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US20090264419A1 - CYCLIC MALONAMIDES AS INHIBITORS OF Abeta PROTEIN PRODUCTION - Google Patents

CYCLIC MALONAMIDES AS INHIBITORS OF Abeta PROTEIN PRODUCTION Download PDF

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US20090264419A1
US20090264419A1 US12/433,925 US43392509A US2009264419A1 US 20090264419 A1 US20090264419 A1 US 20090264419A1 US 43392509 A US43392509 A US 43392509A US 2009264419 A1 US2009264419 A1 US 2009264419A1
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phenyl
substituted
alkyl
occurrence
independently selected
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US12/433,925
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Richard E. Olson
Michael G. Yang
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Bristol Myers Squibb Pharma Co
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Bristol Myers Squibb Pharma Co
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Priority to US12/433,925 priority Critical patent/US20090264419A1/en
Priority to US12/552,652 priority patent/US20100009965A1/en
Priority to US12/603,186 priority patent/US20100041639A1/en
Publication of US20090264419A1 publication Critical patent/US20090264419A1/en
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    • 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
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel cyclic malonamides 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.
  • Alzheimer's disease is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability.
  • a ⁇ is a common cause of progressive dementia in humans and is one of the major causes of death in the United States.
  • a ⁇ has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents A ⁇ 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 ⁇ 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.
  • a ⁇ is the major protein found in amyloid plaques.
  • a ⁇ is neurotoxic and may be causally related to neuronal death observed in A ⁇ patients.
  • 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 A ⁇ .
  • ⁇ APP mutations have been described in familiar forms of A ⁇ .
  • 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 A ⁇ .
  • Methods of treatment could target the formation of A ⁇ through the enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • Compounds that inhibit P or ⁇ secretase activity could control the production of A ⁇ .
  • compounds that specifically target ⁇ secretases could control the production of A ⁇ .
  • Such inhibition of ⁇ or ⁇ secretases could thereby reduce production of A ⁇ , which, thereby, could reduce or prevent the neurological disorders associated with A ⁇ protein.
  • metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity particularly collagenase and or stromelysin activity.
  • the compounds of the invention are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors.
  • the compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
  • EP 0652009A1 relates to the general formula:
  • lactam ring B is substituted by succinamide and a carbocyclic, aryl, or heteroaryl group.
  • 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 or prodrug form thereof.
  • It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • R 3 , R 6 , B, C, W, X, Y, and Z are effective inhibitors of the production of A ⁇ .
  • the present invention provides a novel compound of Formula (I):
  • Ring C is selected from:
  • Ring C is substituted with 0-2 R 21 ; and Ring B is selected from:
  • Ring B is selected from:
  • each benzo fused ring is substituted with 0-1 R 13 ;
  • the present invention provides a compound of Formula (I), wherein:
  • the present invention provides a compound of Formula (Id) and (Ie)
  • the present invention provides a compound of Formula (Id) and (Ie) wherein:
  • the present invention provides a compound of Formula (Id) and (Ie) wherein:
  • the present invention provides a compound of Formula (Id) and (Ie) wherein:
  • the present invention provides for a method for the treatment of neurological disorders 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 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 neurological disorders 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 present invention provides a method for 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:
  • 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-terminus of A ⁇ , 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.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • a substituent is keto (i.e., ⁇ O)
  • 2 hydrogens on the atom are replaced.
  • any variable e.g., R 5b
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 5b the definition of R 5b
  • R 5b at each occurrence is selected independently from the definition of R 5b .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • 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, “C 1 -C 6 alkyl” denotes alkyl having 1, 2, 3, 4, 5, or 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.
  • Preferred “alkyl” group unless otherwise specified, is “C 1 -C 4 alkyl”.
  • propyl denotes n-propyl or i-propyl
  • butyl denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
  • 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.
  • Examples of “C 2 -C 6 alkenyl” 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 or “alkyloxy” 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. “Counterion” 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.
  • 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).
  • Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopent
  • 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 independently selected from the group consisting of N, O 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.
  • 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 O atoms in the heterocycle is not more than 1.
  • heterocycles include, but are not limited to, 1H-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, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
  • 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, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.
  • 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; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds 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. Preferred “aryl” is phenyl.
  • aryl may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF 3 , SCH 3 , S(O)CH 3 , SO 2 CH 3 , —N(CH 3 ) 2 , N(CH 3 )H, CN, NO 2 , OCF 3 , C( ⁇ O)CH 3 , CO 2 H, CO 2 CH 3 , or C 1 -C 4 haloalkyl.
  • 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 may optionally be unsaturated or partially unsaturated (i.e. two adjacent atoms in the ring form a double bond) wherein the backbone of lactam ring B may contain one, two or three double bonds.
  • lactam ring B include:
  • lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13.
  • substituent R 10 or R 11 on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-trifluoromethylphenyl)methyl, and 2-, 3-, and 4-pyridinyl.
  • R 13 on lactam B are F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.
  • 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,
  • racemic material can be achieved by methods known in the art.
  • 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.
  • examples of 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.
  • Examples of 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.
  • Solid 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.
  • 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 which are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up 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.
  • the compounds of Formula (I) of the present invention can be prepared from carboxylic acid 1 and amine 2 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings, as illustrated in Scheme 1.
  • amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings, as illustrated in Scheme 1.
  • protecting groups or precursor functionality convertible to the desired groups may be desirable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis , (Wiley 1991).
  • Cyclic carboxylic acid intermediates such as 4, are useful for the synthesis of the current invention, and may be synthesized by a number of ways well known in the art.
  • One of the preferred syntheses of the compounds of this invention is shown in Scheme 4.
  • a convergent route is employed, which joins the acid 11 and the amine together to afford the key intermediate 12 using standard bond-forming procedures (Synthesis 1989, 37-38).
  • the desired carboxylic acid 4 may be prepared from the known malonate ester 10 (e.g. Chung, S. K. Korean J. Med. Chem. 1995, 5, 94-111) via a three-step protocol as shown in Scheme 4.
  • HPLC Condition A 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
  • HPLC Condition B reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 90% acetonitrile in water.
  • the title compound was prepared in a manner similar to that described for Example 57.
  • the product was obtained as a white solid.
  • the enantiomers were separated by chiral HPLC using the following conditions: Column, Chiralcel OD column (5 cm ⁇ 50 cm); Eluent, 95:5 Hexanes/2-Propanol; Flow rate, 100 mL/min; Monitoring wavelength, 270 nm.
  • Tables 1-4 below provide representative Examples of the compounds of Formula (I) of the present invention.
  • a ⁇ production has been implicated in the pathology of Alzheimer's Disease (A ⁇ ).
  • the compounds of the present invention have utility for the prevention and treatment of A ⁇ by inhibiting A ⁇ production.
  • Methods of treatment target formation of A ⁇ production through the enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • the compounds of the present invention have utility for the prevention and treatment of disorders involving A ⁇ production, such as cerebrovascular disorders.
  • Compounds of Formula (I) are expected to possess 7-secretase inhibitory activity.
  • the ⁇ -secretase inhibitory activity of the compound of the present invention is demonstrated using assays for such activity, for example, using the assay described below.
  • Compounds of the present invention have been shown to inhibit the activity of ⁇ -secretase, as determined by the A ⁇ immunoprecipitation assay.
  • ⁇ g denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ L denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • ⁇ M denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • SDS denotes sodium dodecyl sulfate
  • DMSO denotes dimethyl sulfoxide
  • EDTA denotes ethylenediaminetetraacetic acid.
  • a compound is considered to be active if it has an IC 50 or K i value of less than about 100 ⁇ M for the inhibition of A ⁇ production.
  • the IC 50 or K i value is less than about 10 ⁇ M; more preferrably the IC 50 or K i value is less than about 0.1 ⁇ M.
  • the present invention has been shown to inhibit A ⁇ protein production with an IC 50 or K i value of less than 100 ⁇ M.
  • a novel assay to evaluate the accumulation of A ⁇ protein was developed to detect potential inhibitors of secretase.
  • the assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.
  • test compounds The effect of test compounds on the accumulation of A ⁇ in the conditioned medium is tested by immunoprecipitation. Briefly, N 9 cells are grown to confluency in 6-well plates and washed twice with 1 ⁇ Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150 uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO (final concentration 1%) are added together with the addition of radiolabel. The cells are incubated for 4 h at 37° C. in a tissue culture incubator.
  • the conditioned medium is harvested and pre-cleared by the addition of 5 ⁇ l normal mouse serum and 50 ⁇ l of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4° C., followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (clone 1101.1; directed against an internal peptide sequence in A ⁇ ) and 50 ⁇ l protein A Sepharose.
  • a monoclonal antibody clone 1101.1; directed against an internal peptide sequence in A ⁇
  • the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5.
  • high salt washing buffer 50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40
  • low salt wash buffer 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40
  • 10 mM Tris pH 7.5.
  • the pellet after the last wash is resuspended in SDS sample buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine
  • the gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of A ⁇ polypeptides.
  • the steady-state level of A ⁇ in the presence of a test compound is compared to wells treated with DMSO (1%) alone.
  • a typical test compound blocks A ⁇ accumulation in the conditioned medium, and is therefore considered active, with an IC 50 less than 100 ⁇ M.
  • test compound The effect of a test compound on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates.
  • N 9 cells are metabolically labeled as above in the presence or absence of test compounds.
  • the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN 3 ).
  • lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 ⁇ l;) and 50 ⁇ l protein A Sepharose for 16 hours at 4° C.
  • the immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments.
  • the steady-state level of C-terminal APP fragments is compared to wells treated with DMSO (1%) alone.
  • a typical test compound stimulates C-terminal fragment accumulation in the cell lysates, and is therefore considered active, with an IC 50 less than 100 ⁇ M.
  • a ⁇ -Immunoprecipitation Assay A ⁇ -Immunoprecipitation Assay
  • This immunoprecipitation assay is specific for ⁇ -secretase (i.e., proteolytic activity required to generate the C-terminal end of A ⁇ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed).
  • N 9 cells are pulse labeled in the presence of a reported ⁇ -secretase inhibitor (MDL 28170) for 1 h, followed by washing to remove radiolabel and MDL 28170. The media is replaced and test compounds are added. The cells are chased for increasing periods of times and A ⁇ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above).
  • test compound is characterized whether a stabilization of C-terminal fragments is observed and whether A ⁇ is generated from these accumulated precursor.
  • a typical test compound prevents the generation of A ⁇ out of accumulated C-terminal fragments and is considered active with an IC 50 less than 100 ⁇ M.
  • the compound of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration.
  • the active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions.
  • the active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier.
  • a valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • the compound of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to ⁇ -amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.
  • the compound of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal.
  • the compound can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
  • the compound can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compound of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compound for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compound herein described in detail can form the active ingredient, and is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Compound of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

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Abstract

This invention relates to novel cyclic malonamides having the formula (I):
Figure US20090264419A1-20091022-C00001
to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-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 β-amyloid production such as Alzheimer's disease and Down's Syndrome.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 12/142,145, filed Jun. 19, 2008 (U.S. Pat. No. 7,528,249), which is a continuation of U.S. patent application Ser. No. 11/841,081, filed Aug. 20, 2007, U.S. patent application Ser. No. 11/327,721, filed Jan. 6, 2006, which is a continuation of U.S. patent application Ser. No. 10/746,769 (U.S. Pat. No. 7,053,081), filed Dec. 24, 2003, which is a continuation of U.S. patent application Ser. No. 09/825,211 (U.S. Pat. No. 6,759,404), filed Apr. 3, 2001, which claims priority from U.S. Provisional Application Ser. No. 60/194,503, filed Apr. 3, 2000 (expired), the contents of which are hereby incorporated by reference herein in their entirety.
    • FIELD OF THE INVENTION
  • This invention relates to novel cyclic malonamides 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 Aβ-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 β-amyloid production such as Alzheimer's disease and Down's Syndrome.
    • BACKGROUND OF THE INVENTION
  • Alzheimer's disease (Aβ) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. Aβ is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. Aβ has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents Aβ 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).
  • Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
  • Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to its deposition in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Aβ was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.
  • Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β amyloid precursor protein (APP). β APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ is derived from cleavage of APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
  • The existence of at least four proteolytic activities has been postulated. They include β secretase(s), generating the N-terminus of Aβ, α secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
  • Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of Aβ. Firstly, Aβ is the major protein found in amyloid plaques. Secondly, Aβ is neurotoxic and may be causally related to neuronal death observed in Aβ patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of β APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of Aβ. In addition, several other β APP mutations have been described in familiar forms of Aβ. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human β APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset Aβ. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the Aβ.
  • It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Aβ in vivo.
  • Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of β amyloid precursor protein. Compounds that inhibit P or γ secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target γ secretases, could control the production of Aβ. Such inhibition of β or γ secretases could thereby reduce production of Aβ, which, thereby, could reduce or prevent the neurological disorders associated with Aβ protein.
  • PCT publication number WO 96/29313 discloses the general formula
  • Figure US20090264419A1-20091022-C00002
  • covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
  • Compounds of general formula:
  • Figure US20090264419A1-20091022-C00003
  • are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
  • European Patent Application number EP 0652009A1 relates to the general formula:
  • Figure US20090264419A1-20091022-C00004
  • and discloses compounds that are protease inhibitors that inhibit Aβ production.
  • U.S. Pat. No. 5,703,129 discloses the general formula:
  • Figure US20090264419A1-20091022-C00005
  • which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Aβ production and are useful in the treatment of Alzheimer's disease.
  • Copending, commonly assigned U.S. patent application Ser. No. 09/370,089 filed Aug. 7, 1999 (equivalent to international application PCT US99/17717) discloses lactams of general formula:
  • Figure US20090264419A1-20091022-C00006
  • wherein the lactam ring B is substituted by succinamide and a carbocyclic, aryl, or heteroaryl group. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.
  • None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
    • SUMMARY OF THE INVENTION
  • One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Aβ 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 or prodrug form thereof.
  • It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):
  • Figure US20090264419A1-20091022-C00007
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug forms thereof, wherein R3, R6, B, C, W, X, Y, and Z are defined below, are effective inhibitors of the production of Aβ.
    • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):
  • Figure US20090264419A1-20091022-C00008
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NR26C(═O)—, —C(═O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or —NR26C(O)NR26—;
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)l—S— (CR7R7a)m—R4,
      • —(CR7R7a)l—O— (CR7R7a)m—R4,
      • —(CR7R7a)l—N(R7b)— (CR7R7a)m—R4,
      • —(CR7R7a)l—S(═O)— (CR7R7a)m—R4,
      • —(CR7R7a)l—S(═O)2—(CR7R7a)m—R4,
      • —(CR7R7a)l—C(═O)— (CR7R7a)m—R4,
      • —(CR7R7a)l—N(R7b)C(═O)— (CR7R7a)m—R4,
      • —(CR7R7a)l—C(═O)N(R7b)— (CR7R7a)m—R4,
      • —(CR7R7a)l—N(R7b)S(═O)2—(CR7R7a)m—R4, or
      • —(CR7R7a)l—S(═O)2N(R7b)— (CR7R7a)m—R4
    • n is 0, 1, 2, or 3;
    • m is 0, 1, 2, or 3;
    • l is 1, 2, or 3;
    • Ring C is a 3 to 8 membered carbocycle,
      • wherein the carbocycle is saturated or partially saturated;
      • optionally, the carbocycle contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R20)—; and
      • wherein the carbocycle is substituted with 0-4 R21;
    • R4 is H, OH, OR14a,
      • C1-C8 alkyl substituted with 0-3 R4a,
      • C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R6 is H;
      • C1-C6 alkyl substituted with 0-3 R6a;
      • C3-C10 carbocycle substituted with 0-3 R6b; or
      • C6-C10 aryl substituted with 0-3 R6b;
    • R6, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl and CF3;
    • R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, C1-C4 alkyl, phenyl substituted with 0-5 R7c;
    • R7a, at each occurrence, is independently selected from H, Cl, F, Br, I, CN, CF3, and C1-C4 alkyl;
    • R7b is independently selected from H and C1-C4 alkyl;
    • R7c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, CF3, C1-C4 alkoxy, and C1-C4 alkyl;
    • B is a 5 to 10 membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains an additional heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19,
      • S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl optionally substituted with 0-3 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; 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 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R10b; C3-C10 carbocycle substituted with 0-3 R10b, 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 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R11a; C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 cycloalkyl substituted with 0-3 R11b; and
      • 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 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
    • additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
    • W is —(CR8R8a)p—;
    • p is 0, 1, 2, 3, or 4;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-3 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • Y is a bond or —(CR9R9a) t-V—(CR9R9a)u—;
    • t is 0, 1, 2, or 3;
    • u is 0, 1, 2, or 3;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl and C3-C8 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C8 alkyl substituted with 1-3 R12; C2-C4 alkenyl substituted with 1-3 R12;
      • C2-C4 alkynyl substituted with 1-3 R12; C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C4 alkenyl substituted with 0-3 R12a; C2-C4 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14 is H, phenyl substituted with 0-4 R14b, benzyl substituted with 0-4 R14b, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
    • R14a is H, C6-C10 aryl, benzyl, heterocycle, or C1-C4 alkyl;
    • R14b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, aryl-(C1-C6 alkyl)- wherein the aryl is substituted with 0-4 R15b, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R15b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or
      • —CH2-aryl substituted by 0-4 R17a;
    • R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R20 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl optionally substituted with 0-2 R20a; C6-C10 aryl substituted with 0-4 R20b;
      • C3-C10 carbocycle substituted with 0-3 R20b; 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 R20b;
    • R20a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, F, ═O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R20b, and heterocycle substituted with 0-4 R20b;
    • R20b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R21, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R21a;
      • C6-C10 aryl substituted with 0-3 R21b;
      • C3-C10 carbocycle substituted with 0-3 R21b; 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 R21b;
    • R21a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • phenyl substituted with 0-3 R21b;
      • C3-C6 cycloalkyl substituted with 0-3 R21b; and
      • 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 0-3 R21b;
    • R21b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
    • additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
    • R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R26 is H;
      • C1-C6 alkyl substituted with 0-3 R26a;
      • C3-C10 carbocycle substituted with 0-3 R26b; or
      • C6-C10 aryl substituted with 0-3 R26b;
    • R26a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl and CF3; and
    • R26b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.
  • [2] In a preferred embodiment the present invention provides a compound of Formula (I), wherein:
      • L is —NR26C(═O)—, —C(═O)NR26—, or —OC(═O)NR26—;
    • R3 is —(CHR7)n—R4,
      • —(CHR7)l—N—(CR7R7a)m—R4, or
      • —(CHR7)l—O— (CR7R7a)m—R4;
    • n is 0, 1 or 2;
    • m is 0, 1 or 2;
    • l is 1;
    • Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R21; optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • R4 is H, OH, OR14a,
      • C1-C6 alkyl substituted with 0-3 R4a, C2-C6 alkenyl substituted with 0-2 R4a,
      • C2-C6 alkynyl substituted with 0-1 R4a,
      • C3-C6 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H,
      • OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, and
      • 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R6 is H;
    • R7, at each occurrence, is independently selected from H, OH, F, CF3, methyl, and ethyl;
    • Ring B is a 7 membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R11)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl optionally substituted with 0-2 R1a; C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R1b; 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 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, phenyl substituted with 0-4 R10b; 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 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-2 R13;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-2 R13;
    • additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-2 R13;
    • W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is H; C1-C6 alkyl; C2-C4 alkenyl; C2-C4 alkynyl;
      • C1-C3 alkyl substituted with 1-2 R12;
      • C2-C3 alkenyl substituted with 1-2 R12; C2-C3 alkynyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, ON, NO2, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
    • R17 is H, methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, phenyl substituted by 0-3 R17a, or —CH2-phenyl substituted by 0-3 R17a;
    • R17a is H, methyl, methoxy, —OH, F, Cl, CF3, or OCF3;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl;
    • R20 is H or C(═O)OR17;
    • R26 is H, methyl, or ethyl.
  • [3] In another preferred embodiment the present invention provides a compound of Formula (I), wherein:
  • Ring C is selected from:
  • Figure US20090264419A1-20091022-C00009
  • wherein Ring C is substituted with 0-2 R21; and
    Ring B is selected from:
  • Figure US20090264419A1-20091022-C00010
  • [4] In another more preferred embodiment the present invention provides a compound of Formula (I), wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a, C2-C6 alkenyl substituted with 0-1 R4a, or C2-C6 alkynyl substituted with 0-1 R4a;
    • R4a, at each occurrence, is independently selected from H, OH, F, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, and
      • 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 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
    • X is a bond, phenyl, C3-C6 cycloalkyl, or
      • 5 to 6 membered heterocycle;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is H; C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkyl substituted with 1-2 R12;
      • C2-C3 alkenyl substituted with 1-2 R12; C2-C3 alkynyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; 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 R12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R12, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; 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 R12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)2—, ethyl-S(═O)2—, and propyl-S(═O)2—;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl;
    • R20 is H.
  • [5] In another more preferred embodiment the present invention provides a compound of Formula (I), wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH(CH3)2, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH(OH)CH2CH(CH3)2, —CH(OH)CH(CH3)2, —CH(NH2)CH2CH(CH3)2, —CH2CH2OCH3, —CH2OCH2CH3, —CF2CH2CH(CH3)2, —CH(NHCH3)CH2CH(CH3)2, —CH(NHSO2CH2CH2CH3)CH2CH(CH3)2, cyclohexyl-, cyclopentyl-, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH(OH)—, cyclohexyl-CH2CH2—, 1—NH2-cyclopentyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, 4-piperidinyl-CH2CH2—, phenyl-CH2CH2CF2—, phenyl-CH2CH(OH)—, imidazolyl-CH2CH(OH)—, or phenyl-CH2OCH2—;
      Ring C is selected from:
  • Figure US20090264419A1-20091022-C00011
  • Ring B is selected from:
  • Figure US20090264419A1-20091022-C00012
  • wherein each benzo fused ring is substituted with 0-1 R13;
    • W is a bond or —CH2—;
    • X is a bond;
  • Figure US20090264419A1-20091022-C00013
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-piperidinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF30-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, or (N-piperidinyl)CH2CH2—;
    • R10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl)CH2CH2—;
    • R11, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 3-F-phenyl, (3-F-phenyl)CH2—, (3-F-phenyl)CH2CH2—, 2-F-phenyl, (2-F-phenyl)CH2—, (2-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 3-Cl-phenyl, (3-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 3-CH3-phenyl, (3-CH3-phenyl)CH2—, (3-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, (4-CF3-phenyl)CH2CH2—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl;
    • R13, at each occurrence, is independently selected from H, F, Cl, OH, —CH3, —CH2CH3, —OCH3, and —CF3; and
    • R20 is H.
  • In another preferred embodiment the present invention provides a compound of Formula (I), wherein:
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)l—S— (CR7R7a)m—R4,
      • —(CR7R7a)l—O—(CR7R7a)m—R4, or
      • —(CR7R7a)l—N(R7b)— (CR7R7a)m—R4;
    • n is 0, 1, or 2;
    • m is 0, 1, or 2;
    • l is 1 or 2;
    • Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R21; optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R20)—;
    • R4 is H, OH, OR14a,
      • C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a, C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b, C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H, methyl, or ethyl;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
    • Ring B is a 7 membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from, —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19,
      • S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl optionally substituted with 0-2 R10a; C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; 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 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, phenyl substituted with 0-4 R10b; 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 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R11a; C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-3 R13;
    • additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
    • additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
    • W is —(CR8R8a)p—;
    • p is 0, 1, or 2;
    • R8 and R6a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-2 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, or 2;
    • u is 0, 1, or 2;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
    • Z is H;
      • C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16f and CF3;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R14a is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or —CH2-aryl substituted by 0-4 R17a;
    • R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—; and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—R20 is H or C(═O)R17;
    • R21, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R21a; C6-C10 aryl substituted with 0-3 R21b;
      • C3-C10 carbocycle substituted with 0-3 R21b; 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 R21b;
    • R21a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • phenyl substituted with 0-3 R21b;
      • C3-C6 cycloalkyl substituted with 0-3 R21b; and
      • 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 0-3 R21b;
    • R21b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23; and
    • R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
  • [6] In another preferred embodiment the present invention provides a compound of Formula (I):
  • Figure US20090264419A1-20091022-C00014
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NR26C(═O)—, —C(═O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or NR26c (═O)NR26—;
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)l—S—R4,
      • —(CR7R7a)l—O—R4;
      • —(CR7R7a)l—N(R7b)—R4,
      • —(CR7R7a)l—S(═O)—R4, or
      • —(CR7R7a)l—S(═O)2—R4;
    • n is 0, 1 or 2;
    • l is 1 or 2;
    • R4 is H,
      • C1-C8 alkyl substituted with 0-3 R4a, C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a, C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-8 membered carbocycle;
      • wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
      • wherein said 3-8 membered carbocycle is substituted with 0-4 R21; and
      • optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
    • additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—,
      • C3-C6 carbocycle, phenyl, and a
      • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
    • R6 is H, methyl, or ethyl;
    • R7, at each occurrence, is independently H or C1-C4 alkyl;
    • R7a, at each occurrence, is independently H or C1-C4 alkyl;
    • R7b is H or C1-C4 alkyl;
      Ring B is selected from:
  • Figure US20090264419A1-20091022-C00015
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19,
      • S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl optionally substituted with 0-3 R10a; C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; 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 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R11a; C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 cycloalkyl substituted with 0-3 R11b; and
      • 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 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • W is a bond or —(CH2)p—;
    • p is 1 or 2;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 carbocycle substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C10 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or
      • —CH2-aryl substituted by 0-4 R17a;
    • R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19b, at each occurrence, is independently is H or C1-C4 alkyl;
    • R20 is H, C1-C4 alkyl, or C(═O)OR17;
    • R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3; and
    • R26 is H or C1-C4 alkyl.
  • [7] In another preferred embodiment the present invention provides a compound of Formula (Ia):
  • Figure US20090264419A1-20091022-C00016
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NR26C(═O)—, —C(═O)NR26—, —NR26c(═O)O—, —OC(═O)NR26, or —NR26c(═O)NR26—;
    • R3 is —(CHR7)n—R4,
      • —(CHR7)l—S—R4,
      • —(CHR7)l—O—R4;
      • —(CR7R7a)l—N(R7b)—R4,
      • —(CR7R7a)l—S(═O)—R4, or
      • —(CR7R7a)l—S(═O)2—R4;
    • n is 0, 1 or 2;
    • l is 1 or 2;
    • R4 is H,
      • C1-C8 alkyl substituted with 0-3 R4a,
      • C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-8 membered carbocycle;
      • wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
      • wherein said 3-8 membered carbocycle is substituted with 0-4 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R20)—;
    • additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
    • additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—,
      • C3-C6 carbocycle, phenyl, and a
      • 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
    • R7, at each occurrence, is independently H, methyl, or ethyl;
    • R7b is H, methyl, or ethyl;
      Ring B is selected from:
  • Figure US20090264419A1-20091022-C00017
    • R11 at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl optionally substituted with 0-3 R11a; C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 cycloalkyl substituted with 0-3 R11b; and
      • 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 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • W is a bond or —(CH2)p—;
    • p is 1 or 2;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 carbocycle substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C10 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or —CH2-aryl substituted by 0-4 R17a;
    • R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;
    • R20 is H, C1-C4 alkyl, or C(═O)OR17;
    • R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3; and
    • R26 is H or C1-C4 alkyl.
  • [8] In another preferred embodiment the present invention provides a compound of Formula (Ic):
  • Figure US20090264419A1-20091022-C00018
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —(CH2)n—R4,
      • —(CH2)l—S—R4,
      • —(CH2)l—O—R4, or
      • (CH2)l—N(R7b)—R4;
    • n is 0, 1 or 2;
    • l is 1 or 2;
    • R4 is C1-C8 alkyl substituted with 0-3 R4a,
      • C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R7b is H, methyl, or ethyl;
    • Ring C is a 3-8 membered carbocycle;
      • wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
      • wherein said 3-8 membered carbocycle is substituted with 0-3 R21; optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—; and
    • R20 is H or C1-C4 alkyl.
  • [9] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, 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 0-3 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, and
      • 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 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle;
      • wherein said 3-6 membered carbocycle is saturated or partially unsaturated;
      • wherein said 3-6 membered carbocycle is substituted with 0-2 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, —OCF3, and —SCF3;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-1 RXb;
      • C3-C6 cycloalkyl substituted with 0-1 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-1 RXb;
    • RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF3;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a; C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R15, at each occurrence, is independently selected from H, C1-C4 alkyl, and benzyl;
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)2—, ethyl-S(═O)2—, and propyl-S(═O)2—; and
    • R20 is H or C1-C4 alkyl.
  • [10] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a, or
      • C2-C6 alkynyl substituted with 0-3 R4a;
    • R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, and
      • 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 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle selected from:
  • Figure US20090264419A1-20091022-C00019
      • wherein said 3-6 membered carbocycle is substituted with 0-1 R21;
    • R21 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF3;
    • W is a bond or —CH2—;
    • X is a bond, phenyl, C3-C6 cycloalkyl or 5 to 6 membered heterocycle;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—,
      • —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
      • phenyl substituted with 0-4 R12b;
      • C3-6 carbocycle substituted with 0-4 R12b; and
      • 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; and
    • R20 is H, methyl, or ethyl.
  • [11] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or OC(═O)NH—;
        Ring C is selected from:
  • Figure US20090264419A1-20091022-C00020
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH(CH3)2, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH(OH)CH2CH(CH3)2, —CH(OH)CH(CH3)2, —CH(NH2)CH2CH(CH3)2, —CH2CH2OCH3, —CH2OCH2CH3, —CF2CH2CH(CH3)2, —CH(NHCH3)CH2CH(CH3)2, —CH(NHSO2CH2CH2CH3)CH2CH(CH3)2, cyclohexyl-, cyclopentyl-, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH(OH)—, cyclohexyl-CH2CH2—, 1-NH2-cyclopentyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, 4-piperidinyl-CH2CH2—, phenyl-CH2CH2CF2—, phenyl-CH2CH(OH)—, imidazolyl-CH2CH(OH)—, or phenyl-CH2OCH2—;
    • W is a bond or —CH2—;
    • X is a bond;
  • Figure US20090264419A1-20091022-C00021
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-piperidinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, or (N-piperidinyl)CH2CH2—;
    • R13, at each occurrence, is independently selected from H, F, Cl, OH, —CH3, —CH2CH3, —OCH3, or —CF3.
    • R20 is H, methyl, or ethyl.
  • [12] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie)
  • Figure US20090264419A1-20091022-C00022
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is—(CH2)n—R4,
      • —(CH2)l—S—R4,
      • —(CH2)l—O—R4, or
      • —(CH2)l—N(R7b)—R4;
    • n is 0, 1 or 2;
    • l is 1 or 2;
    • R4 is C1-C8 alkyl substituted with 0-3 R4a,
      • C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R7b is H, methyl, or ethyl;
    • Ring C is a 3-8 membered carbocycle;
      • wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
      • wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R11, at each occurrence, is independently selected from H, ═O, NR18R19, CF3;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a; C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16,
      • CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
    • R20 is H or C1-C4 alkyl.
  • [13] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, 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 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, 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 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle;
      • wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
      • wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, —OCF3, and —SCF3;
    • R11, at each occurrence, is independently selected from H, ═O, NR18R19, CF3;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-1 RXb;
      • C3-C6 cycloalkyl substituted with 0-1 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-1 RXb;
    • RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF3;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)2—, and ethyl-S(═O)2—;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R20 is H or C1-C4 alkyl.
  • [14] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a, or
      • C2-C6 alkynyl substituted with 0-3 R4a;
    • R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, 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 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle selected from:
  • Figure US20090264419A1-20091022-C00023
      • wherein said 3-6 membered carbocycle is substituted with 0-1 R21;
    • R21 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF3;
    • R11, at each occurrence, is independently selected from H, ═O, NR18R19;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond or —CH2—;
    • X is a bond, phenyl, C3-C6 cycloalkyl or 5 to 6 membered heterocycle;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
  • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
      • phenyl substituted with 0-4 R12b;
      • C3-6 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R20 is H, methyl, or ethyl.
  • [15] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or OC(═O)NH—;
        Ring C is selected from:
  • Figure US20090264419A1-20091022-C00024
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH(CH3)2, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH(OH)CH2CH(CH3)2, —CH(OH)CH(CH3)2, —CH(NH2)CH2CH(CH3)2, —CH2CH2OCH3, —CH2OCH2CH3, —CF2CH2CH(CH3)2, —CH(NHCH3)CH2CH(CH3)2, —CH(NHSO2CH2CH2CH3)CH2CH(CH3)2, cyclohexyl-, cyclopentyl-, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH(OH)—, cyclohexyl-CH2CH2—, 1—NH2-cyclopentyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, 4-piperidinyl-CH2CH2—, phenyl-CH2CH2CF2—, phenyl-CH2CH(OH)—, imidazolyl-CH2CH(OH)—, or phenyl-CH2OCH2—;
    • W is a bond or —CH2—;
    • X is a bond;
  • Figure US20090264419A1-20091022-C00025
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-piperidinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, or (N-piperidinyl)CH2CH2—;
    • R11, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 3-F-phenyl, (3-F-phenyl)CH2—, (3-F-phenyl)CH2CH2—, 2-F-phenyl, (2-F-phenyl)CH2—, (2-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 3-Cl-phenyl, (3-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 3-CH3-phenyl, (3-CH3-phenyl)CH2—, (3-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, (4-CF3-phenyl)CH2CH2—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and
    • R13, at each occurrence, is independently selected from H, F, Cl, OH, —CH3, —CH2CH3, —OCH3, or —CF3.
  • [16] In another preferred embodiment the present invention provides a compound of Formula (If):
  • Figure US20090264419A1-20091022-C00026
  • or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —(CH2)n—R4,
      • —(CH2)l—S—R4,
      • —(CH2)l—O—R4, or
      • —(CH2)l—N(R7b)—R4;
    • n is 0, 1 or 2;
    • l is 1 or 2;
    • R4 is C1-C8 alkyl substituted with 0-3 R4a,
      • C2-C8 alkenyl substituted with 0-3 R4a,
      • C2-C8 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R7b is H, methyl, or ethyl;
      Ring C is a 3-8 membered carbocycle;
      • wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
      • wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R11 is selected from
      • H, ═O, NR18R19, CF3;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
    • R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
    • R20 is H or C1-C4 alkyl.
  • [17] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:
      • L is —NHC(—O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C6 carbocycle substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, 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 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, 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 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle;
      • wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
      • wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R21;
      • optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
    • R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, —OCF3, and —SCF3;
    • R11 is selected from H, ═O, NR18R19, CF3;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH2CH2—;
    • X is a bond;
      • phenyl substituted with 0-1 RXb;
      • C3-C6 cycloalkyl substituted with 0-1 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-1 RXb;
    • RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF3;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)2—, and ethyl-S(═O)2—;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R20 is H or C1-C4 alkyl.
  • [18] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:
      • L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
    • R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
    • R4 is C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a, or
      • C2-C6 alkynyl substituted with 0-3 R4a;
    • R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
      • C3-C6 carbocycle substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, 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 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
      • C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
      • C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
    • Ring C is a 3-6 membered carbocycle selected from:
  • Figure US20090264419A1-20091022-C00027
      • wherein said 3-6 membered carbocycle is substituted with 0-1 R21;
    • R21 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF3;
    • R11 is selected from
      • H, ═O, NR18R19;
      • C1-C4 alkyl optionally substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • 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 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
    • R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond or —CH2—;
    • X is a bond, phenyl, C3-C6 cycloalkyl or 5 to 6 membered heterocycle;
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
    • Z is H;
      • C1-C8 alkyl substituted with 0-3 R12a;
      • C2-C6 alkenyl substituted with 0-3 R12a;
      • C2-C6 alkynyl substituted with 0-3 R12a;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
      • phenyl substituted with 0-4 R12b;
      • C3-6 carbocycle substituted with 0-4 R12b; 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 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
    • R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R20 is H, methyl, or ethyl.
  • [19] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:
      • L is —NHC(O)—, —C(═O)NH—, or —OC(═O)NH—;
        Ring C is selected from:
  • Figure US20090264419A1-20091022-C00028
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH(CH3)2, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH(OH)CH2CH(CH3)2, —CH(OH)CH(CH3)2, —CH(NH2)CH2CH(CH3)2, —CH2CH2CCH3, —CH2OCH2CH3, —CF2CH2CH(CH3)2, —CH(NHCH3)CH2CH(CH3)2, —CH(NHSO2CH2CH2CH3)CH2CH(CH3)2, cyclohexyl-, cyclopentyl-, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH(OH)—, cyclohexyl-CH2CH2—, 1—NH2-cyclopentyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—,
      • (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, 4-piperidinyl-CH2CH2—, phenyl-CH2CH2CF2—, phenyl-CH2CH(OH)—, imidazolyl-CH2CH(OH)—, or phenyl-CH2OCH2—;
    • W is a bond or —CH2—;
    • X is a bond;
  • Figure US20090264419A1-20091022-C00029
    • Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-piperidinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, or (N-piperidinyl)CH2CH2—; and
    • R11, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 3-F-phenyl, (3-F-phenyl)CH2—, (3-F-phenyl)CH2CH2—, 2-F-phenyl, (2-F-phenyl)CH2—, (2-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 3-Cl-phenyl, (3-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 3-CH3-phenyl, (3-CH3-phenyl)CH2—, (3-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, (4-CF3-phenyl)CH2CH2—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
  • [20] In another preferred embodiment the present invention provides a compound of Formula (I) selected from:
    • {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
    • {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
    • [(N-butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
    • 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}acetamide;
    • 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}acetamide;
    • 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}acetamide;
    • 3-cyclopentyl-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide;
    • 2-(3,5-difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide;
    • phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidinecarboxylate;
    • 4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
    • N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]cyclopentyl}carboxamide;
    • (2S)—N-{[N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopropyl}-2-hydroxy-4-methylpentanamide;
    • (2S)—N-{[N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopentyl}-2-hydroxy-3-methylbutanamide;
    • 2,2-difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide;
    • N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide;
    • (2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
    • 3-cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
    • (2R)-2-hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
    • 2-ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
    • 3-cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
    • (2S)-2-hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide;
    • (2S)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
    • (2R)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
    • (2S)-2-amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
    • [(cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
    • {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
    • 4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
    • (2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
    • 3-methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
    • (2S)-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide;
    • N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide;
    • (2S)-2-hydroxy-3-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}butanamide;
    • (2S)-2-hydroxy-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
    • 3-cyclopentyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
    • (2S)-2-cyclohexyl-2-hydroxy-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}acetamide;
    • 3-cyclopropyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
    • N-{[N-(1-butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
    • N-{[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
    • (2S)-2-hydroxy-3-methyl-N—[(N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]carbamoyl]cyclopentyl) butanamide;
    • (2S)-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-2-[(propylsulfonyl)amino]pentanamide;
    • (2S)-2-amino-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
    • 2,2-difluoro-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
    • 4-methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
    • N—({N-[5-(3,3-dimethyl-2-oxobutyl)-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
    • 4-methyl-N—[(N-{6-oxo-5-[(3-phenoxyphenyl)methyl](7H-dibenzo[d,f]azaperhydroepin-7-yl)}carbamoyl)cyclopentyl]pentanamide;
    • N-{[N-(5-butyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
    • 4-methyl-N—[(N-{6-oxo-5-benzyl(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)pentanamide;
    • N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
    • N—({N-[5-(tert-butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide; and
    • N—({N-[5-butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide.
  • In another embodiment the present invention provides for a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I):
  • Figure US20090264419A1-20091022-C00030
  • or a pharmaceutically acceptable salt or prodrug thereof.
  • It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention.
  • In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
  • In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.
  • In a fourth embodiment, the present invention provides a method for inhibiting γ-secretase activity for the treatment of a physiological disorder associated with inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.
  • Thus, the present invention provides a method for inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.
  • In a preferred embodiment the physiological disorder associated with inhibiting γ-secretase activity is Alzheimer's Disease.
  • In a fifth embodiment, the present invention provides a compound of Formula (I) for use in therapy.
  • In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer's Disease.
  • In a sixth embodiment, 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.
  • It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention.
    • DEFINITIONS
  • As used herein, the term “Aβ” denotes the protein designated Aβ, β-amyloid peptide, and sometimes β/A4, in the art. Aβ 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
    Asp Ala Glu Phe Arg His Asp Ser Gly Tyr
    11
    Glu Val His His Gln Lys Leu Val Phe Phe
    21
    Ala Glu Asp Val Gly Ser Asn Lys Gly Ala
    31
    Ile Ile Gly Leu Met Val Gly Gly Val Val
    41
    Ile Ala Thr
  • The term “APP”, as used herein, refers to the protein known in the art as β amyloid precursor protein. This protein is the precursor for Aβ and through the activity of “secretase” enzymes, as used herein, it is processed into Aβ. Differing secretase enzymes, known in the art, have been designated β secretase, generating the N-terminus of Aβ, a secretase cleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, as used herein, generating C-terminal Aβ 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. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.
  • When any variable (e.g., R5b) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5b, then said group may optionally be substituted with up to two R5b groups and R5b at each occurrence is selected independently from the definition of R5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • As used herein, “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, “C1-C6 alkyl” denotes alkyl having 1, 2, 3, 4, 5, or 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. Preferred “alkyl” group, unless otherwise specified, is “C1-C4 alkyl”. Additionally, unless otherwise specified, “propyl” denotes n-propyl or i-propyl; “butyl” denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
  • As used herein, “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. Examples of “C2-C6 alkenyl” 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.
  • As used herein, “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” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of 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. Similarly, “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. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of 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, “C3-C6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • As used herein, “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. Examples of such 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). Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • As used herein, the term “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 independently selected from the group consisting of N, O 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 O atoms in the heterocycle is not more than 1.
  • Examples of heterocycles include, but are not limited to, 1H-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, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. 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, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. 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; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • As used herein, the term “aryl”, “C6-C10 aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred “aryl” is phenyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, —N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(═O)CH3, CO2H, CO2CH3, or C1-C4 haloalkyl.
  • The phrase “additional lactam carbons”, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I). Formula (I″):
  • Figure US20090264419A1-20091022-C00031
  • 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. It is further understood that lactam ring B may optionally be unsaturated or partially unsaturated (i.e. two adjacent atoms in the ring form a double bond) wherein the backbone of lactam ring B may contain one, two or three double bonds. Examples of lactam ring B include:
  • Figure US20090264419A1-20091022-C00032
    Figure US20090264419A1-20091022-C00033
  • but are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R10 or R11 on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-trifluoromethylphenyl)methyl, and 2-, 3-, and 4-pyridinyl. Preferred examples of R13 on lactam B are F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.
  • 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. For example carbon 3 of lactam ring B Formula (I″) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (I″) is considered part of the invention. An example of such configuration includes,
  • Figure US20090264419A1-20091022-C00034
  • but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art.
  • The phrase “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.
  • As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of 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. For example, 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.
  • 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. Generally, 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. Examples of 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.
    • Synthesis
  • 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 herein by reference.
  • The 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 which are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up 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.
  • In a preferred method of synthesis, the compounds of Formula (I) of the present invention can be prepared from carboxylic acid 1 and amine 2 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings, as illustrated in Scheme 1. Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertible to the desired groups may be desirable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991).
  • Figure US20090264419A1-20091022-C00035
  • Additionally, the syntheses of a representative malonamide and a representative acetamide of Formula (I) are illustrated in Scheme 2 and Scheme 3, respectively. As will be readily apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 2 and 3, and the reaction conditions described below can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other compounds of the present invention.
  • Figure US20090264419A1-20091022-C00036
  • Figure US20090264419A1-20091022-C00037
  • Methods for the synthesis of lactams useful as intermediates in the synthesis of compounds of the present invention, including amino bisbenzodiazepine 5 and amino benzodiazepine 8, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporated by reference. Additional references include Bock, et. al., J. Org. Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677; and Brown, at. al., Tetrahedron Letters, 1971, 8, 667-670.
  • Cyclic carboxylic acid intermediates, such as 4, are useful for the synthesis of the current invention, and may be synthesized by a number of ways well known in the art. One of the preferred syntheses of the compounds of this invention is shown in Scheme 4. Typically a convergent route is employed, which joins the acid 11 and the amine together to afford the key intermediate 12 using standard bond-forming procedures (Synthesis 1989, 37-38). The desired carboxylic acid 4 may be prepared from the known malonate ester 10 (e.g. Chung, S. K. Korean J. Med. Chem. 1995, 5, 94-111) via a three-step protocol as shown in Scheme 4.
  • Figure US20090264419A1-20091022-C00038
  • One of the preferred syntheses of cyclic amino acids, such as 7 which is useful in the preparation of compounds of Formula (I), is outlined in Scheme 5. As illustrated for the synthesis of carboxylic acid 7, the desired intermediate ester 18 is prepared by the initial coupling reaction of acid 14 and amine 13 under standard conditions using EDC and HOBt. Both the acids and the amines employed as starting materials in this invention are either commercially available or can be prepared from commercially available materials using conventional procedures and reagents. As apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 5 and the reaction conditions described will allow the preparation of many other analogs of 7 by selecting the appropriate starting materials and reagents.
  • Figure US20090264419A1-20091022-C00039
  • Methods for the synthesis of lactams useful as intermediates in the synthesis of compounds of the present invention are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporated by reference. Additional references include Bock, et. al., J. Org. Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677; and Brown, at. al., Tetrahedron Letters, 1971, 8, 667-670.
  • One of the preferred syntheses of the lactam intermediates, such as 23, is outlined in Scheme 6.
  • Figure US20090264419A1-20091022-C00040
    • a) Preparation of 21
  • To a suspension of 19 (30.0 g, 155 mmol) in dry Et2O (300 mL) under N2 at −70° C. was added t-BuLi (205 mL, 1.7 M in pentane) and stirred for 4 h between −20° C. and −10° C. The reaction was cooled to −70° C. and transferred via canula to a round bottom containing 20 (23.0 mL, 186 mmol) in dry Et2O (150 mL) under N2 at −70° C. The reaction was stirred while warming to rt for 14 h and quenched with 20% citric acid. The resulting layers were separated and the organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. The oil was dissolved in EtOH—HCl (200 mL) and stirred overnight. The solvent was removed in vacuo at 70° C. and the resulting oil triturated with Et2O. The resultant solid was filtered and washed with Et2O to afford 21 HCl (23.9 g, 64%) as a orange solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (d, 1H), 7.66 (t, 1H), 7.56 (t, 1H), 7.51 (d, 1H), 1.41 (s, 9H); ESI MS m/z=178 [C11H15NO+H]+.
  • The orange solid was dissolved in 1N NaOH and EtOAC and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford 21 (21 g, 99%) as a yellow oil: 1H NMR (500 MHz, CD3OD) δ 7.70 (d, 1H), 7.16 (t, 1H), 6.78 (d, 1H), 6.59 (t, 1H), 1.38 (s, 9H)
    • b) Preparation of Example 23
  • To a solution of 22 (5.5 g, 17.0 mmol) in dry THF (50 mL) at 0° C. was added oxalyl chloride (1.47 mL, 17.0 mmol) and DMF (0.2 mL) and stirred for 1.25 h. A solution of 21 (3.3 g, 15.4 mmol) and N-methylmorpholine (4.7 mL, 42.4 mmol) in dry THF (20 mL) was added to the reaction dropwise and the reaction was stirred at rt for 1.5 h. The reaction was filtered and MeOH (100 mL) and NH4OH (50 mL) was added to the filtrate and the reaction was sealed. After 45 min, the reaction was concentrated to half its volume and added dropwise to a cooled solution (15° C.) of ammonium acetate (5.75 g) in acetic acid (120 ml). The reaction was stirred over night at rt, dissolved in Et2O (100 mL), made basic with 6 N NaOH, and cooled in ice while stirring for 1 h. The resulting solid was filtered, washed with H2O and Et2O, and dried in a vacuum oven at 30° C. to afford 23 (3.5 g, 63%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.78-7.16 (m, 10H), 5.12 (s, 2 H), 1.27 (s, 9H).
  • Abbreviations used in the description of the chemistry and in the examples that follow are:
    • Ac acetyl or acetate
    • aq aqueous
    • Bn benzyl
    • Boc t-butyloxycarbonyl
    • Cbz benzyloxycarbonyl
    • DIEA N,N′-diisopropylethylamine
    • DMAP 4-dimethylaminopyridine
    • DME ethylene glycol dimethyl ether
    • DMF N,N′-dimethylformamide
    • DMSO dimethylsulfoxide or methyl sulfoxide
    • EDC•HCL 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
    • HOBT 1-hydroxybenzotriazole
    • HPLC high performance liquid chromatography
    • LiHMDS lithium hexamethyldisilazide
    • MeCN acetonitrile
    • MS mass spectrometry
    • satd saturated
    • rt or RT room temperature
    • TFA trifluoroacetic acid
    • THF tetrahydrofuran
    • TLC thin layer chromatography
    EXAMPLES
  • The examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrate of the invention and not limit the reasonable scope thereof.
  • 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. HPLC Condition A: 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). Alternatively: HPLC Condition B: 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 {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide
  • Figure US20090264419A1-20091022-C00041
    • (a) Methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentane-carboxylate
  • To 1-(methoxycarbonyl)cyclopentanecarboxylic acid (630 mg, 3.7 mmol) in CH2Cl2/DMF (5:1, 37 mL) at 0° C. was added HOBT (730 mg, 4.8 mmol) and EDC (920 mg, 4.8 mmol). The mixture was stirred for 10 min then 3-methylbutylamine (640 mg, 7.4 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid (800 mg, 90%). MS [M+H]+243.
    • (b) Methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentane-carboxylic acid
  • To a solution of methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentanecarboxylate (820 mg, 3.4 mmol) in 25 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (260 mg, 6.12 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 700 mg (90%) of methyl 1-[N-(3-methylbutyl)carbamoyl]-cyclopentanecarboxylic acid as a white solid. MS [M+H]+ 228.
  • (c) {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide
  • To 1-[N-(3-methylbutyl)carbamoyl]cyclopentane carboxylic acid (38 mg, 0.16 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (28 mg, 0.18 mmol) and EDC (34 mg, 0.18 mmol). The mixture was stirred for 10 min then 7-amino-5-methyl-7H-dibenzoazaperhydroepin-6-one (40 mg, 0.16 mmol) (obtained as the first eluting peak of a racemic mixture on a CHIRALCEL OD column with 20% iPrOH/Hexane with diethylamine) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid (67 mg, 94%). 1H NMR (300 MHz, CD3OD) δ 7.20-7.80 (m, 9H), 6.25 (m, 1H), 5.25 (d, 1H), 3.38 (s, 3H), 3.27 (m, 1H), 2.58-2.05 (m, 5H), 1.80-1.25 (m, 8H), 0.95, (m, 6H). MS [M+H]+ 448.
    • Example 2 {[N-(3-Methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide
  • Figure US20090264419A1-20091022-C00042
  • The title compound was prepared in a manner similar to that described for Example 1. The product was obtained as a solid. MS [M+H]+ 475.
    • Example 3 [(N-Butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide
  • Figure US20090264419A1-20091022-C00043
  • The title compound was prepared in a manner similar to that described for Example 1. The product was obtained as a solid. MS [M+H]+ 461.
    • Example 4 2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}-acetamide
  • Figure US20090264419A1-20091022-C00044
    • (a) {[(tert-Butoxy)carbonylamino]cyclohexyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide
  • Diisopropylethylamine (2.5 mL, 15.0 mmol) and HATU (2.85 g, 7.5 mmol) were added to a solution of 1-[(tert-butoxy)carbonylamino]cyclohexanecarboxylic acid (1.75 g, 7.2 mmol) in CH2Cl2 (10 mL) at 0° C. and stirred for 10 min. (S)-3-amino-1-methyl-5-phenyl-3H-benzoazepin-2-one (3.0 g, 6.0 mmol) was then added. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The organic layer was separated and washed with a saturated solution of NaHCO3, 20% citric acid, brine, dried over Na2SO4, filtered and concentrated to afford a white solid (2.98 g, 99%). This compound underwent no further purification: 1H NMR (500 MHz, CD3OD) δ 7.33-7.13 (m, 9H), 5.35 (s, 1H), 3.48 (s, 3H), 2.21-1.29 (m, 10H), 1.50, (s, 9H).
    • (b) (Aminocyclohexyl)-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide
  • A saturated solution of HCl in EtOAc (50 mL) was added to a solution of {[(tert-butoxy)carbonylamino]cyclohexyl}-(S)-3-N-(1-methyl-2-oxo-5-phenyl(3H-benzoazepin-3-yl))carboxamide (2.9 g, 5.9 mmol) in EtOAc (75 mL) and stirred at room temperature overnight. The reaction was quenched with 1N NaOH (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid (1.76 g, 77%). mp 106-110° C.; 1H NMR (500 MHz, CD3OD) δ 7.33-7.13 (m, 9H), 5.32 (s, 1H), 3.48 (s, 3H), 1.98-1.25 (m, 10H); CI MS m/z=391 [C23H26N4O2+H]+; HPLC 100%, tr=9.17 min. (HPLC Conditions A).
    • (c) 2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]-cyclohexyl}acetamide
  • Diisopropylethylamine (0.87 ml, 5.15 mmol) and HATU (979 mg, 2.58 mmol) were added to a solution of 2-(3,5-difluorophenyl)acetic acid (426 mg, 2.47 mmol) in CH2Cl2 (40 mL) at 0° C. and stirred for 5 min. (Aminocyclohexyl)-(S)-3-N-(1-methyl-2-oxo-5-phenyl(3H-benzoazepin-3-yl))carboxamide (800 mg, 2.06 mmol) was then added, and the solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The organic layer was separated and washed with a saturated solution of NaHCO3, 20% citric acid, brine, dried over Na2SO4, filtered and concentrated to give a white solid. Further purification by flash column chromatography afforded the title compound (659 mg, 60%) as a white solid:
  • mp 126-129° C.; 1H NMR (500 MHz, CD3OD) δ 7.72-7.32 (m, 9H), 6.97 (d, 2H), 6.80 (t, 1H), 5.31 (s, 1H), 3.70 (s, 2H), 3.48 (s, 3H), 2.24-1.30 (m 10H); API MS m/z=545 [C31H30F2N4O3+H]+; HPLC 99.5%, tr=22.26 min. (HPLC Conditions A).
    • Example 5 2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-acetamide
  • Figure US20090264419A1-20091022-C00045
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 112-117° C.; 1H NMR (500 MHz, CD3OD) δ 7.72-7.31 (m, 9H), 6.96 (d, 2H), 6.81 (t, 1H) 5.33 (s, 1H), 3.63 (s, 2H), 3.47 (s, 3H), 2.41-1.72 (m, 8H); API MS m/z=531 [C30H28F2N4O3+H]+; HPLC 99.4%, tr=21.23 min. (HPLC Conditions A).
    • Example 6 2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}-acetamide
  • Figure US20090264419A1-20091022-C00046
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 212-214° C.; 1H NMR (500 MHz, CD3OD) δ 7.71-7.30 (m, 9H), 6.98 (d, 2H), 6.81 (t, 1H), 5.28 (s, 1H), 3.65 (s, 2H), 3.48 (s, 3H), 1.48 (m, 2H), 1.08 (m, 2H); API MS m/z=503 [C28H24F2N4O3+H]+; HPLC 97.7%, tr=19.48 min. (HPLC Conditions A).
    • Example 7 3-Cyclopentyl-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide
  • Figure US20090264419A1-20091022-C00047
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 88-103° C.; 1H NMR (500 MHz, CD3OD) δ 7.71-7.30 (m, 9H), 5.28 (d, 1H), 3.51 (d, 3H), 2.39-0.82 (m, 23 H); CI MS m/z=516 [C31H38N4O3+H]+; HPLC 96.5%, tr=14.79 min. (HPLC Conditions A).
    • Example 8 2-(3,5-Difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide
  • Figure US20090264419A1-20091022-C00048
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.15-7.60 (m, 10H), 6.05-6.80 (m, 3H), 5.40 (d, 1H), 3.60 (s, 2H), 3.40 (s, 3H), 2.90 (m, 2H), 2.60 (m, 2H), 2.05, (m, 4H). MS [M+H]+ 546.
    • Example 9 Phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidine carboxylate
  • Figure US20090264419A1-20091022-C00049
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-7.40 (m, 15H), 6.45-6.80 (m, 3H), 5.40 (d, 1H), 5.15 (s, 2H), 4.85 (s, 3H), 3.85 (m, 1H), 3.60 (s, 2H), 3.40 (s, 3H), 2.20, (m, 4H). MS [M+H]+ 680.
    • Example 10 4-Methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide
  • Figure US20090264419A1-20091022-C00050
  • The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the amino bisbenzazepine obtained as the first eluting peak of a racemic mixture on a CHIRALCEL OD column with 20% iPrOH/Hexane with diethylamine. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-7.60 (m, 8H), 6.59 (s, 1H), 5.20 (d, 1H), 3.40 (s, 3H), 2.40-1.60 (m, 13H), 0.9, (d, 6H). MS [M+H]+ 448.
    • Example 11 N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]-cyclopentyly}carboxamide
  • Figure US20090264419A1-20091022-C00051
  • The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the corresponding amino benzodiazepine that, as the CBz protected form, was the first eluting peak of the racemic mixture on a CHIRALCEL Aβ column using acetonitrile. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-7.40 (m, 13H), 5.2 (s, 2H), 5.60 (m, 1H), 5.40 (d, 1H), 5.15 (s, 2H), 3.45 (s, 3H), 2.40 (m, 2H), 2.05-1.80 (m, 6H). MS [M+H]+ 579.
    • Example 12 (2S)—N-{[N-(1-{[3-(4-Fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopropyl}-2-hydroxy-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00052
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.00-6.70 (m, 8H), 4.45 (m, 5H), 4.15 (m, 1H), 3.10-3.40 (m, 2H), 2.00-1.00 (m, 12H), 0.90, (m, 6H). MS [M+H]+526.
    • Example 13 (2S)—N-{[N-(1-{[3-(4-Fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopentyl}-2-hydroxy-3-methylbutanamide
  • Figure US20090264419A1-20091022-C00053
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-6.80 (m, 8H), 4.60 (m, 3H), 4.00 (d, 1H), 3.5 (m, 1H), 3.20 (m, 1H), 2.40-1.05 (m, 17H), 1.00 (d, 3H), 0.90 (d, 3H). MS [M+H]+ 540.
    • Example 14 2,2-Difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide
  • Figure US20090264419A1-20091022-C00054
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.90-7.00 (m, 13H), 5.45 (d, 1H), 3.45 (s, 3H), 2.80 (m, 2H), 2.60-2.20 (m, 6H), 1.80-1.90 (m, 8H). MS [M+H]+ 627.
    • Example 15 N—[(N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide
  • Figure US20090264419A1-20091022-C00055
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 8.00-7.20 (m, 9H), 6.10 (s, 1H), 5.40 (d, 1H), 5.15 (s, 2H), 3.60 (m, 1H), 3.40 (3, 3H), 3.15 (m, 1H), 2.60-1.20 (m, 14H). MS [M+H]+ 584.
    • Example 16 (2S)-2-Hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide
  • Figure US20090264419A1-20091022-C00056
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. MS [M+H]+ 559.
    • Example 17 3-Cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide
  • Figure US20090264419A1-20091022-C00057
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.60-7.20 (m, 8H), 5.40 (m, 1H), 3.45 (s, 3H), 2.70 (s, 2H), 2.40 (m, 4H), 2.05-1.09 (m, 14H), 0.4 (m, 1H), 0.00 (m, 1H). MS [M+H]+ 541.
    • Example 18 (Aminocyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide
  • Figure US20090264419A1-20091022-C00058
  • The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the BZD amine that, as a CBz protected form, was the first peak of the racemic mixture on the CHIRALCEL Aβ column with acetonitrile. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-7.80 (m, 8H), 5.45 (m, 1H), 3.45 (s, 3H), 2.20 (m, 3H), 2.00-1.60 (m, 5H). MS [M+H]+ 445.
    • Example 19 {[(Aminocyclopentyl)carbonylamino]cyclopentyl}-N—((S)1-methyl-2-oxo-5-phenyl(3H-benzo[f]1,4-diazepin-3-yl))carboxamide
  • Figure US20090264419A1-20091022-C00059
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD) δ 7.20-7.60 (m, 9H), 5.45 (d, 1H), 3.45 (s, 3H), 2.80-2.00 (m, 8H), 1.90-1.50 (m, 8H). MS [M+H]+ 445.
    • Example 20 (2R)-2-Hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide
  • Figure US20090264419A1-20091022-C00060
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 9.16 (d, 1H), 7.69-7.52 (m, 5H), 7.33 (d, 1H), 7.24-7.15 (m, 3H), 5.45 (d, 1H), 3.42 (s, 3H), 2.24-2.14 (m, 3H), 2.11-1.84 (m, 1H), 1.83-1.72 (m, 4H), 1.66-1.56 (m, 2H); MS [M+H]+ 583.
    • Example 21 2-Ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide
  • Figure US20090264419A1-20091022-C00061
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.17 (d, 1H), 7.76-7.60 (m, 5H), 7.40 (d, 1H), 7.32-7.23 (m, 1H), 6.99 (s, 1H), 5.52 (d, 1H), 4.01 (d, 2H), 3.67-3.60 (q, 2H), 3.48 (s, 3H), 2.48-2.40 (m, 2H), 2.14-2.08 (m, 2H), 1.89-1.83 (m, 3H), 1.64 (s, 2H), 1.29 (s, 3H); MS [M+H]+ 531.
    • Example 22 3-Cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide
  • Figure US20090264419A1-20091022-C00062
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.00 (d, 1H), 7.68-7.51 (m, 5H), 7.32 (d, 1H), 7.23-7.17 (m, 2H), 5.85 (s, 1H), 5.41 (d, 1H), 3.39 (s, 3H), 2.42-2.22 (m, 2H), 2.20 (t, 2H), 2.10-1.90 (m, 2H), 1.76-1.44 (m, 13H), 1.10-1.0 (m, 2H); MS [M+H]+569.
    • Example 23 (2S)-2-Hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide
  • Figure US20090264419A1-20091022-C00063
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.50 (d, 1H), 7.76-7.61 (m, 4H), 7.41 (d, 1H), 7.32-7.28 (m, 1H), 7.03 (s, 1H), 5.53-5.51 (m, 1H), 4.06 (d, 1H), 3.48 (s, 3H), 2.57-2.35 (m, 2H), 2.30-2.10 (m, 2H), 2.09-1.90 (m, 1H), 1.80-1.70 (m, 5H), 1.05 (d, 3H), 0.94 (d, 3H); MS [M+H]+ 545.
    • Example 24 (2S)-2-Cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide
  • Figure US20090264419A1-20091022-C00064
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.04 (d, 1H), 7.67-7.51 (m, 4H), 7.31 (d, 1H), 7.23-7.18 (m, 1H), 7.02 (s, 1H), 5.42 (d, 1H), 3.94 (m, 1H), 3.78 (s, 3H), 2.42-2.25 (m, 2H), 2.18-1.90 (m, 2H), 1.80-1.65 (m, 9H), 1.30-1.00 (m, 6H); MS [M+H]+ 585.
    • Example 25 (2R)-2-Cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide
  • Figure US20090264419A1-20091022-C00065
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.17 (d, 1H), 7.67-7.52 (m, 4H), 7.32 (d, 1H), 7.23-7.15 (m, 1H), 6.89 (s, 1H), 5.45 (d, 1H), 3.92 (d, 1H), 3.39 (s, 3H), 2.45-2.25 (m, 2H), 2.10-1.95 (m, 2H), 1.80-1.50 (m, 10H), 1.25-1.00 (m, 6H); MS [M+H]+ 585.
    • Example 26 (2S)-2-Amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide
  • Figure US20090264419A1-20091022-C00066
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.95 (s, 1H), 7.79-7.63 (m, 5H), 7.40-7.30 (m, 2H), 5.46 (s, 1H), 4.20 (d, 2H), 4.0-3.90 (m, 1H), 3.51 (s, 3H), 2.40-2.20 (m, 2H), 2.10 2.00 (m, 2H), 1.90-1.70 (m, 4H), 1.40-1.20 (m, 2H), 1.10-1.00 (m, 3H), 1.00-0.90 (m, 3H); MS [M+H]+ 559.
    • Example 27 [(Cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide
  • Figure US20090264419A1-20091022-C00067
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H-NMR (CDCl3) 8.10 (d, 1H), 7.75-7.62 (m, 3H), 7.42-7.39 (m, 3H), 7.30-7.20 (m, 1H), 6.11 (s, 1H), 5.47 (d, 1H), 3.46 (s, 3H), 2.50-2.45 (m, 2H), 2.30-2.10 (m, 1H), 2.09-1.75 (m, 9H), 1.70-1.60 (m, 1H), 1.50-1.40 (m, 2H), 1.39-1.20 (m, 3H); MS [M+H]+ 555.
    • Example 29 {[N-(3-Methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide
  • Figure US20090264419A1-20091022-C00068
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.78-7.60 (m, 5H), 7.48-7.22 (m, 3H), 5.47 (d, 1H), 3.49 (s, 3H), 3.30 (m, 2H), 2.38-2.22 (m, 4H), 1.84-1.38 (m, 7H), 0.90 (d, 6H). MS [M+H]+ 543.
    • Example 30 4-Methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide
  • Figure US20090264419A1-20091022-C00069
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.78-7.56 (m, 5H), 7.42-7.20 (m, 3H), 5.46 (d, 1H), 3.44 (s, 3H), 2.48-2.20 (m, 4H), 2.05 (m, 2H), 1.80 (m, 4H), 1.58 (m, 3H), 0.88 (d, 6H). MS [M+H]+543.
    • Example 31 (2S)-2-Hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide
  • Figure US20090264419A1-20091022-C00070
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.78-7.58 (m, 5H), 7.43-7.20 (m, 3H), 5.49 (d, 1H), 4.17 (m, 1H), 3.45 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.92-1.50 (m, 8H), 0.92 (m, 6H). MS [M+H]+ 559.
    • Example 32 3-Methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide
  • Figure US20090264419A1-20091022-C00071
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.78-7.56 (m, 5H), 7.40-7.20 (m, 3H), 5.51 (d, 1H), 3.72 (m, 2H), 3.44 (s, 3H), 3.39 (s, 3H), 2.58-2.30 (m, 4H), 2.02 (m, 2H), 1.88 (m, 4H). MS [M+H]− 531.
    • Example 33 (2S)-2-Hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide
  • Figure US20090264419A1-20091022-C00072
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.72-7.57 (m, 5H), 7.40-7.20 (m, 3H), 5.48 (d, 1H), 4.37 (m, 1H), 3.42 (s, 3H), 3.20 (q, 1H), 2.97 (q, 1H), 2.38 (m, 2H), 1.96 (m, 2H), 1.80-1.52 (m, 4H). MS [M+H]+ 593.
    • Example 34 N—[(N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide
  • Figure US20090264419A1-20091022-C00073
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.74-7.55 (m, 5H), 7.40-7.20 (m, 3H), 5.48 (d, 1H), 4.61 (q, 2H), 4.12 (q, 2H), 3.44 (s, 3H), 2.42 (m, 2H), 2.05 (m, 2H), 1.80 (m, 4H). MS [M+H]+ 593.
    • Example 35 (2S)-2-Hydroxy-3-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-butanamide
  • Figure US20090264419A1-20091022-C00074
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.64-7.35 (m, 8H), 5.25 (d, 1H), 4.06 (d, 1H), 3.35 (s, 3H), 2.42-2.05 (m, 6H), 1.80 (m, 4H), 1.05 (d, 3H), 0.95 (d, 3H). MS [M+H]+ 450.
    • Example 36 (2S)-2-Hydroxy-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide
  • Figure US20090264419A1-20091022-C00075
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.64-7.32 (m, 8H), 5.24 (d, 1H), 4.20 (q, 1H), 3.34 (s, 3H), 2.38 (m, 2H), 2.20-1.60 (m, 9H), 0.97 (m, 6H). MS [M+H]+ 464.
    • Example 37 3-Cyclopentyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide
  • Figure US20090264419A1-20091022-C00076
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.64-7.35 (m, 8H), 5.25 (d, 1H), 3.36 (s, 3H), 2.42-1.45 (m, 21H). MS [M+H]+ 474.
    • Example 38 (2S)-2-Cyclohexyl-2-hydroxy-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-acetamide
  • Figure US20090264419A1-20091022-C00077
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.62-7.36 (m, 8H), 5.24 (d, 1H), 3.98 (d, 1H), 3.33 (s, 3H), 2.42-1.04 (m, 19H). MS [M+H]+ 490.
    • Example 39 3-Cyclopropyl-N-{[N—((S)-5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-propanamide
  • Figure US20090264419A1-20091022-C00078
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.56-7.24 (m, 8H), 5.16 (d, 1H), 3.27 (s, 3H), 2.38-2.15 (m, 4H), 2.10-1.82 (m, 2H), 1.78-1.42 (m, 6H), 0.64 (m, 1H), 0.36 (m, 2H), 0.02 (m, 2H). MS [M+H]+ 446.
    • Example 40 N-{[N-(1-Butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00079
  • The amino benzodiazepine core was made in a manner similar to that described in the Scheme 6. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.60-7.22 (m, 4H), 5.25 (d, 1H), 4.36 (m, 1H), 3.56 (m, 1H), 3.31 (m, 1H), 2.40-0.78 (m, 34H). MS [M+H]+ 509.
    • Example 41 N-{[N-(5-Cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00080
  • The amino benzodiazepine core was made in a manner similar to that described in the Scheme 6. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.58-7.20 (m, 4H), 5.30 (d, 1H), 3.38 (s, 3H), 3.30 (m, 1H), 2.40-1.20 (m, 21H), 0.89 (d, 6H). MS [M+H]+ 467.
    • Example 42 (2S)-2-Hydroxy-3-methyl-N—({N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]carbamoyl}cyclopentyl) butanamide
  • Figure US20090264419A1-20091022-C00081
  • The amino benzoazepine core was made in a manner similar to that described in J. Med. Chem. 1999, 42, 2621. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.34-7.10 (m, 9H), 5.16 (m, 1H), 4.76 (m, 1H), 4.42 (m, 1H), 3.94 (m, 1H), 2.64-1.64 (m, 13H), 1.00-0.86 (m, 6H). MS [M+H]+ 478.
    • Example 43 (2S)-4-Methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-2-[(propylsulfonyl)amino]pentanamide
  • Figure US20090264419A1-20091022-C00082
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.62-7.32 (m, 8H), 5.40 (d, 1H), 5.24 (d, 1H), 4.02 (m, 1H), 3.34 (s, 3H), 2.98 (m, 2H), 2.42-1.58 (m, 13H), 0.94-0.85 (m, 9H). MS [M+H]+ 569.
    • Example 44 (2S)-2-Amino-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide
  • Figure US20090264419A1-20091022-C00083
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.60-7.30 (m, 8H), 5.22 (d, 1H), 3.32 (s, 3H), 3.08 (m, 1H), 2.48 (s, 3H), 2.46-1.45 (m, 11H), 0.98-0.92 (q, 6H). MS [M+H]+ 477.
    • Example 45 2,2-Difluoro-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-pentanamide
  • Figure US20090264419A1-20091022-C00084
  • The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. 1H NMR (300 MHz CDCl3) 7.62-7.30 (m, 8H), 5.23 (d, 1H), 3.34 (s, 3H), 2.42-1.80 (m, 11H), 1.00 (d, 6H). MS [M+H]+ 484.
    • Example 56 4-Methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide
  • Figure US20090264419A1-20091022-C00085
  • The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. 1H NMR (300 MHz, CD3OD): δ 7.91 (d, J=6.7 Hz, 1H), 7.63 (m, 1H), 7.51-7.28 (m, 7H), 7.08 (d, J=7.0 Hz, 1H), 5.84 (s, 1H), 5.25 (d, J=6.7 Hz, 1H), 2.41-0.89 (m, 19H); ESI MS m/z=434 [C26H31N3O3+H]+.
    • Example 57 N—({N-[5-(3,3-Dimethyl-2-oxobutyl)-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00086
  • To a solution of 4-methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide (540 mg, 1.3 mmol), in DMF (25 mL) was added K2CO3 (0.52 g, 3.7 mmol) and bromopinacolone (0.45 g, 2.5=mol), and the solution was allowed to stir for 40 h at room temperature. The contents of the flask were partitioned between EtOAc and a 5% LiCl solution (150 mL each), the organic phase washed with 5% LiCl (2×50 mL), dried over anhydrous Na2SO4 and concentrated to yield a white solid. This was further purified by column chromatography [silica gel, EtOAc/hexanes (35:6)] to yield the title compound (340 mg, 51%) as a white solid. The title compound were separated by chiral HPLC using the following conditions: Column, Chiralpak AD column (5 cm×50 cm); Eluent, 96:4 Hexanes/2-Propanol; Flow rate, 100 mL/min; Monitoring wavelength, 220 nm.
  • Enantiomer A: 158 mg: mp 126-130° C.; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=6.7 Hz, 1H), 7.62-7.13 (m, 8H), 5.82 (s, 1H), 5.35 (d, J=7.4 Hz, 1H), 4.62 (q b, J=14.1 Hz, 2H), 2.47-1.59 (m, 13H), 1.22 (s, 9H), 0.92 (d, J=5.8 Hz, 6H); IR (KBr) 3410, 2958, 2475, 1724, 1663 cm−1; ESI MS m/z=532 [C32H41N3O4+H]+; HPLC 97.8%, tr=24.83 min. (HPLC Conditions A).
  • Enantiomer B: 165 mg; mp 126-130° C.; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=6.7 Hz, 1H), 7.62-7.13 (m, 8H), 5.82 (s, 1H), 5.35 (d, J=7.4 Hz, 1H), 4.62 (qab, J=14.1 Hz, 2H), 2.47-1.59 (m, 13H), 1.22 (s, 9H), 0.92 (d, J=5.8 Hz, 6H); IR (KBr) 3410, 2958, 2475, 1724, 1663 cm−1; ESI MS m/z 532 [C32H41N3O4+H]+; HPLC 97.8%, tr=24.83 min. (HPLC Conditions A).
    • Example 58 4-Methyl-N—[(N-{6-oxo-5-[(3-phenoxyphenyl)methyl](7H-dibenzo[d,f]azaperhydroepin-7-yl)}carbamoyl)cyclopentyl]pentanamide
  • Figure US20090264419A1-20091022-C00087
  • The title compound was prepare in a manner similar to that described for Example 57. The product was obtained as a white solid: mp 94-100° C.; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=6.9 Hz, 1H), 7.58-6.43 (m, 17H), 5.82 (a, 1H), 5.39 (d, J=7.4 Hz, 1H), 5.12 (qab, J=14.5 Hz, 2H), 2.47-1.57 (m, 13H), 0.82 (d, J=6.1 Hz, 6H); IR (KBr) 3332, 2955, 1660, 1584, 1487 cm−1; ESI MS m/z=616 [C39H41N3O4+H]; HPLC 99.4%, tr=19.54 min. (HPLC Conditions A).
    • Example 59 N-{[N-(5-Butyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00088
  • The title compound was prepared in a manner similar to that described for Example 57. The product was obtained as a white solid. The enantiomers were separated by chiral HPLC using the following conditions: Column, Chiralcel OD column (5 cm×50 cm); Eluent, 95:5 Hexanes/2-Propanol; Flow rate, 100 mL/min; Monitoring wavelength, 270 nm.
  • Enantiomer A: 197 mg: mp 123-126° C.; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=7.0 Hz, 1H), 7.58-6.43 (m, 8H), 5.91 (s, 1H), 5.26 (d, J=7.4 Hz, 1H), 4.29 (m, 2H), 3.52 (m, 2H), 2.43-1.19 (m, 15H), 0.95 (d, J=6.1 Hz, 6H), 0.62 (m, 3H); IR (KBr) 3325, 2957, 2871, 1655, 1498 cm−1; ESI MS m/z=490 [C30H39N3O3+H]+; HPLC 100%, tr=20.25 min. (HPLC Conditions A).
  • Enantiomer B: 167 mg: mp 110-115° C.; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=7.0 Hz, 1H), 7.58-6.43 (m, 8H), 5.91 (s, 1H), 5.26 (d, J=7.4 Hz, 1H), 4.29 (m, 2H), 3.52 (m, 2H), 2.43-1.19 (m, 15H), 0.95 (d, J=6.1 Hz, 6H), 0.62 (m, 3H); IR (KBr) 3325, 2957, 2871, 1655, 1498 cm−1; ESI MS m/z=490 [C30H39N3O3+H]−; HPLC 100%, tr=20.26 min. (HPLC Conditions A).
    • Example 60 4-Methyl-N—({N-[6-oxo-5-benzyl(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)pentanamide
  • Figure US20090264419A1-20091022-C00089
  • The title compound was prepared in a manner similar to that described for Example 57. The product was obtained as a white solid:
  • mp 103-106° C.; 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J=6.8 Hz, 1H), 7.52-7.25 (m, 8H), 7.05 (m, 3H), 6.78 (m, 2H), 5.84 (s, 1H), 5.36 (d, J=7.4 Hz, 1H), 5.04 (qab, J=14.7 Hz, 2H), 2.41-1.26 (m, 13H), 0.91 (d, J=5.8 Hz, 6H); IR (KBr) 3325, 2956, 1655, 1498, 1396 cm1; ESI MS m/z=524 [C33H37N3O3+H]+; HPLC 100%, tr=27.04 min. (HPLC Conditions A).
    • Example 61 N—({N-[5-(tert-Butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00090
  • Figure US20090264419A1-20091022-C00091
    • c) Preparation of 25
  • To a stirred solution of 23 (see Scheme 6) (1.0 equiv) in CH2Cl2 (0.1 M) was added a 30% solution of HBr in acetic acid (16 equiv). The mixture was stirred for 14 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc and water and separated. The aqueous layer was made basic using 6 N NaOH and was extracted with CH2Cl2. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting solid was dissolved in CH2Cl2 and added to a stirring solution of the acid 24 (1.2 equiv), EDC-HCl (1.5 equiv), HOBt (1.5 equiv), and DIPEA (5.0 equiv) in CH2Cl2 (0.15 M). The reaction was stirred overnight, quenched with water, washed with 20% citric acid (3×), sat NaHCO3 (2×), brine, dried over Na2SO4, filtered and concentrated. Crude material was recrystallized from EtOAc and Et2O to give 25 (4.4 g, 95%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.71-6.98 (m, 6H), 5.87 (s, 1H), 5.29 (d, 1H), 2.38 (m, 2H), 2.21 (t, 2H) 2.01 (m, 2H), 1.52 (m, 7H), 1.23 (s, 9H), 0.88 (d, 6H).
    • d) Preparation of Example 61.
  • To a suspension of 25 (1 equiv) and freshly powdered K2CO3 (3.0 equiv) in DMF (0.05 M) was added methyl iodide (1.5 equiv). The mixture was stirred (5 h). To the reaction was added EtOAc and water and the layers separated. The organic layer was washed with 5% LiCl (2×), brine, dried over Na2SO4, filtered and concentrated. The resulting material was dissolved in Et2O and concentrated in vacuo providing N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}-cyclopentyl)-4-methylpentanamide (60 mg, 66%) as a white powder: mp 175-178° C.; 1H NMR (500 MHz, CDCl3) δ 7.71-7.17 (m, 5 H), 5.89 (s, 1H), 5.23 (d, 1H), 3.34 (s, 3H), 2.41-2.29 (m, 3H), 2.21 (m, 2H), 2.04 (m, 3H), 1.80 (m, 4H), 1.60 (m, 1H), 1.18 (s, 9 H), 0.90 (d, 6H); ESI MS m/z=455 [C26H38N4O3+H]+; IR (KBr)=3324, 2958, 1677, 1508, 1366, 1197 cm−1; HPLC 96.8%, tr=15.75 min. (HPLC Conditions A).
    • Example 62 N—({N-[5-(tert-Butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00092
  • The title compound was prepared in a manner similar to that described for Example 62. The product was obtained as a white powder (450 mg, 70%): mp 175-177° C.; 1H NMR (500 MHz, CDCl3) δ 7.71-7.13 (m, 5H), 5.89 (s, 1H), 5.20 (d, 1 H), 4.36 (m, 1H), 3.50 (m, 1H), 2.32 (m, 3H) 2.20 (m, 2 H), 2.02 (m, 3H), 1.80 (m, 4H), 1.57 (m, 1H), 1.35 (m, 2 H) 1.26 (s, 9H), 1.21 (m, 2H), 0.89 (d, 6H), 0.83 (t, 3 H); ESI MS m/z=497 [C29H44N4O3+H]+; IR (KBr)=3321, 2959, 2363, 1676, 1508, 1365 cm−1; HPLC 95.4%, tr=19.69 min. (HPLC Conditions A).
    • Example 63 N—({N-[5-Butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide
  • Figure US20090264419A1-20091022-C00093
  • The title compound was prepared in a manner similar to that described for Example 62. The product was obtained as a white powder: mp 63-67° C.; 1H NMR (CDCl3) δ 8.46-7.11 (m, 8H), 5.89 (s, 1H), 5.40 (d, J=6.87 Hz, 1H), 5.28 (d, J=15.77 Hz, 1H), 5.12 (d, J=15.82 Hz, 1H), 2.74 (m, 2 H), 2.43-0.77 (m, 27H); ESI MS m/z=532 [C31H41N5O3+H]+; IR (KBr) 3310 (br.), 1670 cm−1; HPLC>95% % tr=17.07 min. (HPLC Conditions A). Anal. Calcd for [C31H41N5O3.0.5H2O]: C, 68.86; H, 7.83; N, 12.95. Found: C, 68.73; H, 7.86; N, 12.79.
  • Tables 1-4 below provide representative Examples of the compounds of Formula (I) of the present invention.
  • TABLE 1
    Figure US20090264419A1-20091022-C00094
    Ex# R3 L C -WXYZ R11
     2 3-Me-butyl NHC(═O) cyclopentyl Me phenyl
     3 n-butyl NHC(═O) cyclopentyl Me phenyl
     4 3,5-diF-benzyl C(═O)NH cyclohexyl Me phenyl
     5 3,5-diF-benzyl C(═O)NH cyclopentyl Me phenyl
     6 3,5-diF-benzyl C(═O)NH cyclopropyl Me phenyl
     7 cyclopentyl ethyl C(═O)NH cyclohexyl Me phenyl
     8 3,5-diF-benzyl C(═O)NH 4-piperidyl Me phenyl
     9 3,5-diF-benzyl C(═O)NH N-benzyloxy- Me phenyl
    carbonyl-4-piperidyl
    11 benzyl O—C(═O)NH cyclopentyl Me 4-CF3-phenyl
    14 3-phenyl-1,1- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    diF-propyl
    15 2-(4-piperidyl) C(═O)NH cyclopentyl Me 4-CF3-phenyl
    ethyl
    16 1-hydroxy-3- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    Me-butyl
    17 2-cyclopropyl-ethyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    19 1-amino cyclopentyl C(═O)NH cyclopentyl Me phenyl
    20 1-hydroxy-2- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    imidazol-2-yl-ethyl
    21 ethyoxy-methyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    22 2-cyclopentyl-ethyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    23 1-hydroxy-2-Me- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    propyl
     24* 1-hydroxy-1- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    cyclohexyl-methyl
     25* 1-hydroxy-1- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    cyclohexyl-methyl
    26 1-NH2-3-Me- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    butyl
    27 cyclohexyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    29 3-Me-butyl NHC(═O) cyclopentyl Me 4-CF3-phenyl
    30 3-Me-butyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    31 1-hydroxy-3-Me- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    butyl
    32 2-methoxy-ethyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    33 1-hydroxy-2-phenyl- C(═O)NH cyclopentyl Me 4-CF3-phenyl
    ethyl
    34 benzyloxy-methyl C(═O)NH cyclopentyl Me 4-CF3-phenyl
    39 2-cyclopropyl-ethyl C(═O)NH cyclopentyl Me phenyl
    40 3-Me-butyl C(═O)NH cyclopentyl n-butyl cyclopentyl
    41 3-Me-butyl C(═O)NH cyclopentyl Me cyclopentyl
    61 3-Me-butyl C(═O)NH cyclopentyl Me t-butyl
    62 3-Me-butyl C(═O)NH cyclopentyl n-butyl t-butyl
    63 3-Me-butyl C(═O)NH cyclopentyl 2- n-butyl
    pyridyl-
    methyl
    *stereoisomers
  • TABLE 2
    Figure US20090264419A1-20091022-C00095
    Ex. # R3 L C Z-Y-X-W-
     1 3-Me-butyl NHC(═O) cyclopentyl Me
    10 3-Me-butyl C(═O)NH cyclopentyl Me
    35 1-hydroxy-2-Me- C(═O)NH cyclopentyl Me
    propyl
    36 1-hydroxy-3-Me- C(═O)NH cyclopentyl Me
    butyl
    37 2-cyclopentyl-ethyl C(═O)NH cyclopentyl Me
    38 1-hydroxy-1- C(═O)NH cyclopentyl Me
    cyclohexyl-methyl
    43 1-(propyl- C(═O)NH cyclopentyl Me
    sulfamide)-3-Me-
    butyl
    44 1-(N-Me-amino)-3- C(═O)NH cyclopentyl Me
    Me-butyl
    45 1,1-diF-3-Me-butyl C(═O)NH cyclopentyl Me
    56 3-Me-butyl C(═O)NH cyclopentyl H
    57 3-Me-butyl C(═O)NH cyclopentyl 3,3-dimethyl-
    2-oxobutyl
    58 3-Me-butyl C(═O)NH cyclopentyl 3-phenoxy-
    benzyl
    59 3-Me-butyl C(═O)NH cyclopentyl n-butyl
    60 3-Me-butyl C(═O)NH cyclopentyl benzyl
  • TABLE 3
    Figure US20090264419A1-20091022-C00096
    Ex. # R3 L C Z-Y-X-W-
    12 1-hydroxy-3-Me- C(═O)NH cyclopropyl 3-(4-F-phenoxy)-
    butyl benzyl
    13 1-hydroxy-3-Me- C(═O)NH cyclopentyl 3-(4-F-phenoxy)-
    propyl benzyl
  • TABLE 4
    Figure US20090264419A1-20091022-C00097
    Ex. # R3 L C Z-Y-X-W-
    42 1-hydroxy-2-Me- C(═O)NH cyclopentyl benzyl
    propyl
    • Utility
  • Aβ production has been implicated in the pathology of Alzheimer's Disease (Aβ). The compounds of the present invention have utility for the prevention and treatment of Aβ by inhibiting Aβ production. Methods of treatment target formation of Aβ production through the enzymes involved in the proteolytic processing of β amyloid precursor protein. Compounds that inhibit β or γ secretase activity, either directly or indirectly, control the production of Aβ. Such inhibition of β or γ secretases reduces production of Aβ, and is expected to reduce or prevent the neurological disorders associated with Aβ protein, such as Alzheimer's Disease.
  • Cellular screening methods for inhibitors of Aβ production, testing methods for the in vivo suppression of Aβ production, and assays for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including J. Med. Chem. 1999, 42, 3889-3898, PCT publication number WO 98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No. 5,593,846; all hereby incorporated by reference.
  • The compounds of the present invention have utility for the prevention and treatment of disorders involving Aβ production, such as cerebrovascular disorders.
  • Compounds of Formula (I) are expected to possess 7-secretase inhibitory activity. The γ-secretase inhibitory activity of the compound of the present invention is demonstrated using assays for such activity, for example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of γ-secretase, as determined by the Aβ immunoprecipitation assay.
  • Compounds provided by this invention should also be useful as a standard and reagent in determining the ability of a potential pharmaceutical to inhibit Aβ production. These would be provided in commercial kits comprising a compound of this invention.
  • As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS” denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide, and “EDTA” denotes ethylenediaminetetraacetic acid.
  • A compound is considered to be active if it has an IC50 or Ki value of less than about 100 μM for the inhibition of Aβ production. Preferrably the IC50 or Ki value is less than about 10 μM; more preferrably the IC50 or Ki value is less than about 0.1 μM. The present invention has been shown to inhibit Aβ protein production with an IC50 or Ki value of less than 100 μM.
    • β Amyloid Precursor Protein Accumulation Assay
  • A novel assay to evaluate the accumulation of Aβ protein was developed to detect potential inhibitors of secretase. The assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.
  • The effect of test compounds on the accumulation of Aβ in the conditioned medium is tested by immunoprecipitation. Briefly, N 9 cells are grown to confluency in 6-well plates and washed twice with 1× Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150 uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO (final concentration 1%) are added together with the addition of radiolabel. The cells are incubated for 4 h at 37° C. in a tissue culture incubator.
  • At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 μl normal mouse serum and 50 μl of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4° C., followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (clone 1101.1; directed against an internal peptide sequence in Aβ) and 50 μl protein A Sepharose. After incubation overnight at 4° C., the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of Aβ polypeptides. The steady-state level of Aβ in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound blocks Aβ accumulation in the conditioned medium, and is therefore considered active, with an IC50 less than 100 μM.
    • C-Terminus β Amyloid Precursor Protein Accumulation Assay
  • The effect of a test compound on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates. N 9 cells are metabolically labeled as above in the presence or absence of test compounds. At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN3). Again, lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 μl;) and 50 μl protein A Sepharose for 16 hours at 4° C. The immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments. The steady-state level of C-terminal APP fragments is compared to wells treated with DMSO (1%) alone. A typical test compound stimulates C-terminal fragment accumulation in the cell lysates, and is therefore considered active, with an IC50 less than 100 μM. Aβ-Immunoprecipitation Assay
  • This immunoprecipitation assay is specific for γ-secretase (i.e., proteolytic activity required to generate the C-terminal end of Aβ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed). N 9 cells are pulse labeled in the presence of a reported γ-secretase inhibitor (MDL 28170) for 1 h, followed by washing to remove radiolabel and MDL 28170. The media is replaced and test compounds are added. The cells are chased for increasing periods of times and Aβ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above). The test compound is characterized whether a stabilization of C-terminal fragments is observed and whether Aβ is generated from these accumulated precursor. A typical test compound prevents the generation of Aβ out of accumulated C-terminal fragments and is considered active with an IC50 less than 100 μM.
    • Dosage and Formulation
  • The compound of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • The compound of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to β-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.
  • The compound of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. The compound can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. The compound can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • The dosage regimen for the compound of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • The compound for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • In the methods of the present invention, the compound herein described in detail can form the active ingredient, and is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Compound of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Claims (27)

1.-24. (canceled)
25. A process for preparing a compound of Formula (I),
Figure US20090264419A1-20091022-C00098
or a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising an amide bond synthesis coupling a carboxylic acid 1 and an amine 2 including amide coupling methods comprising HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings:
Figure US20090264419A1-20091022-C00099
wherein the product, 3, comprises Formula (I)
wherein:
L is —NR26C(═O)—, —C(═O)NR26—, —NR26c (═O)O—, —OC(═O)NR26, or —NR26C(═O)NR26—;
R3 is (CR7R7a)n—R4,
—(CR7R7a)l—S— (CR7R7a)m—R4,
—(CR7R7a)l—O— (CR7R7a)m—R4,
—(CR7R7a)1—N(R7b)— (CR7R7a)m—R4,
—(CR7R7a)l—S(═O)— (CR7R7a)m—R4,
—(CR7R7a)l—S(═O)2—(CR7R7a)m—R4,
—(CR7R7a)l—C(═O)— (CR7R7a)m—R4,
—(CR7R7a)l—N(R7b)C(═O)— (CR7R7a)m—R4,
—(CR7R7a)l—C(═O)N(R7b)— (CR7R7a)m—R4,
—(CR7R7a)l—N(R7b)S(═O)2—(CR7R7a)m—R4, or
—(CR7R7a)l—S(═O)2N(R7b)— (CR7R7a)m—R4;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
l is 1, 2, or 3;
Ring C is a 3 to 8 membered carbocycle,
wherein the carbocycle is saturated or partially saturated;
optionally, the carbocycle contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R20)—; and
wherein the carbocycle is substituted with 0-4 R21;
R4 is H, OH, OR14a,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b, aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl and CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, C1-C4 alkyl, phenyl substituted with 0-5 R7c;
R7a, at each occurrence, is independently selected from H, Cl, F, Br, I, CN, CF3, and C1-C4 alkyl;
R7b is independently selected from H and C1-C4 alkyl;
R7c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, CF3, C1-C4 alkoxy, and C1-C4 alkyl;
B is
Figure US20090264419A1-20091022-C00100
R11 is H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
W is —(CR8R8a)p—;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from
H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl and C3-C8 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 1-3 R12;
C2-C4 alkenyl substituted with 1-3 R12;
C2-C4 alkynyl substituted with 1-3 R12;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a;
C2-C4 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12, at each occurrence, is independently selected from
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl substituted with 0-4 R14b, benzyl substituted with 0-4 R14b, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, C6-C10 aryl, benzyl, heterocycle, or C1-C4 alkyl;
R14b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, aryl-(C1-C6 alkyl)- wherein the aryl is substituted with 0-4 R15b, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R15b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R16, at each occurrence, is independently selected from
H, C1-C6 alkyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl,
aryl substituted by 0-4 R17a, or
—CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from
H, C1-C6 alkyl, phenyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R19, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R20 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19,
S(═O)2NR18R19, S(═O)2R17;
C1-C6 alkyl optionally substituted with 0-2 R20a;
aryl substituted with 0-4 R20b;
C3-C10 carbocycle substituted with 0-3 R20b; 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 R20b;
R20a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, F, ═O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R20b, and heterocycle substituted with 0-4 R20b;
R20b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R21, at each occurrence, is independently selected from
H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R21a;
aryl substituted with 0-3 R21b;
C3-C10 carbocycle substituted with 0-3 R21b; 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 R21b;
R21a, at each occurrence, is independently selected from
H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R21b;
C3-C6 cycloalkyl substituted with 0-3 R21b; and
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 0-3 R21b;
R21b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
additionally, two R21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
R23, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R26 is H;
C1-C6 alkyl substituted with 0-3 R26a;
C3-C10 carbocycle substituted with 0-3 R26b; or
aryl substituted with 0-3 R26b;
R26a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl and CF3; and
R26b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.
26. The process according to claim 25 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NR26C(═O)—, —C(═O)NR26—, or —OC(═O)NR26—;
R3 is —(CHR7)n—R4,
—(CHR7)l—N—(CR7R7a)m—R4, or
—(CHR7)l—O— (CR7R7a)m—R4;
n is 0, 1 or 2;
m is 0, 1 or 2;
l is 1;
Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R21;
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
R4 is H, OH, OR14a,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-2 R4a,
C2-C6 alkynyl substituted with 0-1 R4a,
C3-C6 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, and
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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and
C1-C2 haloalkoxy;
R6 is H;
R7, at each occurrence, is independently selected from H, OH, F, CF3, methyl, and ethyl;
B is
Figure US20090264419A1-20091022-C00101
R11 is selected from
H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
R11a, at each occurrence, is independently selected from
H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
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 R1b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is H; C1-C6 alkyl; C2-C4 alkenyl; C2-C4 alkynyl;
C1-C3 alkyl substituted with 1-2 R12;
C2-C3 alkenyl substituted with 1-2 R12;
C2-C3 alkynyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12, at each occurrence, is independently selected from aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
R16, at each occurrence, is independently selected from
H, OH, C1-C4 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2—;
R17 is H, methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,
phenyl substituted by 0-3 R17a, or
—CH2-phenyl substituted by 0-3 R17a;
R17a is H, methyl, methoxy, —OH, F, Cl, CF3, or OCF3;
R18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from
H, methyl, and ethyl;
R20 is H or C(═O)OR17;
R26 is H, methyl, or ethyl.
27. The process according to claim 26 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Ring C is selected from:
Figure US20090264419A1-20091022-C00102
wherein Ring C is substituted with 0-2 R21; and
Ring B is
Figure US20090264419A1-20091022-C00103
28. The process according to claim 27 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R3 is R4, —CH2OR4, or —CH2CH2OR4;
R4 is C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-1 R4a, or
C2-C6 alkynyl substituted with 0-1 R4a;
R4a, at each occurrence, is independently selected from
H, OH, F, NR15R16, CF3,
C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, and
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 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
X is a bond, phenyl, C3-C6 cycloalkyl, or 5 to 6 membered heterocycle;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is H; C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
C1-C3 alkyl substituted with 1-2 R12;
C2-C3 alkenyl substituted with 1-2 R12;
C2-C3 alkynyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; 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 R12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R12, at each occurrence, is independently selected from
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; 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 R12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,
methyl-C(═O)—, ethyl-C(═O)—,
methyl-S(═O)2—, ethyl-S(═O)2—, and propyl-S(═O)2—;
R18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from
H, methyl, and ethyl;
R20 is H.
29. A process for preparing a compound of Formula (I)
Figure US20090264419A1-20091022-C00104
or a stereoisomer, pharmaceutically acceptable salt thereof, comprising an amide bond synthesis coupling a carboxylic acid 1 and an amine 2 including methods comprising HATU, TBTU, BOP, EDC, CDI, and DCC-mediated amide couplings,
Figure US20090264419A1-20091022-C00105
wherein the reaction product 3 comprises Formula (I):
L is —NR26C(═O)—, —C(═O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or —NR26C(═O)NR26—;
R3 is (CR7R7a)n—R4,
—(CR7R7a)l—S—R4,
—(CR7R7a)1—O—R4;
—(CR7R7a)—N(R7b)—R4,
—(CR7R7a)n—S(═O)—R4, or
—(CR7R7a)l—S(═O)2—R4;
n is 0, 1 or 2;
l is 1 or 2;
R4 is H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from
H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C10 carbocycle substituted with 0-3 R4b, aryl substituted with 0-3 R4b, 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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
wherein said 3-8 membered carbocycle is substituted with 0-4 R21; and
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl,
alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—,
C3-C6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R6 is H, methyl, or ethyl;
R7, at each occurrence, is independently H or C1-C4 alkyl;
R7a, at each occurrence, is independently H or C1-C4 alkyl;
R7b is H or C1-C4 alkyl;
Ring B is
Figure US20090264419A1-20091022-C00106
R11 is H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
W is a bond or —(CH2)p—;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 carbocycle substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—, aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R16, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R18, at each occurrence, is independently selected from
H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19b, at each occurrence, is independently is H or C1-C4 alkyl;
R20 is H, C1-C4 alkyl, or C(═O)OR17;
R23, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3; and
R26 is H or C1-C4 alkyl.
30. The process according to claim 29 for preparing a compound of Formula (Ia):
Figure US20090264419A1-20091022-C00107
or a stereoisomer, pharmaceutically acceptable salt, wherein:
L is —NR26C(═O)—, —C(═O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or —NR26C(═O)NR26—;
R3 is —(CHR7)n—R4,
—(CHR7)l—S—R4,
—(CHR7)l—O—R4;
—(CR7R7a)l—N(R7b)—R4,
—(CR7R7a)l—S(═O)—R4, or
—(CR7R7a)l—S(═O)2—R4;
n is 0, 1 or 2;
l is 1 or 2;
R4 is H.
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from
H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
wherein said 3-8 membered carbocycle is substituted with 0-4 R21;
optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R20)—;
additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl,
alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—,
C3-C6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R7, at each occurrence, is independently H, methyl, or ethyl;
R7b is H, methyl, or ethyl;
Ring B is selected from:
Figure US20090264419A1-20091022-C00108
R11 is H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
W is a bond or —(CH2)p—;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 carbocycle substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, NR19bC(═O)—, —NR19bS(═O)2—,
—S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—, aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R16, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R18, at each occurrence, is independently selected from
H, C1-C6 alkyl, phenyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2;
—R19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;
R20 is H, C1-C4 alkyl, or C(═O)OR17;
R23, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3; and
R26 is H or C1-C4 alkyl.
31. The process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
R4 is C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, 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 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, 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 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
Ring C is a 3-6 membered carbocycle selected from:
Figure US20090264419A1-20091022-C00109
wherein said 3-6 membered carbocycle is substituted with 0-1 R21;
R21 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF3;
R10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or
(4-CF3-phenyl)CH2CH2—;
W is a bond, —CH2—, —CH2CH2—;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-1 RXb; or
5 to 6 membered heterocycle substituted with 0-1 RXb;
RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF3;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,
methyl-C(═O)—, ethyl-C(═O)—,
methyl-S(═O)2—, and ethyl-S(═O)2—;
R18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
R20 is H or C1-C4 alkyl.
32. The process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R3 is —R4, —CH2R4, —CH2CH2R4, —CH2OR4, or —CH2CH2OR4;
R4 is C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a, or
C2-C6 alkynyl substituted with 0-3 R4a;
R4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, 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 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
Ring C is selected from:
Figure US20090264419A1-20091022-C00110
W is a bond or —CH2—;
X is a bond, phenyl, C3-C6 cycloalkyl or 5 to 6 membered heterocycle;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
phenyl substituted with 0-4 R12b;
C3-6 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
R18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl; and
R20 is H, methyl, or ethyl.
33. A process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
Ring C is selected from:
Figure US20090264419A1-20091022-C00111
R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2CH2CH(CH3)2, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH(OH)CH2CH(CH3)2, —CH(OH)CH(CH3)2, —CH(NH2)CH2CH(CH3)2, —CH2CH2OCH3, —CH2OCH2CH3, —CF2CH2CH(CH3)2, —CH(NHCH3)CH2CH(CH3)2, —CH(NHSO2CH2CH2CH3)CH2CH(CH3)2, cyclohexyl-, cyclopentyl-, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH(OH)—, cyclohexyl-CH2CH2—, 1-NH2-cyclopentyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, 4-piperidinyl-CH2CH2—, phenyl-CH2CH2CF2—, phenyl-CH2CH(OH)—, imidazolyl-CH2CH(OH)—, or phenyl-CH2OCH2—;
W is a bond or —CH2—;
X is a bond;
Figure US20090264419A1-20091022-C00112
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-piperidinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, or (N-piperidinyl)CH2CH2—;
R13, at each occurrence, is independently selected from
H, F, Cl, OH, —CH3, —CH2CH3, —OCH3, or —CF3.
34. A process according to claim 29 for preparing compound of Formula (Id)
Figure US20090264419A1-20091022-C00113
or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R3 is —(CH2)n—R4,
—(CH2)l—S—R4,
—(CH2)l—O—R4, or
—(CH2)l—N(R7b)—R4;
n is 0, 1 or 2;
l is 1 or 2;
R4 is C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from
H, OH, F, Cl, Br, I, NR15R16, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, 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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3,
S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R7b is H, methyl, or ethyl;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R21;
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R11, at each occurrence, is independently selected from
H, ═O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, Cl, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, —CH2—, —CH2CH2—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—,
—N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—,
—S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R16, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, benzyl, phenethyl, alkyl)-C(═O)—, and (C1-C4 alkyl)-S(═O)2;
R18, at each occurrence, is independently selected from
H, C1-C6 alkyl, phenyl, benzyl, phenethyl, alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
R20 is H or C1-C4 alkyl.
35. A process according to claim 34 for preparing a racemic mixture of compound of Formula (Id)
Figure US20090264419A1-20091022-C00114
or stereoisomer or pharmaceutically acceptable salt form thereof, wherein carbon 3 of lactam ring B may exist in an S or R configuration.
36. A process according to claim 25 for preparing a compound of Formula (I) consisting of N—({N-[5-(tert-Butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide,
Figure US20090264419A1-20091022-C00115
the process comprising the following steps as illustrated in scheme 7:
Figure US20090264419A1-20091022-C00116
wherein step 1 comprises:
adding added a 30% solution of HBr in acetic acid (16 equiv) to a stirred solution of intermediate compound 23 (1.0 equiv) in CH2—C2 (0.1 M), continuing to stir the resulting mixture for 14 h.;
concentrating the reaction mixture in vacuo, and dissolving it in EtOAc and water, followed by separating and extracting the mixture with an aqueous layer made basic using 6 N NaOH and a layer of CH2Cl2;
washing the organic extracts with brine, drying them over Na2SO4;
filter and concentrate the extracts;
dissolving the resulting solid in CH2Cl2 and adding it to a stirring solution of the acid form of intermediate compound 24 (1.2 equiv), EDC-HCl (1.5 equiv), HOBt (1.5 equiv), and DIPEA (5.0 equiv) in CH2Cl2 (0.15 M);
stirring the reaction overnight, quenching it with water, washing it with 20% citric acid (3×), sat NaHCO3 (2×), brine, drying over Na2SO4, filtering and concentrating; and
recrystallizing the crude material from EtOAc and Et2O to yield intermediate compound 25 (4.4 g, 95%) as a white powder which showed analytical data of 1H NMR (500 MHz, CDCl3) δ 7.71-6.98 (m, 6H), 5.87 (s, 1H), 5.29 (d, 1H), 2.38 (m, 2H), 2.21 (t, 2H) 2.01 (m, 2H), 1.52 (m, 7H), 1.23 (s, 9H), 0.88 (d, 6H); and
the step 2 comprises:
adding methyl iodide (1.5 equiv) to a suspension of 25 (1 equiv) and freshly powdered K2CO3 (3.0 equiv) in DMF (0.05 M);
stirring the mixture was stirred (5 h) to the reaction was added EtOAc and water and separating the layers; washing the organic layer with 5% LiCl (2×), and brine, followed by drying over Na2SO4, filtering and concentrating; dissolving the resulting material in Et2O and concentrating it in vacuo providing N—(N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl-cyclopentyl)-4-methylpentanamide (60 mg, 66%) as a white powder; having the characteristics of mp 175-178° C.; 1H NMR (500 MHz, CDCl3) δ 7.71-7.17 (m, 5H), 5.89 (s, 1 H), 5.23 (d, 1H), 3.34 (s, 3H), 2.41-2.29 (m, 3H), 2.21 (m, 2H), 2.04 (m, 3H), 1.80 (m, 4H), 1.60 (m, 1H), 1.18 (s, 9H), 0.90 (d, 6H); ESI MS m/z=455 [C26H38N4O3+H]+; IR (KBr)=3324, 2958, 1677, 1508, 1366, 1197 cm−1; HPLC 96.8%, tr=15.75 min. (HPLC Conditions A).
37. A process according to claim 25 for preparing a compound of Formula (I), stereoisomer, or pharmaceutically acceptable salt thereof, selected from:
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
[(N-butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}acetamide;
2-(3,5-difluorophenyl)-N—{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}acetamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}acetamide;
3-cyclopentyl-N—{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide;
2-(3,5-difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide;
phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidinecarboxylate;
N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]cyclopentyl}carboxamide;
2,2-difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2R)-2-hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
2-ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
3-cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide;
(2S)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2R)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2S)-2-amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
[(cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide;
N-{[N-(1-butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
N-{[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
N—({N-[5-(tert-butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide; and
N—({N-[5-butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide.
38. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 25, and a pharmaceutically acceptable carrier.
39. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 26, and a pharmaceutically acceptable carrier.
40. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 27, and a pharmaceutically acceptable carrier.
41. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 28, and a pharmaceutically acceptable carrier.
42. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 29, and a pharmaceutically acceptable carrier.
43. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 30, and a pharmaceutically acceptable carrier.
44. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 31, and a pharmaceutically acceptable carrier.
45. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 32, and a pharmaceutically acceptable carrier.
46. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 33, and a pharmaceutically acceptable carrier.
47. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 34, and a pharmaceutically acceptable carrier.
48. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 35, and a pharmaceutically acceptable carrier.
49. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 36, and a pharmaceutically acceptable carrier.
50. A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 37, and a pharmaceutically acceptable carrier.
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