EP1212306A2 - HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b) - Google Patents

HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)

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Publication number
EP1212306A2
EP1212306A2 EP00963374A EP00963374A EP1212306A2 EP 1212306 A2 EP1212306 A2 EP 1212306A2 EP 00963374 A EP00963374 A EP 00963374A EP 00963374 A EP00963374 A EP 00963374A EP 1212306 A2 EP1212306 A2 EP 1212306A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
substituted
methyl
alkyl
occurrence
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Withdrawn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
EP00963374A
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German (de)
English (en)
Inventor
Richard Eric Olson
Hong Liu
Lorin Andrew Thompson, Iii
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.)
Bristol Myers Squibb Pharma Co
Original Assignee
Bristol Myers Squibb Co
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Filing date
Publication date
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Publication of EP1212306A2 publication Critical patent/EP1212306A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Definitions

  • This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of A ⁇ -peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to ⁇ -amyloid production such as Alzheimer's disease and Down's Syndrome.
  • AD Alzheimer's disease
  • AD is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability.
  • AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States.
  • AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta) -protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373- 403) .
  • a ⁇ ⁇ - amyloid peptide
  • a ⁇ ⁇ /A4
  • a ⁇ venules .
  • a ⁇ was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys . Res. Commun. 120: 885-890).
  • a ⁇ is an internal polypeptide derived from a type 1 integral membrane protein, termed ⁇ amyloid precursor protein (APP) .
  • APP amyloid precursor protein
  • ⁇ APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans.
  • a ⁇ is derived from cleavage of ⁇ APP by as yet unknown enzyme (protease) system(s), collectively termed secretases .
  • proteolytic activities include ⁇ secretase (s) , generating the N-terminus of A ⁇ , ⁇ secretase (s) cleaving around the 16/17 peptide bond in A ⁇ , and ⁇ secretases, generating C-terminal A ⁇ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
  • missense DNA mutations at position 717 in the 770 isoform of ⁇ APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD.
  • ⁇ APP mutations have been described in familiar forms of AD.
  • similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human ⁇ APP.
  • individuals with Down's syndrome have an increased gene dosage of ⁇ APP and develop early-onset AD.
  • One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of A ⁇ protein or pharmaceutically acceptable salts or prodrugs thereof.
  • It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form or prodrug form thereof .
  • the present invention provides a novel compound of Formula (I):
  • Q 1 is C ⁇ -C 8 alkyl substituted with 0-3 R la ; C 2 -C 8 alkenyl substituted with 0-3 R la ; C 2 -C 8 alkynyl substituted with 0-3 R la ; C 3 -C 10 cycloalkyl substituted with 0-3 R lb ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C 6 -C 10 aryl substituted with 0-3 R lb ; or
  • 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R la is independently selected from H, C 1 -C 6 alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; c 3 ⁇ Cio carbocycle substituted with 0-3 R lb ; C 6 -C 10 aryl substituted with 0-3 R lb ; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 2 is H, methyl, ethyl, propyl, or butyl
  • R 5 is H, OR 14 ;
  • 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R 5c ;
  • R 5a is H, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl
  • R 5 and R 5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5c ; optionally the cycloalkyl ring formed by combining R 5 and R 5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R 5c ;
  • R 6 is H or C 1 -C 6 alkyl
  • W is -(CR 8 R 8a ) p -;
  • p 0, 1, 2, 3, or 4;
  • R 8 and R 8a are independently selected from H, F, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C -C 4 alkynyl and C 3 -C 8 cycloalkyl;
  • X is a bond
  • Y is a bond or - (CR 9 R 9a ) t -V- (CR 9 R 9a ) u - ;
  • t 0, 1, 2, or 3;
  • u 0, 1, 2, or 3;
  • R 9 and R 9a are independently selected from H, F, Ci-Cg alkyl or C 3 -C 8 cycloalkyl;
  • Z is H; C ⁇ -C 8 alkyl substituted with 0-2 R 12 '
  • R 11 substituents on adjacent atoms may be combined to form C 3 -C 6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S; wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R 13 ;
  • R 13 at each occurrence, is independently selected from H, OH, C ⁇ -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 2 ,
  • R 14 is independently selected from H, phenyl, benzyl, C 1 -C 6 alkyl, and C 2 -C 6 alkoxyalkyl;
  • R 14a is H, phenyl, benzyl, or C ⁇ -C 6 alkyl
  • R 17 is H, Ci-C ⁇ alkyl, or C 2 -C 6 alkoxyalkyl, aryl substituted by 0-4 R 17a , or aryl-CH 2 - wherein said aryl is substituted by by 0-4
  • -NR 17 R 18 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
  • R 19b is independently selected from H and Ci-C ⁇ alkyl
  • R 20 is H, OH, C 1 -C 4 alkyl, phenyl, benzyl, or phenethyl;
  • R 21 at each occurrence, is independently selected from H, C ⁇ -C 6 alkyl, phenyl, benzyl, and phenethyl; and R 22 , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, phenyl, benzyl, and phenethyl.
  • Q 1 is Ci-Ce alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R la ; C 3 -C 10 cycloalkyl substituted with 0-3 R lb ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C ⁇ -Cio aryl substituted with 0-3 R lb ; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 2 is H, methyl, ethyl, propyl, or butyl
  • R 5 is H, OR 14 ;
  • R 5a is H, C 1 -C 4 alkyl, or C 2 -C alkenyl
  • R 5 and R 5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5c ;
  • R 5b at each occurrence, is independently selected from:
  • 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;
  • R 6 is H, methyl, or ethyl
  • W is - (CR 8 R 8a ) p -;
  • p 0, 1, or 2;
  • R 8 and R 8a are independently selected from H, F, methyl, and ethyl;
  • X is a bond; phenyl substituted with 0-3 R xb ;
  • Y is a bond or - (CR 9 R 9a ) t -V- (CR 9 R 9a ) u -;
  • t 0, 1, or 2;
  • R 9 and R 9a are independently selected from H, F, methyl, and ethyl;
  • Z is H, halo
  • R 11 substituents on adjacent atoms may be combined to form C 3 -C 6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, 0, and S; wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R 13 ;
  • R 12 at each occurrence is independently selected from H,
  • R 13 at each occurrence, is independently selected from H, OH, C ⁇ -C 6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 , and CF 3 ;
  • R 14 at each occurrence, is independently selected from H, phenyl, benzyl, Ci-Cg alkyl, and C 2 -C 6 alkoxyalkyl;
  • -NR 15 R 16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
  • R 17 is H, aryl, aryl-CH 2 -, Ci-C ⁇ alkyl, or C -C 6 alkoxyalkyl ;
  • -NR 17 R 18 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
  • R 20 is H, OH, C 1 -C 4 alkyl, phenyl, benzyl, or phenethyl;
  • R 21 at each occurrence, is independently selected from H, Ci-Ce alkyl, phenyl, benzyl, and phenethyl;
  • R 22 at each occurrence, is independently selected from H, C]_-C 6 alkyl, phenyl, benzyl, and phenethyl.
  • each benzo fused radical is substituted with 0-3 R 13 .
  • Q 1 is Ci-C ⁇ alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R la ; C 3 -C 10 cycloalkyl substituted with 0-3 R lb ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C ⁇ -Cio aryl substituted with 0-3 R lb ; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R la at each occurrence, is independently selected from H, Ci-C ⁇ alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C 6 -C 10 aryl substituted with 0-3 R lb ; and
  • 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 2 is H, methyl, or ethyl
  • R 5 is H, OR 14 ;
  • 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R 5c ;
  • R 5a is H, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl
  • R 5 and R 5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5c ;
  • W is -(CR 8 R 8a ) p - ;
  • p 0, 1, or 2;
  • R 8 and R 8a are independently selected from H, F, methyl, and ethyl;
  • X is a bond; phenyl substituted with 0-3 R xb ;
  • Y is a bond or - (CR 9 R 9a ) t -V- (CR 9 R 9a ) u -; t is 0, 1, or 2 ;
  • u 0, 1, or 2;
  • R 9 and R 9a are independently selected from H, F, methyl, and ethyl;
  • Z is H, halo
  • Ring B is selected from:
  • R 12 at each occurrence is independently selected from H,
  • R 13 at each occurrence, is independently selected from H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 , NR 15 R 16 and CF 3 ;
  • R 14 at each occurrence, is independently selected from H, phenyl, benzyl, C ⁇ -C 6 alkyl, and C 2 -C 6 alkoxyalkyl;
  • -NR 15 R 16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
  • R 17 is H, aryl, aryl-CH 2 -, C 1 -C 6 alkyl, or C 2 ⁇ C 6 alkoxyalkyl ;
  • -NR 18 R 19 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and
  • R 20 is H, OH, C 1 -C 4 alkyl, phenyl, benzyl, or phenethyl.
  • Ring B is selected from:
  • Q is Q 1 or (C 1 -C 3 alkyl) -O-Q 1 ;
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R l ; C 3 -C 10 cycloalkyl substituted with 0-3 R lb ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C 6 -C 10 aryl substituted with 0-3 R lb ; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R la at each occurrence, is independently selected from H, C ⁇ -C 6 alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; C 3 -C 10 carbocycle substituted with 0-3 R lb ; C ⁇ -Cio aryl substituted with 0-3 R lb ; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 2 is H, methyl, or ethyl
  • R 5 is H, OR 14 ;
  • R 5a is H, C 1 -C 4 alkyl, or C 2 -C alkenyl; alternatively, R 5 and R 5a may be combined to form a C 4 ⁇ C 7 cycloalkyl ring;
  • W is -(CR 8 R 8a ) p -;
  • p 0, 1, or 2;
  • R 8 and R 8a are independently selected from H, methyl, and ethyl;
  • X is a bond; phenyl substituted with 0-3 R xb ;
  • Y is a bond or - (CR 9 R 9a ) -V- (CR 9 R 9a ) u - ;
  • t 0, 1, or 2;
  • u 0, 1, or 2;
  • R 9 and R 9a are independently selected from H, F, methyl, and ethyl;
  • Z is H, F, Cl, Br
  • R 12 at each occurrence is independently selected from H,
  • R 13 at each occurrence, is independently selected from H, OH, Ci-Ce alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 , and CF 3 ;
  • R 14 at each occurrence, is independently selected from H, phenyl, benzyl, C ⁇ -C 6 alkyl, and C 2 -C 6 alkoxyalkyl;
  • -NR 15 R 16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and
  • R 17 is H, aryl, aryl-CH 2 -, Ci-C ⁇ alkyl, or C 2 -C 6 alkoxyalkyl ;
  • -NR 18 R 19 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and
  • R 19 is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl .
  • Q is Q 1 ;
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R l ; C -C ⁇ alkynyl substituted with 0-3 R la ;
  • R la at each occurrence, is independently selected from H, Ci-C ⁇ alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; c 3 ⁇ C ⁇ o carbocycle substituted with 0-3 R lb ; C 6 "C ⁇ o aryl substituted with 0-3 R lb ; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 2 is H, methyl, or ethyl
  • R5 is H, OR 14 ;
  • R 5a is H, methyl, ethyl, propyl, butyl, or C -C 4 alkenyl
  • R 5 and R 5a may be combined to form a C 4 -C- 7 cycloalkyl ring
  • R 5b at each occurrence, is independently selected from:
  • I, 0, NR 15 R 16 , C 3 -C cycloalkyl substituted with 0-3 R 5c ; C 3 -C 7 carbocycle substituted with 0-3 R 5c ; phenyl substituted with 0-3 R 5c ; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5c ;
  • W is -(CHR 8 ) p -;
  • p is 0 or 1;
  • R 8 is H, methyl, or ethyl
  • X is a bond
  • phenyl substituted with 0-2 R xb C 5 -C 6 cycloalkyl substituted with 0-3 R xb ; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 R xb ;
  • Y is a bond, -V- , -CH 2 -V-, -V-CH 2 -, or -CH 2 -V-CH 2 -;
  • Z is H, F, Cl, Br, C 1 -C 4 alkyl substituted with 0-2 R 12 --
  • R 12 at each occurrence is independently selected from H,
  • R 13 at each occurrence, is independently selected from H, OH, Ci-Ce alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 , and CF 3 ;
  • R 14 at each occurrence, is independently selected from H, phenyl, benzyl, C 1 -C 4 alkyl, and C 2 -C 4 alkoxyalkyl;
  • R 15 is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl ;
  • R 17 is H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;
  • R 18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R 19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl.
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R la ; C 3 -C 6 cycloalkyl substituted with 0-3 R lb ; phenyl substituted with 0-3 R lb ; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R lb ;
  • R la at each occurrence, is independently selected from
  • R 2 is H or methyl ;
  • R 5 is H, OR 14 ;
  • R 5a is H, methyl, ethyl, propyl, or butyl
  • R 5 and R 5a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring;
  • R 5b at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F,
  • 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5c ; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
  • W is a bond, -CH 2 -, or -CH(CH 3 )-;
  • X is a bond; phenyl substituted with 0-1 R xb ; C 5 -C 6 cycloalkyl substituted with 0-1 R xb ; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 R xb ; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl;
  • Y is a bond, -V-, -V-CH 2 -, or -CH 2 V-;
  • Z is H, F, Cl, Br,
  • R llb at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C ⁇ -C 2 haloalkoxy;
  • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 12b ;
  • R 1 b at each occurrence, is independently selected from
  • R 13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 15 R 16 , and CF 3 ;
  • R 14 is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
  • R 15 is independently selected from H, methyl, ethyl, propyl, or butyl;
  • R 16 is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
  • R 18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and R 19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl .
  • Q is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 ,
  • benzyl-CH(NH 2 ) -, benzyl-CH (NHC ( 0) -O-tBu) -, benzyloxy-CH 2 - , pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-;
  • R 2 is H or methyl
  • R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH (CH 3 ) CH 2 CH 2 CH 3 , -CH 2 CH (CH 3 ) CH 2 CH 3 , -CH 2 CH (CH 3 ) CH 2 CH 3 , -CH 2 CH 2 CH(CH3)2, -CH (CH 2 CH 3 ) 2 ,
  • phenyl-CH 2 - (2-F-phenyl) CH -, (3-F-phenyl) CH 2 -, (4-F-phenyl)CH 2 -, (3 , 5-diF-phenyl) CH 2 - , 2-furanyl-CH - ,
  • phenyl-CH 2 CH 2 - (2-F-phenyl) CH 2 CH 2 - , (3-F-phenyl) CH 2 CH 2 -, (4-F-phenyl)CH 2 CH 2 -, furanyl-CH 2 CH 2 -, thienyl-CH 2 CH 2 -, pyridyl-CH2CH 2 -, l-imidazolyl-CH 2 CH 2 - , oxazolyl-CH 2 CH 2 -, isoxazolyl-CH CH 2 -;
  • R 5a is H
  • R 5 and R 5a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl;
  • W is a bond, -CH 2 -, or -CH(CH 3 )-;
  • X is a bond
  • Y is a bond, -CH 2 -V-, -V- , or -V-CH 2 -;
  • Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl,
  • phenyl-CH 2 CH 2 - (phenyl) 2 CHCH 2 -, (2-F-phenyl) CH 2 CH 2 -, (3 -F-phenyl ) CH 2 CH 2 - , ( 4-F-phenyl ) CH 2 CH 2 - , ( 2 -Cl-phenyl ) CH 2 CH 2 - , (3 -Cl-phenyl ) CH 2 CH 2 - , ( 4-Cl-phenyl )CH 2 CH 2 -, (2 , 3-diF-phenyl) CH 2 CH 2 -, (2,4-diF-phenyl) CH 2 CH 2 - , (2 , 5-diF-phenyl ) CH 2 CH 2 - , (2,6-diF-phenyl ) CH 2 CH 2 - , (3,4-diF-phenyl ) CH 2 CH 2 - , (3,5-diF-phenyl ) CH 2 CH 2 - , (2,
  • R 11 is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, eyelohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 - phenyl, 4-MeO-phenyl-, 4-CF
  • R 13 at each occurrence, is independently selected from H, MeO, F, and Cl .
  • the present invention provides a compound of Formula of Formula (Ic) ;
  • the present invention provides a compound of Formula (Id);
  • the present invention provides a compound selected from:
  • the present invention provides a compound of Formula (I) wherein the stereochemistry of carbon 3 in lactam ring B is of the S configuration .
  • the present invention provides a compound of Formula (I) wherein the stereochemistry of carbon 3 in lactam ring B is of the R configuration .
  • Ring B is selected from:
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C ⁇ alkenyl substituted with 0-3 R la ; C -C 6 alkynyl substituted with 0-3 R la ; C 3 -C10 cycloalkyl substituted with 0-3 R lb ; C 3 -C10 carbocycle substituted with 0-3 R lb ; C6 _ C ⁇ o aryl substituted with 0-3 R lb ; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R la is independently selected from H, C ⁇ -C 6 alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; C3-C1 0 carbocycle substituted with 0-3 R lb ; C6-C10 aryl substituted with 0-3 R lb ; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R lb ;
  • R 5 is OR 14 ;
  • R 5a is H, methyl, ethyl, propyl, butyl, or C2-C4 alkenyl
  • R 5 and R 5a may be combined to form a C4-C 7 cycloalkyl ring
  • R 5b at each occurrence, is independently selected from:
  • I, 0, NR 15 R 16 , C3-C7 cycloalkyl substituted with 0-3 R 5c ; C3-C- 7 carbocycle substituted with 0-3 R 5c ; phenyl substituted with 0-3 R 5c ; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5c ;
  • p is 0 or 1 ;
  • R 8 is H, methyl, or ethyl
  • X is a bond; phenyl substituted with 0-2 R xb ; C 5 -C 6 cycloalkyl substituted with 0-3 R xb ; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 R xb ;
  • Y is a bond, -V- , -CH 2 -V-, -V-CH 2 -, or -CH 2 -V-CH 2 -;
  • Z is H, F, Cl, Br,
  • C3-C6 carbocycle substituted with 0-3 R llb or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R llb ; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl , thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
  • R 12 at each occurrence, is independently selected from H,
  • R 13 at each occurrence, is independently selected from H, OH, C ⁇ -C 6 alkyl, C 3. -C 4 alkoxy, Cl, F, Br, I, CN, N0 2 , NR 15 R 16 and CF3 .
  • R 14 at each occurrence, is independently selected from H, phenyl, benzyl, C 1 -C 4 alkyl, and C 2 -C 4 alkoxyalkyl;
  • R 15 is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl ;
  • R 17 is H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;
  • R 18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl ;
  • R 19 is independently selected from H, OH, methyl, ethyl, propyl, and butyl.
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R la ; C 3 -C 6 cycloalkyl substituted with 0-3 R lb ; phenyl substituted with 0-3 R lb ; or
  • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R lb ;
  • R la at each occurrence, is independently selected from
  • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R lb ;
  • R 5 is OR 14 ; C 1 -C 4 alkyl substituted with 0-1 R 5b ;
  • R a is H, methyl, ethyl, propyl, or butyl
  • R 5 and R 5a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring;
  • R 5b at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F,
  • 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5c ; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
  • W is a bond, -CH 2 -, or -CH(CH 3 )-;
  • X is a bond; phenyl substituted with 0-1 R xb ; C 5 -C 6 cycloalkyl substituted with 0-1 R xb ; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 R xb ; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl;
  • R xb at each occurrence, is independently selected from
  • Y is a bond, -V-, -V-CH 2 -, or -CH 2 V- ;
  • Z is H, F, Cl, Br, C 1 -C 4 alkyl substituted with 0-2 R 12 - '
  • R 11 at each occurrence, is independently selected from H , NR 18 R 19 , CF 3 ;
  • R llb at each occurrence, is independently selected from H,
  • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 12b ;
  • R 12b is independently selected from
  • R 13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 15 R 15 , and CF 3 ;
  • R 14 is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
  • R 15 is independently selected from H, methyl, ethyl, propyl, or butyl;
  • R 16 is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
  • R 18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and R 19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl .
  • Q 1 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 ,
  • benzyl-CH(NH 2 ) -, benzyl-CH (NHC ( 0) -O-tBu) -, benzyloxy-CH 2 -, pyrrolidin-2-yl- , or 3-t-butoxycarbonylpyrrolidin-2-y1- ;
  • phenyl-CH 2 - (2-F-phenyl) CH 2 - , (3-F-phenyl) CH 2 -, (4-F-phenyl )CH 2 -, (3 , 5-diF-phenyl) CH -, 2-furanyl-CH 2 - , 3-furanyl-CH 2 -, 2-thienyl-CH 2 - , 3-thienyl-CH 2 - , 2-pyridyl-CH 2 -, 3 -pyridyl-CH 2 - ,
  • phenyl-CH 2 CH 2 - (2-F-phenyl) CH 2 CH 2 -, (3-F-phenyl) CH 2 CH 2 -, (4-F-phenyl )CH 2 CH 2 -, furanyl-CH 2 CH 2 -, thienyl-CH 2 CH 2 -, pyridyl-CH 2 CH -, l-imidazolyl-CH 2 CH 2 -, oxazolyl-CH 2 CH 2 - , isoxazolyl-CH2CH2- ;
  • R 5a is H
  • R 5 and R 5a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl;
  • W is a bond, -CH 2 -, or -CH(CH 3 )-;
  • X is a bond;
  • Y is a bond, -CH 2 -V-, -V- , or -V-CH 2 -;
  • Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl,
  • phenyl-CH 2 CH 2 - (phenyl) 2 CHCH 2 - , (2-F-phenyl) CH 2 CH 2 -, (3-F-phenyl) CH 2 CH 2 -, (4-F-phenyl) CH 2 CH 2 - , (2-Cl-phenyl ) CH 2 CH 2 - , (3 -Cl-phenyl ) CH 2 CH 2 - , (4-Cl-phenyl ) CH 2 CH - , (2,3-diF-phenyl ) CH 2 CH 2 - , (2 , 4-diF-phenyl ) CH 2 CH 2 - , (2 , 5-diF-phenyl) CH 2 CH 2 - , (2, 6-diF-phenyl )CH 2 CH 2 -, (3 , 4-diF-phenyl) CH 2 CH -, (3, 5-diF-phenyl )CH 2 CH 2 -, (2 , 3 -diCl-phen
  • R 11 is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, eye1opentylmethy1, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, eyelohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 - phenyl, 4-MeO-phenyl-,
  • R 13 at each occurrence, is independently selected from H, MeO, F, and Cl .
  • the present invention provides a compound of Formula (If) ;
  • the present invention provides a compound of Formula (Ig);
  • the present invention provides all herein disclosed embodiments with the proviso that when R 5 and R 5a are not simultaneaously H.
  • the present invention provides all herein disclosed embodiments with the proviso that when Q is a 9 membered benzofused heterocyclic group substituted by 0 , 1, or 2 R la , then R 3 is H. In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when - XYZ is a tertiary butyl group and R 5 is either C 1 -C 4 alkyl or C 2 alkenyl, then Q is not phenyl substituted by 0, 1 or 2 R la .
  • the present invention provides all herein disclosed embodiments with the proviso that when R 5 is C 1 -C 3 alkyl, then Q is not phenyl substituted by 0 , 1 or 2 R la .
  • OH O of Formula (I), et seq. is not a Ci-Cs alkyl, C 2 -Cs alkenyl, C 2 -Cs alkynyl, C 3 -C 10 cycloalkyl-C ⁇ -C 4 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 4 alkyl-0-C ⁇ -C 4 alkyl, C1-C 4 alkyl-S-C ⁇ -C 4 alkyl, C 2 -C alkyl-NR 20 -C 2 -C alkyl, C -C 4 alkyl-C 6 -C ⁇ 0 aryl, C 2 -C 4 alkyl-C ⁇ -Cio cycloalkyl, C 2 -Cs alkenyl, C 6 -C ⁇ 0 aryl-C ⁇ C 4 alkyl, C ⁇ -Cio aryl-C 2 -C 4 -alkynyl, indol-3-yl
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the present invention provides a method for the treatment of a neurological disorder associated with ⁇ -amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I) •
  • the neurological disorder associated with ⁇ -amyloid production is Alzheimer's Disease .
  • the present invention provides a method for inhibiting ⁇ -secretase activity for the treatment of a physiological disorder associated with inhibiting ⁇ -secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits ⁇ -secretase activity.
  • the physiological disorder associated with inhibiting ⁇ -secretase activity is Alzheimer's Disease.
  • the present invention provides a compound of Formula (I) for use in therapy.
  • the present invention provides a compound of Formula (I) for use in therapy of Alzheimer's Disease.
  • the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer's Disease.
  • a ⁇ denotes the protein designated A ⁇ , ⁇ -amyloid peptide, and sometimes ⁇ /A4, in the art.
  • a ⁇ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules .
  • the isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
  • the 43 amino acid sequence is : 1
  • APP refers to the protein known in the art as ⁇ amyloid precursor protein. This protein is the precursor for A ⁇ and through the activity of "secretase” enzymes, as used herein, it is processed into A ⁇ . Differing secretase enzymes, known in the art, have been designated ⁇ secretase, generating the N- erminus of A ⁇ , ⁇ secretase cleaving around the 16/17 peptide bond in A ⁇ , and " ⁇ secretases”, as used herein, generating C- terminal A ⁇ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides
  • the compounds herein described may have asymmetric centers.
  • any variable e.g., R la , R a , R 13 etc.
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R la e.g., R la , R a , R 13 etc.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-C ⁇ alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl .
  • alkyl group is "C1-C 4 alkyl” wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl, are specifically preferred.
  • C 1 -C 3 alkyl whether a terminal substituent or a alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain.
  • C 2 -C 6 alkenyl examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2- pentenyl, 3-pentenyl, hexenyl, and the like.
  • alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, and the like.
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge .
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • alkylthio or “thioalkoxy” is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge .
  • Halo or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro.
  • Counteririon is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl , pentachloroethyl, 2 , 2 , 2-trifluoroethyl , 2 , 2-difluoroethyl, heptafluoropropyl, and heptachloropropyl .
  • Haloalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2- trifluoroethoxy, and the like.
  • Halothioalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge .
  • Cycloalkyl is intended to include saturated ring groups, having the specified number of carbon atoms. For example, "C 3 -C 6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Carbocycle is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13 -membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin) , [2.2.2 ] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
  • C 3 -C 10 carbocycle or "C 3 -C 6 carbocycle” is C 3 - CQ cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heterocycle or “heterocyclic ring” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2 , or 3 heteroatoms, independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1 , 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl , 6H-1, 2 , 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,
  • Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl , thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, isoxazolidinyl , benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl .
  • Preferred 5 to 7 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 7 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, and tetrazolyl.
  • Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; Also included are fused ring and containing, for example, the above heterocycles .
  • aryl As used herein, the term "aryl”, “C 6 -C 10 aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl.
  • additional lactam carbons is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I) .
  • Formula (la) is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I) .
  • lactam ring B represents the lactam ring B of Formula (I) .
  • Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula.
  • the additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur.
  • Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven.
  • lactam ring B include:
  • lactam ring B are Bl , B2 , B5 , B6, B8 , B9 , B13, and B16; more preferred examples of lactam ring B are Bl, B6, B8, B9 , and B13.
  • Preferred examples of substituent R 10 or R 11 on lactam B are methyl, ethyl, phenyl, 4- fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4- fluorophenyl) methyl, (4-chlorophenyl) methyl , and (4- trifluorophenyl) methyl .
  • substituent R 13 on fused rings of lactam B are methyl, fluoro, and chloro.
  • the compounds herein described may have asymmetric centers.
  • One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer.
  • carbon 3 of lactam ring B Formula (I") may exist in either an S or R configuration.
  • an R or S configuration at carbon 3 in Formula (I") is considered part of the invention.
  • An example of such configuration includes,
  • the carbon atoms to which the OH and R 5 are attached may describe chiral carbons which may display superior biiological activity over the opposite enantiomer.
  • Q and R 5 are not H
  • the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • Aldol derivatives can be prepared by the procedure of Evans (D. A. Evans et al, Org . Synth . 1990, 68, 83-90), which is outlined in Scheme 1 where acylation of an oxazolidinone with an acid chloride provides structure 2. Asymmetric aldol reaction to form 3_ followed by cleavage of the chiral auxiliary yielding ⁇ -hydroxycarboxylic acid 4. Additional examples are found in D. A. Evans Aldrichimica Acta 1982, 15, 23-32. Alternative syntheses of structures 4 can be accomplished by the methods of Crimmins ( M. T. Crimmins et al, J. Am . Chem . Soc .
  • Anti-aldols may be synthesized according to: (a) A. K. Ghosh, J. Am. Chem. Soc. 1996, 118, 2527-2528, or (b) S. Masamune et al . , J. Am. Chem. Soc. 1997, 119, 2586.
  • Carboxylic acids of formula 4 can be coupled to anappropriate lactam intermediate using methods commonly used in peptide syntheses, such as DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU and phenyl ester mediated coupling, as described in A. R. Chamberlin, Chem . Rev. 1997, 91, 2243- 2266.
  • Compound 6 is synthesized, as illustrated in Scheme 2, by coupling acid 4 with 3-amino-l, 4-benzodiazepin-2-one 5 under the catalysis of EDC and HOBt providing the final compound 6 (S. Nozaki et al, Bull . Chem . Soc . Jpn . 1982, 55, 2165-2168) .
  • aldehyde Q-CHO with general structure of 9 is shown in Scheme 3 (H. C. Arndt, Synthesis 1979, 202-204) .
  • Allyl ether 8 can be made from the action of an alkoxide generated in DMF with allyl bromide, which is converted to ⁇ -alkoxy- or aryloxyaldehyde 9 using a two- phase osmium tetraoxide oxidation.
  • aldehyde Q-CHO of general structure 12 can be prepared in the same fashion from the corresponding allyl benzyl ether, which is readily available according to the procedure described by P. Kocienski (P. Kocienski Tetrahedron 1990, 46, 1767-1782) .
  • the aldehydes used in Scheme 1 are either commercially available, prepared from commercially available or readily accessible alcohols, or prepared from commercially available or readily accessible carboxylic acids.
  • a inoaldehydes used in the synthesis of the compounds of the invention may be prepared by oxidation of corresponding amino alcohols or reduction of corresponding amino acids; see (a) J. Jurczak et al . , Synlett 1993, 241; and (b) S. G. Davis et al . , Synlett 1995, 700.
  • Sulfur containing aldehydes used in the synthesis of compounds of the invention may be made by conjugate addition of a thiol to ⁇ , ⁇ -unsaturated aldehydes or reaction of a thiol with a halosubstituted aldehyde. See T. Cohen et al . , J. Org. Chem . 1995, 60, 2022; Tetrahdron
  • Sulfoxides and sulfones are prepared from the corresponding sulfide by oxidation. See M. Hudlicky,
  • Examples Chemical abbreviations used in the Examples are defined as follows: "DMPU” for 1, 3-dimethyl-3 , 4, 5 , 6- tetrahydro-2 (IH) -pyrimidone; "TBTU” for O- (lH-benzotriazol- 1-yl) -N,N,N' , N' -tetramethyluronium tetrafluoroborate; "BOP” for benzotriazol-1-yloxytris-dimethylamino) - phosphonium hexafluorophosphate; "Bu 2 BOTf” for dibutylboron triflate; "EDC” for 1- [3- (dimethylamine) propyl] -3- ethylcarbodiimide hydrochloride; "HOBt” for 1- hydroxybenzotriazole; and "TEA” for triethylamine.
  • DMPU for 1, 3-dimethyl-3 , 4, 5 , 6- tetrahydro-2 (I
  • HPLC is an abbreviation used herein for high pressure liquid chromatography.
  • Compounds of the present invention are generally purified by HPLC using conditions known to one skilled in the art. However, unless otherwise indicated, the following conditions are generally applicable.
  • Reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 100 % buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid).
  • buffer A water containing 0.1% trifluoroacetic acid
  • buffer B 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid
  • reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 90 % acetonitrile in water.
  • Example 1 3- (2 (J?) -Cyclopentylmethyl-3 ( S) -hydroxyl-1-oxo-5- phenylpentyl ) amino-1-methyl- 5-phenyl-2 , 3-dihydro-lH-l, 4- benzodiazepin-2-one .
  • the reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 10°C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary evaporator. The resulting slurry was extracted with three 20 mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 2-135 The general procedure for Example 1 was followed using the corresponding acid chloride, aldehyde, and substituted benzodiazepine, azepane or bisbenzodiazepine. Starting materials were either commercially available or prepared by methods known to one skilled in the art.
  • Example 2. 3- (2 (R) -Cyclopentylmethyl-3 ( S) -hydroxyl-1-oxo-5- phenylpentyl ) amino-l-methyl-5- (4-fluoro-phenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 542 (M+H).
  • Example 10 3- (2 (if?)- Isobutyl -3 (5) -hydroxyl-l-oxo-4- cyclohexyloxybutyl) mino-1-methyl-5-phenyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one. MS (ESI): 506 (M+H).
  • Example 11 3- (2 (R) -Methyl-3 ( S) -hydroxyl-l-oxo-4- phenoxybutyl ) amino-7-chloro-1-methyl-5-phenyl-2 , 3-dihydro- lf-l,4-benzodiazepin-2-one. MS (ESI): 492 (M+H).
  • Example 18 3- (2 (R) -Methyl-3 ( S) -hydroxyl-l-oxo-4- (2 , 4- difluorobenzyloxy) butyl) amino-7-chloro-l-methyl-5-phenyl- 2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 542 (M+H) .
  • Example 20 3- (2 (R) -Vinyl-3 ( S) -hydroxyl-l-oxo-4- benzyloxybutyl ) amino-7-chloro-l-methyl-5-phenyl-2 , 3- dihydro-lf-1, 4-benzodiazepin-2-one. MS (ESI): 536 (M+H).
  • Example 25a 3- (2 ⁇ R) -Isobutyl-3 (5) -hydroxyl-1-oxo- heptyl) amino-1-methyl-5-phenyl-2 , 3 -dihydro-1H-1, 4- benzodiazepin-2-one.
  • MS (ESI) 450 (M+H) .
  • Example 25b 3- (R) - (2 (R) -Isobutyl-3 (S) -hydroxyl-1-oxo- heptyl ) amino-1-methyl-5-pheny1-2 , 3 -dihydro- IH- 1 , 4- benzodiazepin-2-one.
  • MS (ESI) 450 (M+H) .
  • Example 25c 3- (S) - (2 ⁇ R) -Isobutyl-3 ( S) -hydroxyl-1-oxo- heptyl) amino-l-methyl-5-phenyl-2, 3-dihydro-li- ⁇ -l, 4- benzodiazepin-2-one.
  • MS (ESI) 450 (M+H) .
  • Example 27 3- (2 (i?) -Isobutyl-3 ( S) -hydroxyl-1-oxo- hexyl) amino-1-methyl-5-phenyl-2, 3 -dihydro-lff-1, 4- benzodiazepin-2-one. MS (ESI) : 436 (M+H) .
  • Example 28 3- (2 (J?) -Isobutyl-3 (S) -hydroxyl-l-oxo-4- phenylbutyl) amino-l-methyl-5-phenyl-2 , 3-dihydro-lff-l, 4- benzodiazepin-2-one.
  • MS (ESI) 484 (M+H) .
  • Example 36 3- (2 (f?) -Methyl-3 ( S) -hydroxyl-1-oxo-hexyl) amino- l-methyl-5-phenyl-2 , 3-dihydro-lff-l, 4-benzodiazepin-2-one .
  • MS (ESI) 394 (M+H) .
  • Example 37 3- (2 (J?) -Methyl-3 ( S) -hydroxyl-l-oxo-3- (4- propoxyphenyl ) propyl ) amino-l-methyl-5-phenyl-2 , 3-dihydro- lff-l , 4-benzodiazepin-2-one .
  • Example 39 2 (R) -cyclopropylmethyl-5- (3 , 5-difluorophenyl) - 3- (S) -hydroxypentanoic acid (2-oxo-l-(3- phenoxybenzyl ) azapan-3 - ( S ) -yl ) amide .
  • Example 40 4-cyclopentyl-2- (R) -cyclopropylmethyl-3- (S) - hydroxybutanoic acid (2 -oxo-1- (3 -phenoxybenzyl) azapan-3 -
  • Example 42 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (2-fluorophenyl) -l-methyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one.
  • Example 43 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (azapan-1-yl) -l-methyl-2 , 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 44 3- (2- (R) -cyclopropylmethyl-5- (3 , 5- difluorophenyl) -3 (S) -hydroxyl-1-oxopentyl) amino-l-methyl-5- (pyridn-2-yl) -2 , 3 -dihydro-1H-1, 4-benzodiazepin-2-one .
  • Example 45 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxopentyl) amino-l-methyl-5- (4-chlorophenyl) -2 , 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 46 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (4-methoxyphenyl) l-methyl-2, 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 47 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (4-methoxyphenyl) -l-methyl-2 , 3-dihydro- lH-l,4-benxodiazepin-2-one.
  • Example 48 3- (S) - (4-cyclopentyl-2- (R) -cyclopropylmethyl- 3- (S) -hydroxyl-1-oxobutyl) amino-1-methyl-5-phenyl-2 , 3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 50 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxohept-6-enyl) amino-l-methyl-5- (4-trifluoromethyl-phenyl) - 2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 514 (M+H). Chromatography Note i. Example 51.
  • the 3- (3 , 5-dimethyl-4-isoxazole)propanal used in the aldol reaction was prepared from: (1) methyl 3- (3, 5- dimethyl-4-isoxazole) propionate (M. C. Marcotullio J. Org. Chem 1994, 59, 2884); (2) DIBAL-H reduction to alcohol ( N. M. Yoon et al J. Org. Chem. 1985, 50, 2443-2450); and (3) TPAP/NMO oxidation to aldehyde (S. V. Ley et al Synthesis 1994, 639).
  • Example 52 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-7-chloro-l-methyl-5-phenyl-2 , 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 53 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1-methyl- (pyridin-2-yl) -2 , 3 -dihydro-lH-1, 4 benzodiazepin-2-one.
  • Example 54 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (4-fluorophenyl) -l-methyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one.
  • the 3-cycloproyl propionic acid which was converted to 3-cycloproyl propionyl chloride used in the aldol reaction, was prepared according to: A. Donetti J. Med.
  • Example 60 3- (5-cyclopentyl-2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1-oxopentyl) amino-5- (4-fluorophenyl) -1-methyl- 2,3-dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 62 3- (S) - (3- (S) -hydroxyl-2- (R) - (thiophen-2- yl)methyl-l-oxoheptyl) amino-1-methyl-5-phenyl-2 , 3-dihydro- lH-l,4-benzodiazepin-2-one.
  • Example 64 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-7-methoxy-l-methyl-5-phenyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one.
  • Example 65 3- (S) - (2- (R) -cyclobutylmethyl-3- (S) -hydroxyl- 1-oxoheptyl) amino-1-methyl-5-phenyl-2 , 3-dihydro-lH-l, 4- benzodiazepin-2-one.
  • Example 68 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxl-1- oxo-5-pheylpentyl) amino-l-methyl-5- (pyridin-2-yl) -2,3- dihydro-lH-benzodiazepin-2-one.
  • Example 69 3- (2- (R) -iso-butyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (4-fluorophenyl) -l-methyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one.
  • Example 70 Example 70.
  • Example 72 3- (2- (R) -cyclopropylmethyl-5- (furan-2-yl) -3- (S) -hydroxyl-1-oxopentyl) amino-l-methyl-5- (4- trifluoromethylphenyl) -2 , 3-dihydro-lH-l, 4-benzodiazepin-2- one.
  • Example 73 3- (5-cyclopentyl-2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1-oxopentyl) amino-l-methyl-5- (4- trifluoromethylphenyl) -2 , 3 -dihydro-lH-1, 4-benzodiazepin-2- one.
  • Example 74 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxooctyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 75 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxononyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 76 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethyl (pyridin-2- yl) )-2,3-dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 77 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethyl (pyridin-2- yl) )-2,3-dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 80 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-methyl-2-pyridyl) -2,3- dihydro-lH-1, 4-benzodiazepin-2-one. MS (ESI): 463 (M+H). Chromatography Note dd.
  • Example 84 3- (S) - (2- (R) -ethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1-methyl-5-phenyl-2 , 3 -dihydro-lH-1, 4- benzodiazepin-2-one. MS (ESI) : 422 (M+H) .
  • Example 85 3- (S) - (2- (R) -propyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5-phenyl-2 , 3-dihydro-l, 4- benzodiazepin-2-one.
  • MS (ESI) 436 (M+H) .
  • Example 88 3- (4- (S) - ( tert-butoxycarbonylamino-3- (R) - hydroxyl-2- (R) -methyl-1-oxo-5-phenyIpentyl) amino-7-chloro- 5- (2-fluorophenyl) -l-methyl-2 , 3 -dihydro-lH-1, 4- benzodiazepin-2-one.
  • Example 90 3- (3- (R) -hydroxyl-2- (R) -methyl-l-oxo-3- (pyrrolidin-2- (R) -yDpropyl) -amino-7-chloro-5- (2- fluorophenyl) -l-methyl-2 , 3 -dihydro-1H-1, 4-benzodiazepin-2- one.
  • Example 91 3- (4-benzyloxy-3- (R) -hydroxyl-2- (R) -iso- propyl-l-oxobutyl-amino-7-chloro-l-methyl-5-phenyl-2, 3- dihydro-lH-1, 4-benzodiazepin-2-one.
  • Example 92 3- (4-benzyloxy-3- (R) -hydroxyl-2- (R) -iso- propyl-l-oxobutyl-amino-7-chloro-l-methyl-5-phenyl-2, 3- dihydro-lH-1, 4-benzodiazepin-2-one.
  • the benzodiazepine was made from 2-aminophenyl- 2 ' thiazolylketone (see A. Furstner et al . , Tetrahedron 1995, 51 (3), 773-786) following the synthetic sequence from: R. G. Sherrill et al . , J. Org. Chem. 1995, 60, 734.
  • Example 96 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-cyclopropylmethyl-5- (4- trifluoromethylphenyl) -2, 3 -dihydro-1H-1, 4-benzodiazepin-2- one.
  • Example 99 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1- (3-pyridinylmethyl) -5- (4-trifluoromethylphenyl) -2 , 3-dihydro-lH-l, 4-benzodiazepin-2-one .
  • Example 100 3- (2- (S) -cyclopropylmethyl-3- (R) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethyl-phenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one.
  • the syn-aldol was made according to Scheme 1, except that (S) -4- (phenylmethy1) -2-oxazolidinone was used instead of the (R) -isomer shown in Scheme 1.
  • Example 102 3- (2- (R) -cyclopropylmethyl-3- (R) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-1, 4-benzodiazepin-2-one.
  • the anti-aldols were made by the method described in: A. K. Ghosh, J. Am . Chem . Soc . 1996, 118, 2527-2528.
  • the carboxylic acid shown was coupled with the corresponding benzodiazepine following a procedure analogous to the procedure of the last step in Example 1.
  • Example 103 3- (2- (S) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 102 Followinged the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used.
  • Example 102 Followinged the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used.
  • Example 105 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-3- (S) -methyl-1-oxoheptyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2 , 3 -dihydro-1H-1, 4-benzodiazepin-2-one.
  • Example 108 3- (3- (S) -acetoxy-2- (R) -iso-butyl-1- oxoheptyl) amino-5- (4-fluorophenyl) -l-methyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one.
  • Example 113 1- (1-hydroxypentyl) cyclohexanecarboxylic acid(5- (4-fluorophenyl) -l-methyl-2-oxo-2 , 3 -dihydro-1H-1, 4- benzodiazepin-3-yl) amide.
  • Example 114 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5-methyl-5H, 7H-dibenzo [b, d] azepin-6-one.
  • Example 115 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxooctyl) amino-5-methyl-5H, 7H-dibenzo [b, d] azepin-6-one .
  • Example 117 3- (2- (R) -cyclopropylmethyl-5- (furan-2-yl) -3- (S) -hydroxyl-1-oxopentyl) amino-5-methyl-5H, 7H- dibenzo[b,d]azepin-6-one. MS (ESI): 459 (M+H), 481 (M+Na), 457 (M-H). Chromatography Note s.
  • Example 118 2- (R) -cyclopropylmethyl-3- (S) -hydroxyl- heptanoic acid (2-oxo-l- (3 -phenylamino-benzyl) azapan-3- (S) - yl) amide. MS (ESI): 492 (M+H), 514 (M+Na), 490 (M-H).
  • Step 1 [2-Oxo-1- (3 -phenylamino-benzyl ) -azepan-3-yl] - carbamic acid tert-butyl ester: In a 100 ml round bottomed flask Binap, (S) - ( -) 2 , 2 ' -Bis (diphenylphosphino) -1, 1 ' - binaphthyl, ( 0.210 g , 0.3375 mmol) dissolved in 15mL toluene was stirred at 80°C for 1 minute .
  • Step 2 3 -Amino-1- (3 -phenylamino-benzyl ) -azepan-2-one, trifluoroacetic acid salt:
  • the ester from Step 1 above 0.025 g , 0.06 mmol
  • the solvent was concentrated to an oil and dried under high vacuum to yield 0.025 g (100%) .
  • Example 120 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5-benzyl-l-methyl-2 , 3-dihydro-lH-l, 4- benzodiazepin-2-one.
  • Chromatography Note b and Note c The benzodiazepine was made from 1- (2-aminophenyl) -2- phenylethanone (see M. W. Partridge et al . , J. Chem . Soc . 1964, 3673) following the synthetic sequence from: R. G. Sherrill, J. Org. Chem. 1995, 60, 734.
  • Example 122 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5-cycloheptyl-l-methyl -2 , 3-dihydro-lH-l, 4- benzodiazepin-2-one.
  • Example 125 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1- (2-pyridinylmethyl) -5- (4- trifluoromethylphenyl) -2 , 3-dihydro-1H-1, 4-benzodiazepin-2- one.
  • Example 126 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1- (3-pyridinylmethyl) -5- (2-fluorophenyl) - 2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 543 (M+H), 541 (M-H). Chromatography Note d and Note e. Example 127.
  • Example 128 3- (2-1 (R) -Cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (N, N-dibutylamino) -2 , 3-dihydro- lH-l,4-benzodiazepin-2-one. MS (ESI): 499 (M+H). Chromatography Note a.
  • Example 133 3- (2- (R) -Isobutyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5-homopiperidino-2 , 3-dihydro-lH- 1,4-benzodiazepin-2-one. MS (ESI): 471 (M+H). Chromatography Note b and Note c. Example 135. 3- (2- (R) -cyclopropylmethyl-1, 3- dioxoheptyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 514 (M+H), 536 (M+Na), 512 (M-H). Chromatography Note i.
  • Example 55 was oxidized to the dicarbonyl compound by TPAP/NMO, see S. V. Ley et al . , Synthesis 1994, 639.
  • Example 136 1-pentyrylcyclohexanecarboxylic acid (5- (4- fluorophenyl) -l-methyl-2-oxo-2 , 3 -dihydro-lH-1, 4- benzodiazepin-3-yl) amide.
  • a the chiral carbon of the benzodiazepine ring is racemic.
  • b the chiral carbon of the benzodiazepine ring is (R) .
  • c the chiral carbon of the benzodiazepine ring is (S) .

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Abstract

L'invention porte sur de nouveaux lactames de formule (I), sur leurs préparations pharmaceutiques, et sur leurs procédés d'utilisation. Ces nouveaux composés inhibent le processus de la protéine précurseur de l'amyloïde et plus spécifiquement la production du peptide Aβ, empêchant par là la formation de dépôts neurologiques de protéines amyloïdes. L'invention porte plus particulièrement le traitement des troubles neurologiques liés à production de l'amyloïde β, tels que la maladie d'Alzheimer et le syndrome de Down.
EP00963374A 1999-09-13 2000-09-13 HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b) Withdrawn EP1212306A2 (fr)

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CN1399634A (zh) 2003-02-26
WO2001019797A3 (fr) 2002-04-11
BR0014269A (pt) 2002-07-02
AU7479700A (en) 2001-04-17
CA2377221A1 (fr) 2001-03-22
AU783914B2 (en) 2005-12-22
JP2003509411A (ja) 2003-03-11
IL147774A0 (en) 2002-08-14
WO2001019797A2 (fr) 2001-03-22
MXPA02001813A (es) 2004-03-19

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