, wo-propyl, wo-pentyl, tert-butylmethyl, cyclopropylmethyl, iso-butyl, n-butyl, or allyl; and
  • R 18 is C3_6alkyl, OC3_6alkyl, Ar, Het, O(CH2) ⁇ -3Ar, or O(CH2) ⁇ -3Het, preferably 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, tert-butoxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 4-tert- butoxycarbonylbenzyloxy, 4-carboxybenzyloxy, 3-tert-butoxycarbonylbenzyloxy, 3- carboxybenzyloxy, 2-methyl-3-pyridinylmethoxy, 6-methyl-3-pyridinylmethoxy, benzyloxy, 2-quinolino, 3-quinolino, 4-quinolino, 5-quinolino, 6-quinoIino, 7-quinolino, 8- quinolino, 1-isoquinolino, 3-isoquinolino, piperidinyl,
  • L is 4-(cis-2,6-dimethyl)-4- morpholinyl, N-cyclopropylmethyl-N-(2-methylpropyl)amino, 4-methyl-l -naphthyl, N- methyl-N-(2-methylpropyl)amino, 1 -naphthyl, 5-acena ⁇ hthyl, N-cyclopropyl-N- cyclopropylmethylamino, N,N-bis-(2-methylpropyl)amino, l-(l,2,3,4-tetrahydroquinolino, N-cyclopropylmethyl-N-propylamino, N-(2-methylpropyl)-N-phenylamino, 2-methoxy-l- naphthyl, 2-benzyloxyphenyl, 2-benzyloxy-l -naphthyl, 9
  • Most particularly preferred compounds of the present invention include: N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • Ci-6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any Ci-6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2, C(0)N(R')2, carbamyl or Ci_4alkyl, where R' is C ⁇ _6alkyl.
  • C ⁇ alkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3- ⁇ cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane.
  • substituents are defined as for "Ci-6alkyl", above.
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C2-6 a l enyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and die several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, Cl, Br, and I.
  • Ar or “aryl” or “Ar”' or “aryl”' means phenyl or naphthyl, optionally independently substituted by one or more of Ph-C ⁇ .galkyl, Het-C ⁇ -galkyl, Cj.galkyl, C ⁇ _ 6 alkoxy, Ph-C 0 . 6 alkoxy, Het-C 0 . 6 alkoxy, OH, (CH 2 ) ⁇ _6NR 8 R 9 , O(CH 2 ) ⁇ .6NR 8 R 9 , CO2R', or halogen.
  • Two C ⁇ .galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring.
  • Ph may be optionally substituted with one or more of C ⁇ alkyl, C ⁇ 6 alkoxy, OH, (CH 2 )i-6NR 8 R 9 , O(CH 2 ) ⁇ _6 R 8 R 9 , C0 2 R', or halogen.
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph- Co_galkyl, Het-C ⁇ .g alkyl, Cj.galkyl, Cj.galkoxy, Ph-C ⁇ .galkoxy, Het-C ⁇ .galkoxy, OH, (CH 2 )i-6 NR 8 R 9 , 0(CH 2 )i-6NR 8 R 9 , C0 2 R'.
  • TWO C galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring.
  • Ph may be optionally substituted with one or more of Cj.galkyl, C j .galkoxy, OH, (CH2) ⁇ _6NR 8 R9, O(CH2)i-6-N R 9 > CO2 ', or halogen.
  • heterocycles include the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrr ' olidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidiny
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • EDC refers to N-ethyl- N'(dimethylaminopropyl)-carbodiimide.
  • HOBT refers to 1 -hydroxy benzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • Lawesson's reagent is 2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide
  • NMM is N-methylmorpholine
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • An acid chloride (such as cyclopropanecarbonyl chloride or isobutyryl choride) (A Scheme 1) is treated with a primary amine (such as aniline, cyclopropylamine, isobutylamine or propylamine) and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Scheme 1. which is treated with lithium aluminum hydride in THF to afford 3-Scheme 1.
  • 3-Scheme 1 may be prepared by treatment of an aldehyde (such as cyclopropanecarboxaldehyde or isobutyraldehyde) (8-Scheme 1 " ) with an amine (such as cyclopropylamine) in methylene chloride to provide 9-Scheme 1. which is treated with a reducing agent (such as lithim aluminum hydride in ether or sodium triacetoxyborohydride in methylene chloride). Treatment of 3-Scheme 1 with thiophosgene and pyridine in methylene chloride, followed by treanment with ammonia in methanol provides 4-Scheme 1.
  • an aldehyde such as cyclopropanecarboxaldehyde or isobutyraldehyde
  • an amine such as cyclopropylamine
  • a reducing agent such as lithim aluminum hydride in ether or sodium triacetoxyborohydride in methylene chloride.
  • 4-Scheme 1 may be prepared by treatment of __ Scheme 1 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. 4-Scheme 1 is treated with hydrazine hydrate in ethanol to give 5-Scheme 1.
  • Ethyl bromopyruvate __ Scheme 2 is treated with thiourea in refluxing ethanol to provide 2-Scheme 2. which is treated successively with sodium nitrite and copper (I) bromide in 16% aqueous HBr, and die product was heated in ethanol with a catalytic amount of HBr to give 3-Scheme 2.
  • arylboronic acid such as 2-benzyloxyphenylboronic acid, 1 -naphthy lboronic acid, 4-methyll -naphthy lboronic acid, 5-acenaphthylboronic acid, 2-methoxy-l -naphthy Iboronic acid, 2-methoxymethoxy-l -naphthy lboronic acid, 9- anthraceny lboronic acid, 9-phenantheny lboronic acid, 2-(4-tert- butoxycarbonylbenzyloxy)phenylboronic acid, 4-methoxymethoxynaphthylboronic acid or 8-quinolineboronic acid), tetrakis(txiphenylphosphine)palladium(0) and sodium bicarbonate in refluxing toluene/ethaonl water provides 4-Scheme 2.
  • 2-benzyloxyphenylboronic acid such as 2-benzyloxyphenylbor
  • 5-Scheme 2 Treatment of 4-Scheme 2 with hydrazine hydrate in ethanol provides 5-Scheme 2. which is treated with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-L- leucine, N-(4-pyridinylmethoxycarbonyl)-L-leucine, N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucine, N-benzyloxycarbonyl-L-leucine, 4-methyl-2-(3- phenylphenyl)pentanoic acid, 4-methyl-2-(3-phenoxyphenyl)pentanoic acid, 4-methyl-2-(4- phenoxyphenyl)pentanoic acid, N-benzyloxycarbonyl-L-b-tert-butylalanine, N- benzyloxycarbonyl
  • a carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) (1 -Scheme 3) is converted to 2-Scheme 3 by treatment with isobutyl chloroformate, N-methylmo ⁇ holine and ammonia in THF.
  • 2-Scheme 3 is treated with Lawesson's reagent in THF to provide the thioamide 3-Scheme 3.
  • This material is converted to the thiazole by condensation with an a-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 3 which is converted to 5-Scheme 3 by treatment with hydrazine monohydrate.
  • This material is treated with a carboxylic acid (such as (1S)- l-benzyloxycarbonylamino-l-(4-carboxythiazol-2-yl)-3-methylbutane) and a peptide coupling reagent (such as EDC- ⁇ C1/1-HOBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 3 where W is C(O).
  • W SO2
  • 5-Scheme 3 is treated with a corresponding sulfonyl chloride, R 3 SU2C1, and n-mediylmo ⁇ holine (NMM) in methylene chloride.
  • This material is treated with a carboxylic acid (such as pryazinecarboxylic acid, picolinic acid, 2-quinolinecarboxylic acid, 3-quinolinecarboxylic acid, 4- quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7- quinolinecarboxylic acid, 8-quinolinecarboxylic acid, 1-isoquinolinecarboxylic acid, 3- isoquinolinecarboxylic acid, N-methylpiperidinecarboxlic acid 4-methylimidazole-5- carboxylic acid, N-benzylproline, N-methy lproline, l-benzyl-5-methylimidazole-4- carboxylic acid, 6-methylnicotinic aicd, 2-methylnicotinic acid, 2-methylisonicotinic acid, 4-dimethyaminomethylbenzoic acid, 4-(4-mo ⁇ holino)benzoic acid, 5- hydroxymethylimidazole-4-carboxy
  • Coupling methods to form amide bonds herein are generally well known to the art.
  • the methods of peptide synthesis generally set forth by Bodansky et al, THE PRAC ⁇ CE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEP ⁇ DES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are inco ⁇ orated herein by reference.
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives diereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li + , Na + , K + , Ca" 1"1" , Mg -1"1- and NH4 "1" are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • compositions of the compounds of Formula I may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mglo about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K.
  • the present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
  • the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
  • the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of a compound or combination of compounds of the present invention.
  • proteases particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family
  • the present invention especially provides metiiods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of an inhibitor of cathepsin K, including a compound or combination of compounds of the present invention.
  • an effective amount is meant that amount of a compound or combination of compounds of the present invention sufficient to ameliorate or cure the clinically undesirable manifestations of disease (e.g. brittle and weakened bone in osteoporosis) caused by said pathological levels of target enzyme, e.g., cathepsin K, by inhibition of the target enzyme.
  • the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to an animal, particularly a mammal, most particularly a human in need thereof an effective amount of a compound or combination of compounds of Formula I, alone or in combination with other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of this invention and an anabolic agent such as bone mo ⁇ hogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
  • parenteral administration of a compound of Formula I is preferred.
  • the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
  • the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
  • an inventive compound which is therapeutically effective is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the compounds of diis invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion or to achieve any other therapeutic indication as disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 20 mg/kg.
  • the compounds of the present invention may be tested in one of several biological assays to determine the concentration of compound which is required to provide a given pharmacological effect.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA.
  • Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product. Inhibition studies
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of KQ
  • / is the concentration of inhibitor.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k ⁇ b s t)J / k 0 bs (2)
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 ⁇ m, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
  • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
  • the beads were mixed with the cells and die suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.
  • the osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to l.SxK ⁇ mL in EMEM medium, supplemented with 10% fetal calf serum and Ug/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium).
  • a positive control (87MEM1 diluted to 100 ug/ L) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubate at 37°C for 30 min.
  • 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate.
  • the slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
  • Cis-2,6-dimethylmo ⁇ holine (1.40 g, 12.17 mmol, 1.5 mL) was dissolved in chloroform (20 mL) and benzoyl isothiocyanate (2.0 g, 12.17 mmol, 1.75 mL) was added. After stirring 45 minutes at room temperature, the solution was concentrated to giv the title compound as a yellow solid (3.94 g, 100%). MS (ESI): 279.2 (M+H)+. b) cis-2,6-dimethy ⁇ -4-mo ⁇ holinothiourea
  • Example 1(a) The compound of Example 1(a) (3.38 g, 12.17 mmol) was dissolved in methanol (40 mL) and water (40 mL), potassium carbonate (8.4 g, 60.84 mmol) was added and the solution was heated at reflux overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate and water, then dried (MgSO4), filtered and concentrated to afford the title compound as a beige solid (1.7 g, 80%). MS (ESI): 174.9 (M+H)+.
  • Example 1(f) To a stirring solution the compound of Example 1(f) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 mL of water followed by LiOH ⁇ O (325 mg, 7.76 mmol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 mL) and 3 NHC1 was added (2.6 mL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 (M+H) + .
  • Triethylamine (1.53 g, 15.09 mmol, 2.1 mL) and isobutylamine (1.10 g, 15.09 mmol, 1.5 mL) were dissolved in methylene chloride (15 mL), cooled to 0°C, and cyclopropane carbonyl chloride (1.58 g, 15.09 mmol, 1.4 mL) was added dropwise. After stirring at 0°C for one hour the mixture was diluted with methylene chloride (60 mL) and washed with NaOH (1M), then with saturated brine, dried (MgS04), filtered and concentrated. The residue was washed with ether and dried to give the title compound as a beige solid (2.1 g, 100%). MS (ESI): 141.9 (M+H)+.
  • Example 1(b) The compound of Example 1(b) was heated at reflux in EtOH (1 L) for lh, then filtered. To the filtrate was added 64 drops of 48% (aq) HBr. After stirring at reflux for 24 h the solution was concentrated and redissolved in EtOAc (1 L). The solution was washed successively with saturated aqueous NaHC ⁇ 3 (1 L) and brine (1 L), dried (MgSO4), filtered, decolorized with charcoal, filtered through Celite, and concentrated to a pale yellow solid (16.95 g, 56%). l H NMR (400 MHz, CDC1 3 ) d 8.14 (s, IH), 4.46, (q, 2H), 1.43 (t, 3H). d) 4-methyl-l -naphthalene boronic acid
  • Example 3(a) The compound of Example 3(a) (2.9 g, 8.99 mmol) was dissolved in THF (40 mL) and metiiyl iodide (2.24 mL, 35.98 mmol) was added. The reaction mixture was cooled to 0°C in a flask protected from moisture. Sodium hydride dispersion (1.214 mg, 13.49 mmol) was added cautiously and the suspension was stirred for 5 h at room temperature. Ethyl acetate was then added (to consume die sodium hydroxide formed from the excess of sodium hydride), followed by water, dropwise, to destroy the excess of sodium hydride. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water.
  • Example 3(b) To the compound of Example 3(b) (2.07 g, 6.15 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperature the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried (MgSU4) and concentrated to afford the title compound as a white solid (1.72 g, 100%). MS (ESI): 281.3 (M+H) + .
  • Example 45 Following the procedure of Example 1(d) and 1(h), except substituting ethyl 2-[2- (4-tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6- dimed ⁇ yl-4-mo ⁇ holino)thiazole-4-carboxylate in step (d) and N-benzyloxycarbonyl-L- leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (0.102 g, 68%). MS (ESI): 673.2 (M+H)+.
  • Example 45 Following the procedure of Example 1(d) and 1(h), except substituting ethyl 2-[2- (4-tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6- dimed ⁇ yl-4
  • Example 48 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (156 mg, 75%). MS (ESI): 500.3 (M+H)+.
  • Example 48 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as
  • step (g) the title compound was prepared as a pale yellow solid (179.1 mg,
  • Example 69 Following the procedure of Example 59(a)-59(d), except substituting 7- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.106 g, 75%). MS (ESI): 538.2 (M+H) + .
  • Example 69
  • Example 75(a) The compound of Example 75(a) (0.300 g, 2.5 mmol) was dissolved in concentrated hydrochloric acid (3 mL). After stirring at reflux for 18 h, the solution was concentrated to yield the title compound as a white solid (0.342 g, 100%). MS (ESI): 137.8 (M+H)+.
  • Example 81 Following the procedure of Example 4(a)-4(d), except substituting 2- pyridylcarbinol for 4-pyridylcarbinol in step (a) and N-cyclopropyl isobutylamine for N- methyl isobutylamine in step (d), the title compound was prepared as a white solid (85 mg, 32%). MS (ESI): 517.3 (M+H)+. Example 81
  • Diazomethane (4.8 mmol in 18 ml Et2 ⁇ ) was added to a solution of the compound of Example 92(a) (0.210 g, 0.48 mmol) in 1 ml Et2 ⁇ at room temperature and was stirred for 5 minutes. Then Pd(OAc)2 (2 mg) was added and the reaction was stirred overnight, filtered through silica gel, concentrated in vacuo, and was used in the next reaction without further purification (205 mg, 95%). MS (ESI): 300.1 (M+Na) + .
  • Example 96 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting bis- (cyclopropylmethyl)amine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- bejnzyloxycarbonyl L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as as a yellow solid (140 mg, 69%). MS (ESI): 514.3 (M+H) + .
  • Example 96 Example 96
  • Example 28(d) Following the procedure of Example 28(d), except substituting ethyl 2-(4-hydroxy- 1 -naphthy l)thiazole-4-carboxy late for ethyl 2- (2-hydroxy-l -naphthy l)thiazole-4- carboxylate and 2-(N,N-dimethylamino)ethanol for benzyl alcohol, the title compound was prepared as a white solid (0.097 g, 52%). MS (ESI): 371.3 (M+H)+.
  • Example 136 Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 2-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.151 g, 86%). MS (ESI): 536.3 (M+H)+.
  • Example 136 Example 136

Abstract

The present invention provides compounds of formula (I) which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy; and metabolic bone disease therewith.

Description

PROTEASE INHIBITORS
FIELD OF THE INVENTION
This invention relates in general to heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
BACKGROUND OF THE INVENTION
Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxy apatite are incorporated. Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma. Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN2) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al, Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. Lerner, et al, J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem., 1994, 56, 118, and Everts, et al, J. Cell. Physiol, 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1106, Inaoka, et al,
Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al, FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K (which has also been called cathepsin O), a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells. The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. Palmer, et al., J. Med. Chem., 1995, 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, a-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. The synthesis of azatides (polyacylhydrazides) as peptide mimetics has recently been disclosed by Han and Janda, J. Am. Chem. Soc. 1996, 118, 2539.
The synthesis of N-phenyl-N'-(2-phenyloxazol-4-ylcarbonyl)hydrazide, as well as its N-(2,4-dinitrophenyl) derivative, have been described in Afridi, A., et al., J. Chem. Soc, Perkin Trans. 1, 1976, 3, 315-20. Benko, A.,et al., Justus LiebigsAnn. Chem., 1968, 717, 148-53 describes the preparation of N-(4-ethoxycarbonylthiazol-2-yl)-N'-[2-(4- pyridinyl)thiazol-4-ylcarbonyl]hydrazide. Thus, a structurally diverse variety of cysteine protease inhibitors have been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance. A need therefore exists for methods of treating diseases caused by pathological levels of proteases, especially cysteine proteases, including cathepsins, especially cathepsin K, and for novel inhibitor compounds useful in such methods.
We have now discovered a novel class of heterocycleloketohydrazide compounds which are protease inhibitors, most particularly of cathepsin K.
SUMMARY OF THE INVENTION
An object of the present invention is to provide heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to
Formula I.
In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I.
In still another aspect, this invention provides methods of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula I:
I wherein:
L is C2-6alkyl, Ar-C0.6alkyl, Het-C0-6alkyl, CH(R4)NR5R6, CH(R4)Ar, CH(R4)OAr', or NR4R7;
Ar is phenyl or naphthyl, optionally independently substituted by one or more of Ph-Co-6alkyl, Het-Co-6alkyl, C^galkyl, Ci.galkoxy, Ph-C()-6alk°χy-- Het-Co-galkoxy,
OH, (CH2)i-6NR8R9, 0(CH2)I_6NR8R9, CO2R', or halogen. Two Cj.galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring. Ph may be optionally substituted with one or more of Cj.galkyl, Ci.galkoxy, OH, (CH2)ι_ 6NR8R9, O(CH2)i-6NR8R9, CO2R\ or halogen. Ar' is phenyl or naphthyl, optionally independently substituted by one or more of Het-C()-6alkyl, Ci.galkyl, Cj.galkoxy, Ph-Cø-galkoxy, Het-Co-galkoxy, OH, (CH2)I-6NR8R9 > O(CH2)i-6N 8R9, or halogen. Ph may be optionally substituted with one or more of C^galkyl, C galkoxy, OH, (CH2)ι_6NR8R9, 0(CH2)i-6NR8R9, CO2R', or halogen. Two Cj-galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar' ring.
Het is a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph-C()-6alkyl, Het-Cθ-6 alkyl, Cj.galkyl, Cj. 6^°^' Ph-C0.6alkoxy, Het-C0-6alkoxy, OH, (CH2)ι_6 NR R9, 0(CH2) ι_6NR8R9, CO2R'. Two Cι_6alkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring. Ph may be optionally substituted with one or more of Cι_6alkyl, C galkoxy, OH, (CH2)i-6NR8R9, 0(CH2)ι_6NR8R9, CO2R', or halogen. Preferably, such heterocycles are selected from the group consisting of the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pryidazinyl, pyrimidinyl, triazinyl, tetrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isothiazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiadiazolyl, and oxadiazolyl rings.
W is C(O) or SO2; X, Y, and Z are independently N, O, S or CR10, provided that at least two of X, Y and Z are heteroatoms and at least one of X, Y and Z is N, or one of X, Y and Z is C=N, C=C or N=N and die other two are CR^υ or N, further provided that at least two of X, Y and Z are N;
» indicates a single or double bond in the five-membered heterocycle; R\ R1, R2, R5, R8, R9, R10, and R12 are independently H, C galkyl, C2. galkenyl, Ar-Crj-όalkyl, or Het-Cø_6alkyl;
R3 is C3.6alkyl, Ar, Het, CH(R! ^Ar, CH(R1 -t)OAr, NR1 ΪR12,
R4, R -11 , and R 15 are independently H, C j _6alky 1, C2-6alkenyl, C3_6cycloalkyl-
Cø_6-alkyl, Ar-Co_6alkyl, or
R7 is Cj.galkyl, Cμgalkenyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C()-6alkyl, or Het- CQ-6alkyl; R4 and R7 may be combined to form a 3-7 membered monocyclic or 7-10- membered bicyclic carbocyclic or heterocyclic ring, optionally independently substituted with 1-4 of C^alkyl, Ar-Co-e-alkyl, Het-Co-6alkyl, Ci .galkoxy, Ar-Cr^galkoxy, Het-CQ. 6alkoxy, OH, (CH2)i-6NR8R9, or 0(CH2)i-6NR8R9;
R6 and R13 are R14, R14C(0), R14C(S), R14OC(0), or R14OC(O)NR9CH(R15)(CO); and
R14 is C2_6alkenyl, Ar-Co_6alkyl, or Het-CQ-6alkyl.
Compounds of Formula I wherein Z = N, X = S, and Y = CH (thiazolo) are preferred. More preferred are such compounds wherein W is C(O). Even more preferred are such compounds wherein Rl and R2 are H.
Yet more preferred are such compounds wherein R3 is:
wherein:
Rl6 is H or C- galkyl, preferably H or Me; R*7 is Ci.galkyl, C2-6alkenyl, and C3. jcycloalkyl-Ci.galkyl, preferably n- propyl, wo-propyl, wo-pentyl, tert-butylmethyl, cyclopropylmethyl, iso-butyl, n-butyl, or allyl; and
R18 is C3_6alkyl, OC3_6alkyl, Ar, Het, O(CH2)θ-3Ar, or O(CH2)θ-3Het, preferably 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, tert-butoxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 4-tert- butoxycarbonylbenzyloxy, 4-carboxybenzyloxy, 3-tert-butoxycarbonylbenzyloxy, 3- carboxybenzyloxy, 2-methyl-3-pyridinylmethoxy, 6-methyl-3-pyridinylmethoxy, benzyloxy, 2-quinolino, 3-quinolino, 4-quinolino, 5-quinolino, 6-quinoIino, 7-quinolino, 8- quinolino, 1-isoquinolino, 3-isoquinolino, piperidinyl, 4-methylpiperidinyl, 4- methylimidazol-5-yl, N-benzyl-pyrrolidinyl, N-methyl-pyrrolidinyl, l-benzyl-5- methylimidazol-4-yl, 1-piperazinyl; 3-(2-pyridyl)benzyl, 2-methyl-3-pyridinyl, 2-methyl-4- pyridinyl, 6-methyl-3-pyridinyl, 4-dimethylaminobenzyloxy, 4-(4- morpholinomethyl)phenyl, 5-hydroxymethylimidazol-4-yl, 5-butyl-2-pyridinyl, 4- fluorophenyl, 3,4-difluorophenyl, 2-(l,8-naphthyridinyl), or 3,4-dimethoxyphenyl. Also yet more preferred are compounds of Formula I wherein Z = N, X = S, and Y
= CH (thiazolo), W is C(O), R1 and R2 are H, and wherein L is 4-(cis-2,6-dimethyl)-4- morpholinyl, N-cyclopropylmethyl-N-(2-methylpropyl)amino, 4-methyl-l -naphthyl, N- methyl-N-(2-methylpropyl)amino, 1 -naphthyl, 5-acenaρhthyl, N-cyclopropyl-N- cyclopropylmethylamino, N,N-bis-(2-methylpropyl)amino, l-(l,2,3,4-tetrahydroquinolino, N-cyclopropylmethyl-N-propylamino, N-(2-methylpropyl)-N-phenylamino, 2-methoxy-l- naphthyl, 2-benzyloxyphenyl, 2-benzyloxy-l -naphthyl, 9-phenanthrenyl, 9-anthracenyl, phenyl, 2-(4-tert-butoxycarbonyl)benzyloxyphenyl, 2-(4-carboxybenzyloxy)phenyl, N- cyclopropylamino, 8-quinolino, N,N-bis-(cyclopropylmethyl)amino, 4-(2,2- dimethy laminoethoxy)- 1 -naphthyl, or 1 -(N-benzy loxycarbony lamino)-3-methylbutyl .
The following compounds are particularly preferred embodiments of the present invention:
N-[2-(cis-2,6-dimethyl-4-morpholino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(4-methyl-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide; N- [2- [N-methy l-N-(2-methy Ipropy l)amino]thiazol-4-y Icarbony 1 ]-N'- [N-methy l-N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(5-acenaphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide;
N- [2- [N-cyclopropylmethy l-N-(2-methy Ipropy l)amino]thiazol-4-y Icarbony 1]-N'- [N- methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[l-(l,2,3,4- tetrahydroquinolino)]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpent-4-enoyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide; N-[N-(2-methylpropyl)-N-(3-phenylphenyl)carbamoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[4-methyl-2-(3-phenyl)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[4-methyl-2-(3-phenyl)phenylpentanoyl]-N'-[2-[N-(2-methylpropyl)-N- pheny lamino]thiazol-4-y Icarbony l]hydrazide;
N-[2-(2-methoxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide; N-[2-(2-benzyloxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-
L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(9-phenanthrenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide;
N-[2-(9-anthracenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(-tert-butoxycarbonyl-L- leucinyl)ydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(L-leucinyl)]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L- leucinyl)hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyrazinecarbonyl)-
L-leucinyl]hydrazide;
N-[N,N-bis-(2-methylpropyl)carbamoyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-(2-phenylthiazol-4-ylcarbonyl)-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[2-(4-tert-butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[2-(4-carboxybenzyloxy)phenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-tert-butoxycarbonyIbenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-
N-phenylamino]thiazol-4-ylcarbonyl]hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-carboxybenzyloxycarbdnyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycaronyl-L-leuciny 1)-N' - [2- [2-(4-tert- butoxy caτbonyl)benzyloxyphenyl]thiazol-4-y Icarbony l]hydrazide ;
N-(N-benzyloxycaronyl-L-leucinyl)-N'-[2-[2-(4-carboxybenzyloxy)phenyl]thiazol-4- ylcarbonyljhydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-(N-benzyloxycarbony 1-L-leuciny 1)-N' - [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-tert-butoxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(2-pyridinylmedιoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-()-L- leucinyl]hydrazide;
N'[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl- L-leucinyl)hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(3-tert-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-leucinyl)hydrazide;
N-fN-(3-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-quinolinoyl)-L-leucinyl]hydrazide;
N- [2-( 1 -naphthyl)thiazol-4-y Icarbony 1]-N'- [N-(4-methy lpiperidinecarbonyl)-L- leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(5-quinolinoyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-(N-benzyl-L-prolinyl-L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(l-benzyl-5-methylimidazol-4-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(3-methylisonicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- y Icarbony ljhydrazide;
N-[2-(N-cyclopropylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[4-methyl-2-(3-phenoxy)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide; N-[N-(2-benzoxazolyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzy loxycarbonyl-L-leuciny 1)-N' - [2- [N,N-bis-(2-methy Ipropy l)amino] oxazol-4- ylcarbonyljhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- ρyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [2-( 1 -naphthyl)thiazol-4-y Icarbony 1]-N' - [N-( 1 -piperazinecarbonyl)-L- leucinyl]hydrazide;
N-[4-methyl-2-(4-phenoxy)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(8-quinolinoyl)-L-leucinyl]-N'-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-L-b-terϊ-butylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyI]hydrazide;
N-(N-benzyloxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[3-(2-pyridyl)phenylacetyl]-L- leucinyljhydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- methylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- methylisonicotinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L- leucinyljhydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L- leucinyljhydrazide; N-[2-[4-(2,2-dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(7- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)- L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-methyl-L-prolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-isoleucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(4-dimethylaminomethylbenzoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norleucinyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[N-(4-dimethylaminomethylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol- 4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(2-benzyloxyphenyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcaιbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide; N-[N-[4-(4-morpholinomethyl)benzoyl]-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(2-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-b-tert-butoxycarbonyl-L-tert-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide; N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-tert-butylalanyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b-tert- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-allylglycinyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-cyclopropylalanyl)hydrazide;
N-[N-(6-methylnicotinoyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide; N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-
4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b- cyclopropylalanyljhydrazide;
N-[N-(6-methylnicotinoyl)-L-b-terϊ-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-b-tert-butylalanyl)hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-tert-butylalanyl]hydrazide; N-(N-tert-butoxycarbony 1-L-b-cyclopropy lalany 1)-N' - [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-allylglycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b- cyclopropylalanyljhydrazide;
N-[N-(3-isoquinolinoyl)-L-b-cyclopropylalanyl]-N'[-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b- cyclopropylalanyljhydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norleucinyl)hydrazide; N-[2-(l-naphd yl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norleucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyI]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-tert-butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b-r-ert- butylalanyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b-tert- butylalanyljhydrazide;
N- [N-( 1 -isoquinolinoyl)-L-b-tert-buty lalany 1]-N' - [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide; N-[N-(3-isoquinolinoyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[N-(6-methylnicotinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-norleucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norleucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(5- hydroxymethylimidazol-4-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-(6- methylnicotinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cycloproρyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)glycinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyI]-N'-[N-(6-methylnicotinoyl)-L- norvalinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylimidazol-5-ylcarbonyl)-L- norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(l-isoquinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L-norvalinyl]hydrazide;
(IS, l'S)-N, N'-bis-[4-[l-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2- ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cycloproρylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-( 1 - isoquinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tert-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- fluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(4-fluorobenzoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N- [2-( 1 -naphthy l)thiazol-4-y lcarbonyl]-N'- [N-(2-pyridiny lmethoxycarbony l)-L-b-tert- butylalanyljhydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N- [2-( 1 -naphthyl)thiazol-4-y Icarbony 1]-N'- [N-(2-pyridiny lmethoxycarbony l)-L-b- cyclopropylalanyljhydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(6-me yl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethdxycarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N,N'-bis-[2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hydrazide; N- [2-(N-cyclopropyl-N-cyclopropy lmethy lamino)thiazol-4-y Icarbony 1]-N'- [N- [2-( 1 , 8- naphthyridinoyl)]-L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- flluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tert-butylalanyl]-N'-[2-(N-cyclopropyI-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; and
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tert-butylalanyl]hydrazide.
Most particularly preferred compounds of the present invention include: N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(4-methyl-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide; N- [2-( 1 -naphthyl)thiazol-4-ylcarbonyl]-N'- [N-(2-py ridiny lmethoxycarbony 1)-L- leucinyljhydrazide;
N-[2-(5-acenaphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide; N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-E2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[ 1 -( 1 ,2,3,4- tetrahydroquinolino)]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3- pyridinylrnethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)- L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(9-phenanthrenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(-terr-butoxycarbonyl-L- leucinyl)ydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L- leucinyl)hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyrazinecarbonyl)-
L-leucinyl]hydrazide; N-[2-[2-(4-tert-butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [2- [2-(4-carboxybenzy loxy)phenyl]thiazol-4-y lcarbonyl]-N' - [N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [N-(4-tert-butoxycarbonylbenzy loxycarbony l)-L-leuciny 1]-N' - [2- [N-(2-methy lpropyl)- N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide; N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-tert-butoxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-()-L- leucinyljhydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-leucinyl)hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [N-(3-tert-butoxycarbony lbenzy loxycarbony l)-L-leuciny 1]-N' - [2-(N-cyclopropy 1-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-leucinyl]hydrazide;
N- [N-(2-methy 1-3-pyridiny lmethoxycarbonyl)-L-leucinyl]-N' - [2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-leucinyl)hydrazide;
N-[N-(3-carboxybenzyloxycarbonyI)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylpiperidinecarbonyl)-L- leucinyljhydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(5-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(3-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[N-(l-benzyl-5-methylimidazol-4-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(3-methylisonicotinoyl)-L-leucinyl]-N'-[2-( 1 -naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N,N-bis-(2-methylpropyl)amino]oxazoI-4- ylcarbonyljhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [2-( 1 -naphthyl)thiazol-4-y Icarbony 1]-N' - [N-( 1 -piperazinecarbonyl)-L- leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(8-quinolinoyl)-L-leucinyl]-N'-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-L-b-tert-butylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-(N-benzyloxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[3-(2-pyridyl)phenylacetyl]-L- leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-leuciny 1)-N' - [2- [N-bis-(cyclopropylmethy l)amino]thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- me ylisonicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L- leucinyljhydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L- leucinyl]hydrazide;
N-[2-[4-(2,2-dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(7- quinolinoyl)-L-leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)-
L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-methyl-L-prolinyl-L- leucinyl)hydrazide; N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-isoleucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norleucinyl)-N' -[2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(4-dimethylaminomethylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol- 4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(2-benzyloxyphenyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide; N- [N- [4-(4-morpholinomethyl)benzoy l]-L-leuciny 1] -N' - [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-b-tert-butoxycarbonyl-L-tert-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-tert-butylalanyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b-tert- butylalanyl]hydrazide;
N-[2-(l-naρhthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-allylglycinyl)hydrazide;
N- [2-( 1 -naρhthyl)thiazol-4-y Icarbony 1] -N' -(N-picolinoyl-L-b-cyclopropylalany l)hydrazide;
N- [N-(6-methy lnicotinoy l)-L-b-cyclopropy lalany 1] -N' - [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide; N- [N-(4-methylimidazol-5-y Icarbony l)-L-b-cyclopropylalany 1]-N' - [2-( 1 -naphthy l)thiazol-
4-ylcarbonyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-b-tert-butylalanyl)hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-(N-tert-butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropy lmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-allylglycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-b-cyclopropylalanyl]-N'[-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide; N-[N-( l-isoquinolinoyl)-L-b-cyclopropylalanyl]-N'-[2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b- cyclopropylalanyljhydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-cycloρropylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norleucinyl)hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norleucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-tert-butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b-terr- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b-tert- butylalanyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[N-(3-isoquinolinoyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(6-methylnicotinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-norleucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norleucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(3-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(5- hydroxymethylimidazol-4-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-(6- methylnicotinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)glycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norvalinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norvalinyl]hydrazide; N-I2-(l-naphthyl)thiazol-4-ylcarbonyl]-N-[N-(6-methylnicotinoyI)-L- norva!inyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylimidazol-5-ylcarbonyl)-L- norvalinyljhydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(l-isoquinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L-norvalinyl]hydrazide;
(IS, l'S)-N, N'-bis-[4-[l-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2- ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-tert-butylaIanyl]hydrazide; N-[N-(5-butylpicolinoyl)-L-b-tert-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- fluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(4-fluorobenzoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyI)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b-tert- butylalanyljhydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-tert-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N,N'-bis-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-[2-(l,8- naphthyridinoyl)]-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- flluorobenzoyl)-L-leucinyl]hydrazide; N-[N-(5-butylpicolinoyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2^[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)-L-b-tert-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tert-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; and N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tert-butylalanyl]hydrazide.
Definitions
The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise. Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). The term "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. "Ci-6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any Ci-6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2, C(0)N(R')2, carbamyl or Ci_4alkyl, where R' is Cι_6alkyl. Cøalkyl means that no alkyl group is present in the moiety. Thus, Ar-Cøalkyl is equivalent to Ar.
"C3-πcycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane. When substituted, substituents are defined as for "Ci-6alkyl", above. "C2-6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6al enyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and die several isomeric pentenes and hexenes. Both cis and trans isomers are included.
"C2-6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
"Halogen" means F, Cl, Br, and I.
"Ar" or "aryl" or "Ar"' or "aryl"' means phenyl or naphthyl, optionally independently substituted by one or more of Ph-Cø.galkyl, Het-Cø-galkyl, Cj.galkyl, C\_ 6alkoxy, Ph-C0.6alkoxy, Het-C0.6alkoxy, OH, (CH2)ι_6NR8R9, O(CH2)ι.6NR8R9, CO2R', or halogen. Two C^.galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring. Ph may be optionally substituted with one or more of Cøalkyl, Cμ6alkoxy, OH, (CH2)i-6NR8R9, O(CH2)ι_6 R8R9, C02R', or halogen.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph- Co_galkyl, Het-Cø.g alkyl, Cj.galkyl, Cj.galkoxy, Ph-Cø.galkoxy, Het-Cø.galkoxy, OH, (CH2)i-6 NR8R9, 0(CH2)i-6NR8R9, C02R'. TWO C galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring. Ph may be optionally substituted with one or more of Cj.galkyl, Cj.galkoxy, OH, (CH2)ι_6NR8R9, O(CH2)i-6-N R9> CO2 ', or halogen. Examples of such heterocycles include the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrr'olidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl rings. "HetAr" or "heteroaryl" means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridine.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. EDC refers to N-ethyl- N'(dimethylaminopropyl)-carbodiimide. HOBT refers to 1 -hydroxy benzotriazole, DMF refers to dimethyl formamide, BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate, Lawesson's reagent is 2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide, NMM is N-methylmorpholine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran.
Methods of Preparation
Compounds of the Formula I wherein X = S, Y = CH, Z = N and L = NR R7, are prepared by methods analogous to those described in Scheme 1.
Scheme 1
R1COCI a > R1CONHR4 b , FPNHR4 ° > R4N7NCSNH2 -> i 2 3 (R1CH2 = R7) 4
R4R N C02Et R4R7' N CONHNH, 6
S 9 3 (R1CH2 = R7)
a) R4NH2, Py, CH2C12; b) LiAlH4, THF; c) i. C12CS, Py, CH2C12; ϋ. NH3, MeOH or I. PhCONCS, CHC13; ii. K2CO3, MeOH, H20; d) Et02CCOCH2Br, EtOH; e) H2NNH2»H2θ, EtOH; f) R3C02H, EDC»HC1, 1-HOBT, DMF or R1 1R12NCOCI, Et3 N, CH2C12 where W is C(O), or R3S02C1, NMM, CH2C12 where W is S02; g) R4NH2, CH2C12; h) LiAlH4, Et20; j) Na(OAc)3BH, CH2C12.
An acid chloride (such as cyclopropanecarbonyl chloride or isobutyryl choride) (A Scheme 1) is treated with a primary amine (such as aniline, cyclopropylamine, isobutylamine or propylamine) and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Scheme 1. which is treated with lithium aluminum hydride in THF to afford 3-Scheme 1. Alternatively, 3-Scheme 1 may be prepared by treatment of an aldehyde (such as cyclopropanecarboxaldehyde or isobutyraldehyde) (8-Scheme 1") with an amine (such as cyclopropylamine) in methylene chloride to provide 9-Scheme 1. which is treated with a reducing agent (such as lithim aluminum hydride in ether or sodium triacetoxyborohydride in methylene chloride). Treatment of 3-Scheme 1 with thiophosgene and pyridine in methylene chloride, followed by treanment with ammonia in methanol provides 4-Scheme 1. Alternatively, 4-Scheme 1 may be prepared by treatment of __ Scheme 1 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. 4-Scheme 1 is treated with hydrazine hydrate in ethanol to give 5-Scheme 1. Treatment of 5-Scheme 1 with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3- pyridinylmethoxycarbonyl)-L-leucine, N-(4-pyridinylmethoxycarbonyl)-L-leucine, N- methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine, N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucine, N-methyl-N-(2-pyridinylmethoxycarbonyl)-L- leucine, 4-methyl-2-(3-phenylphenyl)pent-4-enoic acid, 4-methyl-2-(3- phenylphenyl)pentanoic acid, N-tert-butoxycarbonyl-L-leucine, N-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucine, N-(6-methyl-3-pyridinylmethoxycarbonyl)- L-leucine, N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-leucine, N-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucine, N-tert-butoxycarbonyl-L-b-tert-butylalanine and N-tert-butoxycarbonyl-L-b-cyclopropylalanine) and a peptide coupling reagent (such as EDC»HCl l-HOBT) in an aprotic solvent (such as DMF) or with a carbamoyl chloride (such as N,N-diisobutylcarbamoyl chloride) and triethylamine in methylene chloride affords 6-Scheme 1.
Scheme 2
Et02CCOCH2Br
N CONHNH,
a) Thiourea, EtOH; b) i. NaN02, 16% aqueous HBr; ii. CuBr, 16% aqueous HBr; iii. HBr (cat.), EtOH; c) ArB(OH)2, Pd(PPh3)4, NaHC03, toluene, EtOH, H20; d) H2NNH2«H20, EtOH; e) R CO2H, EDC«HC1, 1-HOBT, DMF where W is C(O), or R3SO2Cl, NMM, CH2CI2 where W is S0 Compounds of the Formula I wherein X = S, Y = CH, Z = N and L = Ar or Het, are prepared by methods analogous to those described in Scheme 2. Ethyl bromopyruvate __ Scheme 2) is treated with thiourea in refluxing ethanol to provide 2-Scheme 2. which is treated successively with sodium nitrite and copper (I) bromide in 16% aqueous HBr, and die product was heated in ethanol with a catalytic amount of HBr to give 3-Scheme 2. Treatment of this material with an arylboronic acid (such as 2-benzyloxyphenylboronic acid, 1 -naphthy lboronic acid, 4-methyll -naphthy lboronic acid, 5-acenaphthylboronic acid, 2-methoxy-l -naphthy Iboronic acid, 2-methoxymethoxy-l -naphthy lboronic acid, 9- anthraceny lboronic acid, 9-phenantheny lboronic acid, 2-(4-tert- butoxycarbonylbenzyloxy)phenylboronic acid, 4-methoxymethoxynaphthylboronic acid or 8-quinolineboronic acid), tetrakis(txiphenylphosphine)palladium(0) and sodium bicarbonate in refluxing toluene/ethaonl water provides 4-Scheme 2. Treatment of 4-Scheme 2 with hydrazine hydrate in ethanol provides 5-Scheme 2. which is treated with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-L- leucine, N-(4-pyridinylmethoxycarbonyl)-L-leucine, N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucine, N-benzyloxycarbonyl-L-leucine, 4-methyl-2-(3- phenylphenyl)pentanoic acid, 4-methyl-2-(3-phenoxyphenyl)pentanoic acid, 4-methyl-2-(4- phenoxyphenyl)pentanoic acid, N-benzyloxycarbonyl-L-b-tert-butylalanine, N- benzyloxycarbonyl-L-b-cyclopropylalanine, N-benzyloxycarbonyl-L-norvaline, N- benzyloxycarbonyl-L-norleucine, N-benzyloxycarbonyl-L-isoleucine, N-(4- dimethylaminomethylbenzyloxycarbonyl-L-leucine), N-tert-butoxycarbonyl-L-leucine, N- (6-methyl-3-pyridinylmethoxycarbonyl)-L-leucine, N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucine, N-(8-quinolinoyl)-L-leucine, N-(8- quinolinoyl)glycine, N-tert-butoxycarbonyl-L-allylglycine, N-t -butoxycarbonyl-L- norleucine, N-tert-butoxycarbonyl-L-norvaline, N-tert-butoxycarbonyl-L-b-tert- butylalanine, N-tert-butoxycarbonyl-L-b-cyclopropylalanine) and a peptide coupling reagent (such as EDCΗC1/1-HOBT) in an aprotic solvent (such as DMF) or with a carbamoyl chloride (N-isobutyl-N-phenylcarbamoyl chloride) and triethylamine in methylene chloride to provide 6-Scheme 2 where W is C(O). Where W = SO2, 5-Scheme 2 is treated with a corresponding sulfonyl chloride, R S02C1, and n-methy lmorpholine (NMM) in methylene chloride.
Compounds of the Formula I wherein X = S, Y = CH and Z = N, are prepared by methods analogous to those described in Scheme 1. Scheme 3
LC02H
a) i-BuOCOCl, NMM, NH3, THF; b) Lawesson's reagent, THF; c) i. EtO2CCOCH2Br; ii. TFAA, Py, CH2C12; d) H2NNH2»H2O, EtOH; e) R3C02H, EDC-HC1, 1-HOBT, DMF where W is C(O), or R3SO2Cl, NMM, CH2C12 where W is SO2.
A carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) (1 -Scheme 3) is converted to 2-Scheme 3 by treatment with isobutyl chloroformate, N-methylmoφholine and ammonia in THF. 2-Scheme 3 is treated with Lawesson's reagent in THF to provide the thioamide 3-Scheme 3. This material is converted to the thiazole by condensation with an a-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 3 which is converted to 5-Scheme 3 by treatment with hydrazine monohydrate. This material is treated with a carboxylic acid (such as (1S)- l-benzyloxycarbonylamino-l-(4-carboxythiazol-2-yl)-3-methylbutane) and a peptide coupling reagent (such as EDC-ΗC1/1-HOBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 3 where W is C(O). Where W = SO2, 5-Scheme 3 is treated with a corresponding sulfonyl chloride, R3SU2C1, and n-mediylmoφholine (NMM) in methylene chloride.
Scheme 4
a) TFA; b) R14CO2H, EDC-»HC1, 1-HOBT, DMF.
Compounds of the Formula I wherein X = S, Y = CH, Z = N, R3 = CH(Rl l)NRl2Rl3 where R*3 = R*4CO are prepared by methods analogous to those described in Scheme 4. 1 -Scheme 4 is treated with trifluoroacetic acid to provide 2c Scheme 4. This material is treated with a carboxylic acid (such as pryazinecarboxylic acid, picolinic acid, 2-quinolinecarboxylic acid, 3-quinolinecarboxylic acid, 4- quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7- quinolinecarboxylic acid, 8-quinolinecarboxylic acid, 1-isoquinolinecarboxylic acid, 3- isoquinolinecarboxylic acid, N-methylpiperidinecarboxlic acid 4-methylimidazole-5- carboxylic acid, N-benzylproline, N-methy lproline, l-benzyl-5-methylimidazole-4- carboxylic acid, 6-methylnicotinic aicd, 2-methylnicotinic acid, 2-methylisonicotinic acid, 4-dimethyaminomethylbenzoic acid, 4-(4-moφholino)benzoic acid, 5- hydroxymethylimidazole-4-carboxylic acid, 5-butylpicolinic acid or 4-fluorobenzoic acid) and a peptide coupling reagent (such as EDC»HCl/l-HOBT) in an aprotic solvent (such as DMF) to provide 3-Scheme 4.
The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).
Coupling methods to form amide bonds herein are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al, THE PRACΗCE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPΗDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incoφorated herein by reference.
Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives diereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li+, Na+, K+, Ca"1"1", Mg-1"1- and NH4"1" are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mglo about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
Utility of the Present Invention
The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds. The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
The present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of a compound or combination of compounds of the present invention. The present invention especially provides metiiods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of an inhibitor of cathepsin K, including a compound or combination of compounds of the present invention. The skilled artisan will understand that by the term "effective amount" is meant that amount of a compound or combination of compounds of the present invention sufficient to ameliorate or cure the clinically undesirable manifestations of disease (e.g. brittle and weakened bone in osteoporosis) caused by said pathological levels of target enzyme, e.g., cathepsin K, by inhibition of the target enzyme. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to an animal, particularly a mammal, most particularly a human in need thereof an effective amount of a compound or combination of compounds of Formula I, alone or in combination with other inhibitors of bone resoφtion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone moφhogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect. The compounds of diis invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resoφtion or to achieve any other therapeutic indication as disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
Biological Assays The compounds of the present invention may be tested in one of several biological assays to determine the concentration of compound which is required to provide a given pharmacological effect.
Determination of cathepsin K proteolytic catalytic activity All assays for cathepsin K were carried out with human recombinant enzyme.
Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product. Inhibition studies
Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound. Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves were linear, apparent inhibition constants (Ki>app) were calculated according to equation 1 (Brandt et al, Biochemitsry, 1989, 28, 140):
v = VmA /[Ka(l + UKi_ app) +A] (1)
where v is the velocity of the reaction with maximal velocity Vm , A is the concentration of substrate with Michaelis constant of KQ, and / is the concentration of inhibitor.
For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give 0h according to equation 2:
[AMC] = vss t + (vo - vss) [1 - exp (-kσbst)J / k0bs (2)
where [AMC] is the concentration of product formed over time t, vo is the initial reaction velocity and vss is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k0bs / inhibitor concentration or kobs I Uli) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol Relat. Areas Mol. Biol, 1988, 61, 201).
Human Osteoclast Resorption Assay
Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 φm, 5 min at 4°C). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension was mixed frequently.
The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 φm, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
The beads were mixed with the cells and die suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.
The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to l.SxK^ mL in EMEM medium, supplemented with 10% fetal calf serum and Ug/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/ L) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37°C for 30 min.
0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
General
Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin- Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm"1). Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
Where indicated, certain of the materials were purchased from the Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Coφ., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky.
Examples
In the following synthetic examples, temperature is in degrees Centigrade (°C). Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder.
Example 1
Preparation of N-r2-(cis-2.6-dimethyl-4-moφholino")thiazoI-4-ylcarbonyll-N'-rN-(4- pyridinylmethoxycarbonylVL-leucinvπhydrazide
a) cis-2,6-dimethyl-4-moφholino-N-benzoylthiourea
Cis-2,6-dimethylmoφholine (1.40 g, 12.17 mmol, 1.5 mL) was dissolved in chloroform (20 mL) and benzoyl isothiocyanate (2.0 g, 12.17 mmol, 1.75 mL) was added. After stirring 45 minutes at room temperature, the solution was concentrated to giv the title compound as a yellow solid (3.94 g, 100%). MS (ESI): 279.2 (M+H)+. b) cis-2,6-dimethyι-4-moφholinothiourea
The compound of Example 1(a) (3.38 g, 12.17 mmol) was dissolved in methanol (40 mL) and water (40 mL), potassium carbonate (8.4 g, 60.84 mmol) was added and the solution was heated at reflux overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate and water, then dried (MgSO4), filtered and concentrated to afford the title compound as a beige solid (1.7 g, 80%). MS (ESI): 174.9 (M+H)+.
c) ethyl 2-(cis-2,6-dimethyl-4-moφholino)thiazole-4-carboxylate The compound of Example 1(b) (1.7 g, 9.74 mmol) was dissolved in ethanol (25 mL) upon heating. The solution was cooled to room temperature and ethylbromopyruvate (1.22 mL, 9.74 mmol) was added. The reaction mixture was heated at reflux for 10 minutes, then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated brine, dried (MgSθ4), filtered and concentrated to an orange oil. The crude product was passed trough silica gel eluting with ethyl acetate/hexane (1:8, then 1:3) to give the title compound as a yellow solid (2.07 g, 79%). MS (ESI): 271.3 (M+H)+.
d) N-[2-(cis-2,6-dimemyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide
The compound of Example 1(c) (2.07 g, 7.65 mmol) was dissolved in ethanol (25 mL) and hydrazine monohydrate (3.7 mL, 76.56 mmol) was added. The solution was heated at reflux for 2 hours, then concentrated to afford the title compound as an orange solid (1.96 g, 100%). MS (ESI): 257.2 (M+H)+
e) a-isocyanato-L-leucine methyl ester
L-leucine methyl ester hydrochloride (25 g, 0.14 mol) was dissolved in methylene chloride (450 mL), cooled to 0 °C, and pyridine (43.5 g, 0.55 mol, 44.5 mL) was added, ien a 1.93 M solution of phosgene in toluene (0.18 mol, 92.7 mL) was added slowly. After stirring at 0 °C for 2 h, the mixture was poured into 0.5 N HCl (1400 mL) and ice (900 mL). The organic layer was washed with 0.5 N HCl (1400 mL) and ice (900 mL). The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with saturated brine (1400 mL) and ice (900 mL), then dried (MgSO4), filtered and concentrated. The residue was distilled (56-58 °C; 0J8 mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). *H NMR (250 MHz,
CDC13) d 4.04 (dd, IH), 3.82 (s, 3H), 1.92-1.72 (m, IH), 1.69-1.62 (m, 2H), 0.96 (d, 3H), 0.94 (d, 3H). f) N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester
A solution of the compound of Example 1(e) (5.10 g, 29.8 mmol) and 4- pyridylcarbinol (3.25 g, 29.8 mmol) in toluene (30 mL) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on 250 g of 230-400 mesh silica gel, eluting with 3:1 ethyl acetate/hexanes, to give the title compound (7.86 g, 94%). 1H NMR (250 MHz, CDC13) d 8.59 (d, 2H), 7.24 (d, 2H), 5.33 (d, IH), 5.13 (s, 3H), 4.40 (dt, IH), 3.75 (s, 3H), 1.81-1.51 (m, 3H), 0.96 (d, 3H), 0.95 (d, 3H).
g) N-(4-pyridinylmethoxycarbonyl)-L-leucine
To a stirring solution the compound of Example 1(f) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 mL of water followed by LiOH^^O (325 mg, 7.76 mmol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 mL) and 3 NHC1 was added (2.6 mL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 (M+H)+.
h) N-[2-(cis-2,6-dimethyl-4-moφholino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide To a stirring solution of the compound of Example 1(g) (104 mg, 0.39 mmol) in
DMF (2.5 mL) was added the compound of Example 1(d) (100 mg, 0.39 mmol), 1- hydroxybenzotriazole (9.5 mg, 0.07 mmol), and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (100 mg, 0.39 mmol). After stirring at room temperature for 16 h, the solution was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed widi saturated brine, dried (MgSθ4), filtered and concentrated. The crude product was purified by column chromatography on silica gel (6% methanol in methylene chloride) to afford the title compound as a white solid (125 mg, 51%). MS (ESI): 505.4 (M+H)+.
Example 2
Preparation of N- f2- rN-cyclopropy lmethyl-N-(2-methylpropy llaminolthiazol-4- ylcarbonyn-N'-rN-(4-pyridinylmethoxycarbonyl -L-leucinyllhydrazide
a) N-cyclopropylmethyl isobutyramide
Triethylamine (1.53 g, 15.09 mmol, 2.1 mL) and isobutylamine (1.10 g, 15.09 mmol, 1.5 mL) were dissolved in methylene chloride (15 mL), cooled to 0°C, and cyclopropane carbonyl chloride (1.58 g, 15.09 mmol, 1.4 mL) was added dropwise. After stirring at 0°C for one hour the mixture was diluted with methylene chloride (60 mL) and washed with NaOH (1M), then with saturated brine, dried (MgS04), filtered and concentrated. The residue was washed with ether and dried to give the title compound as a beige solid (2.1 g, 100%). MS (ESI): 141.9 (M+H)+.
b) N-cyclopropylmethyl isobutylamine
To a stirring solution of 1M LiAlH4 in THF (11.3 mL, 11.3 mmol), cooled to 0°C, was added slowly over 20 minutes a solution of the the compound of Example 2(a) (1.595 g, 11.3 mmol) in THF (20 mL). After the addition was complete, the ice bath was removed and the solution was heated at 55°C for 30 minutes. The mixture was cooled to 0°C and quenched with water (0.43 mL) and 15% aqueous NaOH (0.43 mL) and water (1.29 mL). The solid was removed by filtration and washed with ether, dried (MgSθ4) and filtered. The filtrate was evaporated to dryness to give the title compound as a a colorless liquid (1.15 g, 80%). MS (ESI): 128.0 (M+H)+.
c) N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl isobutylamine for cis-2,6-dimethylmoφholine in step (a), the title compound was prepared as a yellow solid (60 mg, 31%). MS (ESI): 517.3 (M+H)+.
Example 3
Preparation of N-r2-(4-methyl-l-naphthyπthiazoI-4-ylcarbonyll-N'-rN-(4- pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
a) ethyl 2-aminothiazole-4-carboxylate hydrobromide
To a stirring suspension of thiourea (46.7 g, 0.614 mol) in EtOH (640 mL) was added ethyl bromopyruvate (120 g, 0.614 mol, 77.2 mL) slowly. After stirring at 45 °C for 16h the solution was cooled to room temperature and placed in the refrigerator overnight. The mixture was filtered, the crystals were washed with cold ethanol and air dried to give the product as pale yellow crystals (132.74 g, 85%). MS (ESI): 172.9 (M+H)+.
b) 2-bromothiazole-4-carboxylic acid
To a stirring suspension of the compound of Example 3(a) (32.11 g, 0.127 mol) in 16% HBr (aq) (400 mL) at 0°C a solution of NaN02 (9.1 lg, 0.132mol) in water (16mL) was added. After stirring for 35min, CuBr (20.6 g, 0.144 mol) was added followed by additional 16% Hbr(aq) (150 mL). The mixture was heated at 70 °C for lh and immediately filtered. The filtrate was saturated with NaCl and extracted with ethyl acetate (2 x 500mL). The organic phases were combined, dried (MgS04), filtered and concentrated to a brown solid. This was combined widi solid collected by filtration and used without further purification or characterization in the next step.
c) ethyl 2-bromothiazole-4-carboxylate
The compound of Example 1(b) was heated at reflux in EtOH (1 L) for lh, then filtered. To the filtrate was added 64 drops of 48% (aq) HBr. After stirring at reflux for 24 h the solution was concentrated and redissolved in EtOAc (1 L). The solution was washed successively with saturated aqueous NaHCθ3 (1 L) and brine (1 L), dried (MgSO4), filtered, decolorized with charcoal, filtered through Celite, and concentrated to a pale yellow solid (16.95 g, 56%). lH NMR (400 MHz, CDC13) d 8.14 (s, IH), 4.46, (q, 2H), 1.43 (t, 3H). d) 4-methyl-l -naphthalene boronic acid
To a stirring solution of l-bromo-4-methylnaphthalene (1.0 g, 4.52 mmol) in THF (5 mL) at -78°C was added N-butyllithium (1.8 mL, 4.52 mmol, 2.5M in hexane) dropwise. After stirring at -78 °C for 1 h, triisopropylborate (4.52 g, 22.6 mmol) was added. After stirring at room temperature for 3 h, the solution was partitioned between 3N HCl and etiiyl acetate. The organic phase was washed successively with saturated aqueous NaHCO3 and brine, then dried (MgS04), filtered and concentrated to a yellow solid which was washed with hexane to yield the title compound as a pale yellow solid (0.5 g, 59%). ---H NMR (400 MHz, CDC13) d 9.35 (d, IH), 8.58 (d, IH), 8.14 (d, IH), 7.64 (m, 2H), 7.54 (d, IH), 2.82, (s, 3H).
e) ethyl 2-(4-methyl-l -naphthy l)thiazole-4-carboxy late
To a stirring mixture of the compound of Example 1(c) (0.30 g, 1.27 mmol), the compound of Example 1(d) (0.355 g, 1.91 mmol), and Pd(Ph3P) (0.059 g, 0.05 mmol)) in EtOH (4 mL) and toluene (4 mL) was added NaHCO3 (4.42 mL, 1.0 M in water). After stirring at reflux for 4 h,the mixture was cooled and partitioned between 1 N HCl (25 mL) and ethyl acetate (25 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield die title compound as a foamy solid. (0.257 g, 68%). MS (ESI): 298.2 (M+H)+.
f) N- [2-(4-methyl- 1 -naphthyl)thiazol-4-y Icarbony l]hydrazide
Following d e procedure of Example 1(d), except substituting ethyl 2-(4-methyl-l- naphthyl)thiazole-4-carboxylate for ethyl 2-(cis-2,6-dimethyl-4-moφholino)thiazole-4- carboxylate, the title compound was prepared as a pale yellow solid (0.245 g, 100%). MS (ESI): 284.2 (M+H)+.
g) N- [2-(4-methy 1- 1 -naphthy l)thiazol-4-y Icarbony 1] -N'- [N-(4-py ridinylmethoxycarbonyl)- L-leucinyl]hydrazide Following the procedure of Example l(e)-l(h), except N-[2-(4-methyl-l- naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6-dimethyl-4-moφholino)thiazol- 4-ylcarbonyl]hydrazide in step (h), the title compound was prepared as a white solid (0.122 g, 48%). MS (ESI): 532.1 (M+H)+. Example 4
Preparation of N-r2-rN-methyl-N-(2-methylpropyl)amino1thiazol-4-ylcarbonyll-N'-fN- methyl-N-(4-pyridinylmethoxycarbonyl')-L-leucinyllhydrazide
a) N-(4-pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester
Following the procedure of Example 1(e)- 1(0, except substituting L-leucine tert- butyl ester hydrochloride for L-leucine methyl ester hydrochloride in step (e), the title compound was prepared as a colorless oil (2.945 g, 64%). MS (ESI): 323.4 (M+H)+.
b) N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester
The compound of Example 3(a) (2.9 g, 8.99 mmol) was dissolved in THF (40 mL) and metiiyl iodide (2.24 mL, 35.98 mmol) was added. The reaction mixture was cooled to 0°C in a flask protected from moisture. Sodium hydride dispersion (1.214 mg, 13.49 mmol) was added cautiously and the suspension was stirred for 5 h at room temperature. Ethyl acetate was then added (to consume die sodium hydroxide formed from the excess of sodium hydride), followed by water, dropwise, to destroy the excess of sodium hydride. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water. The ether layer was washed with saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate, the extract was washed with water, dried (MgS04), filtered and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate/ hexane, 3:1) to give a yellow oil (2.07 mg, 68%). MS (ESI): 337.5 (M+H)+.
c) N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine
To the compound of Example 3(b) (2.07 g, 6.15 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperature the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried (MgSU4) and concentrated to afford the title compound as a white solid (1.72 g, 100%). MS (ESI): 281.3 (M+H)+.
d) N-[2-[N-med yl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-methyl isobutylamine for cis-2,6-dimethylmoφholine in step (a), and N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a pale yellow solid (91.8 mg; 43%). MS (ESI): 491.3 (M+H)+.
Example 5
Preparation of N-[2-(l -naphthy l)thiazol-4-ylcarbonyn-N'-rN-(3- pyridinylmethoxycarbonviyL-leucinyπhvdrazide
a) N-(3-pyridinylmetiιoxycarbonyl)-L-leucine Following the procedure of Example 1(f)- 1(g), except substituting 3- pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid. MS (ESI): 267.2 (M+H)+.
b) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthylboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N-(3- pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.029 g, 28%). MS (ESI): 518.2 (M+H)+.
Example 6
Preparation of N-[2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-FN-(2- pyridinylmethoxycarbonyiyL-leucinyllhydrazide
Following the procedure of Example 5(a)-5(b), except substituting 2- pyridylcarbinol for 3-pyridylcarbinol in step (a), the title compound was prepared as a white solid (0.084 g, 82%). MS (ESI): 518.2 (M+H)+. Example 7
Preparation of N-[2-(5-acenaphthyl)thiazol-4-ylcarbonyll-N'-rN-(4- pyridinylmethoxycarbonylVL-leucinyllhydrazide
Following the procedure of Example 3(a)-3(g), except substituting 5- bromoacenaphthene for l-bromo-4-methylnaphthalene in step (d), the title compound was prepared as a white solid (0.166 g, 74%). MS (ESI): 544.2 (M+H)+.
Example 8
Preparation of N-[2-rN-cyclopropylmethyl-N-(2-methylpropyl)aminolthiazol-4- ylcarbonyn-N'-rN-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 2(a)-2(c), except substituting N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (c), the title compound was prepared as a yellow solid (50 mg, 25%). MS (ESI): 531.3 (M+H)+.
Example 9
Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(4-pyridinylmethoxycarbonyl)-L-leucinynhydrazide
a) N-cyclopropylmethyl cyclopropylamine
Cyclopropylamine (1.14 g, 20.0 mmol, 1.4 mL) and cyclopropanecarboxaldehyde (1.40 g, 20.0 mmol, 1.5 mL) were dissolved in methylene chloride (10 mL) and stirred at room temperature. After two hours, the solution was dried (MgSθ4), and concentrated to afford the pure imine. The compound was dissolved in ether (10 mL), the solution was cooled to 0 °C and lithium aluminum hydride (30 mL, 30 mmol, 1 M in ether) was added slowly. The solution was stirred for two hours and then quenched at 0 °C with water (1.14 mL), 15% sodium hydroxyde (1.14 mL), water (3.42 mL). The solid was removed by filtration and washed with ether. The filtrate was dried (MgSU4), filtered and concentrated to afford a colorless liquid (1.58 g, 71%). MS (ESI): 111.9 (M+H)+. b) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a), the title compound was prepared as a white solid (165 mg, 88% yield). MS (ESI): 501.4 (M+H)+.
Example 10
Preparation of N-F2-rN-cyclopropylmethyl-N-(2-methylpropyl aminolthiazol-4- ylcarbonyll-N'-rN-(3-pyridinylmethoxycarbonyIVL-leucinyllhydrazide
Following the procedure of Example 2(a)-2(c), except substituting N-(3- pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (c), the title compound was prepared as a yellow solid (154 mg, 89%). MS (ESI): 517.4 (M+H)+.
Example 11
Preparation of N-[2-rN-cyclopropylmethyl-N-(2-methylpropyl)aminolthiazol-4- ylcarbonyll-N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl1hydrazide
Following the procedure of Example 2(a)-2(c), except substituting N-(2- pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (c), the title compound was prepared as a yellow solid (100 mg, 65%). MS (ESI): 517.3 (M+H)+.
Example 12
Preparation of N-f2-rN-cvclopropylmethyl-N-(2-methylpropyl)amino1thiazol-4- ylcarbonvn-N'-rN-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 4(a)-4(d), except substituting 3- pyridylcarbinol for 4-pyridylcarbinol in step (a) and N-cyclopropylmethyl isobutylamine for N-methyl isobutylamine in step (d), the title compound was prepared as a yellow solid (30 mg, 22%). MS (ESI): 531.4 (M+H)+. Example 13
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'- [N-(3-pyridinylmethoxycarbonyl -L-leucinyl1hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmθφholine in step (a) and 3- pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (85 mg, 43%). MS (ESI): 501.4 (M+H)+.
Example 14
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-methyl-N-(4-pyridinylmethoxycarbonylVL-leucinyllhydrazide
Following the procedure of Example 4(a)-4(d), except substituting N- cyclopropylmethyl cyclopropylamine for N-methyl isobutylamine in step (d), the title compound was prepared as a white solid (58 mg, 35%). MS (ESI): 515.3 (M+H)+.
Example 15
Preparation of N-r2-rN.N-bis-(2-methylpropyl)amino1thiazol-4-ylcarbonyll-N'-rN-(2- pyridinylmethoxycarbonylVL-leucinvπhvdrazide
Following the procedure of Example 1(a)- 1(h), except substituting diisobutylamine for cis-2,6-dimethylmoφholine in step (a) and 2-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a yellow solid (140 mg, 77%). MS (ESI): 519.4 (M+H)+.
Example 16
Preparation of N-rN-(4-pyridinylmethoxycarbonylVL-leucinyll-N'-r2-ri-(l .2.3.4- tetrahydroquinolino'HthiazoI-4-ylcarbonyπhydrazide
Following the procedure of Example l(a)-l(h), except substituting 1,2,3,4- tetrahydroquinoline for cis-2,6-dimethylmoφholine in step (a), the title compound was prepared as a yellow solid (168 mg, 88%). MS (ESI): 523.4 (M+H)+. Example 17
Preparation of N-r4-methyl-2-(3-phenoxy)phenylpentanoyll-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhvdrazide
a) 2-(3-phenoxyphenyl)-4-methylpent-4-enoic acid
To a stirring solution of diisopropylamine (4.99 g, 49.3 mmol) in THF (50 mL) cooled to -78 °C was added n-butyllithium (19.4 mL, 48.5 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at -78°C, a solution of 3-phenoxyphenylacetic acid (5.0 g, 21.9 mmol) in THF (20 mL) was added dropwise. The mixture was warmed to 0 °C then cooled to -78 °C and 3-bromo-2-methylpropene (4.4 g, 32.9 mmol) was added to die mixture in one portion. After stirring at -78 °C for 2h, the reaction was quenched with 10 mL of water then concentrated. The residue was redissolved in water and extracted with etiier (200 mL). The aqueous layer was acidified (3 N HCl) and extracted with etiier (2 X 200 mL). The organic layers were combined, dried (MgS04), filtered and concentrated to yield the title compound as a white solid (5.4 g, 87%). 1H NMR (400 MHz, CDCI3) d 7.36 (m, 3H), 7.14 (m, 2H), 7.01 (m, 4H), 4.78 (d, 2H), 3.82 (t, IH), 2.83 (dd, IH), 2.47 (dd, IH), 1.75 (s, 3H).
b) 2-(3-phenoxyphenyl)-4-methylpentanoic acid
To a stirring solution of the compound of Example 17(a) (5.4 g, 19.1 mmol) in ethyl acetate (75 mL) was added palladium on carbon (2.0 g). After stirring under a balloon of hydrogen for 16 h, the mixture was filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (2.1 g, 39%). MS (ESI): 283.2 (M-H)-.
c) (±)-N-[4-methyl-2-(3-phenoxy)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide
Following the procedure of Example 1(h), except substituting 2-(l- naphthyl)thiazol-4-ylcarbonylhydrazide forN-[2-(cis-2,6-dimethyl-4-moφholino)thiazol-4- ylcarbonyljhydrazide and 2-(3-phenoxyphenyl)-4-methylpentanoic acid for N-(4- pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.246g, 82%). MS (ESI): 536.2 (M+H)+. Example 18
Preparation of N-r2-rN-methyl-N-(2-methylpropyl)aminolthiazol-4-ylcarbonyl1-N'-r4- methyl-2-(3-phenyDphenylpent-4-enoyllhydrazide
a) 2-(3-phenylphenyl)-4-methylpent-4-enoic acid
Following the procedure of Example 17(a), except substituting 3-biphenylacetic acid for 3-phenoxyacetic acid, the title compound was prepared as a white solid. MS (ESI):
265.3 (M-H)-.
b) N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpent-4-enoyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-methyl isobutylamine for cis-2,6-dimethylmoφholine in step (a), and 2-(3-phenylphenyl)-4- methylpent-4-enoic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid. MS (ESI): 477.3 (M+H)+.
Example 19
Preparation of N-r2-rN.N-bis-(2-methylpropyl)amino1thiazol-4-ylcarbonvn-N'-lN-methyl- N-(3-pyridinylmethoxycarbonyD-L-leucinyllhydrazide
Following the procedure of Example 1(a)- 1(h), except substituting diisobutylamine for cis-2,6-dimethylmoφholine in step (a) and 3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a yellow solid (110 mg, 30%). MS (ESI):
519.4 (M+H)+.
Example 20
Preparation of N-r2-(N-cyclopropyl-N-cycloρropylmethylamino)thiazol-4-ylcarbonyl1-N'- [N-methyl-N-(3-pyridinylmethoxycarbonylVL-leucinvHhvdrazide
Following the procedure of Example 4(a)-4(d), except substituting 3- pyridylcarbinol for 4-pyridylcarbinol in step (a) and N-cyclopropylmethyl cyclopropylamine for N-methyl isobutylamine in step (d), the title compound was prepared as a yellow solid (33 mg, 25%). MS (ESI): 515.4 (M+H)+. Example 21
Preparation of N- r2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-y lcarbonyll-N'- fN-f 3- pyridinylmethoxycarbonyl)-L-leucinyllhvdrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-cyclopropyl propylamine for cis-2,6-dimethylmoφholine in step (a) and 3-pyridylcarbinol for 4- pyridylcarbinol in step (f), the title compound was prepared as a yellow solid (40 mg, 25%). MS (ESI): 503.3 (M+H)+.
Example 22
Preparation of N-r2-rN-methyl-N-(2-methylpropyl)amino1thiazol-4-ylcarbonyll-N'-f4- methyl-2-(3-phenyl)phenylpentanoyllhydrazide
a) 2-(3-phenylphenyl)-4-methylpentanoic acid
Following the procedure of Example 17(a)- 17(b), except substituting 3- biphenylacetic acid for 3-phenoxyacetic acid, the title compound was prepared as a white solid. MS (ESI): 267.4 (M-H)".
b) N-[2-[N-metiιyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-methyl isobutylamine for cis-2,6-dimethylmoφholine in step (a), and 2-(3-phenylphenyl)-4- methylpentanoic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (185 mg, 88%). MS (ESI): 479.4 (M+H)+.
Example 23
Preparation of N-IN-(2-methylpropyl)-N-(3-phenylphenyl)carbamovn-N'-r2-(l- naphthyl~)thiazol-4-ylcarbonyllhydrazide
a) 3-phenylaniline
To a stirring solution of 3-nitrobiphenyl (1.2 g, 6.0 mmol) in ethyl acetate (25 mL) was added 10% Palladium on carbon (500 mg, 40% w/w). After stirring under a balloon of hydrogen for 24 h, the mixture was filtered through Celite and concentrated to yield the title compound as a white solid (0.956 g, 94%). MS (ESI): 170.0 (M+H)+. b) N-(3-phenyl)phenyl isobutylamine
Following the procedure of Example 2(a)-2(b), except substituting 3-phenylaniline for isobutylamine, and isobutyryl chloride for cyclopropane carbonyl chloride in step (a), the title compound was prepared as a brown oil (1.1 g, 90%). MS (ESI): 226.1 (M+H)+.
c) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[[N-isobutyl-N-(3-biphenyl)]amido]hydrazine To a solution of phosgene (0.289 mL, 1.93M in toluene) was added a mixture of the compound of Example 23(b) (0.126 g, 0.558 mmol) and N-methylmoφholine (0.056 g, 0.55 8mmol) in dichloromethane (3 mL) dropwise. After stirring for 20 min., 2-(l- naphthyl)thiazol-4-ylcarbonylhydrazide (0.150 g, 0.558 mmol) and N-mediylmoφholine
(0.056 g, 0.558 mmol) in dichlorometiiane (3 mL) was added followed by DMF (3 mL).
After stirring at 50 °C for 16 h, the solution was diluted witii ethyl acetate and washed successively with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was, dried (MgSθ4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.122 g, 42%). MS (ESI): 521.3 (M+H)+.
Example 24
Preparation of N-r4-methyl-2-f3-phenyl)phenylpentanoyll-N' 2-π-naphthyl)thiazol-4- ylcarbonyllhvdrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphdiylboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and 2-(3- phenylphenyl)-4-methylpentanoic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.119 g, 49%). MS (ESI): 520.3 (M+H)+.
Example 25
Preparation of N-r4-methyl-2-(3-phenyπphenylpentanovn-N'-r2-rN-(2-methylpropyI')-N- phenylaminolthiazol-4-ylcarbonvnhvdrazide
Following the procedure of Example 2(a)-2(c), except substituting aniline for isobutylamine and isobutyryl chloride for cyclopropane carbonyl chloride in step (a), and 2- (3-phenylphenyl)-4-methylpentanoic acid for N-(4-pyridinylmetiιoxycarbonyl)-L-leucine in step (c), the title compound was prepared as a white solid (72 mg, 52%). MS (ESI): 541.3 (M+H)+.
Example 26
Preparation of N-r2-(2-methoxy- 1 -naphthyl)thiazol-4-ylcarbonyll-N'-rN-<'4- pyridinylmethoxycarbonylVL-leucinyllhydrazide
Following the procedure of Example 3(a)-3(g), except substituting l-bromo-2- methoxynaphthalene for l-bromo-4-methylnaphthalene in step (d), die title compound was prepared as a white solid (0.194 g, 85%). MS (ESI): 548.3 (M+H)+.
Example 27
Preparation of N-r2-(2-benzyloxyphenyl)thiazol-4-ylcarbonvIl-N'-r4-methyl-2-(3- phenyDphenylpentanoyllhydrazide
a) 2-benzyloxybromobenzene
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added K2CO3 (12.0 g, 86.7 mmol). After stirring at reflux for 4h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSθ4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield die title compound as a colorless oil (15.2 g, 57.8 mmol). ΪHNMR (400 MHz, CDCI3) d 7.62 (m, IH), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, IH), 7.28 (m, IH), 6.98 (m, IH), 6.91 (m, IH), 5.17 (s, 2H).
b) 2-benzyloxyphenylboronic acid
To a stirring solution of the compound of Example 27(a) (15.2 g, 57.8 mmol) in THF (100 mL) at -78°C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 mmol). The mixture stirred at -78°C for 25 min when added via cannulation to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF (100 mL) at -78°C. After warming to room temperature and stirring for 3h, the mixture was poured into 3N HCl (100 mL) and extracted with ethyl acetate (3 X 200mL). The organic layers were combined, washed successively with water and brine, dried (MgS04), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow solid (6.9 g, 30.3 mmol). 1HNMR (400 MHz, CDCI3) d 7.90 (d, IH), 7.42 (m, 6H), 7.07 (t, IH), 7.02 (d, IH), 6.05 (s, 2H), 5.16 (s, 2H).
c) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 2- benzyloxypheny lboronic acid acid for 4-methy 1-1 -naphthalene boronic acid in step (e) and 2-(3-phenylphenyl)-4-methylpentanoic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.194 g, 85%). MS (ESI): 576.3 (M+H)+.
Example 28
Preparation of N-r2-(2-benzyloxy-l-naphthyI)thiazol-4-ylcarbonvπ-N'-rN-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
a) 1 -bromo-2-methoxy methoxynaphthalene
To a stirred suspension of sodium hydride (1.6 g, 40.3 mmol, 60% dispersion in mineral oil) in DMF (150 mL) at 0°C was added l-bromo-2-naphthol (5.0 g, 22.4 mmol) dropwise. After stirring for 20min, bromomethyl methyl ether (2.8 g, 22.4 mmol) was added slowly. After warming to room temperature and stirring for 4 h, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 and brine then dried (MgSU4), filtered and concentrated to a red oil (5.98 g, 100%). - NMR (400 MHz, CDCI3) d 8.27 (d, IH), 7.79 (d, 2H), 7.60 (t, IH), 7.46 (m, 2H), 5.38 (s, 2H), 3.61 (s, 3H).
b) ethyl 2-(2-medιoxymethoxy-l-naphthyl)thiazole-4-carboxylate
Following the procedure of Example 3(a)-3(e), except substituting l-bromo-2- methoxymethoxynaphthalene for l-bromo-4-methylnaphthalene in step (d), the title compound was prepared as an off-white solid (0.136 g, 15%). MS (ESI): 344.2 (M+H)+. c) ethyl 2-(2-hydroxy-l -naphthy l)thiazole-4-carboxy late
To a stirring solution of the compound of Example 28(b) (0.136 g, 0.397 mmol) in EtOH (3 mL) was added concentrated hydrochloric acid (5 drops). After stirring at reflux for 3 h, the solution was concentrated, redissolved in ethyl acetate, and washed successively with saturated aqueous NaHCθ3 and brine. The organic layer was dried (MgS04), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield die title compound as a white solid (0.080 g, 67%). MS (ESI): 300.2 (M+H)+.
d) etiiyl 2-(2-benzyloxy-l -naphthy l)thiazole-4-carboxy late
To a stirring solution of the compound of Example 28(c) (0.080 g, 0.268 mmol), benzyl alcohol (0.038 g, 0.348 mmol) and triphenylphosphine (0.091 g, 0.348 mmol) in THF (3 mL) at 0 °C was added diisopropyl azodicarboxylate (0.070 g, 0.348 mmol) dropwise. After stirring at room temperature for 16 h, the solution was concentrated and the residue purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.060 g, 58%). lH NMR (400 MHz, CDCI3) d 8.41 (s, IH), 8.12 (d, IH), 7.91 (d, IH), 7.80 (d, IH), 7.52 (t, IH), 7.41 (t, IH), 7.34 (m, 6H), 5.24 (s, 2H), 4.49 (q, 2H), 1.44 (t, 3H).
e) N-[2-(2-benzyloxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(d)- 1(h), except substituting ethyl 2-(2- benzyloxy-l-naphthyl)thiazole-4-carboxylate for ethyl 2-(cis-2,6-dimethyl-4- moφholino)thiazole-4-carboxylate (d), die title compound was prepared as a white solid (0.050 g, 52%). MS (ESI): 624.2 (M+H)+.
Example 29
Preparation of N-r2-[N.N-bis-(2-methylpropyl amino1thiazol-4-ylcarbonvn-N'-rN-methyl- N-(2-pyridinylmethoxycarbonyl -L-leucinvnhvdrazide
Following the procedure of Example 4(a)-4(d), except substituting 2- pyridylcarbinol for 4-pyridylcarbinol in step (a) and diisobutylamine for N-methyl isobutylamine in step (d), the title compound was prepared as a yellow solid (40 mg, 20%). MS (ESI): 533.4 (M+H)+.
Example 30 Preparation of N-r2-(9-phenanthrenyl)thiazol-4-ylcarbonyll-N'-rN-(4- pyridinylmethoxycarbonyD-L-leucinyllhydrazide
Following the procedure of Example 3(a)-3(g), except substituting 9- bromophenanthrene for l-bromo-4-methylnaphthalene in step (d), die title compound was prepared as an off-white solid (0.085 g, 48%). MS (ESI): 568.2 (M+H)+.
Example 31
Preparation of N-r2-(9-anthracenyDthiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl~|hydrazide
Following the procedure of Example 3(a)-3(g), except substituting 9- bromoanthracene for l-bromo-4-methylnaphthalene in step (d), the title compound was prepared as a white solid (0.101 g, 67%). MS (ESI): 568.2 (M+H)+.
Example 32
Preparation of N-r2-rN.N-bis-(2-methylpropyl)aminolthiazol-4-ylcarbonyll-N'-(-tert- butoxycarbonyl-L-leucinyl)ydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting diisobutylamine for cis-2,6-dimethylmoφholine in step (a) and N-tert-butoxycarbonyl-L- leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a yellow solid (950 mg, 78% yield). MS (ESI): 484.3 (M+H)+.
Example 33
Preparation of N-r2-rN.N-bis-(2-methylpropyDaminolthiazol-4-ylcarbonvIl-N'-rN-(L- leucinyPlhydrazide
Following the procedure of 4(c), except substituting N-[2-[N,N-bis-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(-tert-butoxycarbonyl-L-leucinyl)ydrazide for N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a yellow solid (370 mg, 85%). MS (ESI): 384.3 (M+H)+. Example 34
Preparation of N-f2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-methyl-N-(3- pyridinylmethoxycarbonylVL-leucinynhydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthy lboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N-methy 1-N- (3-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.100 g, 59%). MS (ESI): 532.2 (M+H)+.
Example 35
Preparation of N-[2-rN.N-bis-(2-methylpropyl)aminolthiazol-4-ylcarbonyn-N'-(N- picolinoyl-L-leucinyl)hydrazide
Following the procedure of Example 1(h), except substituting N-[2-[N,N-bis-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(L-leucinyl)]hydrazide for N-[2-(cis-2,6- dimedιyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide and picolinic acid for N-(4- pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a yellow solid (40 mg, 30%). MS (ESI): 489.3 (M+H)+.
Example 36
Preparation of N-r2-rN.N-bis-(2-methylpropyDaminolthiazol-4-ylcarbonyl1-N'-rN-(2- pyrazinecarbonyl -L-leucinyllhydrazide
Following the procedure of Example 1 (h), except substituting N-[2-[N,N-bis-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(L-leucinyl)]hydrazide for N-[2-(cis-2,6- dimedιyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide and pyrazinecarboxylic acid for N- (4-pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a yellow solid (45 mg, 35%). MS (ESI): 490.3 (M+H)+.
Example 37
Preparation of N-rN.N-bis-(2-methylpropyl arbamovn-N'-r2-[N-(2-methylpropylVN- phenylaminolthiazol-4-ylcarbonyllhvdrazide a) N-isobutylaniline
Following the procedure of Example 2(a)-2(d), except substituting aniline for isobutylamine and isobutyryl chloride for cyclopropane carbonyl chloride in step (a), the title compound was prepared as an orange liquid (2.11 g, 83% yield). MS (ESI): 172.2 (M+Na)+.
b) N-[2-[N-(2-methylpropyl)-N-phenyl]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(a)- 1(d), except substituting N- isobutylaniline for cis-2,6-dimethylmoφholine in step (a), the title compound was prepared as a white solid. MS (ESI): 291.3 (M+H)+.
c) N-[N,N-bis-(2-methylpropyl)carbamoyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 23(c), except substituting N-[2-[N-(2- metiiy Ipropy l)-N-phenyl]thiazol-4-ylcarbonyl]hydrazide for 2-( 1 -naphthy l)thiazol-4- ylcarbonylhydrazide and diisobutylamine for N-(3-phenyl)phenyl isobutylamine, the title compound was prepared as a white solid (25 mg, 25%). MS (ESI): 446.3 (M+H)+.
Example 38
Preparation of N-(2-phenylthiazol-4-ylcarbonylVN'-rN-(4-pyridinylmethoxycarbonylVL- leucinyllhvdrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting pheny lboronic acid for 4-methyl-l -naphthalene boronic acid in step (e), the title compound was prepared as a white solid (0.077 g, 27%). MS (ESI): 468.2 (M+H)+.
Example 39
Preparation of N-r2-r2-(4-terr-butoxycarbonyI)benzyloxyphenyllthiazol-4-ylcarbonyll-N'- rN-(4-pyridinylmethoxycarbonyl)-L-leucinyπhydrazide
a) tert-butyl 4-bromomethylbenzoate To a stirring solution of 4-bromomethylbenzoic acid (4.0 g, 18.6 mmol) in cyclohexane (37 mL), dichloromethane (19 mL) and THF (2 mL) was added a solution of tert-butyl-2,2,2-trichloroacetimidate (8.1 g, 37.2 mmol) in cyclohexane (12 mL) followed by a catalytic amount of boron trifluoride etherate. After stirring at room temperature for 18 h, NaHCO3 (4 g) was added and die mixture filtered. The mixture was filtered dirough a short plug of silica gel and concentrated to yield the title compound as a colorless oil that solidifies on standing (3.6 g, 71%). ltt NMR (400 MHz, CDC13) d 7.98 (d, 2H), 7.44 (d, 2H), 4.50 (s, 2H), 1.59 (s, 9H).
b) ethyl 2-(2-hydroxyphenyl)thiazole-4-carboxylate
Following the procedure of Example 28(a)-28(c), except substituting 2- bromophenol for l-bromo-2-naphthol in step (a), the title compound was prepared as a white solid (0.560 g, 53%). MS (ESI): 250.1 (M+H)+.
c) ethyl 2-[2-(4-terr-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate
To a stirring mixture of the compound of Example 39(b) (0.094 g, 0.379 mmol) and potassium carbonate (0.136 g, 0.985 mmol) in acetone (10 mL) was added die compound of Example 39(a) (0.133 g, 0.417 mmol). After stirring at reflux for 16 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSU4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.160 g, 96%). MS (ESI): 440.2 (M+H)+.
d) N-[2-[2-(4-tert-butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(d)- 1(h), except substituting ethyl 2-[2-(4- tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6-dimethyl- 4-moφholino)thiazole-4-carboxylate in step (d), the title compound was prepared as a white solid (0.124 g, 47%). MS (ESI): 674.2 (M+H)+.
Example 40
Preparation of N-f2-r2-(4-carboxybenzyloxy)phenyIlthiazol-4-ylcarbonyll-N'-[N-(4- pyridinylmethoxycarbonylVL-leucinyllhydrazide
Following the procedure of 4(c), except substituting N-[2-[2-(4-tert- butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide for N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine t butoxycarbonyl ester, the title compound was prepared as a pale yellow solid (0.130 g, 100%). MS (ESI): 618.2 (M+H)+. Example 41
Preparation of N-rN-(4-tert-butoxycarbonyIbenzyloxycarbonylVL-leucinyl1-N'-r2-rN-(2- methylpropyl)-N-phenylaminolthiazol-4-ylcarbonyl1hydrazide
a) N-isobutylaniline
Following the procedure of Example 2(a)-2(b), except substituting aniline for isobutylamine and isobutyryl chloride for cyclopropane carbonyl chloride in step (a), the title compound was prepared as an orange liquid (2.11 g, 83%). MS (ESI): 335.3 (M+Na)+.
b) (4-tert-butoxycarbonyl)benzyl alcohol
Water (5 mL) and potassium carbonate (710 mg, 5.15 mmol) were added to a solution of the compound of Example 39(a) (280 mg, 1.03 mmol) in dioxane (5 mL). The mixture was heated at reflux overnight, then the dioxane was removed under reduced pressure. Methylene chloride was added followed by treatment with dilute HCl until all solid had dissolved. The organic phase was separated, washed with aqueous sodium bicarbonate, dried (MgS04), filtered and concentrated to afford the title compound as a white solid (214 mg, 100% ). ^ NMR (400 MHz, CDC13) d 7.89 (d, 2H), 7.33 (d, 2H), 4.67 (s, 2H), 3.08 (s, IH), 1.57 (s, 9H) .
c) N-[N-(4-tert-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2- methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 1(a)- 1(h), except substituting N- isobutylaniline for cis-2,6-dimethylmoφholine in step (a) and (4- rertbutoxycarbonyl)benzyl alcohol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (15 mg, 17%). MS (ESI): 638.2 (M+H)+.
Example 42
Preparation of N-[2-[N.N-bis-(2-methylpropyl)aminolthiazol-4-ylcarbonyll-N'-rN-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 1(a)- 1(h), except substituting diisobutylamine for cis-2,6-dimethylmoφholine in step (a) and (4-tertbutoxycarbonyl)benzyl alcohol for 4- pyridylcarbinol in step (f), the title compound was prepared as a white solid (35 mg, 16%). MS (ESI): 618.4 (M+H)+.
Example 43
Preparation of N-rN-(4-carboxybenzyloxycarbonylVL-leucinyIl-N'-r2-rN-(2- methylpropylVN-phenylaminolthiazol-4-ylcarbonynhydrazide
Following the procedure of 4(c), except substituting N-[N-(4-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide for N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a yellow solid (10 mg, 85%). MS (ESI): 582.2 (M+H)+.
Example 44
Preparation of N-(N-benzyloxycaronyl-L-leucinyl)-N'-[2-r2-(4-tert- butoxycarbonyl)benzyloxyphenyIlthiazol-4-ylcarbonynhydrazide
Following the procedure of Example 1(d) and 1(h), except substituting ethyl 2-[2- (4-tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6- dimedιyl-4-moφholino)thiazole-4-carboxylate in step (d) and N-benzyloxycarbonyl-L- leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (0.102 g, 68%). MS (ESI): 673.2 (M+H)+. Example 45
Preparation of N-(N-benzyloxycaronyl-L-leucinyl)-N'-[2-[2-(4- carboxybenzyloxy)phenyllthiazol-4-ylcarbonyl1hydrazide
Following the procedure of 4(c), except substituting N-(N-benzyloxycaronyl-L- lerfcinyl)-N'-[2-[2-(4-t-2rt-butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]hydrazide for N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a pale yellow solid (0.103 mg, 100%). MS (ESI): 632.2 (M+H)+.
Example 46
Preparation of N-rN-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyll-N'-r2-(l- naphthyl thiazol-4-ylcarbonyllhydrazide
a) 6-methyl-3-pyridylcarbinol
Following the procedure of Example 2(b), except substituting methyl 6- methylnicotinate for N-cyclopropylmethyl isobutyramide, the title compound was prepared as a yellow oil (4.32 g, 83%). MS (ESI): 123.8 (M+H)+.
b) N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide
Following the procedure of Example 5(a)-5(b), except substituting 6-methyl-3- idylcarbinol for 3-pyridylcarbinol in step (a), the title compound was prepared as a white solid (0.155 g, 63%). MS (ESI): 532.2 (M+H)+.
Example 47
Preparation of N-(N-benzy lox vcarbon yl-L-leuciny 1)-N' - r2-(N-cvclopropyl-N- cyclopropylmethylamino thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (156 mg, 75%). MS (ESI): 500.3 (M+H)+. Example 48
Preparation of N- r2-(N-cyclopropyl-N-cyclopropylmethylamino thiazol-4-y lcarbonyll-N'- rN-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimetiιylmoφholine in step (a) and 2- pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (260 mg, 73%). MS (ESI): 501.1 (M+H)+.
Example 49
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyllhvdrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and 6- methyl-3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (151 mg, 71%). MS (ESI): 515.3 (M+H)+.
Example 50
Preparation of N-(N-tert-butoxycarbonyl-L-leucinyD-N'-r2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonynhydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and N- tert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), die title compound was prepared as a white solid (1.2 g, 72%). MS (ESI): 466.3 (M+H)+. Example 51
Preparation of N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-methyl-N-(2-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 4(a)-4(d), except substituting 2- pyridylcarbinol for 4-pyridylcarbinol in step (a) and cyclopropylmethyl cyclopropylamine for N-methyl isobutylamine in step (d), the title compound was prepared as a white solid (60 mg, 25%). MS (ESI): 515.3 (M+H)+.
Example 52
Preparation of N-[2-(2-benzyloxyphenyl thiazol-4-ylcarbonyll-N'-rN-(4-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
a) N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucine
Following the procedure of Example 1(f)- 1(g), except substituting 6-methyl-3- pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as an off- white solid (5.8 g, 100%). 1H NMR (400 MHz, CDC13) d 8.36 (s, IH), 7.61 (d, IH), 7.15 (d, IH), 5.85 (d, IH), 5.01 (s, 2H), 4.20 (m, IH), 2.50 (s, 3H), 1.62 (m, 2H), 1.49 (m, IH), 0.87 (t, 6H).
b) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 2- benzyloxypheny lboronic acid acid for 4-methyl-l -naphthalene boronic acid in step (e) and N-(6-methyl-3-pyridinylmethoxycarbonyl-L-leucine forN-(4-pyridinylmethoxycarbonyl)- L-leucine in step (g), the title compound was prepared as a white solid (178 mg, 99%). MS (ESI): 588.3 (M+H)+.
Example 53
Preparation of N-r2-(2-benzyloxyphenyl')thiazol-4-ylcarbonyIl-N'-rN-(2-methyl-3- pyridinylmethoxycarbonylVL-leucinyllhydrazide
a) 2-methyl-3-pyridylcarbinol Following the procedure of Example 2(b), except substituting methyl 2- methylnicotinate for N-cyclopropylmethyl isobutyramide, the title compound was prepared as a pale yellow oil (4.89 g, 100%). MS (ESI): 123.8 (M+H)+.
b) N-3-(6-methyl)pyridylmethoxycarbonyl-(L)-leucine
Following the procedure of Example 1(f)- 1(g), except substituting 2-methyl-3- pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (6.73 g, 100%). MS (ESI): 281.3 (M+H)+.
c) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 2- benzyloxypheny lboronic acid acid for 4-methyl-l -naphthalene boronic acid in step (e) and N-(2-methyl-3-pyridinylmethoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-
L-leucine in step (g), the title compound was prepared as a pale yellow solid (179.1 mg,
99%). MS (ESI): 588.3 (M+H)+.
Example 54
Preparation of N-r2-rN-methyl-N-(2-methylpropy aminolthiazol-4-ylcarbonyl1-N'-rN-(6- methyl-3-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-methyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and 6-methyl-3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a pale yellow solid (215 mg, 100%). MS (ESI): 491.3 (M+H)+. Example 55
Preparation of N-r2-rN-methyl-N-(2-methylpropyl aminolthiazol-4-ylcarbonyn-N'-fN-(2- methyl-3-pyridinylmethoxycarbonyl)-L-leucinyllhvdrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-methyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and 2-methyl-3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a pale yellow solid (215 mg, 100%). MS (ESI): 491.3 (M+H)+.
Example 56
Preparation of N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'-
(N-picolinoyl-L-leucinyl)hydrazide
a) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)]thiazol-4-yl-carbonyl]-N'-(L- leucinyl)hydrazide
Following the procedure of 4(c), except substituting N-(N-tert-butoxycarbonyl-L- leucinyl)-N'-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a white solid (668 mg, 81%). MS (ESI): 366.3 (M+H)+.
b) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N- picolinoyl-L-leucinyl)hydrazide Following the procedure of Example 1(h), except substituting N-[2-(N- cyclopropyl-N-cyclopropylmethylamino)]thiazol-4-yl-carbonyl]-N'-(L-leucinyl)hydrazide for N-[2-(cis-2,6-dimemyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide and picolinic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (183 mg, 95%). MS (ESI): 471.2 (M+H)+.
Example 57
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'- [N-(2-methyl-3-pyridinylmethoxycarbonyl')-L-leucinvnhvdrazide
Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and 2- methyl-3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (310 mg, 84%). MS (ESI): 515.4 (M+H)+.
Example 58
Preparation of N- rN-(3-tert-butoxycarbonylbenzy loxycarbony D-L-leucinyll-N' - 12-(N- cyclopropyl-N-cvclopropylmethylamino thiazol-4-ylcarbonyllhydrazide
a) 3-bromomethylbenzoic acid A mixture of 3-toluic acid (15.0 g, 110 mmol), N-bromosuccinimide (19.60 g, 110 mmol) and t-butyl peroxybenzoate (2.1 mL, 110 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue obtained was washed with carbon tetrachloride and filtered under vacuum. The filtrate was evaporated to dryness to yield a white solid (12.57 g, 53%). *H NMR (400 MHz, CDC13) d 7.93 (m, 2H), 7.43 (m, 2H), 4.55 (s, 2H).
b) tert-butyl 3-bromomethylbenzoate
Followiong the procedure of Exmaple 39(a), except substituting 3- bromomethylbenzoic acid for 4-brornomethylbenzoic acid, the title compound was prepared as a yellow oil (7.9 g, 100%). -1H NMR (400 MHz, CDCI3) d 7.93 (m, 2H), 7.43 (m, 2H), 4.55 (s, 2H), 1.55 (s, 9H).
c) (3-tert-butoxycarbonyl)benzyl alcohol
Followiong the procedure of Exmaple 41(b), except substituting tert-butyl 3- bromomethylbenzoate for tert-butyl 4-bromomethylbenzoate, the title compound was prepared as a yellow oil (5.6 g, 92%). MS (ESI): 208.1 (M+H)+.
d) N-[N-(3-tert-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 1(a)- 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimedιylmoφholine in step (a) and (3- tertbutoxycarbonyl)benzyl alcohol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (90 mg, 29%). MS (ESI): 600.4 (M+H)+.
Example 59 Preparation of N-r2-(l-naphthyl')thiazol-4-ylcarbonyll-N'-rN-(8-quinolinoyl')-L- leucinyllhvdrazide
a) N- [2-( 1 -naphthy l)thiazol-4-ylcarbonyl]hy drazide Following die procedure of Example 3(a)-3(f), except substituting 1 -naphthalene boronic acid for 4-methyl-l -naphthalene boronic acid in step (e), the title compound was prepared as a pale yellow solid. MS (ESI): 270.1 (M+H)+.
b) N-(N-tert-butoxycarbonyl-L-leucinyl)-N' - [2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hy drazide Following die procedure of Example 1(h), except substituting N-[2-(l- naphthyl)thiazol-4-y Icarbony l]hy drazide for N- [2-(cis-2,6-dimethyl-4-moφholino)thiazol- 4-ylcarbonyl]hydrazide in and N-tert-butoxycarbonyl-L-leucine for N-(4- pyridinylmethoxycarbonyl)-L-leucine in step, the title compound was prepared as a white solid (2.2 g, 96%). MS (ESI): 483.2 (M+H)+.
c) N-(L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of 4(c), except substituting N-(N-tert-butoxycarbonyl-L- leucinyl)-N'-[2-( l-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine t butoxycarbonyl ester, the title compound was prepared as an off-white solid (1.7 g, 97%). MS (ESI): 383.3 (M+H)+.
d) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(h), except substituting N-(L-leucinyl)-N'- [2-( 1 -naphthy l)thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6-dimethyl-4- moφholino)thiazol-4-ylcarbonyl]hydrazide and 8-quinolinecarboxylic acid for N-(4- pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (118 mg, 84%). MS (ESI): 538.2 (M+H)+.
Example 60
Preparation of N-rN-(2-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyll-N'-f 2-( 1 - naphthyl thiazol-4-ylcarbonynhydrazide
Following the procedure of Example 5(a)-5(b), except substituting 2-methyl-3- idylcarbinol for 3-pyridylcarbinol in step (a), the title compound was prepared as a white solid (0.160 g, 65%). MS (ESI): 532.2 (M+H)+. Example 61
Preparation of N-f2-( 1 -naphthyl')thiazol-4-ylcarbonyn-N'-(N-picolinoyl-L- leucinyDhydrazide
Following the procedure of Example 59(a)-59(c), except substituting picolinic acid for8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.086 g, 54%). MS (ESI): 488.3 (M+H)+.
Example 62
Preparation of N-rN-(3-carboxybenzyloxycarbonyl)-L-leucinyn-N'-r2-(N-cyclopropyl-N- cyclopropylmethylamino')thiazol-4-ylcarbonyl1hydrazide
Following the procedure of 4(c), except substituting N-[N-(3-tert- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-Methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a white solid (21 mg, 93%). MS (ESI): 544.3 (M+H)+.
Example 63
Preparation of N-r2-(l-naphthvDthiazol-4-ylcarbonvH-N'-rN-(2-quinolinoylVL- leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 2- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), die title compound was prepared as a white solid (0.123 g, 80%). MS (ESI): 538.2 (M+H)+.
Example 64
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonyll-N'-rN-(3-quinolinoylVL- leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 3- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.109 g, 77%). MS (ESI): 538.2 (M+H)+. Example 65
Preparation of N-f2-( 1 -naphthyI)thiazol-4-ylcarbonyll-N'-lN-f4-methylpiperidinecarbonyiy L-leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 1- methylpiperidine-4-carboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.059 g, 45%). MS (ESI): 508.2 (M+H)+.
Example 66
Preparation of N- ϊ2-( 1 -naphthyPthiazol-4-ylcarbon yl 1-N'- rN-(4-quinolinoy D-L- leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 4- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.096 g, 68%). MS (ESI): 538.3 (M+H)+.
Example 67
Preparation of N-f2-( 1 -naphthyDthiazoM-ylcarbonyn-N'-fNJS-quinolinoyP-L- leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 5- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), die title compound was prepared as a white solid (0.089 g, 63%). MS (ESI): 538.3 (M+H)+.
Example 68
Preparation of N-r2-π-naphthyDthiazol-4-ylcarbonyll-N'-rN-(7-quinolinoyl)-L- leucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 7- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.106 g, 75%). MS (ESI): 538.2 (M+H)+. Example 69
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-(6-quinolinoyl)-L- leucinyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting 6- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.111 g, 79%). MS (ESI): 538.2 (M+H)+.
Example 70
Preparation of N-rN-π-isoquinolinoyl)-L-leucinyI1-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 1- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.076 g, 54%). MS (ESI): 538.2 (M+H)+.
Example 71
Preparation of N-rN-(3-isoquinolinoyl)-L-leucinyll-N'-r2-(l-naphthyl')thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 3- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.055 g, 39%). MS (ESI): 538.2 (M+H)+.
Example 72
Preparation of N-rN-(4-methyliιτιidazol-5-ylcarbonyl)-L-leucinyll-N'-[2-π- naphthyl)thiazol-4-ylcarbonyl]hvdrazide
a) 4-methylimidazole-5-carboxylic acid
Following the procedure of Example 1(g), except substituting ethyl 4- methylimidazole-5-carboxylate for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (0.428 g, 52%). MS (ESI): 126.8 (M+H)+. b) N-[N-(4-methylimidazol-5-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide
Following the procedure of Example 1(h), except substituting N-(L-leucinyl)-N'- [2-( 1 -naphthy l)thiazol-4-ylcarbonyl]hydrazide for N- [2-(cis-2,6-dimethyl-4- moφholino)thiazol-4-ylcarbonyl]hydrazide and 4-methylimidazole-5-carboxylic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.108 g, 84%). MS (ESI): 491.3 (M+H)+.
Example 73
Preparation of N-(N-benzyl-L-prolinyl-L-leucinyD-N'-r2-(l-naphthyDthiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-benzyl proline for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.075 g, 50%). MS (ESI): 570.2 (M+H)+
Example 74
Preparation of N-rN-(l-benzyl-5-methylimidazol-4-ylcarbonyl)-L-leucinyll-N,-r2-(l- naphthyl~)thiazol-4-ylcarbonynhydrazide
Following the procedure of Example 72(a)-72(b), except substituting l-benzyl-5- metiιylimidazole-4-carboxylic acid for 4-methylimidazole-5-carboxylic acid in step (a), the title compound was prepared as a white solid (0.115 g, 75%). MS (ESI): 581.1 (M+H)+.
Example 75
Preparation of N-rN-r3-methylisonicotinoyl)-L-leucinyn-N'-r2-(l-naphthyl thiazol-4- ylcarbonyllhvdrazide
a) 4-cyano-2-methylpyridine
To neat picoline N-oxide (10.0 g, 91.7 mmol) at room temperature was added iodoethane (51.5 g, 330 mmol) dropwise. After standing for 24 h, the salt was filtered off and washed with etiier. The solid was dissolved in edianol/water (70 mL/30 mL) and potassium cyanide (11.0 g, 172 mmol) in water (31 mL) was added dropwise over 100 min at 48-50 °C. After the addition was complete, the solution continued stirring at the same temperature for 30 min. The solution was then extracted witii chloroform. The organic layer was washed with brine, dried (MgS04), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow oily solid (3.9 g, 36%). MS (ESI): 118.8 (M+H)+.
b) 2-methylpyridine-4-carboxylic acid
The compound of Example 75(a) (0.300 g, 2.5 mmol) was dissolved in concentrated hydrochloric acid (3 mL). After stirring at reflux for 18 h, the solution was concentrated to yield the title compound as a white solid (0.342 g, 100%). MS (ESI): 137.8 (M+H)+.
c) N-[N-(3-methylisonicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)dιiazol-4- ylcarbonyljhydrazide Following the procedure of Example 1(h), except substituting N-(L-leucinyl)-N'-
[2-( l-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6-dimethyl-4- mθφholino)thiazol-4-ylcarbonyl]hydrazide and 2-methylpyridine-4-carboxylic acid for N- (4-pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.095 g, 72%). MS (ESI): 502.2 (M+H)+.
Example 76
Preparation of N-r2-rN-cyclopropylamino)thiazol-4-ylcarbonyl1-N'-rN-(2- pyridinylmethoxycarbonylVL-leucinyllhydrazide
Following the procedure of Example 1(a)- 1(h), except substituting cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and 2-pyridylcarbinol for 4- pyridylcarbinol in step (f), the title compound was prepared as a white solid (140 mg, 50%). MS (ESI): 447.3 (M+H)+.
Example 77
Preparation of N-rN-(2-benzoxazolyl)-L-leucinyn-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhydrazide
A solution of die compound of Example 59(c) (100 mg, 0.26 mmol), 2- chlorobenzoxazole (40.2 mg, 0.26 mmol, 0.03 mL) and triethylamine (26.5 mg, 0.26 mmol, 0.365 mL) in 1:1 THF/methanol (1 mL) was heated at 60 °C for 48 h. The solution was diluted with ethyl acetate, washed with saturated aqueous NaHCU3, water (2 X) and saturated brine, then dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on 4 g of 230-400 mesh silica gel, eluting with 1:1 ethyl acetate/hexanes, to give the title compound as a pale yellow solid (50.2 mg, 38%). MS (ESI): 500.2 (M+H)+.
Example 78
Preparation of N-(N-benzyloxycarbonyl-L-leucinylVN'-r2-rN.N-bis-(2- methylpropyl)amino]oxazol-4-ylcarbonynhydrazide
a) N,N-diisobutylurea
A solution of diisobutylamine (4.5 g, 34.8 mmol, 6.08 mL) and chlorosulfonyl isocyanate (4.93 g, 34.8 mmol, 3.03 mL) in THF (200 mL) was allowed to stir at room temperature for 20 min, then water (10 mL) was added and the solution was allowed to stir at room temperature for 17 h. The solution was concentrated, the residue was redissolved in ethyl acetate, washed with water, saturated aqueous NaHC03 and saturated brine, then dried (MgSθ4), filtered and concentrated to give the title compound as a colorless oil which crystallized upon standing (6.0 g, 100%). MS (ESI): 173.3 (M+H)+. b) N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N,N-bis-(2-methylpropyl)amino]oxazol-4- ylcarbonyl]hydrazide
Following the procedure of Examples l(c)-l(d) and 1(h), except substituting N,N- diisobutylurea for cis-2,6-dimethyl-4-moφholinothiourea in step (c) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (126 mg, 64%). MS (ESI): 502.3 (M+H)+.
Example 79
Preparation of N-r2-I -cyclopropyl-N-(2-methylpropyI)aminolthiazol-4-ylcarbonyl1-N'- rN-(2-pyridinylrnethoxycarbonylVL-leucinyllhydrazide
a) N-cyclopropyl isobutylamine
Following the procedure of Example 9(a), except substituting isobutyraldehyde for cyclopropane carboxaldehyde, the title compound was prepared as a colorless oil (1.9 g, 58%). MS (ESI): 113.9 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-cyclopropyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and 2-pyridyocarbinol for 4- pyridylcarbinol in step (f), the title compound was prepared as a white solid (150 mg, 69% yield). MS (ESI): 503.2 (M+H)+.
Example 80
Preparation of N-r2-rN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-ylcarbonyl]-N'- rN-methyl-N-(2-pyridinylmethoxycarbonyl)-L-leucinvflhvdrazide
Following the procedure of Example 4(a)-4(d), except substituting 2- pyridylcarbinol for 4-pyridylcarbinol in step (a) and N-cyclopropyl isobutylamine for N- methyl isobutylamine in step (d), the title compound was prepared as a white solid (85 mg, 32%). MS (ESI): 517.3 (M+H)+. Example 81
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonyn-N'-rN-(l-piperazinecarbonyl -L- leucinyllhydrazide
a) N- [2-( 1 -naphthy l)thiazol-4-y lcarbonyl]-N' - [N-(4-tert-butoxy carbonyl- 1 - piperazinecarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 23(c), except substituting N-tert- butoxycarbonylpiperazine for N-(3-phenyl)phenyl isobutylamine, the title compound was prepared as a white solid (131 mg, 85%). MS (ESI): 595.2 (M+H)+.
b) N- [2-( 1 -naphthy l)thiazol-4-y Icarbony 1]-N' - [N-( 1 -piperazinecarbonyl)-L- leucinyl]hydrazide
Following the procedure of 4(c), except substituting N-[2-(l -naphthy l)thiazol-4- ylcarbonyl]-N'-[N-(4-tert-butoxycarbonyl-l-piperazinecarbonyl)-L-leucinyl]hydrazide for N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a white solid (47 mg, 54%). MS (ESI): 495.2 (M+H)+.
Example 82
Preparation of N-r4-methyl-2-(4-phenoxy)phenylpentanoyn-N'-r2-(l-naphthyl')thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 17(a)-17(c), except substituting 4- phenoxyphenylacetic acid for 4-phenoxyphenylacetic acid in step (a), the title compound was prepared as a white solid (134 mg, 67%). MS (ESI): 536.2 (M+H)+.
Example 83
Preparation of N-r2-rN-bis-(cvclopropylmethyl)aminolthiazol-4-ylcarbonyll-N'-fN-(2- pyridinylmethoxycarbonvD-L-leucinyllhydrazide
a) bis-(cyclopropylmethyl)amine
Following the procedure of Example 9(a), except substituting aminomethylcyclporopane for cyclopropylamine, the title compound was prepared as a colorless liquid (2.5 g, 96%). MS (ESI): 125.8 (M+H)+. b) N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except bis- (cyclopropylmethyl)amine for cis-2,6-dimethylmoφholine in step (a) and 2- pyridyocarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a yellow solid (115 mg, 30%). MS (ESI): 515.3 (M+H)+.
Example 84
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'- rN-(2-quinolinoyl)-L-leucinynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 2- quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (125 mg, 59%). MS (ESI): 521.2 (M+H)+.
Example 85
Preparation of N-rN-(8-quinolinoyl)-L-leucinyl1-N'-r2-(8-quinolinyl)thiazol-4- ylcarbonyllhvdrazide
a) N-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 3(a)-3(f), except substituting 8- bromoquinoline for l-bromo-4-methylnaphthalene in step (d), the title compound was prepared as a pale yellow solid (0.306 g, 100%). MS (ESI): 271.2 (M+H)+.
b) N-[N-(8-quinolinoyl)-L-leucinyl]-N'-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 59(b)-59(d), except substituting N-[2-(8- quinoliny l)thiazol-4-y Icarbony l]hydrazide for N- [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hy drazide in step (b), the title compound was prepared as a white solid (0.111 g, 66%). MS (ESI): 539.2 (M+H)+. Example 86
Preparation of N-(N-benzyloxycarbonyl-L-leucinyl)-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhvdrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthy lboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.145 g, 60%). MS(ESI): 517.3 (M+H)+.
Example 87
Preparation of N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(3-quinolinoyl)-L-leucinynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 3- quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (150 mg, 75%). MS (ESI): 521.2 (M+H)+.
Example 88
Preparation of N-[2-(N-cyclopropyl-N-cyclopropylmethylamino thiazol-4-ylcarbonyl1-N'- rN-(3-isoquinolinoyl)-L-leucinynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 3- isoquinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (187 mg, 82%). MS (ESI): 521.1 (M+H)+.
Example 89
Preparation of N-r2-(N-cvclopropyl-N-cvclopropylmethylamino)thiazol-4-ylcarbonyn-N'- rN-(6-quinolinoyl)-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 6- quinolinecarboxylic acid for picolinic acid in step (b), the tide compound was prepared as a white solid (155 mg, 59%). MS (ESI): 521.3 (M+H)+. Example 90
Preparation of N-r2-rN-bis-(cyclopropylmethyl aminolthiazol-4-ylcarbonyll-N'-rN-(2- methyl-3-pyridinylmethoxycarbonyl")-L-leucinyl1hydrazide
Following the procedure of Example 83(a)-83(b), except substituting 2-methyl-3- pyridylcarbinol for 2-pyridylcarbinol in step (b), the title compound was prepared as a yellow solid (105 mg, 46%). MS (ESI): 529.3 (M+H)+
Example 91
Preparation of N-(N-benzyloxycarbonyl-L-b-tert-butylalanyl)-N'-r2-(l-naphthyπthiazol-4- ylcarbonyllhydrazide
a) N-benzyloxycarbonyl-L-b-tert-butylalanine
To a stirring solution of L-b-tert-butylalanine (1.0 g, 6.89 mmol) in water (2.1 mL) and 5 N NaOH (1.38 mL) at 0 °C was added benzyl chloroformate (1.3 g, 7.58 mmol) and 2
N NaOH (3.8 mL) in ten alternating portions, over 1.5 h. After the additions are complete the mixture was stirred for another 30 min. at room temperature. The pH is then taken to
10 and the mixture is extracted with ether (50 mL). The aqueous layer was acidified to pH
3 with 3 N HCl and extracted with ether (3 x 50 mL). The organic layers are combined, dried (MgSO4), filtered and concentrated to yield die title compound as a colorless oil (1.59 g, 83%). MS(ESI): 278.2 (M+H)".
b) N-(N-benzyloxycarbonyl-L-b-tert-butylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthy lboronic acid for 4-medιyl-l -naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-L-tert-butylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.214 g, 87%). MS (ESI): 531.3
(M+H)+. Example 92
Preparation of N-(N-benzyloxycarbonyl-L-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyllhvdrazide
a) N-benzyloxycarbonyl-L-allylglycine
Following the procedure of Example 91(a), except substituting L-allylglycine for L-tert-butylalanine, the title compound was prepared.
b) N-benzyloxycarbonyl-L-cyclopropylalanine methyl ester
Diazomethane (4.8 mmol in 18 ml Et2θ) was added to a solution of the compound of Example 92(a) (0.210 g, 0.48 mmol) in 1 ml Et2θ at room temperature and was stirred for 5 minutes. Then Pd(OAc)2 (2 mg) was added and the reaction was stirred overnight, filtered through silica gel, concentrated in vacuo, and was used in the next reaction without further purification (205 mg, 95%). MS (ESI): 300.1 (M+Na)+.
c) N-benzyloxycarbonyl-L-cyclopropylalanine
Following the procedure of Example 1 (g) except substituting N- benzyloxycarbonyl-L-cyclopropylalanine methyl ester for N-(4- pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (165 mg, 82%). MS (ESI): 264.2 (M+H)+.
d) N-(N-benzyloxycarbonyl-L-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthylboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-(L)-terr-butylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.054 g, 67%). MS (ESI): 515.2 (M+H)+.
Example 93
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-r3-(2-pyridyl')phenyIacetyn- L-leucinyllhydrazide
a) methyl 3-9trifluoromethanesulfonyloxyphenylacetate
To an oven-dried flask under Argon atmosphere containing sodium hydride (2.54 g, 60% dispersion in mineral oil, 63.5 mmol) was added anhydrous pentane (20 mL). The slurry was stirred for 5 min, allowed to settle, most of the pentane was removed, and anhydrous THF (40 mL) was added. To this suspension was added a solution of methyl 3- hydroxyphenylacetate (9.99 g, 60.1 mmol) in anhydrous THF (20 mL) and the reaction was stirred at room temperature for 20 min. To this mixture was then added a solution of N- phenyltrifluoromethanesulfonimide (22.53 g, 63 J mmol)) in anhydrous THF (40 mL) and the reaction was stirred at room temperature until TLC analysis indicated the complete consumption of starting material (1.5 h). The reaction was quenched by the addition of
H2O (10 mL), concentrated to one half original volume, then diluted with CHCI3 (200 mL) and washed with H2O. The aqueous layer was washed with fresh CHCI3 (50 mL), the combined organic layers were washed with 10% Na2Cθ3, H2O, and brine, then dried (MgS04), filtered and concentrated. Column chromatography of the residue (silica gel, 5:95 EtOAc: hexanes, then 10:90 EtOAc: hexanes) gave 17.47 g of the title compound. -1H NMR (400 MHz, CDCI3) d 7.42 (m, IH), 7.31-7.19 (m, 3H), 3.72 (s, 3H), 3.68 (s, 2H).
b) methyl 3-(2-pyridyl)phenylacetate
To a solution of the compound of Example 93(a) (6.86 g, 23.0 mmol) in anhydrous dioxane (100 mL) was added 2-pyridylstannane (8.89 g, 24.1 mmol), LiCl (2.94 g, 69.3 mmol), 2,6-di-tert-butyl-4-methylphenol (a few crystals), and Pd(PPh3)4 (632.1 mg, 0.55 mmol). The reaction was protected from light with foil and heated to reflux overnight. The reaction was allowed to cool to room temperature and concentrated. Column chromatography of the residue (silica gel, 1:3 EtOAc: hexanes, then 1:2 EtOAc: hexanes) gave 3.85 g of the title compound: MS (ESI): 228.1 (M+H)+.
c) 3-(2-pyridyl)phenyl acetic acid
Following the procedure of Examples 1(g), except substituting methyl 3-(2- pyridyl)phenylacetate for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared. MS (ESI): 214.3 (M+H)+. e) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[3-(2-pyridyl)phenylacetyl]-L- leucinyljhydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthylboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and 3-(2- pyridyl)phenylacetic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (0.149 g, 79%). MS (ESI): 578.1 (M+H)+.
Example 94
Preparation of N-F2-rN-bis-fcvclopropylmethyl aminolthiazol-4-ylcarbonyπ-N'-fN- picolinyl-L-leucinyllhvdrazide
a) N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-rert- butoxycarbonyl-L-leucinyl)hydrazide Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting bis-
(cyclopropylmethyl)amine cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and N-tert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as an orange oil. MS (ESI): 480.3 (M+H)+.
b) N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinyl-L- leucinyl)hydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-[2-[N-bis-
(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leucinyl)hydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a), the title compound was prepared as a yellow solid (74 mg, 41%). MS (ESI): 485.3 (M+H)+.
Example 95
Preparation of N-(N-benzyloxycarbonyl-L-leucinyl)-N'-r2-rN-bis- (cyclopropylmethyl aminolthiazol-4-ylcarbonynhvdrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting bis- (cyclopropylmethyl)amine for cis-2,6-dimethylmoφholine in step (a) and N- bejnzyloxycarbonyl L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as as a yellow solid (140 mg, 69%). MS (ESI): 514.3 (M+H)+. Example 96
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'- [N-(6-methylnicotinoyl)-L-leucinyllhydrazide
a) 61methylnicotinic acid
Following the procedure of Example 1(g), except substituting methyl-6- methylnicotinate for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (506 mg, 100%). MS (ESI): 137.9 (M+H)+.
b) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylnicotinoyl)-L-leucinyl]hydrazide
Following the procedure of Example 56(a)-56(b), except substituting 6- methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (150 mg, 41%). MS (ESI): 485.4 (M+H)+.
Example 97
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'- rN-(2-methylnicotinoylVL-leucinyllhydrazide
a) 2-methylnicotinic acid
Following the procedure of Example 1(g), except substituting methyl-2- mediylnicotinate for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (1.6 g, 100%). MS (ESI): 138.2 (M+H)+.
b) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- methylnicotinoyl)-L-leucinyl]hydrazide Following the procedure of Example 56(a)-56(b), except substituting 2- methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (170 mg, 71%). MS (ESI): 485.3 (M+H)+. Example 98
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'- [N-G-methylisonicotinoyD-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 2- methylpyridine-4-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (120 mg, 57%). MS (ESI): 485.2 (M+H)+.
Example 99
Preparation of N- r2-(N-cvclopropyl-N-cvclopropylmethy lamino)thiazol-4-y lcarbonyll-N'- rN-(8-quinolinoyl)-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 8- quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (200 mg, 94%). MS (ESI): 521.2 (M+H)+.
Example 100
Preparation of N-f2-rN-bis-(cvclopropylmethyl amino1thiazol-4-ylcarbonyll-N'-rN-(8- quinolinoyl)-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-[2-[N-bis- (cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leuciny l)hy drazide for N- [2-(N-cyclopropyl-N-cyclopropylmethy lamino)thiazol-4- ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 8- quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a yellow solid (25 mg, 12%). MS (ESI): 535.3 (M+H)+.
Example 101
Preparation of N-r2-rN-bis-(cyclopropylmethyl)aminolthiazol-4-ylcarbonyπ-N'-rN-(3- isoquinolinoylVL-leucinyπhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-[2-[N-bis- (cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leucinyl)hydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 3- isoquinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a yellow solid (25 mg, 10%). MS (ESI): 535.3 (M+H)+.
Example 102
Preparation of N-F2-r4-(2.2-dimethylaminoethoxy> 1 -naphthyllthiazol-4-ylcarbonyU-N'-rN- (8-quinolinoyl)-L-leucinynhydrazide
a) 4-bromo- 1 -naphthol
To a vigorously stirred suspension of 1 ,4-dibromonaphthalene (15.3 g, 53.7 mmol) in hexane/THF (300 mL) at -78 °C was added n-butyllithium (22.3 mL, 56.4 mmol, 2.5 M in hexane) dropwise. After stirring for an additional 30 min. at -78 °C, bis(trimethylsilyl)peroxide (11 g, 61.8 mmol) [Taddei, M., Ricci, A., Synthesis, 1986, 633] was added slowly via syringe. After warming to room temperature and stirring an additional 3 h, the mixture was diluted with ethyl acetate and washed with 1 N HCl then brine. The organic layer was dried (MgS04), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as an off-white solid (6.5 g, 54%). MS (ESI): 221 J (M+H)".
b) 4-bromo-l -naphthyl rerr-butyl ether
Following the procedure of Example 39(a), except substituting 4-bromo-l -naphthol for 4-bromomethylbenzoic acid, the title compound was prepared as a colorless oil (2.34 g, 62%). !H NMR (400 MHz, CDC13) d 8.28 (d, IH), 8.18 (d, IH), 7.67 (d, IH), 7.60 (t, IH), 7.54 (t, IH), 7.01 (d, IH), 1. 1 (s, 9H).
c) ethyl 2-(4-terr-butoxy-l -naphthy l)thiazole-4-carboxylate
Following the procedure of Example 3(a)-3(e), except substituting 4-bromo-l- naphthyl tert-butyl ether for l-bromo-4-methylnaphthalene in step (d), the title compound was prepared as a white solid (0J83 g, 67%). MS (ESI): 356.2 (M+H)+.
d) ethyl 2-(4-hydroxy-l -naphthy l)thiazole-4-carboxy late
Following the procedure of 4(c), except substituting ethyl 2-(4-tert-butoxy-l- naphthyl)thiazole-4-carboxylate for N-Methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tertbutoxycarbonyl ester, the title compound was prepared as a yellow solid (0.580 g, 88%). MS (ESI): 300.1 (M+H)+. e) ethyl 2- [4-(2-N,N-dimethylaminoethoxy)- 1 -naphthy l]thiazole-4-carboxylate
Following the procedure of Example 28(d), except substituting ethyl 2-(4-hydroxy- 1 -naphthy l)thiazole-4-carboxy late for ethyl 2- (2-hydroxy-l -naphthy l)thiazole-4- carboxylate and 2-(N,N-dimethylamino)ethanol for benzyl alcohol, the title compound was prepared as a white solid (0.097 g, 52%). MS (ESI): 371.3 (M+H)+.
f) N-(8-quinolinoyl)-L-leucine methyl ester
Following the procedure of Example 1(h), except substituting L-leucine methyl ester hydrochloride for N-[2-(cis-2,6-dimethyl-4-moφholino)thiazol-4- ylcarbonyl]hydrazide and 8-quinoline carboxylic acid for N-(4-pyridylmethoxycarbonyl)- L-leucine, the title compound was prepared as a white solid (0.637 g, 41%). MS (ESI): 301.2 (M+H)+.
g) N-(8-quinolinoyl)-L-leucine
Following the procedure of Example 1(g), except substituting N-(8-quinolinoyl)-L- leucine methyl ester for N-(4-pyridylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (0.150 g, 25%). 1H NMR (400 MHz, CDCI3) d 8.89 (t, IH), 8.78 (d, IH), 8.21 (d, IH), 7.90 (d, IH), 7.57 (t, IH), 7.43 (t, IH), 4.88 (m, IH), 1.92 (m, 3H), 1.03 (m, 6H).
h) N-[2-[4-(2,2-dimedιylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(d), except substituting ethyl 2-[4-(2-N,N- dimethylaminoethoxy)-l-naphthyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6-dimethyl-4- moφholino)thiazole-4-carboxylate, the title compound was prepared as a yellow solid (0.091 g, 100%). MS (ESI): 357.2 (M+H)+.
i) N-[2-[4-(2,2-dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide Following the procedure of Example 1(h), except substituting N-[2-[4-(2,2- dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6- dimedιyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide and N-(8-quinolinoyl)-L-leucine for N-(4-pyridylmethoxycarbonyl)-L-leucine, the title compound was prepared as a yellow solid (0.050g, 31%). MS (ESI): 625.2 (M+H)+. Example 103
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'- rN-(7-quinolinoviyL-leucinyπhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 7- quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (100 mg, 50%). MS (ESI): 521.2 (M+H)+.
Example 104
Preparation of N-r2-rN-bis-(cyclopropylmethyl aminolthiazol-4-ylcarbonyH-N'-[N-(6- methylnicotinoylVL-IeucinyPhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-[2-[N-bis-
(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-rert-butoxycarbonyl-L- leucinyl)hydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-terr-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 6- methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a yellow solid (40 mg, 15%). MS (ESI): 499.3 (M+H)+.
Example 105
Preparation of N-r2-rN-bis-(cyclopropylmethyl')aminolthiazol-4-ylcarbonyll-N'-(N-methyl- L-prolinyl-L-leucinyl)hydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-methyl-L- proline for picolinic acid in step (b), the title compound was prepared as a white solid (62 mg, 48%). MS (ESI): 477.3 (M+H)+.
Example 106
Preparation of N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-r2-(l-naphthyl')thiazol-4- ylcarbonynhydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthy lboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-L-norvaline for N-(4-ρyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (180 mg, 96%). MS (ESI): 503.2 (M+H)+.
Example 107
Preparation of N-(N-benzyloxycarbonyl-L-isoleucinyl)-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhvdrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthy lboronic acid for 4-methyl-l -naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-L-isoleucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (167 mg, 87%). MS (ESI): 517.1 (M+H)+.
Example 108
Preparation of N-rN-(4-dimethylaminomethylbenzoyl')-L-leucinyll-N'-r2-(l - naphthyl)thiazol-4-ylcarbonyl]hydrazide
a) methyl 4-(N,N-dimethylaminomethyl)benzoate
Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a saturated solution of dimethylamine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between IN NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSθ4), filtered, and concentrated to provide the title compound as a colorless liquid (1.67 g, 99%). -1H NMR (250 MHz, CDC13) d 8.00 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H), 3.47 (d, 2H), 2.25 (s, 6H).
b) 4-(N,N-dimethylaminomethyl)benzoic acid Following the procedure of Example 1(g), except substituting methyl 4-(N,N- dimethylaminomethyl)benzoate for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid (1.6 g, 100%). 1H NMR (400 MHz, CD3OD) d 7.94 (d, 2H), 7.36 (d, 2H), 3.64(s, 2H), 2.35 (s, 6H).
c) N-[N-(4-dimethylaminomethylbenzoyl)-L-leucinyl]-N'-[2-( l-naphthyl)thiazol-4- y Icarbony 1] hy drazide Following the procedure of Example 59(a)-59(d), except substituting 4-(N,N- dimethylaminomethyl)benzoic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (87 mg, 61%). MS (ESI): 544.2 (M+H)+.
Example 109
Preparation of N-(N-benzyloxycafbonyl-L-norleucinyl)-N'-r2-(l-naphthyl thiazol-4- ylcarbonyllhydrazide
Following the procedure of Examples 3(a)-3(c) and 3(e)-3(g), except substituting 1- naphthylboronic acid for 4-methyl-l-naphthalene boronic acid in step (e) and N- benzyloxycarbonyl-L-norleucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (184 mg, 96%). MS (ESI): 517.1 (M+H)+.
Example 110
Preparation of N-rN-(4-dimethylaminomethylbenzyloxycarbonyl")-L-leucinyll-N'-r2-(l- naphthyPthiazo -ylcarbonyllhydrazide
a) 4-(N,N-dimethylamino)benzyl alcohol
To a stirring solution of the compound of Example 108(a) (1.63 g, 8.4 mmol) in 25 mL of ether, cooled to 0 °C, was added dropwise a 1 M solution of lithium aluminum hydride (8.4 mmol, 8.4 mL). After 5 min, the reaction was quenched by the addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL) and water (1.0 mL). The precipitate was removed by filtration, washed widi ether 2 times and the filtrate was concentrated to provide the title compound as a colorless oil (1.36 g, 98%). -Η NMR (250 MHz, CDCI3) d 7.32 (d, 2H), 7.28 (d, 2H), 4.68 (s, 2H), 3.41 (s, 2H), 2.22 (s, 6H).
b) N-[N-(4-dimetiιylaminomethylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(e)- 1(h), except substituting 4-(N,N- dimethylamino)benzyl alcohol for 4-pyridylcarbinol in step (f) and N-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6-dimethyl-4-moφholino)thiazol- 4-ylcarbonyl]hydrazide, the title compound was prepared as a white solid (186 mg, 87%).
MS (ESI): 574.3 (M+H)+. Example 111
Preparation of N-(N-benzyloxycarbonyl-L-norvalinylVN'-r2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyllhvdrazide
Following the procedure of Example 27(a)-27(c), except substituting N- berizyloxycarbonyl-L-norvaline for 2-(3-phenylphenyl)-4-methylpentanoic acid in step (c), the title compound was prepared as a white solid. MS (ESI): 559.0 (M+H)+.
Example 112
Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino')thiazol-4-ylcarbonyl1-N'- rN-(4-methylimidazol-5-ylcarbonyD-L-leucinyHhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 4- methylimidazole-5-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (100 mg, 65%). MS (ESI): 474.3 (M+H)+.
Example 113
Preparation of N-rN-r4-(4-moφholinomethyl benzoyll-L-leucinyll-N'-r2-( 1 - naphthyl")thiazol-4-ylcarbonynhvdrazide
Following the procedure of Example 108(a)- 108(c), except substituting moφholine for dimethylmaine in step (a), the title compound was prepared as a white solid (0.097 g, 51%). MS (ESI): 586.2 (M+H)+.
Example 114
Preparation of N-rN-(2-methylnicotinoyl)-L-leucinvn-N'-r2-(l-naphthyl>)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 2- methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.103 g, 60%). MS (ESI): 502.2 (M+H)+. Example 115
Preparation of N-[N-(6-methylnicotinoylVL-leucinvn-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 6- methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.134 g, 79%). MS (ESI): 502.2 (M+H)+.
Example 116
Preparation of N-rN-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyIl-N'-r2-π- naphthyl)thiazol-4-ylcarbonyllhydrazide
a) N-tert-butoxycarbonyl-L-allylglycine
To a stirring solution of L-allylglycine (6.28 g, 54.5 mmol) in dioxane/water/1 N NaOH (110 mL/55 mL/55 mL) at 0 °C was added di-tert-butyl dicarbonate (12.5 g, 57.2 mmol). After stirring for 30 min., the solution was concentrated and redissolved in 60 mL of water. A layer of ethyl acetate was added and the aqueous layer was acidified to pH 3 witii 0.3 N KHSO4. The aqueous layer was extracted with ethyl acetate (2 X). The organic layers were combined, washed with water (2 X), dried (MgS04), filtered and concentrated to yield the title compound as a white solid (10.11 g, 86%). MS (ESI): 453.2 (2M+Na)+.
b) N-[N-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-allylglycine for N-tert-butoxycarbonyl-L-leucine in step (b) and 4- methylimidazole-5-carboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.112 g, 67%). MS (ESI): 475.1 (M+H)+.
Example 117
Preparation of N-(N-b-tert-butoxycarbonyl-L-tert-butylalanyl)-N'-r2-(N-cyclopropyl-N- cvclopropylmethylamino thiazol-4-ylcarbonyllhydrazide
a) N-tert-butoxycarbonyl-L-b-tert-butylalanine Following the procedure of Example 116(a), except substituting L-tert-butylalanine for L-allylglycine, the title compound was prepared as a white solid (2.36 g, 70%). MS(ESI): 268.3 (M+Na)+.
b) N-(N-b-tert-butoxycarbony 1-L-tert-buty lalany 1)-N'- [2-(N-cyclopropy 1-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and N- tert-butoxycarbonyl-L-b-rert-butylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (0.96 g, 100%). MS (ESI): 480.3 (M+H)+.
Example 118
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- FN-(8-quinolinoyl)-L-b-tgrt-butylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-b-tert- butoxycarbonyl-L-tert-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 8-quinolinecarboxylic acid for picolinic acid in step (b), die title compound was prepared as a white solid (160 mg, 82%). MS (ESI): 535.3 (M+H)+.
Example 119
Preparation of N-rN-(4-methylimidazol-5-ylcarbonyl)-L-b-rgrt-butylalanyll-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-tgrt-butylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 4-medιylimidazole-5-carboxylic acid for 8-quinolinecarboxylic acid in step (d), die title compound was prepared as a white solid (0.096 g, 58%). MS (ESI): 505.2 (M+H)+.
Example 120 Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonvn-N'- [N-(4-methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-b-tgrt- butoxycarbony 1-L-tert-buty lalany 1)-N'- [2-(N-cyclopropy 1-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 4-methylimidazole-5-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (180 mg, 78%). MS (ESI): 488.2 (M+H)+.
Example 121
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-(N-picolinoyl-L-b-tgrt- butylalanvPhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-tgrt-butylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and picolinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.098 g, 62%). MS (ESI): 502.3 (M+H)+.
Example 122
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyl1-N'-rN-(8-quinolinoyD-L-b-rgrt- butylalanyl]hydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-tgrt-butylalanine for N-tert-butoxycarbonyl-L-leucine in step (b), the title compound was prepared as a white solid (0.083 g, 46%). MS (ESI): 552.2 (M+H)+.
Example 123
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyll-N,-(N-picolinoyl-L- allylglycinyPhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-allylglycine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and picolinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.141 g, 84%). MS (ESI): 472.2 (M+H)+.
Example 124
Preparation of N-r2-(l-naphthyl)thiazoI-4-ylcarbonyll-N'-(N-picolinoyl-L-b- cyclopropylalanyPhydrazide
a) N-tgrϊ-butoxycarbonyl-L-b-cyclopropylalanine methyl ester To a stirring solution of the compound of Example 116(a) (7.81 g, 36.3 mmol) in ether (100 mL) at 0 °C was added a solution of diazometiiane (made from 10 eq of 1- methyl-3-nitro-l-nitrosoguanidine in ether (500 mL) and 40% NaOH (500 mL) at 0 °C). After stirring for 10 min., Pd(OAc)2 (0.300 g) was added to the solution. After 20 min., the solution was concentrated and the residue was filtered through a short plug of silica gel to remove unused catalyst. Concentration of the solution yielded the title compound as a golden yellow oil (8.29 g, 99%). *H NMR (400 MHz, CDC13) d 5.17 (d, IH), 4.39 (m, IH), 3.73 (s, 3H), 1.66 (t, 2H), 1.44 (s, 9H), 0.68 (m, IH), 0.49 (m, 2H), 0.08 (m, 2H).
b) N-rert-butoxycarbonyl-L-b-cyclopropylalanine Following the procedure of Example 1(g), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine methyl ester for N-(4-pyridinylmethoxycarbonyl)- L-leucine methyl ester, the title compound was prepared as a golden yellow oil (6.37 g, 82%). MS (ESI): 252.3 (M+Na)+.
c) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-cyclopropylalanyl)hydrazide Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and picolinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.114 g, 71%). MS (ESI): 486.1 (M+H)+.
Example 125
Preparation of N- rN-(6-methylnicotinoyl)-L-b-cyclopropylalany 11-N' -\2-( 1 - naphthyl)thiazol-4-ylcarbonyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 6-methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.097 g, 59%). MS (ESI): 500.1 (M+H)+.
Example 126
Preparation of N-rN-(4-methylimidazol-5-ylcarbonylVL-b-cyclopropylalanyn-N,-r2-(l- naphthyl thiazol-4-ylcarbonvnhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-cyclopropylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 4-methylimidazole-5-carboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.095 g, 59%). MS (ESI): 489.1 (M+H)+.
Example 127
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyl1-N'-rN-(8-quinolinoyl)-L-b- cyclopropylalanyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b), the title compound was prepared as a white solid (0.138 g, 78%). MS (ESI): 536.2 (M+H)+.
Example 128
Preparation of N-rN-(6-methylnicotinoyl -L-b-rgrt-butylalanyll-N'-r2-(l-naphthyl)thiazoI- 4-ylcarbonyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-tgrt-butylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 6-methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.124 g, 73%). MS (ESI): 516.1 (M+H)+.
Example 129
Preparation of N-[2-(N-cvclopropyl-N-cyclopropylmethvIamino)thiazol-4-ylcarbonyll-N'- (N-picolinoyl-L-b-tgrt-butvIalanyllhydrazide Following the procedure of Example 56(a)-56(b), except substituting N-(N-b-tert- butoxycarbonyl-L-tert-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a), the title compound was prepared as a white solid (143 mg, 83%). MS (ESI): 485.1 (M+H)+.
Example 130
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino thiazol-4-ylcarbonyll-N'- [N-(3-isoquinolinoyl -L-b-tgrt-butylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-b-tgrt- butoxycarbonyl-L-tert-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrr-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 3-isoquinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (138 mg, 85%). MS (ESI): 535.1 (M+H)+.
Example 131
Preparation of N-(N-tgrr-butoxycarbonvI-L-b-cvclopropylalanyl)-NM2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and N- tgrt-butoxycarbonyl-L-b-cyclopropylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (1.375 g, 76%). MS (ESI): 464.2 (M+H)+.
Example 132
Preparation of N-[2-(N-cyclopropylmethyl-N-propylamino thiazol-4-ylcarbonyn-N'-rN-(6- methyl-S-pyridinylmethoxycarbonvIVL-leucinyllhydrazide Following the procedure of Example 1(a)- 1(h), except substituting N-cyclopropyl propylamine for cis-2,6-dimethylmoφholine in step (a) and 6-methyl-3-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as an orange solid (84 mg, 33%). MS (ESI): 517.3 (M+H)+.
Example 133
Preparation of N-rN-(6-methylnicotinoyl -L-allylglycinyll-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-allylglycine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 6- methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared prepared as a white solid (0.097 g, 66%). MS (ESI): 486.1 (M+H)+.
Example 134
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonvπ-N'-rN-(8-quinolinoyl)-L- allylglvcinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-allylglycine for N-tert-butoxycarbonyl-L-leucine in step (b), the title compound was prepared as a white solid (0.105 g, 74%). MS (ESI): 522.1 (M+H)+.
Example 135
Preparation of N-12-(l-naphthyl thiazol-4-ylcarbonyπ-N'-rN-(2-quinolinoyl)-L-b- cyclopropylalanyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 2-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.151 g, 86%). MS (ESI): 536.3 (M+H)+. Example 136
Preparation of N-[N-(3-isoquinolinoyl)-L-b-cyclopropylalanyll-NT-r2-(l-naphthyl)thiazoI- 4-ylcarbonyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 3-isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.145 g, 82%). MS (ESI): 536.1 (M+H)+.
Example 137
Preparation of N- TN-( 1 -isoquinolinoyl)-L-b-cvclopropy lalanyll-N' - \2-( 1 -naphth vDthiazol- 4-ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-b-cyclopropylalanine for N-rgrt-butoxycarbonyl-L-leucine in step (b) and 1 -isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.143 g, 81%). MS (ESI): 536.1 (M+H)+.
Example 138
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonyll-N'-fN-(7-quinolinoyl)-L-b- cyclopropylalanyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 7-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.138 g, 78%). MS (ESI): 536.1 (M+H)+.
Example 139
Preparation of N-[2-(N-cyclopropyl-N-cyclopropylmethylamino')thiazol-4-ylcarbonyn-N'* FN-(8-quinolinoyiyL-b-cvclopropylalanyπhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrr-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 8-quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (120 mg, 73%). MS (ESI): 519.1 (M+H)+.
Example 140
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(4-methylimidazol-5-ylcarbonylVL-b-cyclopropylalanyUhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-cyclopropylalany 1)-N' - [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 4-methylimidazole-5-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (120 mg, 81%). MS (ESI):
472.1 (M+H)+.
Example 141
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyn-N'- rN-(3-isoquinolinoyl)-L-b-cvclopropylalanyπhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-y lcarbonyl]hydrazide for N- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 3-isoquinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared obtained as a white solid (140 mg, 82%). MS (ESI):
519.2 (M+H)+. Example 142
Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(6-methylnicotinoylVL-b-cvclopropylalanynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 6-methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (105 mg, 62%). MS (ESI): 483.2 (M+H)+.
Example 143
Preparation of N-rN-(4-methylimidazol-5-ylcarbonyl)-L-norleucinyl1-N'-[2-π- naphthyl)thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-terr- butoxycarbonyl-L-nbrleucine for N-rgrf-butoxycarbonyl-L-leucine in step (b) and 4- metiιylimidazole-5-carboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.112 g, 70%). MS (ESI): 491.1 (M+H)+.
Example 144
Preparation of N-f2-( 1 -naphthyl)thiazol-4-ylcarbonyll-N'-(N-picolinoyl-L- norleucinylthydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-norleucine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and picolinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.114 g, 72%). MS (ESI): 488.2 (M+H)+. Example 145
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonyn-N'-rN-(8-quinolinoyl)-L- norleucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting Η-tert- butoxycarbonyl-L-norleucine for N-tgrt-butoxycarbonyl-L-leucine in step (b), the title compound was prepared as a white solid (0.082 g, 47%). MS (ESI): 538.1 (M+H)+.
Example 146
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(2-quinolinoylVL-b-cyclopropylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrr- butoxycarbonyl-L-b-cyclopropylalany 1)-N' - [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-rgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 2-quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (150 mg, 81%). MS (ESI): 519.2 (M+H)+.
Example 147
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl1-N'- TN-( 1 -isoquinolinoyl)-L-b-cyclopropylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-fgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 1 -isoquinolinecarboxylic acid for picolinic acid in step (b), die title compound was prepared as a white solid (130 mg, 87%). MS (ESI): 519.2 (M+H)+. Example 148
Preparation of N-r2-[N-cycIopropyl-N-(2-methylpropyl aminolthiazol-4-ylcarbonyl]-N'- rN-('6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide
Following the procedure of Example 1(a)- 1(h), except substituting N-isobutyl cyclopropylamine for cis-2,6-dimethylmoφholine in step (a) and 6-methyl-3- pyridylcarbinol for 4-pyridylcarbinol in step (f)> the title compound was prepared as a white solid (220 mg, 88%). MS (ESI): 517.2 (M+H)+.
Example 149
Preparation of N-(N-tgrr-butoxycarbonyl-L-leucinyl -N'-r2-rN-cyclopropyl-N-C2- methylpropyl")aminolthiazol-4-ylcarbonyl1hvdrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and N-tgrr- butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (1.01 g, 89%). MS (ESI): 466.3 (M+H)+.
Example 150
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-(7-quinolinoyl -L-b-tgrt- butylalanyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-b-rgrt-butylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 7-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.139 g, 80%). MS (ESI): 552.2 (M+H)+.
Example 1 1
Preparation of N-f 2-( 1 -naphthyl thiazol-4-ylcarbonyll-N'-[N-(2-quinolinoyl')-L-b-tgrt- butylalanyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-b-tgrt-butylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 2-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.158 g, 91%). MS (ESI): 552.2 (M+H)+
Example 152
Preparation of N-rN-(l-isoquinolinoyIVL-b-tgrt-butylalanyπ-N'-r2-π-naphthyl)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-tgrt-butylalanine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 1 -isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.143 g, 82%). MS (ESI): 552.2 (M+H)+.
Example 153
Preparation of N-rN-(3-isoquinolinoylVL-b-tgrt-butylalanyπ-N'-f2-π-naphthyI)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-tert-butylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 3-isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.130 g, 75%). MS (ESI): 552.2 (M+H)+.
Example 154
Preparation of N- rN-(6-methylnicotinoviy L-norleucinyll-N' - \2-( 1 -naphthyl thiazol-4- ylcarbonyllhvdrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-norleucine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 6- methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.109 g, 67%). MS (ESI): 502.2 (M+H)+.
Example 155
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl -L- norleuciny 11 hydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-norleucine for N-rgrt-butoxycarbonyl-L-leucine in step (b) and 7- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.104 g, 59%). MS (ESI): 538.1 (M+H)+.
Example 156
Preparation of N- 2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-(2-quinolinoyl)-L- norleucinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-norleucine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 2- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), die title compound was prepared as a white solid (0.153 g, 87%). MS (ESI): 538.1 (M+H)+.
Example 157
Preparation of N-rN-(l-isoquinolinovD-L-norleucinyl1-N'-r2-(l-naphthyl)thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-norleucine for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 1- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.151 g, 86%). MS (ESI): 538.1 (M+H)+.
Example 158
Preparation of N- rN-(3-isoquinolinoyl)-L-norleucinyn-N' - \2-( 1 -naphthyPthiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-norleucine for N-rgrr-butoxycarbonyl-L-leucine in step (b) and 3- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.126 g, 72%). MS (ESI): 538.1 (M+H)+.
Example 159
Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino thiazol-4-vIcarbonyll-N'- rN-(5-hvdroxymethylimidazol-4-ylcarbonyl -L-b-cyclopropylalanynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cycloproρyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 5-hydroxymehylimidazole-4-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (50 mg, 44%). MS (ESI): 488.2 (M+H)+. Example 160
Preparation of N-r2-rN-cyclopropyl-N-f2-methylpropyl aminolthiazol-4-ylcarbonyll-N'- [N-(8-quinolinoyD- L-b-cyclopropylalanyllhydrazide
a) N-(N-tert-butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and N-tert- butoxycarbonyl-L-b-cyclopropylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (1.01 g, 89%). MS (ESI): 466.3 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tørt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 8-quinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (135 mg, 100%). MS (ESI): 521.2 (M+H)+.
Example 161
Preparation of N-r2-(N-cvclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyll-N'- (N-(6-methylnicotinoyI)-L-b-te -butylalanyπhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-[2-(N- cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-rgrr-butoxycarbonyl- L-b-rgrt-butylalanyl)hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 6-methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (85 mg, 79%). MS (ESI): 499.2 (M+H)+. Example 162
Preparation of N-r2-rN-cyclopropyI-N-(2-methylpropyl')aminolthiazol-4-ylcarbonyn-N'- [N-(4-methylimidazol-5-ylcarbonyD- L-b-cvclopropylalanyllhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 4-methylimidazole-5-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (100 mg, 73%). MS (ESI): 474.2 (M+H)+.
Example 163
Preparation of N-r2-rN-cvclopropyl-N-(2-methylpropyl')aminolthiazol-4-ylcarbonyn-N'- [N-(2-quinolinoyl)- L-b-cyclopropylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 2-quinolinecarboxylic acid for picolinic acid in step (b), die title compound was prepared as a white solid (75 mg, 59%). MS (ESI): 521.2 (M+H)+.
Example 164
Preparation of N-r2-rN-cyclopropyl-N-(2-methylpropyl')aminolthiazoI-4-vIcarbonyll-N'- rN-(6-methylnicotinoyl)- L-b-cyclopropylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyI-L-b-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-rgrt-butoxycarbonyl-L- leucinyl)hy drazide in step (a) and 6-methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (112 mg, 65%). MS (ESI): 485.3 (M+H)+. Example 165
Preparation of N-[2-(l-naphthyl)thiazol-4-ylcarbonyll-N'-rN-(8- quinolinoyDglycinyllhydrazide
a) N-(8-quinolinoyl)glycine
Following the procedure of Example 102(f)- 102(g), except substituting glycine methyl ester hydrochloride for L-leucine methyl ester in step (f), the title compound was prepared as a pale yellow solid (0.207 g, 95%). MS (ESI): 231.1 (M+H)+.
b) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)glycinyl]hydrazide
Following the procedure of Example 1(h), except substituting N-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(cis-2,6-dimethyl-4-moφholino)thiazol- 4-ylcarbonyl]hy drazide and N-(8-quinolinoyl)glycine for N-(4-pyridylmethoxycarbonyl)-L- leucine, the title compound was prepared as a tan solid (0.028 g, 12%). MS (ESI): 482.1 (M+H)+.
Example 166
Preparation of N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-rN-(8-quinolinoyl)-L- norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-norvaline for N-rgrt-butoxycarbonyl-L-leucine in step (b), the title compound was prepared as a white solid (0.131 g, 74%). MS (ESI): 524.1 (M+H)+.
Example 167
Preparation of N-[2-(l-naphthyl thiazol-4-ylcarbonyll-N'-rN-(2-quinolinoyl)-L- norvalinyl]hydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-norvaline for N-tert-butoxycarbonyl-L-leucine in step (b) and 2- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.135 g, 75%). MS (ESI): 524.1 (M+H)+. Example 168
Preparation of N-f2-( 1 -naphthyl")thiazol-4-ylcarbonyll-N'-(N-picolinoyl-L- norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-norvaline for N-tgrt-butoxycarbonyl-L-leucine in step (b) and picolinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.126 g, 79%). MS (ESI): 474.2 (M+H)+.
Example 169
Preparation of N-f2-( 1 -naphthyπthiazol-4-ylcarbonyll-N'-rN- 6-methylnicotinoyl VL- norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrr- butoxycarbonyl-L-norvaline for N-terr-butoxycarbonyl-L-leucine in step (b) and 6- methylnicotinic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.141 g, 85%). MS (ESI): 488.2 (M+H)+.
Example 170
Preparation of N-f2-π-naphthyDthiazol-4-ylcarbonyπ-N'-rN-(4-methylimidazol-5- ylcarbonviyL-norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tert- butoxycarbonyl-L-norvaline for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 4- methylimidazole-5-carboxylic acid for 8-quinolinecarboxylic acid in step (d), die title compound was prepared as a white solid (0.098 g, 51%). MS (ESI): 477.1 (M+H)+.
Example 171
Preparation of N-f 2-( 1 -naphthyl)thiazol-4-y lcarbonyll-N'- TN-( 1 -isoquinolinovD-L- norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-norvaline for N-tert-butoxycarbonyl-L-leucine in step (b) and 1- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the tide compound was prepared as a white solid (0.146 g, 82%). MS (ESI): 524.2 (M+H)+.
Example 172
Preparation of N-f2-( 1 -naphthyl)thiazol-4-ylcarbonyl]-N'-rN-(3-isoquinolinoyl)-L- norvalinyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-norvaline for N-tgrt-butoxycarbonyl-L-leucine in step (b) and 3- isoquinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.138 g, 78%). MS (ESI): 524.2 (M+H)+.
Example 173
Preparation of (IS. l'SVN. N'-bis-r4-[l-(N-benzyloxycarbonylaminoV3- methylbutyllthiazol-2-ylcarbonyllhvdrazide
a) N-benzyloxycarbonyl-L-leucinamide To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3 mmol) in
THF, cooled to -40 °C, was added N-methylmoφholine (3.68 g, 36.4 mmol; 4.0 mL) and isobutyl chloroformate (2.37 g, 17.3 mmol; 2.25 mL). After stirring for 15 min, ammonia was bubbled tiirough the solution for 5 min. The solution was warmed to room temperature, evaporated, and the residue was dissolved in ethyl acetate, washed with 0.1 N Hcl, and saturated brine, then dried (MgSθ4), filtered and evaporated to dryness to give the title compound as a white solid (4.58 g, 100%).
b) N-benzyloxycarbonyl-L-leucinethioamide
A solution of the compound of Example 1(a) (4.58 g, 17.3 mmol) and Lawesson's reagent (4.21 g, 10.4 mmol) in THF was allowed to stir at room temperature for 16 h. The solution was concentrated and the residue was purified by flash chromatography on 230- 400 mesh silica gel, eluting with 1 :3 EtOAc/hexanes, to provide the title compound as a pale yellow solid (3.74 g, 77%).
c) (lS)-l-benzyloxycarbonylamino-l-(4-carboethoxythiazol-2-yl)-3-methylbutane
The compound of Example 1(b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 mL), cooled to -10 °C, and ethyl bromopyruvate (1.68 g, 8.62 mmol, 1.08 mL) was added.
I l l After stirring for 1 h, the solution was poured into methylene chloride/water, then into saturated aqueous NaHCθ3. The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with saturated brine, dried (MgS04), filtered and concentrated. The residue was dissolved in methylene chloride, cooled to -20 ° C, pyridine (1.36 g, 17.2 mmol, 1.39 mL) and trifluroracetic anhydride (1.81 g, 8.62 mmol, 1.22 mL) were added. After stirring for 1 h, the solution was washed with saturated squeous NaHCθ3 and saturated brine, then dired (MgS04), filtered, and concentrated. The residue was purified by flash chromatography on 90 g of 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hexanes, to provide the title compound as a pale yellow oil (2.36 g, 80%). -1H NMR (400 MHz, CDC13) d 8.08 (s, IH), 7.38 (m, 5H), 5.42 (s, 3H), 5.23-5.07 (m, 3H), 4.42 (q, 2H), 2.01-1.62 (m, 3H), 1.41 (t, 3H), 0.99 (d, 6H).
d) (1S)-1 -benzyloxycarbonylamino- 1 -(4-hydrazinocarbonylthiazol-2-y l)-3-methy Ibutane
Following the procedure of Example 1(d), except substituting (1S)-1- benzyloxycarbonylamino- 1 -(4-carboethoxythiazol-2-yl)-3-methy Ibutane for ethyl 2-(cis- 2,6-dimethyl-4-moφholino)thiazole-4-carboxylate, the title compound was prepared as a pale yellow foam (2.01 g, 97%). 1H NMR (400 MHz, CDCI3) d 8.35 (bs, IH), 8.03 (s, IH), 7.37 (m, 5H), 5.29 (d, IH), 5.14-5.09 (m, 3H), 4.07 (bs, 2H), 1.92-1.82 (m, IH), 1.79- 1.66 (m, 2H), 1.00 (d, 6H).
e) ( 1 S)- 1 -benzyloxycarbonylamino- 1 -(4-carboxythiazol-2-yl)-3-methylbutane
Following the procedure of Example 1(g), except substituting (1S)-1- benzyloxycarbonylamino- 1 -(4-carboethoxythiazol-2-yl)-3-methy Ibutane for N-(4- pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid. MS (ESI): 349.2 (M+H)+.
f) (IS, l'S)-N, N'-bis-[4-[l-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2- ylcarbonyl]hydrazide
Following the procedure of Example 1(h), except substituting (1S)-1- benzyloxycarbonylamino- 1 -(4-hydrazinocarbony lthiazol-2-y l)-3-methylbutane for N- [2- (cis-2,6-dimethyl-4-moφholino)thiazol-4-ylcarbonyl]hydrazide and (1S)-1- benzyloxycarbonylamino- 1 -(4-carboxythiazol-2-yl)-3-methy Ibutane for N-(4- pyridylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.028 g, 59%). MS (ESI): 693.1 (M+H)+. Example 174
Preparation of N-f2-[N-cycIopropyl-N-(2-methylpropyI)aminolthiazol-4-ylcarbonyll-N'- [N-(6-methylnicotinoyl)-L-b-tgrt-butylalanvπhvdrazide
a) N-(N-tert-butoxycarbonyl-L-b-tert-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropyl isobutylamine for cis-2,6-dimethylmoφholine in step (a) and N-tgrt- butoxycarbonyl-L-b-tgrt-butylalanine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (0.44 g, 100%). MS (ESI): 482.3 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- metiiylnicotinoy l)-L-b-tgrt-butylalanyl]hy drazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-rgrr- butoxycarbonyl-L-b-tert-butylalanyl)-N' - [2- [N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 6-methylnicotinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (70 mg, 66%). MS (ESI): 501.2 (M+H)+.
Example 175
Preparation of N-r2-[N-cyclopropyl-N-(2-methylpropyl)amino1thiazol-4-ylcarbonyll-N'- rN-(4-methylimidazol-5-ylcarbonyl -L-b-tgr?-butylalanynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-rgrr- butoxycarbonyl-L-b-tgrt-butylalany 1)-N' - [2- [N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hy drazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrr-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 4-methylimidazole-5-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (70 mg, 39%). MS (ESI): 490.2 (M+H)+. Example 176
Preparation of N-f2-(N-cyclopropyl-N-cyclopropylmethylamino')thiazol-4-ylcarbonyn-N'- fN-(l-isoquinolinoyl)-L-b-tgrt-butylalanyl]hydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-tgrt-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 1 -isoquinolinecarboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (123 mg, 88%). MS (ESI): 535.3 (M+H)+.
Example 177
Preparation of N-rN-(5-butylpicolinoyl)-L-b-tgrt-butylalanyll-N'-r2-(N-cyclopropyl-N- cyclopropylmethylarnino thiazol-4-ylcarbonvπhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-tgrt-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 5-butylpicolinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (90 mg, 85%). MS (ESI): 541.3 (M+H)+.
Example 178
Preparation of N-r2-(N-cycIopropyl-N-cyclopropylmethylamino thiazoI-4-ylcarbonyl1-N'- rN-(6-methylpicolinoyl)-L-b-fgrr-butylalanyllhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- butoxycarbonyl-L-b-tgrt-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 6-methylpicolinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (170 mg, 86%). MS (ESI): 499.2 (M+H)+. Example 179
Preparation of N-r2-(N-cyclopropyl-N-cvclopropylmethylamino)thiazol-4-ylcarbonyll-N'- rN-(4-fluorobenzoyD-L-leucinyπhydrazide
Following the procedure of Example 56(a)-56(b), except substituting 4- fluorobenzoic acid for picolinic acid in step (b), the title compound was prepared as a white solid (88 mg, 97%). MS (ESI): 488.2 (M+H)+.
Example 180
Preparation of N-rN-(4-fluorobenzovO-L-leucinyl1-N'-r2-π-naphthyl thiazol-4- ylcarbonyllhydrazide
Following the procedure of Example 59(a)-59(d), except substituting 4- fluorobenzoic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.113 g, 69%). MS (ESI): 505.1 (M+H)+.
Example 181
Preparation of N-r2-(l-naphthyl)thiazol-4-ylcarbonyn-N'-rN-(2- pyridinylmethoxycarbonvI)-L-b-fgrt-butylalanvπhvdrazide
a) L-b-fgrt-butylalanine methyl ester hydrochloride To a suspension of L-b-tert-butylalanine (2.0 g, 13.8 mmol) in 2,2- dimethoxypropane (75 mL) was added concentrated hydrochloric acid (12 mL). After standing at room temperature for 16 h, the solution was concentrated, redissolved in ethyl acetate and washed with 7.5% Na2Cθ3 (2 X). The organic layer was dried (MgSθ4), filtered and concentrated to yield the free base (1.3g, 8.2 mmol). This was dissolved in etiier and HCl (8.2 mL, 1.0 M in ether) added. The white precipitate was collected by filtration yield the title compound as a white solid (1.32 g, 49%). MS (ESI): 159.7 (M+H)+. b) N-(2-pyridinylmethoxycarbonyl)-L-b-tert-butylalanine
Following the procedure of Example l(e)-5(g), except substituting L-b-tgrt- butylalanine methyl ester hydrochloride for L-leucine metiiylo ester hydrochloride in step (e) and 2-pyridylcarbinol for 4-pyridylcarbinol in step (f), the title compound was prepared as a white solid (0.55 g, 100%). MS (ESI): 281.3 (M+H)+.
c) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b-rgrr- butylalanyl]hydrazide
Following the procedure of Example 1(h), except substituting N-[2-(l- naphthyl)thiazol-4-y lcarbonyl]hydrazide for N- [2-(cis-2,6-dimethyl-4-moφholino)thiazol- 4-ylcarbonyl]hydrazide and N-(2-pyridinylmethoxycarbonyl)-L-b-tgrt-butylalanine for N- (4-pyridylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.155 g, 47%). MS (ESI): 532.2 (M+H)+.
Example 182
Preparation of N-rN-(2-methyl-3-pyridinylmethoxycarbonviyL-b-fgrf-butylalanyl1-N'-r2- ( 1 -naphthyl~)thiazol-4-ylcarbonvπhydrazide
Following the procedure of Example 181(a)- 181(c), except substituting 2-methyl-3- pyridylcarbinol for 2-pyridylcarbinol in step (b), the title compound was prepared as a white solid (0.169 g, 67%). MS (ESI): 546.2 (M+H)+.
Example 183
Preparation of N-r2-(l-naphthyl thiazol-4-ylcarbonvn-N'-rN-(2- pyridinylmethoxycarbonyπ-L-b-cyclopropylalanyl]hydrazide
a) L-b-cyclopropylalanine methyl ester hydrochloride
Following the procedure of Example 181(a), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine methyl ester for L-b-tgrt-butylalanine, the title compound was prepared as a white solid (2.2 g, 30%). MS (ESI): 144.0 (M+H)+. b) N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b- cyclopropylalanyl]hydrazide
Following the procedure of Example 181(b)-181(c), except substituting L-b- cyclopropylalanine methyl ester hydrochloride for L-b-tert-butylalanine methyl ester hydrochloride in step (b), the title compound was prepared as a white solid (0.147 g, 61%). MS (ESI): 516.1 (M+H)+.
Example 184
Preparation of N-rN-(2-methyl-3-pyridinylmethoxycarbonyl")-L-b-cyclopropylalanyl1-N'- \2-( 1 -naphthyDthiazol-4-ylcarbonyπhydrazide
Following the procedure of Example 181(a)-181(c), except substituting N-tert- butoxycarbonyl-L-b-cyclopropylalanine methyl ester for L-b-tgrt-butylalanine in step (a) and 2-methyl-3-pyridylcarbinol for 2-pyridylcarbinol in step (b), the title compound was prepared as a white solid (0.159 g, 65%). MS (ESI): 530.2 (M+H)+.
Example 185
Preparation of N-rN-(6-methyI-3-pyridinylmethoxycarbonyl -L-b-cvclopropylalanyll-N'- [2-( 1 -naphthyl thiazol-4-ylcarbony llhvdrazide
Following the procedure of Example 181(a)-181(c), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine methyl ester for L-b-tgrt-butylalanine in step (a) and 6-methyl-3-pyridylcarbinol for 2-pyridylcarbinol in step (b), the title compound was prepared as a white solid (0.169 g, 69%). MS (ESI): 530.2 (M+H)+.
Example 186
Preparation of N-rN-(6-methyl-3-pyridinylmethoxycarbonylVL-b-tert-butylalanyll-N'-r2- ( 1 -naphthyl~)thiazol-4-ylcarbonyllhvdrazide
Following the procedure of Example 181(a)-181(c), except substituting 6-methyl-3- pyridylcarbinol for 2-pyridylcarbinol in step (b), the title compound was prepared as a white solid (0.194 g, 77%). MS (ESI): 546.2 (M+H)+. Example 187
Preparation of N.N'-bis-r2-(l-naphthyl')thiazol-4-ylcarbonyllhydrazide
a) ethyl 2-(l-naphthyl)thiazole-4-carbohydrazide
Following the procedure of Example 3(a)-3(c) and 3(e), except substituting 1- naphthylboronic acid for 4-methyl-l -naphthy lboronic acid in step (e), the title compound was prepared as a pale yellow solid. MS (ESI): 270.1 (M+H)+.
a) ethyl 2-(l -naphthy l)thiazole-4-carbohy drazide
Following the procedure of Example 1(g), except substituting ethyl 2-(l- naphthyl)thiazole-4-carbohydrazide for N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a white solid. MS (ESI): 256.0 (M+H)+.
Example 188
Preparation of N-r2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyIl-N'- rN-r2-(1.8-naphthyridinoyI)l-L-b-cvclopropylalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-rerr- butoxycarbony 1-L-b-cyclopropy lalany 1)-N' - [2-(N-cy clopropy 1-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-rgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and l,8-naphthyridine-2-carboxylic acid for picolinic acid in step (b), the title compound was prepared as a white solid (100 mg, 59%). MS (ESI): 520.2 (M+H)+.
Example 189
Preparation of N-f2-rN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-ylcarbonyn-N'- rN-(3.4-difluorobenzoylV L-b-cvclopropyIalanyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tert- but(5xycarbonyl-L-b-cyclopropylalany 1)-N' - [2- [N-cyclopropyl-N-(2- methy Ipropy l)amino]thiazol-4-ylcarbonyl]hydrazide for N- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 3,4-difluorobenzoic acid for picolinic acid in step (b), the title compound was prepared as a white solid (208 mg, 100%). MS (ESI): 506.1 (M+H)+.
Example 190
Preparation of N- 2-rN-cyclopropyl-N-(2-methylpropyl)amino1thiazoI-4-ylcarbonyl1-N'- rN-(4-flluorobenzoyl)-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4- ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 4- fluorobenzoic acid for picolinic acid in step (b), the title compound was prepared as a white solid (130 mg, 70%). MS (ESI): 490.2 (M+H)+.
Example 191
Preparation of N-[N-(5-butylpicolinovD-L-leucinyH-N'-r2-(N-cvclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonynhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4- ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 5- butylpicolinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (100 mg, 63%). MS (ESI): 529.3 (M+H)+. Example 192
Preparation of N-r2-rN-cyclopropyl-N-(2-methyIpropyl)aminolthiazol-4-ylcarbonyl1-N'- [N-(3.4-dimethoxybenzoyl)-L-leucinyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4- ylcarbonyljhydrazide for N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4- ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 3,4- dimethoxybenzoic acid for picolinic acid in step (b), the title compound was prepared as a white solid (130 mg, 84%). MS (ESI): 532.2 (M+H)+.
Example 193
Preparation of N-r2-rN-cvclopropyl-N-(2-methylpropyl)aminolthiazol-4-ylcarbonyll-N'- rN-(3.4-difluorobenzoyl)-L-b-tgrr-butylalanvnhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbonyl-L-b-tgrt-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 3,4-difluorobenzoic acid for picolinic acid in step (b), the title compound was prepared as a white solid (120 mg, 78%). MS (ESI): 522.2 (M+H)+.
Example 194
Preparation of N-r2-fN-cyclopropyl-N-(2-methylpropyl)amino1thiazol-4-ylcarbonyll-N'- [N-(3.4-dimethoxybenzoyl)-L-b-tgrt-butylalanyllhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrr- butoxycarbonyl-L-b-tert-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hy drazide in step (a) and 3,4-dimethoxybenzoic acid for picolinic acid in step (b), die title compound was prepared as a white solid (73 mg, 51%). MS (ESI): 546.3 (M+H)+. Example 195
Preparation of N-rN-(5-butylpicolinoyl)-L-b-tert-butylalanyπ-N'-r2-(N-cvclopropyl-N- cyclopropylmethylamino')thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-tgrt- butoxycarbony 1-L-b-tgrt-butylalany 1)-N ' - [2- [N-cyclopropy l-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-tgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 5-butylpicolinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (120 mg, 77%). MS (ESI): 543.2 (M+H)+.
Example 196
Preparation of N-r2-fN-cyclopropyl-N-(2-methylpropyl")aminolthiazol-4-ylcarbonyll-N'- rN-(6-methylpicolinoyl -L-b-?grt-butylalanynhvdrazide
Following the procedure of Example 56(a)-56(b), except substituting N-(N-rgrt- butoxycarbonyl-L-b-tgrt-butylalanyl)-N' - [2- [N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyI]hydrazide for N-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-fgrt-butoxycarbonyl-L- leucinyl)hydrazide in step (a) and 6-methylpicolinic acid for picolinic acid in step (b), the title compound was prepared as a white solid (104 mg, 72%). MS (ESI): 501.3 (M-t-H)+.
The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incoφorated herein by reference as though fully set forth.

Claims

We claim:
1. A compound of Formula I:
wherein:
L is C2_6alkyl, Ar-C0.6alkyl, Het-C0.6alkyl, CH(R4)NR-5R6, CH(R4)Ar, CH(R4)OAr', or NR4R7;
Ar is phenyl or naphthyl; Ar' is phenyl or naphthyl;
Het is a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, said heterocyclic ring being attached at any heteroatom or carbon atom which results in a stable structure, or any bicyclic group in which any of said monocyclic heterocyclic rings is fused to a benzene ring; W is C(O), S02; X, Y, and Z are independently N, O, S or CR 1 °, provided that at least two of X, Y and Z are heteroatoms and at least one of X, Y and Z is N, or that one of X, Y and Z is C=N, C=C or N=N and the other two are CR υ or N, further provided that at least two of X, Y and Z are N;
~ indicates a single or double bond in the five-membered heterocycle; R', R1, R2, R5, R8, R9, R10, and R12 are independently H, Cχ.6alkyl, C2. galkenyl, Ar-Cø_galkyl, or Het-Cø-galkyl;
R3 is C3.6alkyl, Ar, Het, CH(Rπ)Ar, CH(Rπ)OAr, NRπR12,
R4, R11, and R15 are independently H, Cχ.6alkyl, C2-6alkenyl, C3.6cycloalkyl-
Cø-g-alkyl, Ar-Cø_6alkyl, or Het-Cø.galkyl;
R7 is Cx-galkyl, C .galkenyl, C3_6cycloalkyl-Cø_6-alkyl, Ar-Cø_6alkyl, or Het- C0.6alkyl; R6 and R13 are R14, R1 C(0), R14C(S), R14OC(0), or R14OC(0)NR9CH(R15)(CO); and
R14 is Cμgalkyl, C2_6alkenyl, Ar-Co-galkyl, or Het-Co_galkyl.
and pharmaceutically acceptable salts, hydrates and solvates thereof.
2. A compound according to Claim 1 wherein Ar is independently substituted by one or more moieties selected from the group consisting of: Ph-Cø_6alkyl, Het-Cø_galkyl, Cχ_ 6alkyl, Cμgalkoxy, OH, (CH2)ι_6NR8R9, 0(CH2)ι_ 6NR8R9, CO2R', or halogen.
3. A compound according to Claim 2 wherein Ph is independently substituted by one or more moieties selected from the group consisting of: Cj.galkyl, Cχ_ alkoxy, OH, (CH2)ι_6NR8R9, 0(CH2)χ-6NR8R9, C02R', and halogen.
4. A compound according to Claim 2 wherein two Cj.galkyl groups are combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring.
5. A compound according to Claim 1 wherein Ar' is independently substituted by one or more moieties selected from the group consisting of: Ph-Co_galkyl, Het-Cø_6alkyl, Cχ_
6alkyl, Het-C0.6alkoxy, OH, (CH2)ι_6NR8R9, 0(CH2)ι_ gNR8R9, CO2R', or halogen.
6. A compound according to Claim 5 wherein Ph is independently substituted by one or more moieties selected from the group consisting of: Cj.^alkyl, Cj.^alkoxy, OH,
(CH2)ι_6NR8R9, 0(CH2)ι_6NR8R9, C02R', and halogen.
7. A compound according to Claim 5 wherein two Cχ.galkyl groups are combined to form a 5-7 membered ring, saturated or unsaturated, fused onto die Ar' ring.
8. A compound according to Claim 1 wherein Het is independently substituted with one or two moieties selected from the group consisting of: Ph-Co_galkyl, Het-Cø_6 alkyl, Cμgalkyl, Cμ6alkoxy, Ph-C0.6alkoxy, Het-C0.6alkoxy, OH, (CH2)i-6 NR8R9, 0(CH2)i-6NR8R9, or C02R'.
9. A compound according to Claim 8 wherein Ph is independently substituted by one or more moieties selected from the group consisting of: Cj.galkyl, Cj.βalkoxy, OH, (CH2)ι_6NR8R9, 0(CH2)ι_6NR8R9, C02R', and halogen.
10. A compound according to Claim 8 wherein two Cj.galkyl groups are combined to form a 5-7 membered ring, saturated or unsaturated, fused onto die Het ring.
11. A compound according to Claim 1 wherein Het is selected from the group consisting of the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pryidazinyl, pyrimidinyl, triazinyl, tetrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isothiazolyl, isoxazolyl, moφholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamoφholinyl sulfoxide, thiamoφholinyl sulfone, thiadiazolyl, and oxadiazolyl rings.
12. A compound according to Claim 1 wherein R4 and R7 may be combined to form a 3-7 membered monocyclic or 7-10-membered bicyclic carbocyclic or heterocyclic ring.
13. A compound according to Claim 12 wherein said 3-7 membered monocyclic or 7- 10-membered bicyclic carbocyclic or heterocyclic ring is independently substituted with 1- 4 moieties selected from the group consisting of: Cj.galkyl, Ar-Co.galkyl, Het-Cø_ alkyl, Het-Co_galkoxy, OH, (CH2)ι_6NR8R9, and 0(CH2)ι_ 6NR8R9.
14. A compound according to Claim 1 wherein Z = N, X = S, and Y = CH.
15. A compound according to Claim 14 wherein R3 is further defined as:
wherein:
R^ is H or Cx.galkyl; R*7 is Cj.fjalkyl, C2_6alkenyl, °r C3-I jcycloalkyl; and R18 is C3-6alkyl, OC3_6alkyl, Ar, Het, 0(CH2)o-3Ar, or O(CH2)0.3Het.
16. A compound according to Claim 15 wherein R*° is H or Me.
17. A compound according to Claim 15 wherein R*7 is n-propyl, wø-propyl, iso- pentyl, tgrr-butylmethyl, cyclopropylmethyl, wo-butyl, n-butyl, or allyl.
18. A compound according to Claim 15 wherein R 8 is selected from the group consisting of: 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, tgrt-butoxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 4-rgrt-butoxycarbonylbenzyloxy, 4- carboxy benzyloxy, 3-tgrt-butoxycarbonylbenzyloxy, 3-carboxybenzyloxy, 2-methyl-3- pyridinylmethoxy, 6-methyl-3-pyridinylmethoxy, benzyloxy, 2-quinolino, 3-quinolino, 4- quinolino, 5-quinolino, 6-quinolino, 7-quinolino, 8-quinolino, 1-isoquinolino, 3- isoquinolino, piperidinyl, 4-methylpiperidinyl, 4-methylimidazol-5-yl, N-benzyl- pyrrolidinyl, N-methyl-pyrrolidinyl, l-benzyl-5-methylimidazol-4-yl, 1-piperazinyl; 3-(2- pyridyl)benzyl, 2-methyl-3-pyridinyl, 2-methyl-4-pyridinyl, 6-methyl-3-pyridinyl, 4- dimethylaminobenzyloxy, 4-(4-moφholinomethyl)phenyl, 5-hydroxymethylimidazol-4-yl, 5-butyl-2-pyridinyl, 4-fluorophenyl, 3,4-difluorophenyl, 2-(l,8-naphthyridinyl), or 3,4- dimethoxyphenyl.
19. A compound according to Claim 14 wherein L is selected from the group consisting of: 4-(cis-2,6-dimethyl)-4-moφholinyl, N-cyclopropylmethyl-N-(2- methylpropyl)amino, 4-methyl-l -naphthyl, N-methyl-N-(2-methylpropyl)amino, 1- naphthyl, 5-acenaphthyl, N-cyclopropyl-N-cyclopropylmethylamino, N,N-bis-(2- methylpropyl)amino, l-( 1 ,2,3,4-tetrahydroquinolino, N-cyclopropylmethyl-N-propylamino, N-(2-methy Ipropy l)-N-phenylamino, 2-methoxy-l -naphthyl, 2-benzyloxyphenyl, 2- benzyloxy-1 -naphthyl, 9-phenanthrenyl, 9-anthracenyl, phenyl, 2-(4-tgrt- butoxycarbonyl)benzyloxyphenyl, 2-(4-carboxybenzyloxy)phenyl, N-cyclopropylamino, 8- quinolino, N,N-bis-(cyclopropylmethyl)amino, 4-(2,2-dimethylaminoethoxy)- 1 -naphthyl, or 1 -(N-benzyloxycarbonylamino)-3-methylbutyl.
20. A compound according to Claim 1 selected from the group consisting of: N-[2-(cis-2,6-dimedιyl-4-moφholino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(4-methyl-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide; N-[2-[N-methyl-N-(2-medιylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(5-acenaphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[l-(l,2,3,4- tetrahydroquinolino)]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpent-4-enoyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N- (3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-metiiyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide; N-[N-(2-medιylpropyl)-N-(3-phenylphenyl)carbamoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hy drazide ;
N* 4-methyl-2-(3-phenyl)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[4-methyl-2-(3-phenyl)phenylpentanoyl]-N'-[2-[N-(2-methylpropyl)-N- pheny lamino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(2-methoxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[4-methyl-2-(3- phenyl)phenylpentanoyl]hydrazide; N-[2-(2-benzyloxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-
L-leuciny l]hy drazide ;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(9-phenantiιrenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(9-anthracenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyljhydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(-tgrt-butoxycarbonyl-L- leucinyl)ydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(L-leucinyl)]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L- leucinyl)hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyrazinecarbonyl)-
L-leucinyl]hydrazide;
N-[N,N-bis-(2-methylpropyl)carbamoyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-(2-phenylthiazol-4-ylcarbonyl)-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[2-(4-tgrt-butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[2-(4-carboxybenzyloxy)phenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-tgrt-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-
N-phenylamino]thiazol-4-ylcarbonyl]hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-tgrt- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycaronyl-L-leucinyl)-N'-[2-[2-(4-tgrt- butoxycarbonyl)benzyloxyphenyl]thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycaronyl-L-leucinyl)-N'-[2-[2-(4-carboxybenzyloxy)phenyl]thiazol-4- ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-rerr-butoxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [2- [N-methyl-N-(2-methy Ipropy l)amino]thiazol-4-y Icarbony 1]-N'- [N-(6-methy 1-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(2-medιylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-()-L- leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-leucinyl)hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(3-tgrt-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-leucinyl)hydrazide;
N-[N-(3-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-medιylpiperidinecarbonyl)-L- leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(5-quinolinoyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyl-L-prolinyl-L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(l-benzyl-5-methylimidazol-4-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(3-methylisonicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[4-methyl-2-(3-phenoxy)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(2-benzoxazolyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N,N-bis-(2-methylpropyl)amino]oxazol-4- ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [2-( 1 -naphthyl)thiazol-4-ylcarbonyl] -N' - [N-( 1 -piperazinecarbony 1)-L- leucinyl]hydrazide;
N-[4-methyl-2-(4-phenoxy)phenylpentanoyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(8-quinolinoyl)-L-leucinyl]-N'-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide; N-(N-benzyloxycarbony 1-L-leuciny 1)-N' -[2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hy drazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-L-b-tgrt-butylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[3-(2-pyridyl)phenylacetyl]-L- leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picoIinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- metiιylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- medιylisonicotinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L- leucinyl]hy drazide ;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L- leucinyl]hydrazide; N-[2-[4-(2,2-dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(7- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)- L-leucinyl]hydrazide;
N-[2-[N-bis-(cycloproρylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-methyl-L-prolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-isoleucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(4-dimethylaminomethylbenzoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-(N-benzyloxycarbonyl-L-norleucinyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(4-dimethylaminomethylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol- 4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(2-benzyloxyphenyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcaι*bonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide; N- [N- [4-(4-moφholinomethy l)benzoy 1] -L-leuciny 1] -N' - [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(2-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-b-tgrf-butoxycarbonyl-L-tgrt-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-tgrt-butylalanyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b-tgrt- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-allylglycinyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-cyclopropylalanyl)hydrazide;
N-[N-(6-methylnicotinoyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-
4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-b-tgrt-butylalanyl]-N' -[2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-b-tgrt-buty lalany l)hy drazide ;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-tgrt-butylalanyl]hydrazide; N-(N-tgrt-butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-allylglycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-b-cyclopropylalanyl]-N'[-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N- [N-( 1 -isoquinolinoyl)-L-b-cyclopropylalanyl]-N' -[2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norleucinyl)hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norleucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-tgrt-butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N- [2-( 1 -naphthyl)thiazol-4-y Icarbony 1]-N'- [N-(7-quinolinoyl)-L-b-tgrt- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b-tgrt- buty lalanyl]hy drazide ;
N-[N-(l-isoquinolinoyl)-L-b-tert-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide; N-[N-(3-isoquinolinoyl)-L-b-tgrr-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N- [N-(6-methylnicotinoy l)-L-norleucinyl]-N' - [2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-norleucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norleucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(5- hydroxymethylimidazol-4-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-(6- methylnicotinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylproρyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)glycinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)-L- norvalinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylimidazol-5-ylcarbonyl)-L- norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(l-isoquinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L-norvalinyl]hydrazide;
(IS, l'S)-N, N'-bis-[4-[l-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2- ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tgrt-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- fluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(4-fluorobenzoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N- [2-( 1 -naphthy l)thiazol-4-y Icarbony 1]-N'- [N-(2-pyridiny lmethoxycarbony l)-L-b-tgrt- butylalanyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-tgrf-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b- cyclopropylalanyljhydrazide;
N-[N-(2-medιyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-rgrt-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N,N'-bis-[2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-[2-(l,8- naphthyridinoyl)]-L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- flluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tgrr-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; and
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- medιylpicolinoyl)-L-b-tgrr-butylalanyl]hydrazide.
21. A compound according to Claim 20 which is selected from the group consisting of:
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyI)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N- [2-(4-methy 1- 1 -naphthyl)thiazol-4-ylcarbonyl]-N'- [N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide; N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide; N-[2-(5-acenaphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N- methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N- (4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[l-(l,2,3,4- tetrahydroquinolino)]thiazol-4-ylcarbonyl]hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucinyI]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- pyridinylmedιoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxy-l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-
L-leucinyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(9-phenanthrenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L- leucinyl]hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(-tgrt-butoxycarbonyl-L- leucinyl)ydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L- leucinyl)hydrazide; N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyrazinecarbonyl)-
L-leucinyl]hydrazide ;
N-[2-[2-(4-tgrt-butoxycarbonyl)frenzyloxyphenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmedιoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[2-(4-carboxybenzyloxy)phenyl]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-tgrt-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-
N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N,N-bis-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-tgrt- butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]hydrazide; N-[N-(4-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-[N-(2-methylpropyl)-N- phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N- [N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-leuciny 1]-N' - [2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-rgrt-butoxycarbonyl-L-leuciny 1)-N'- [2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-methyl-N-
(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-medιyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-()-L- leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-leucinyl)hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(3-tgrt-butoxycarbonylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-leucinyl)hydrazide;
N-[N-(3-carboxybenzyloxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)dιiazol-4-ylcarbonyl]-N'-[N-(3-quinolinoyl)-L-leucinyl]hydrazide; N-[2-( l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylpiperidinecarbonyl)-L- leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(5-quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-leucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-quinolinoyl)-L-leucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(l-benzyl-5-methylimidazol-4-ylcarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(3-methylisonicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N,N-bis-(2-methylpropyl)amino]oxazol-4- ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-methyl-N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [2-( 1 -naphthyl)thiazol-4-ylcarbonyl]-N' -[N-( 1 -piperazinecarbonyl)-L- leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-leucinyl]hydrazide; N-[N-(8-quinolinoyl)-L-leucinyl]-N'-[2-(8-quinolinyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyI]-N'-[N-(2-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-L-b-rgrt-butylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[3-(2-pyridyl)phenylacetyl]-L- leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-picolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4- ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyI-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- methylisonicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L- leucinyljhydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L- leucinyl]hydrazide; N-[2-[4-(2,2-dimethylaminoethoxy)-l-naphthyl]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-leucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(7- quinolinoyl)-L-leucinyl]hydrazide;
N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)-
L-leucinyl]hydrazide; N-[2-[N-bis-(cyclopropylmethyl)amino]thiazol-4-ylcarbonyl]-N'-(N-methyl-L-prolinyl-L- leucinyl)hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-isoleucinyl)-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norleucinyl)-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(4-dimed ylaminomethylbenzyloxycarbonyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-
4-ylcarbonyl]hydrazide;
N-(N-benzyloxycarbonyl-L-norvalinyl)-N'-[2-(2-benzyloxyphenyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide;
N-[N-[4-(4-moφholinomethyl)benzoyl]-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-leucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide; N-(N-b-tgrt-butoxycarbonyl-L-tgrt-butylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-allylglycinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N- [N-(4-methylimidazol-5-ylcarbonyl)-L-b-tgrt-buty lalany 1]-N' - [2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-tgrt-butylalanyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b-tgrt- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-allylglycinyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-b-cyclopropylalanyl)hydrazide; N-[N-(6-methylnicotinoyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide; N-[N-(4-methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l-naphthyl)thiazol-
4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide; N-[N-(6-methylnicotinoyl)-L-b-fgrr-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-f2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-
L-b-tgrt-butylalanyl)hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-(N-rgrt-butoxycarbonyl-L-b-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropylmethyl-N-propylamino)thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [N-(6-methylnicotinoyl)-L-allylglycinyl]-N' - [2-( 1 -naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-allylglycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b- cyclopropy lalanyl] hydrazide ; N-[N-(3-isoquinolinoyl)-L-b-cyclopropylalanyl]-N' [-[2-( 1 -naphthy l)thiazol-4- ylcarbonyl]hydrazide;
N-[N-( 1 -isoquinolinoyl)-L-b-cyclopropylalanyl]-N' - [2-( 1 -naphthyl)thiazol-4- ylcarbonyljhydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b- cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(3- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[N-(4-methylimidazol-5-ylcarbonyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norleucinyl)hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norleucinyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)-L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-methyl-3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-tgrt-butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2- methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-b-tgrt- butylalanyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-b-tgrt- butylalanyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-b-fgrt-butylalanyl]-N'-[2-(l-naphthyl)tiιiazol-4- ylcarbonyl]hydrazide; N-[N-(3-isoquinolinoyl)-L-b-fgrt-butylalanyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[N-(6-methylnicotinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4- ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(7-quinolinoyl)-L-norleucinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norleucinyl]hydrazide;
N-[N-(l-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(3-isoquinolinoyl)-L-norleucinyl]-N'-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(5- hydroxymethylimidazol-4-ylcarbonyl)-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(8- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-(6- methylnicotinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2- quinolinoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)- L-b-cyclopropylalanyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)glycinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(8-quinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-quinolinoyl)-L-norvalinyl]hydrazide; N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-(N-picolinoyl-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-methylnicotinoyl)-L- norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(4-methylimidazol-5-ylcarbonyl)-L- norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(l-isoquinolinoyl)-L-norvalinyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(3-isoquinolinoyl)-L-norvalinyl]hydrazide;
(IS, l'S)-N, N'-bis-[4-[l-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2- ylcarbonyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- methylnicotinoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- methylimidazol-5-ylcarbonyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(l- isoquinolinoyl)-L-b-tert-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tgrt-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(6- methylpicolinoyl)-L-b-tgrt-butylalanyl]hydrazide; N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(4- fluorobenzoyl)-L-leucinyl]hydrazide;
N-[N-(4-fluorobenzoyl)-L-leucinyl]-N'- [2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b-rgrt- butylalanyl]hydrazide; N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-tgrt-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcaτbonyl]hydrazide;
N-[2-(l-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-b- cyclopropylalanyl]hydrazide;
N-[N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-cyclopropylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-b-tgrt-butylalanyl]-N'-[2-(l- naphthyl)thiazol-4-ylcarbonyl]hydrazide; N,N'-bis-[2-(l-naphthyl)thiazol-4-ylcarbonyl]hy drazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-[2-(l,8- naphthyridinoyl)]-L-b-cyclopropylalanyl]hydrazide; N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)- L-b-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- flluorobenzoyl)-L-leucinyl]hydrazide; N-[N-(5-butylpicolinoyl)-L-leucinyl]-N'-[2-(N-cycloρropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- difluorobenzoyl)-L-b-tgrt-butylalanyl]hy drazide ;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4- dimethoxybenzoyl)-L-b-tgrt-butylalanyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-b-tgrt-butylalanyl]-N'-[2-(N-cyclopropyl-N- cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide; and N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6- medιylpicolinoyl)-L-b-tgrt-butylalanyl]hydrazide.
22. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
23. A pharmaceutical composition comprising a compound according to Claim 21 and a pharmaceutically acceptable carrier, diluent or excipient.
24. A method of inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease, comprising administering to a patient in need thereof an effective amount of a compound according to Claim 1.
25. A method of inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease, comprising administering to a patient in need thereof an effective amount of a compound according to Claim 21.
26. A method according to Claim 24 wherein said protease is a cysteine protease.
27. A method according to Claim 25 wherein said protease is a cysteine protease.
28. A method according to Claim 26 wherein said cysteine protease is cathepsin K.
29. A method according to Claim 27 wherein said cysteine protease is cathepsin K.
30. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 1.
31. A method according to Claim 30 wherein said disease is osteoporosis.
32. A method according to Claim 30 wherein said disease is periodontitis.
33. A method according to Claim 30 wherein said disease is gingivitis.
34. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to Claim 1.
35. A method according to Claim 34 wherein said disease is osteoarthritis.
36. A method according to Claim 34 wherein said disease is rheumatoid arthritis.
37. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 21.
38. A method according to Claim 37 wherein said disease is osteoporosis.
39. A method according to Claim 37 wherein said disease is periodontitis.
40. A method according to Claim 37 wherein said disease is gingivitis.
41. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to Claim 21.
42. A method according to Claim 41 wherein said disease is osteoarthritis.
43. A method according to Claim 41 wherein said disease is rheumatoid arthritis.
44. A method for preparing compounds according to Claim 1, comprising the step of reacting an intermediate:
CONHNH2
with a carboxylic acid, R3CO2H, and a peptide coupling reagent in an aprotic solvent.
45. A method according to Claim 44 wherein said peptide coupling reagent is EDCrHCl/1-HOBT when a carboxylic acid is used.
46. A method according to Claim 45 wherein said aprotic solvent is DMF.
47. A method for preparing compounds according to Claim 1, comprising the step of reacting an intermediate:
LA-r ___
X-Y with a carbamoyl chloride, R3COCl, and triethylamine in methylene chloride.
48. A method for preparing compounds according to Claim 1, comprising the step of reacting an intermediate:
LA-V CONHNH2
X-Y with a sulfonyl chloride, R3S02C1, and NMM in CH2C12.
49. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease.
50. A use according to Claim 49 wherein said protease is a cysteine protease.
51. A use according to Claim 51 wherein said cysteine protease is cathepsin K.
52. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in treating a disease characterized by bone loss.
53. A use according to Claim 52 wherein said disease is osteoporosis.
54. A use according to Claim 52 wherein said disease is periodontitis.
55. A use according to Claim 52 wherein said disease is gingivitis.
56. Use of a compound according to any one of claims 1 to 21 in d e manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation.
57. A use according to Claim 56 wherein said disease is osteoarthritis.
58. A use according to Claim 56 wherein said disease is rheumatoid arthritis.
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AU7365198A (en) 1998-11-24
HUP0001294A2 (en) 2001-04-28
BR9809333A (en) 2000-07-04
HUP0001294A3 (en) 2001-06-28
NO995268L (en) 1999-11-15
AR012622A1 (en) 2000-11-08
KR20010020391A (en) 2001-03-15
PL337725A1 (en) 2000-08-28
CO4940477A1 (en) 2000-07-24
NO995268D0 (en) 1999-10-28
EP1019046A4 (en) 2002-11-27

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