WO2006041404A1 - Substituted amino-compounds and uses thereof - Google Patents

Substituted amino-compounds and uses thereof Download PDF

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Publication number
WO2006041404A1
WO2006041404A1 PCT/SE2005/001533 SE2005001533W WO2006041404A1 WO 2006041404 A1 WO2006041404 A1 WO 2006041404A1 SE 2005001533 W SE2005001533 W SE 2005001533W WO 2006041404 A1 WO2006041404 A1 WO 2006041404A1
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Prior art keywords
alkyl
aryl
heterocyclyl
nhc
compound
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PCT/SE2005/001533
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French (fr)
Inventor
Jeffrey Scott Albert
Don Andisik
James Arnold
Dean Brown
Owen Callaghan
James Campbell
Robin Arthur Ellis Carr
Gianni Chessari
Miles Stuart Congreve
Phil Edwards
James R. Empfield
Martyn Frederickson
Gerard M. Koether
Jennifer Krumrine
Russ Mauger
Christopher William Murray
Sahil Patel
Mark Sylvester
Scott Throner
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Astrazeneca Ab
Astex Therapeutics
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Priority to EP05793318A priority Critical patent/EP1802587A4/en
Priority to JP2007536655A priority patent/JP2008516945A/en
Priority to US11/577,155 priority patent/US20090221579A1/en
Publication of WO2006041404A1 publication Critical patent/WO2006041404A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—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 alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D403/08—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 carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to novel substituted amino-compounds, their pharmaceutical compositions, methods of use and processes to make such compounds.
  • the present invention relates to therapeutic methods for the treatment and/or prevention of amyloid- ⁇ -protein-related pathologies ("A ⁇ -related pathologies”) such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI (“mild cognitive impairment”), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral
  • ⁇ -secretase activity Hussain et al, 1999; Lin et. al, 2000; Yan et. al, 1999; Sinha et. al., 1999 and Vassar et. al., 1999).
  • ⁇ -secretase is also known in the literature as Asp2 (Yan et. al, 1999), Beta site APP (amyloid precursor protein) Cleaving Enzyme (BACE) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 2000).
  • BACE was identified using a number of experimental approaches such as EST database analysis (Hussain et al.
  • BACE was found to be a pepsin-like aspartic proteinase, the mature enzyme consisting of the N-terminal catalytic domain, a transmembrane domain, and a small cytoplasmic domain.
  • BACE has an optimum activity at pH 4.0-5.0 (Vassar et al, 1999)) and is inhibited weakly by standard pepsin inhibitors such as pepstatin. It has been shown that the catalytic domain minus the transmembrane and cytoplasmic domain has activity against substrate peptides (Lin et al, 2000).
  • BACE is a membrane bound type 1 protein that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue.
  • a ⁇ amyloid- ⁇ -protein
  • a ⁇ or amyloid- ⁇ -protein is the major constituent of the brain plaques which are characteristic of Alzheimer's disease (De Strooper et al, 1999).
  • a ⁇ is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein called APP, or amyloid precursor protein.
  • a ⁇ -secretase activity cleaves this protein between residues Met671 and Asp672 (numbering of 770aa isoform of APP) to form the N-terminus of A ⁇ .
  • a second cleavage of the peptide is associated with ⁇ -secretase to form the C-terminus of the A ⁇ peptide.
  • Alzheimer's disease is estimated to afflict more than 20 million people worldwide and is believed to be the most common form of dementia.
  • Alzheimer's disease is a progressive dementia in which massive deposits of aggregated protein breakdown products - amyloid plaques and neurofibrillary tangles accumulate in the brain. The amyloid plaques are thought to be responsible for the mental decline seen in Alzheimer's patients.
  • Alzheimer's disease increases with age, and as the aging population of the developed world increases, this disease becomes a greater and greater problem.
  • this disease becomes a greater and greater problem.
  • any individuals possessing the double mutation of APP known as the Swedish mutation (in which the mutated APP forms a considerably improved substrate for BACE) have a much greater chance of developing AD, and also of developing it at an early age ⁇ see also US 6,245,964 and US 5,877,399 pertaining to transgenic rodents comprising APP-Swedish). Consequently, there is also a strong need for developing a compound that can be used in a prophylactic fashion for these individuals.
  • APP The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Down's syndrome.
  • Down's syndrome patients tend to acquire Alzheimer's disease at an early age, with almost all those over 40 years of age showing Alzheimer's-type pathology (Oyama et al., 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APP ⁇ causing the high prevalence of Alzheimer's disease seen in this population.
  • inhibitors of BACE could be useful in reducing Alzheimer's-type pathology in Down's syndrome patients.
  • Drugs that reduce or block BACE activity should therefore reduce A ⁇ levels and levels of fragments of A ⁇ in the brain, or elsewhere where A ⁇ or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of A ⁇ or fragments thereof (Yankner, 1996; De Strooper and Konig, 1999).
  • BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms
  • W is C or N
  • R 3 is selected from R 1 , C 1-6 alkylR c , C 1-6 alkylNR c R c , C 1-6 alkylOR c , C 1-6 alkylSR c , Ci.ealkylNHCi.ealkylCs-earylR' 3 , C 1-6 alkylNHC 6-10 arylR d , C 1-6 alkylNHC(O)C 6-10 arylR d , C 1-6 alkyl0C 1-6 alkylC 5-6 arylR d , C 1-6 alkylSC 1-6 alkylC 5-6 arylR d , C 1-6 aIkylC 5-9 heterocyclylR d , C 1-6 alkylC 3-9 cycloalkylR d , C 1-6 alkylNHC 1-6 alkylC 5-9 heterocyclylR d , C 1-6 alkylNHC 5-9 heterocyclyl(R d )
  • R d is selected from H, C 1-3 alkyl, NH 2 , OH, COOH, OC ⁇ alkyl, or 0C 1-3 alkyl0H.
  • compositions comprising a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, and and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention further provides methods of modulating activity of BACE comprising contacting the BACE with a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
  • the present invention further provides methods of treating or preventing an A ⁇ -related pathology in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
  • the present invention further provides a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for use as a medicament.
  • the present invention further provides a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for the manufacture of a medicament.
  • W is C or N
  • Q is selected from C 3-12 CyClOaIlCyI, C 3-12 cycloalkenyl, C 6-14 aryl, or C 5-15 heterocyclyl; each R 1 is, independently, selected from H, halogen, C 2-6 alkenyl, C 1-6 alkyl, C 3 . 12 cycloalkyl, C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, or C 5 - 15 heterocyclyl wherein said C 1-6 alkyl, said C 3 .
  • X, Y, and Z are, independently, selected from NH, O, S, S(O), SO 2 , NHS(O), NHSO 2 , S(O)NH, SO 2 NH 5 NHC(O), C(O)NH 5 NR 2 SO 2 , NR a S(O), NR a C(O), C(O)NR a , S(O) 2 NR a , S(O)NR a , or C 1-6 alkyl wherein said is optionally substituted by 1, 2, or 3 substituents independently selected from R a ; m is O, 1, 2 or 3; n, q, r, s, and u are each, independently, O or 1 ;
  • R 3 is selected from R 1 , C 1-6 alkylR°, C 1-6 alkylNR c R c , C 1-6 alkyl0R c , C 1-6 alkylSR c , C 1-6 alkylNHC(0)C 6-1 oarylR d , C 1-6 alkyl0C 1-6 al]iylC 5-6 arylR d , C 1-6 alkylSC 1-6 all ⁇ lC 5-6 arylR d , C 1-6 aUcylC 5 . 9 heterocyclylR d , C 1-6 alkylC 3 .
  • R d is selected from H, Ci -3 alkyl, NH 2 , OH, COOH, OC 1-3 alkyl, or OC 1-3 alkylOH.
  • W is N
  • R 2 is C 1-4 alkyl
  • q is O
  • r is O
  • s is 0, then [R 1 KV) n ] m-Q is other than phenyl.
  • W is N
  • R 2 is C 1-4 alkyl
  • q is 0, r is 0, s is 0,
  • Q is phenyl
  • m is 1, then R 1 ⁇ V) n - is other than bromo, pyridyl, or methoxyphenyl.
  • W is N 5 and — [X] q — [Y] r — [Z] s — is -CH 2 - then [R ⁇ (V) n ] m -Q is other than phenyl.
  • W is N 5 — [X]q-[Y] r -[Z] s - is -CH 2 - or -CH(CH 3 )-, Q is phenyl, and m is 2, then at least one of R J -(V) n - is other than fluoro.
  • W is N
  • -[X] q -[Y] r -[Z] s - is - NH-
  • Q is phenyl
  • m is 2, then at least one of R ⁇ (V) n - is other than C 1-4 alkyl.
  • W is N
  • -[X] q -[Y] r -[Z] s - is -O- then [R ⁇ (V) n ] m -Q is other than phenyl.
  • compounds of the present invention have the structure of formula Ia.
  • compounds of the present invention have the structure of formula Ib.
  • W is N.
  • R 3 is selected from H, C 1-6 alkyl, C 1-6 alkylNR c R c , C 1-6 alkylOR c , C 1-6 alkylC 6 . 10 arylR d , C 1-6 alkylC 5-9 heterocyclylR d , or C 1-6 alkylC 3-9 cycloalkylR d .
  • R 3 is selected from H, C 1-6 alkyl, C 1-6 alkylNR c R c , or C 1-6 alkyl-C 5-9 heterocyclylR d .
  • R 3 is C 1-3 alkyl.
  • Q is C 6-10 aryl, C 3-10 cycloalkyl or C 3-10 cycloalkenyl.
  • Q is C 6 aryl or C 3-10 cycloalkenyl.
  • Q is C 6 aryl. hi some embodiments, Q is C ⁇ iocycloalkenyl.
  • -[X] q -[Y] r -[Z] s - is OC 1-3 alkyl, N(C 1-3 alkyl)C 1-3 alkyl, C 1-3 alkyl0C 1-3 alkyl, C 1-3 alkylN(H)C 1-3 alkyl or C 1-3 alkyl optionally substituted by OH.
  • -[X] q -[Y] r -[Z] s - is OC 1-3 alkyl or C 1-3 alkyl0C 1-3 alkyl.
  • -[X]q-[Y] r -[Z] s - is OC 1-3 aIkyl.
  • q is 0, r is 0 and s is 0 (i.e., -[X] q -[Y]r-[Z] s - is absent).
  • each R 1 is, independently, selected from C 6-10 aryl or C 5-10 heterocyclyl, each optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OC 1-4 alkyl, C 5-6 heterocyclyl or -C 6 arylR a ; and
  • R a is H 5 OH, C 1-6 alkyl or OC 1-6 alkyl.
  • R 3 is H or C ⁇ aUcyl.
  • Q is C 6 aryl or Cs.gheterocyclyl
  • W is N
  • R 2 is C 1-3 alkyl.
  • compounds of the invention have formula Ib;
  • Q is C 6-10 aryl
  • W is N
  • -[XJq-[Y] -[Z]s- is OCi. 3 alkyl; m is 1; n is 0; and
  • R 1 is C 6-1 oaryl optionally substituted by 1 or 2 substituents independently selected from: OC 1-4 alkyl and -C 6 aryl-OC 1-4 alkyl.
  • compounds of the invention have formula Ib;
  • Q is C 3-10 cycloalkenyl
  • R 1 is C 6-10 aryl optionally substituted by 1 or 2 substituents independently selected from: OC 1-4 alkyl and -C 6 aryl-OC 1-4 alkyl.
  • compounds of the invention have formula Ia;
  • Q is C ⁇ -ioaryl, C 3-10 cycloalkyl or C 3-10 cycloalkenyl; W is N;
  • -[X] q -[Y] -[Z] s - is OCi -3 alkyl, N(C 1-3 alkyl)Ci -3 alkyl, C 1-3 alkyl0C 1-3 alicyl, C 1-3 alkylN(H)C 1-3 alkyl or C 1-3 alkyl optionally substituted by OH; m is 1;
  • V is S; n is 0 or 1; and
  • the present invention provides compounds of formula Ia or formula Ib selected from the following:
  • novel compounds of structural formula Ha or formula lib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof:
  • W is selected from C or N;
  • Q is selected from C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 5-14 aryl or Cs-uheterocyclyl;
  • R b is independently selected from H, C 1-6 alkyl, C 5-6 aryl, or C 5-6 heterocyclyl;
  • V is selected from N, O, S 5 S(O), SO 2 , NHS(O), NHSO 2, S(O)NH, SO 2 NH, NHC(O), C(O)NH, NR a SO 2 , NR 3 S(O), NR a C(O), C(O)NR a , S(O) 2 NR a , S(O)NR a or optionally substituted C 1-6 alkyl wherein such substituent is/are independently selected from R a ;
  • X is selected from N, O, S, S(O), SO 2 , NHS(O), NHSO 2 , S(O)NH, SO 2 NH, NHC(O), C(O)NH, NR 3 SO 2 , NR 3 S(O), NR 3 C(O), C(O)NR 3 , S(O) 2 NR 3 , S(O)NR 3 or optionally substituted C 1-6 alkyl wherein such substituent is/are independently selected from R a ;
  • Y is selected from N, O, S, S(O), SO 2 , NHS(O), NHSO 2 , S(O)NH, SO 2 NH, NHC(O), C(O)NH, NR 3 SO 2 , NR 3 S(O), NR 3 C(O), C(O)NR 3 , S(O) 2 NR 3 , S(O)NR 3 or optionally substituted Q- ⁇ alkyl wherein such substituent is/are independently selected from R 3 ;
  • Z is selected from N, O, S, S(O), SO 2 , NHS(O), NHSO 2 , S(O)NH, SO 2 NH, NHC(O), C(O)NH, NR 3 SO 2 , NR a S(O), NR 3 C(O), C(O)NR 3 , S(O) 2 NR 3 , S(O)NR 3 or optionally substituted Q ⁇ alkyl wherein such substituent is/are independently selected from R 3 ; • m is O, 1, 2 or 3; n is O or 1; p is O or 1; q is O or 1; r is O or 1; s is O or 1; t is O or 1; u is O or 1; with the proviso that m, n, p, q, r, s, t, and u cannot all be O simultaneously.
  • R 2 is independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 5-10 aryl, optionally substituted C 1-6 alkyl-C 5-1 oaryl, optionally substituted C5.
  • R 3 is independently selected from Rl 5 H, C 1-6 alkyl, C 1-6 alkylR c R c , C 1-6 alkylNR Q R c , C 1-6 alkylOR c R c , C 1-6 alkylSR c R c , C 1-6 alkylNC 1-6 alkylC 5-6 arylR d , or C 1-6 alkyl0C 1-6 alkylC 5-6 arylR d , C 1-6 alkylSC 1-6 alkylC 5-6 arylR d , C 1-6 alkylC 5-9 lieterocyclylR d , C 1-6 alkylNC 1-6 alkylC 5-9 heterocyclylR d , C 1-6 alkylOC 1-6 alkylC 5-9 rierocyclylR d , C 1-6 alkylSC 1-6 alkylC 5-9 lieterocyclylR d , C 1-6 alkylNC 1-6 alkylC 5
  • R d is independently selected from H, C 1-3 alkyl, NH 2 , OH, COOH, OC 1 . 3 alkyl, OC ⁇ alkylOH.
  • One embodiment of the present invention provides a compound of formula IIa or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein Q is C 5-6 aryl and W, R 1 , R ⁇ R b , V, X, Y, Z, m, n, o, p, q, r, s, t, u, R 2 , R 3 , R c and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein Q is Qaryl and W, R 1 , R a , R b , V, X, Y, Z, m, n, o, p, q, r, s, t, u, R 2 , R 3 , R c and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides compounds of formula Ha or formula Eb, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein R 2 is C 1-3 alkyl and Q, W 3 R 1 , R a , R b , V, X, Y, Z, m, n, o, p, q, r, s, t, u, R 3 , R c and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein R 3 is C 1-3 alkyl and Q, W, R 1 , R a , R b , V, X, Y, Z, m, n, o, p, q, ⁇ , s, t, u, R 2 , R 0 and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides compounds of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzVo-hydrolysable precursors wherein Q is Cgheterocyclyl and W, R 1 , R a , R b , V, X, Y, Z, m, n, o, p, q, r, s, t, u, R 2 , R 3 , R c and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides compounds of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
  • Q is C 6-1 oaryl or C 5-9 heterocyclyl
  • X is C 1-3 alkyl; q is 0 or 1 ; m is 0 or 1 or 2;
  • R 2 is H, C 1-6 alkyL t is O or 1;
  • R 3 is independently selected from H, C 1-3 alkyl.
  • One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
  • W is N
  • Q is C 6 aryl or Cgheterocyclyl
  • X is C 1-3 alkyl; q is O or 1; m is O or 1 or 2; R 1 is independently selected from H, halogen, optionally substituted C 6 aryl, or optionally substituted C 5-6 heterocyclyl wherein such substituent(s) are independently selected from: halogen, OH 3 NH 2 , CN, C(O)NH 2 , C 1-6 alkyl, OCi.
  • R 2 is C 1-3 alkyl; t is O or 1; and V, Y, Z, n, o,p, r, s, u, R 3 , R c and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
  • W is N
  • Q is C 6 aryl or Cgheterocyclyl
  • X is C 1-3 alkyl; q is O or l; m is O or 1 or 2;
  • R 2 is C 1-3 alkyl; t is O orl;
  • R 3 is H, C 1-6 alkyl, C 1-6 alkylNR c R c , C 1-6 alkyl-C 5-9 heterocyclylR d ; and V, Y, Z, n, o,p, r, s, u, R c , and R d have any of the meanings as defined hereinabove.
  • One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
  • Q is C 6 aryl or Cgheterocyclyl
  • X is C 1-3 alkyl; q is O or l; m is 0 or 1 or 2;
  • R 2 is C 1-3 alkyl; t is O or 1;
  • R 3 is C 1-3 alkyl; and u is 1.
  • Compounds of the present invention also include pharmaceutically acceptable salts, tautomers and in vzvo-hydrolysable precursors of the compounds of formula Ia and/or formula Ib.
  • Compounds of the invention further include hydrates and solvates.
  • the present invention provides compounds of formula Ia or formula Ib, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, for use as medicaments.
  • the present invention provides compounds described herein for use as as medicaments for treating or preventing an A ⁇ -related pathology.
  • the A ⁇ -related pathology is Downs syndrome, a ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • MCI mimild cognitive impairment
  • the present invention provides compounds of formula Ia or formula Ib, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, in the manufacture of a medicament for the treatment or prophylaxis of A ⁇ -related pathologies.
  • the A ⁇ -related pathologies include such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • MCI mimild cognitive impairment
  • the present invention provides a method of inhibiting activity of BACE comprising contacting the BACE with a compound of the present invention.
  • BACE is thought to represent the major ⁇ -secretase activity, and is considered to be the rate-limiting step in the production of amyloid- ⁇ -protein (A ⁇ ).
  • a ⁇ amyloid- ⁇ -protein
  • BACE is an important candidate for the development of drugs as a treatment and/or prophylaxis of A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated
  • the present invention provides a method for the treatment of A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, comprising administering to a mammal (including human) a therapeutically effective amount of a compound of formula Ia or formula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid
  • the present invention provides a method for the prophylaxis of A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration comprising administering to a mammal (including human) a therapeutically effective amount of a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydroly sable precursors.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral
  • the present invention provides a method of treating or preventing A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration by administering to a mammal (including human) a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors and a cognitive and/or memory enhancing agent.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral am
  • the present invention provides a method of treating orpreventingtng A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration by administering to a mammal (including human) a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein constituent members are provided herein, and a choline esterase inhibitor or anti-inflammatory agent.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amy
  • the present invention provides a method of treating orpreventingtng A ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, or any other disease, disorder, or condition described herein, by administering to a mammal (including human) a compound of the present inventionand an atypical antipsychotic agent.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage,
  • Atypical antipsychotic agents includes, but not limited to, Olanzapine (marketed as Zyprexa), Aripiprazole (marketed as Ability), Risperidone (marketed as Risperdal), Quetiapine (marketed as Seroquel), Clozapine (marketed as Clozaril), Ziprasidone (marketed as Geodon) and Olanzapine/Fluoxetine (marketed as Symbyax).
  • the mammal or human being treated with a compound of the invention has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the mammal or human being treated is in need of such treatment. Diagnosis, however, need not be previously performed.
  • the present invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention herein together with at least one pharmaceutically acceptable carrier, diluent or excipent.
  • compounds of the present invention When used for pharmaceutical compositions, medicaments, manufacture of medicaments, inhibiting activities of BACE, or treating or preventing A ⁇ -related pathologies, compounds of the present invention include the compounds of formula Ia and/or formula Ib, and pharmaceutically acceptable salts, tautomers and in vivo-hydrolysable precursors thereof. Compounds of the present invention further include hydrates and solvates.
  • substitution means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. In the event a substitution is desired then such substitution means that any number of hydrogens on the designated atom or moiety is replaced with a selection from the indicated group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH 3 ) is optionally substituted, then 3 hydrogens on the carbon atom can be replaced.
  • a methyl group i.e., CH 3
  • a variety of compounds in the present invention may exist in particular geometric or stereoisomer ⁇ forms.
  • the present invention takes into account all such compounds, including cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group.
  • AU such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • 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.
  • optically active forms such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • separation of the racemic material can be achieved by methods known in the art.
  • 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.
  • alkyl As used herein, "alkyl”, “alkylenyl” or “alkylene” used alone or as a suffix or prefix, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 1-6 alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • C 1-3 alkyl whether a terminal substituent or an alkylene (or atkylenyl) group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • aromatic refers to hydrocarbyl groups having one or more polyunsaturated carbon rings having aromatic characters, (e.g., 4ri + 2 delocalized electrons) and comprising up to about 14 carbon atoms.
  • aryl refers to an aromatic ring structure made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be a polycyclic moiety in which at least one carbon is common to any two adjoining rings therein (for example, the rings are "fused rings"), for example naphthyl.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls or cycloalkynyls.
  • ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups, having the specified number of carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or bridged rings) groups.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene, cyclohexane, and the like.
  • cycloalkyl further includes saturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems.
  • Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure.
  • C 3-6 cycloalkyl denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenyl refers to ring-containing hydrocarbyl groups having at least one carbon-carbon double bond in the ring, and having from 3 to 12 carbons atoms.
  • cycloalkynyl refers to ring-containing hydrocarbyl groups having at least one carbon-carbon triple bond in the ring, and having from 7 to 12 carbons atoms.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively or positively charged species such as chloride (CV), bromide (Br ' ), hydroxide (OH “ ), acetate (CH 3 COO “ ) , sulfate (SO4 2” ), tosylate (CH 3 -phenyl-SO 3 " ), benezensulfonate (phenyl-SO 3 " ), sodium ion (Na + ), potassium (K + ), ammonium (NH 4 + ), and the like.
  • heterocyclyl or “heterocyclic” or “heterocycle” refers to a ring-containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising from 3 to 20 atoms in the rings, more preferably 3- to 7- membered rings.
  • the number of ring-forming atoms in heterocyclyl are given in ranges herein.
  • C 5-10 heterocyclyl refers to a ring strcture comprising from 5 to 10 ring-forming atoms wherein at least one of the ring-forming atoms is N, O or S.
  • Heterocyclic groups may be saturated or partially saturated or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring as in the case of polycyclic systems.
  • the heterocyclic rings described herein may be substituted on carbon or on a heteroatom atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocyclyl may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another.
  • heterocyclyls include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H- 1, 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-
  • 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, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy.
  • alkylthio or “thioalkoxy” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or sulfur
  • R represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R J ' or a pharmaceutically acceptable salt
  • R' represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) H i-R", where m is an integer less than or equal to ten
  • R" is alkyl, cycloalkyl, alkenyl, aryl, or heteroaryl.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R is represented by but not limited to hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • substitutents can occur at multiple times.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • 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 (i.e., also include counterions).
  • 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, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that 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 used.
  • in vivo hydrolysable precursors means an in vivo hydroysable (or cleavable) ester of a compound of formula Ia or formula Ib that contains a carboxy or a hydroxy group.
  • amino acid esters C 1-6 alkoxymethyl esters like methoxymethyl; C 1-6 alkanoyloxymethyl esters like pivaloyloxymethyl; C 3 . 8 cycloalkoxycarbonyloxy C 1-6 alkyl esters like 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, or phosphoramidic cyclic esters.
  • tautomer means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, keto-enol tautomerism where the resulting compound has the porperties of both a ketone and an unsturated alchol.
  • 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.
  • Compounds of the invention further include hydrates and solvates.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An "isotopically" or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to H (also written as D for deuterium), H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl 3 82 Br, 75 Br, 76 Br, 77 Br, 123 I 3 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H 3 14 C 3 82 Br 3 125 1 , 131 1, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F 3 125 1, 123 I 3 124 I 3 131 I, 75 Br 3 76 Br or 77 Br will generally be most useful.
  • a "radio-labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting Of 3 H 3 14 C 3 125 1 , 35 S and 82 Br.
  • the anti-dementia treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional chemotherapy.
  • Such chemotherapy may include one or more of the following categories of agents:
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention.
  • Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
  • An effective amount of a compound of the present invention for use in therapy of dementia is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of dementia, to slow the progression of dementia, or to reduce in patients with symptoms of dementia the risk of getting worse.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, trifluoroacetate and the like.
  • the present invention provides a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
  • composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
  • this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical compositions can be in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • compositions may be formulated for any suitable route and means of administration.
  • Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • the compounds of the invention may be derivatised in various ways.
  • derivatives of the compounds includes salts (e.g. pharmaceutically acceptable salts), any complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination complexes with metal ions such as Mn 2+ and Zn 2+ ), esters such as in vivo hydrolysable esters, free acids or bases, polymorphic forms of the compounds, solvates (e.g. hydrates), prodrugs or lipids, coupling partners and protecting groups.
  • prodrugs is meant for example any compound that is converted in vivo into a biologically active compound.
  • Salts of the compounds of the invention are preferably physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art. All such salts are within the scope of this invention, and references to compounds include the salt forms of the compounds.
  • Compounds having acidic groups can form salts with alkaline or alkaline earth metals such as Na 5 K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds having both acidic and basic groups can form internal salts.
  • alkaline or alkaline earth metals such as Na 5 K, Mg and Ca
  • organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, be
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • the compounds may contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the invention.
  • Compounds containing an amine function may also form N-oxides.
  • a reference herein to a compound that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • prodrugs which are prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • prodrugs are activated enzymatically to yield the active compound, or a - compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Coupled derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it.
  • Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody or an inhibitor.
  • Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • Other derivatives include formulating the compounds with liposomes.
  • the quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 pg/kg to 10 mg/kg per day.
  • dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.
  • the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
  • Beta secretase including BACE
  • Inhibitors of beta secretase have been shown to be useful in blocking formation or aggregation of A ⁇ peptide and therefore have a beneficial effects in treatment of Alzheimer's Disease and other neurodegenerative diseases associated with elevated levels and/or deposition of A ⁇ peptide. Therefore it is believed that the compounds of the present invention may be used for the treatment of Alzheimer disease and disease associated with dementia
  • compounds of the present invention and their salts are expected to be active against age-related diseases such as Alzheimer, as well as other A ⁇ related pathologies such as Downs syndrome and b-amyloid angiopathy. It is expected that the compounds of the present invention would most likely be used in combination with a broad range of cognition deficit enhancement agents but could also be used as a single agent.
  • the compounds of the present invention have been identified in one or both assays described below as having an IC 50 value of 100 micromolar or less.
  • the compound of example number 34 has an IC 5O value of 36nM.
  • Enzyme is diluted 1:30 in 4OmM MES pH 5.0.
  • Stock substrate is diluted to 12uM in 4OmM MES pH 5.0.
  • PALMEB solution is added to the substrate solution (1:100 dilution).
  • DMSO stock solutions of compounds or DMSO alone are diluted to the desired concentration in 4OmM MES pH 5.0.
  • the assay is done in a 96 well PCR plate from Nunc. Compound in DMSO (3 ⁇ L) is added to the plate then enzyme is added (27 ⁇ L) and pre-incubated with compound for 5 minutes. Then the reaction is started with substrate (30 ⁇ L).
  • the final dilution of enzyme is 1:60; the final concentration of substrate is 6 uM (Km is 150 ⁇ M).
  • reaction After a 20 minute reaction at room temperature, the reaction is stopped by removing 10 ⁇ l of the reaction mix and diluting it 1 :25 in 0.20M Tris pH 8.0. The compounds are added to the plate by hand then all the rest of the liquid handling is done on the CyBi- well instrument.
  • AU antibodies and the streptavidin coated beads are diluted into PBS containing 0.5% BSA and 0.5% Tween20.
  • the product is quantified by adding 50 ⁇ L of a 1:5000 dilution of the neoepitope antibody to 50 ⁇ L of the 1:25 dilution of the reaction mix. Then, 100 ⁇ L of PBS (0.5% BSA, 0.5% Tween20) containing 0.2mg/ml IGEN beads and a 1:5000 dilution of ruthinylated goat anti-rabbit (Ru-Gar) antibody is added.
  • the final dilution of neoepitope antibody is 1:20,000
  • the final dilution of Ru-GAR is 1:10,000
  • the final concentration of beads is 0.1 mg/ml.
  • the mixture is read on the IGEN instrument with the Cindy AB40 program after a 2-hour incubation at room temperature. Addition of DMSO alone is used to define the 100% activity.
  • 2OuM control inhibitor is used to define 0% of control activity and 10OnM inhibitor defines 50% control of control activity in single-poke assays. Control inhibitor is also used in dose response assays with an IC50 of 10OnM.
  • Enzyme is diluted 1 :30 in 4OmM MES pH 5.0.
  • Stock substrate is diluted to 30 uM in 4OmM MES pH 5.0.
  • PALMEB solution is added to the substrate solution (1:100 dilution).
  • Enzyme and substrate stock solutions are kept on ice until the placed in the stock plates.
  • the Platemate-plus instrument is used to do all liquid handling.
  • Enzyme (9 ⁇ L) is added to the plate then 1 ⁇ L of compound in DMSO is added and pre-incubated for 5 minutes.
  • the dilutions are done in neat DMSO and the DMSO stocks are added as described above.
  • Substrate (10 ⁇ L) is added and the reaction proceeds in the dark for 1 hour at room temperature.
  • the assay is done in a Corning 384 well round bottom, low volume, non-binding surface (Corning #3676).
  • the final dilution of enzyme is 1:60; the final concentration of substrate is 15uM (Km of 25 ⁇ M).
  • the fluorescence of the product is measured on a Victor II plate reader with an excitation wavelength of 360nm and an emission wavelength of 485nm using the protocol labeled Edans peptide.
  • the DMSO control defines the 100% activity level and 0% activity is defined by using 5OuM of the control inhibitor, which completely blocks enzyme function.
  • the control inhibitor is also used in dose response assays and has an IC50 of 95nM.
  • the cDNA encoding full length BACE was fused in frame with a three amino acid linker (Ala-Val-Thr) to the Fc portion of the human IgGl starting at amino acid 104.
  • the BACE-Fc construct was then cloned into a GFP/pGEN-IRES-neoK vector (a proprietary vector of AstraZeneca) for protein expression in mammalian cells.
  • the expression vector was stably transfected into HEK-293 cells using a calcium phosphate method. Colonies were selected with 250 ⁇ g/mL of G-418. Limited dilution cloning was performed to generate homogeneous cell lines. Clones were characterized by levels of APP expression and A ⁇ secreted in the conditioned media using an ELISA assay developed in-house. A ⁇ secretion of BACE/Fc clone Fc33-1 was moderate.
  • HEK293 cells stably expressing human BACE were grown at 37 0 C in DMEM containing 10% heat-inhibited FBS, 0.5mg/mL antibiotic-antimycotic solution, and 0.05 mg/mL of the selection antibiotic G-418.
  • Cells were harvested when between 80 to 90% confluent. 100 ⁇ L of cells at a cell density of 1.5 million/mL were added to a white 96- well cell culture plate with clear flat bottom (Costar 3610), or a clear, flat bottom 96-well cell culture plate (Costar 3595), containing 100 ⁇ L of inhibitor in cell culture medium with DMSO at a final concentration of 1%. After the plate was incubated at 37 0 C for 24 h, 100 ⁇ L cell medium was transferred to a round bottom 96-well plate (Costar 3365) to quantify A ⁇ 40 levels. The cell culture plates were saved for ATP assay as described in ATP assay below.
  • the plate was shaken at 22 0 C on a plate shaker for 1 h, and then the plates were then measured for ECL counts in an IGEN M8 Analyzer.
  • a ⁇ standard curves were obtained with 2-fold serial dilution of an A ⁇ stock solution of known concentration in the same cell culture medium used in cell-based assays.
  • BACE was assayed on a Biacore3000 instrument by attaching either a peptidic transition state isostere (TSI) or a scrambled version of the peptidic TSI to the surface of a Biacore CM5 sensor chip.
  • TSI transition state isostere
  • the surface of a CM5 sensor chip has 4 distinct channels that can be used to couple the peptides.
  • the scrambled peptide KFES-statine-ETIAEVENV was coupled to channel 1 and the TSI inhibitor KTEEISEVN-statine-V AEF was couple to channel 2 of the same chip.
  • the two peptides were dissolved at 0.2 mg/ml in 20 mM Na Acetate pH 4.5, and then the solutions were centrifuged at 14K rpm to remove any particulates.
  • Carboxyl groups on the dextran layer were activated by injecting a one to one mixture of O.5M N-ethyl-N' (3-dimethylaminopropyl)-carbodiimide (EDC) and 0.5M N-hydroxysuccinimide (NHS) at 5 ⁇ L/minute for 7 minutes. Then the stock solution of the control peptide was injected in channel
  • the BACE Biacore assay was done by diluting BACE to 0.5 ⁇ M in Na Acetate buffer at pH 4.5 (running buffer minus DMSO). The diluted BACE was mixed with DMSO or compound diluted in DMSO at a final concentration of 5% DMSO. The BACE/inhibitor mixture was incubated for 1 hour at 4 0 C then injected over channel 1 and 2 of the CM5 Biacore chip at a rate of 20 ⁇ L/minute. As BACE bound to the chip the signal was measured in response units (RU). BACE binding to the TSI inhibitor on channel 2 gave a certain signal. The presence of a BACE inhibitor reduced the signal by binding to BACE and inhibiting the interaction with the peptidic TSI on the chip. Any binding to channel 1 was non-specific and was subtracted from the channel
  • the DMSO control was defined as 100% and the effect of the compound was reported as percent inhibition of the DMSO control.
  • 2-Amino-3-methyl-6-(2-naphthalen-2-yl- ethyl)-3H-pyrimidin-4-one, AZ12066871 inhibited BACE binding in the BACE Biacore assay by 69% when tested at a concentration of ImM.
  • 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. Such methods include, but are not limited to, those described below.
  • AU references cited herein are hereby incorporated in their entirety by reference.
  • the novel compounds of this invention may be prepared using the reactions and techniques described herein. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • temperatures are given in degrees Celsius (°C); unless otherwise stated, operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0 C;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using deuterated chloroform (CDCl 3 ), dimethylsulphoxide (d 6 -DMSO) or dimethylsulphoxide/TFA (de-DMSO/TFA) as solvent; conventional abbreviations for signal shape are used; for AB spectra the directly observed shifts are reported; coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made;
  • Phosphonoacetate used to prepare olefins such as that in (Scheme 1, A) may be either trimethylphosphonoacetate, ethyl dimethylphosphonoacetate, tert-butyl dimethylphosphonoacetate, triethylphosphonoacetate, methyl diethylphosphonoacetate, or tert-butyl diethylphosphonoacetate.
  • XXI Normal phase chromatography conditions: Flash chromatography employed as a method for purification for selected intermediates.
  • Isco CombiFlash Sq 16x instrument pre-packaged disposable RediSep SiO 2 stationary phase columns (4, 12, 40, 120 gram sizes) with gradient elution at 5-125 mL/min of selected bi-solvent mixture, UV detection (190-760nm range) or timed collection, 0.1mm flow cell path length.
  • Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex; only diagnostic signals are reported, arm: atmospheric pressure; Boc: t-butoxycarbonyl; Cbz: benzyloxycarbonyl; DCM: methylene chloride; DIPEA: diisopropylethylamine; DMF: N;N-dimethyl form- amide; DMSO: dimethyl sulfoxide; Et 2 O: diethyl ether; EtOAc: ethyl acetate; h: hour(s); HPLC: high pressure liquid chromatography; minute(s): min.; NMR: nuclear magnetic resonance; psi: pounds per square inch; TFA: trifluoroacetic acid; THF: tetrahydrofuran; ACN: acetonitrile.
  • the olefin used in the cyclization may be one of a diverse set of esters, for example methyl, ethyl, isopropyl or t-butyl.
  • esters for example methyl, ethyl, isopropyl or t-butyl.
  • t-butyl esters are sometimes less efficient in the cyclization reaction.
  • the t-butyl ester can be converted to a methyl ester via Fisher ester synthesis, i.e. by treatment with concentrated sulfuric acid in methanol (1:10 V: V).
  • Example 2 The HPLC purification of Example 2 resulted in isolation of the title compound as a white powder (4.7 mg, 10%).
  • IHNMR 300.132 MHz, DMSO
  • the reaction was filtered through Celite and filtrate concentrated under reduced pressure. The resulting orange solid was put under high vacuum. A crude purification was done using silica gel eluting with 15:85:0.1 MeOH: DCM: acetic acid. The resulting orange solid was triturated with methanol to give the first batch of the title compound. The solvents were removed from the filtrate under reduced pressure and the resulting orange solid was triturated with ethanol to give a second batch of the title compound. The batches were combined to give the title compound (8.75 g, 79%) as an off white solid.
  • the l-(4-metholxy-benzylamino) group can be replaced with a 1-benzylamino group.
  • cleavage of the benzyl group can be accomplished by catalytic transfer hydrogenation 10% Pd/C in 5% formic acid/methonal. (e.g. Example 5, Table
  • the following compounds were synthesized using methods analogous to those previously described for Examples 1 or 4 employing the appropriate commercially available boronic acid.
  • the column “Method” contains three rows: the first is the scheme used; the second is the Suzuki method described in Example 2 (A) or Example 6 (B); and the third is the arylbromide used in the Suzuki. NA denotes that the Suzuki coupling with an arylbromide was not used.
  • Example 28 To an ambient stirred solution of Example 28 (0.25 g, 0.94 mmol) in DMF (5 mL) was added dimethylformamide dimethylacetal (0.16 mL, 1.17 mmol) and the reaction was stirred for 2 hrs. The DMF was removed under reduced pressure to yield a pale yellow oil. The oil was purified by ether tritruation (2 X 20 mL) to give the title compound as a clear, colorless oil (0.30 g, 99%).
  • This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 3-(2-bromophenyl)propionic acid was used in place of 3-(3-bromophenyl)propionic acid.
  • This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 3-(4-bromophenyl)propionic acid was used in place of 3-(3-bromophenyl)propionic acid.
  • This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 2-amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one was used in place of 2-ammo-6-[2-(3-bromophenyl)ethyl]pyrimidin-4(3H)-one.
  • Ethyl 5-(lH-indol-6-yl)-3-oxopentanoate (approximately 65% pure with over-reduced product as the major contaminant), (20 g, 77 mmol) was dissolved ethanol (160 mL) under argon and to this was added guanidine carbonate (9.Og, 50 mmol). The reaction was heated under reflux overnight then concentrated until approximately 50 mL of ethanol remained. To this was added water (50 mL) and the mixture was stirred for 3 h.
  • Ethyl 5-(2-naphthyl)-3-oxopentanoate was prepared as follows.
  • the reaction was allowed to stir for 3 h at 0 0 C then quenched with a mixture of concentrated HCl (5.2 mL), water (14 mL), and diethyl ether (40 mL). The mixture was stirred 20 min. then partitioned between diethyl ether (300 mL) and water (150 mL). The layers were separated and the aqueous again extracted with diethyl ether (150 mL). The combined organics were washed approximately 10 times with water (10x100 mL), dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 79 2-Amino-3-[2-(ben2ylamino)e%l]-6- ⁇ 2-[3-(2-furyl)phenyl]e%l ⁇ pyrimidin-4(3H)-one.
  • a thick-walled glass vial was charged with a stir bar
  • Si-TAAcOH resin (Silicycle, 100 mg) was added as a palladium scavenger and the resulting mixture stirred for 1 hour then filtered. The volatiles were evaporated on a Genevac HT-4 and the residue purified by mass-directed LCMS. [Waters Exterra column, 30x100 mm, 5 ⁇ , eluting with 12-88% acetonitrile/water buffered with 2.5 mM ammonium carbonate at 52 mL/min] to yield the title compound as a off-white solid. (23 mg, 43%).
  • Example 29 The following compounds in Table were synthesized using methods analogous to those previously described for Example 36 employing the appropriate boronic acid with the precursor aryl bromide of the title compound in Example 29.
  • This material was prepared according to the procedure described for Example 246 with the exception that l-bromo-3-(tetrahydropyranyloxy)propane was used in place of cyclohexylmethyl bromide. After deprotection of the DMF dimethyl acetal (with ammonium hydroxide, as described) the mixture was diluted with 6M HCl and incubated until the tetrahydropyran deprotection was complete. The mixture was neutralized and purified by preparative reverse phase HPLC to afford the desired product as the trifluoroacetate salt.
  • Scheme 9 The precursor compounds in Scheme 9 were prepared as follows. 4-(3-Bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 9, A)
  • the clear biphasic mixture was separated, wherein the organic layer was concentrated by rotary evaporation to a residue and treated with ethyl acetate (80 mL) while the aqueous remains were further extracted into ethyl acetate (2 x 50 mL).
  • the combined organic extracts were washed with a saturated sodium carbonate aqueous solution (2 x 80 mL) and brine (1 x 50 mL), dried over MgSO 4 and concentrated in vacuo to afford the desired 4-(3-bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 100, A) as a clear yellow oil (5.93 g, quantitative).
  • a thick-walled glass vial was charged with a stir bar, 2-amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, C) (120 mg, 0.2 mmol), 3-vinylphenylboronic acid (46 mg, 0.39 mmol), dichlorobis(triphenylphosphine)-palladium (II) (approximately 6 mg, 0.006 mmol), Cs 2 CO 3 (246 mg, 0.76 mmol) and DME/H 2 O/EtOH (7:3:2; 5 mL).
  • the vial was crimp sealed and subjected to microwave radiation for 5 min at 150 0 C.
  • a glass reaction vessel was charged with palladium (10% on activated carbon, approximately 5 mg, -25% w/w) and 2-amino-3-methyl-6-(3'-vinyl-biplienyl-3-ylmethyl)-3H-pyrimidin-4-one (Scheme 9, D) (21 mg, 0.07 mmol) in ethanol (1 mL) then subjected to hydrigen (40psi) for 5 min at 27°C. The resultant black slurry was filtered, washed with ethanol (3 x 3 mL) then concentrated in vacuo overnight to afford the title compound as a colorless film (18 mg, 82%).
  • a thick-walled glass vial was charged with a stir bar, 2-amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, C) (130 mg, 0.44 mmol), 3-vinylanisole (89 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol), tetrafluoroborate (10 mg, 0.035 mmol), iV.N-dicyclohexyhnethylamine (104 mg, 0.53 mmol) and anhydrous 1,4-dioxane (2 mL).
  • the reaction vial was sealed and subject to microwave radiation for 1 h at 150 0 C.
  • a glass Endeavor ® reaction vessel was charged palladium (10% on activated carbon, approximately 9 mg, ⁇ 10% w/w), and 2-amino-6- ⁇ 3-[(E)-2-(3-methoxy-phenyl)-vinyl]-benzyl ⁇ -3-methyl-3H-pyrimidin-4-one (Example 258, Scheme 9, F) (98 mg, 0.28 mmol) in ethyl acetate/ethanol (1:4, 5 mL) then subjected to hydrogen (40psi) for 20 min at 27 0 C. The resultant black slurry was filtered, washed with ethanol (3 x 3 mL) then concentrated in vacuo.

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Abstract

This invention relates to novel compounds having the structural formula Ia or formula Ib: Ia Ib and their pharmaceutically acceptable salts, tautomers or in vivo hydrolysable precursors, compositions and methods of use thereof. These novel compounds provide a treatment or prophylaxis of Aβ related pathologies such as cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

Description

SUBSTITUTED AMINO-COMPOUNDS AND USES THEREOF
Field of the invention
The present invention relates to novel substituted amino-compounds, their pharmaceutical compositions, methods of use and processes to make such compounds. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of amyloid-β-protein-related pathologies ("Aβ-related pathologies") such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Background of the invention
Several groups have identified and isolated aspartate proteinases that have β-secretase activity (Hussain et al, 1999; Lin et. al, 2000; Yan et. al, 1999; Sinha et. al., 1999 and Vassar et. al., 1999). β-secretase is also known in the literature as Asp2 (Yan et. al, 1999), Beta site APP (amyloid precursor protein) Cleaving Enzyme (BACE) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 2000). BACE was identified using a number of experimental approaches such as EST database analysis (Hussain et al. 1999); expression cloning (Vassar et al. 1999); identification of human homologs from public databases of predicted C elegans proteins (Yan et al. 1999) and finally utilizing an inhibitor to purify the protein from human brain (Sinha et al. 1999). Thus, five groups employing three different experimental approaches led to the identification of the same enzyme, making a strong case that BACE is a β-secretase. Mention is also made of the patent literature: WO96/40885, EP871720, U.S. Patents Nos. 5,942,400 and 5,744,346, EP855444, US 6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665, US 6,313,268.
BACE was found to be a pepsin-like aspartic proteinase, the mature enzyme consisting of the N-terminal catalytic domain, a transmembrane domain, and a small cytoplasmic domain. BACE has an optimum activity at pH 4.0-5.0 (Vassar et al, 1999)) and is inhibited weakly by standard pepsin inhibitors such as pepstatin. It has been shown that the catalytic domain minus the transmembrane and cytoplasmic domain has activity against substrate peptides (Lin et al, 2000). BACE is a membrane bound type 1 protein that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is thought to represent the major β-secretase activity, and is considered to be the rate-limiting step in the production of amyloid-β-protein (Aβ). It is thus of special interest in the pathology of Alzheimer's disease, and in the development of drugs as a treatment for Alzheimer's disease.
Aβ or amyloid-β-protein is the major constituent of the brain plaques which are characteristic of Alzheimer's disease (De Strooper et al, 1999). Aβ is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein called APP, or amyloid precursor protein. Aβ-secretase activity cleaves this protein between residues Met671 and Asp672 (numbering of 770aa isoform of APP) to form the N-terminus of Aβ. A second cleavage of the peptide is associated with γ-secretase to form the C-terminus of the Aβ peptide.
Alzheimer's disease (AD) is estimated to afflict more than 20 million people worldwide and is believed to be the most common form of dementia. Alzheimer's disease is a progressive dementia in which massive deposits of aggregated protein breakdown products - amyloid plaques and neurofibrillary tangles accumulate in the brain. The amyloid plaques are thought to be responsible for the mental decline seen in Alzheimer's patients.
The likelihood of developing Alzheimer's disease increases with age, and as the aging population of the developed world increases, this disease becomes a greater and greater problem. In addition to this, there is a familial link to Alzheimer's disease and consequently any individuals possessing the double mutation of APP known as the Swedish mutation (in which the mutated APP forms a considerably improved substrate for BACE) have a much greater chance of developing AD, and also of developing it at an early age {see also US 6,245,964 and US 5,877,399 pertaining to transgenic rodents comprising APP-Swedish). Consequently, there is also a strong need for developing a compound that can be used in a prophylactic fashion for these individuals.
The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Down's syndrome. Down's syndrome patients tend to acquire Alzheimer's disease at an early age, with almost all those over 40 years of age showing Alzheimer's-type pathology (Oyama et al., 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APPβ causing the high prevalence of Alzheimer's disease seen in this population. Thus, inhibitors of BACE could be useful in reducing Alzheimer's-type pathology in Down's syndrome patients.
Drugs that reduce or block BACE activity should therefore reduce Aβ levels and levels of fragments of Aβ in the brain, or elsewhere where Aβ or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Aβ or fragments thereof (Yankner, 1996; De Strooper and Konig, 1999). BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
It would therefore be useful to inhibit the deposition of Aβ and portions thereof by inhibiting BACE through inhibitors such as the compounds provided herein.
The therapeutic potential of inhibiting the deposition of Aβ has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors {see, e.g., WO01/23533 A2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO02/25276, US5,942,400, US6,245,884, US6.221.667, US6,211,235, WO02/02505, WO02/02506, WO02/02512, WO02/02518, WO02/02520, WO02/14264).
Summary of the Invention
Provided herein are novel compounds of structural formula Ia or formula Ib:
Figure imgf000005_0001
Ia
Figure imgf000006_0001
Ib or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, wherein:
W is C or N;
Q is selected from C3-12CyClOaIlCyI, C3-12cycloalkenyl, C6-14aryl, or Cs-isheterocyclyl; each R1 is, independently, selected from H, halogen, C2-6alkenyl, Chalky!, C3-12cycloalkyl, C6-10aryl, C1-6alkyl-C6-10aryl, or Cs-isheterocyclyl wherein said C1-6alkyl, said C3-12cycloalkyl, said C6-10aryl, said C1-6alkyl-C6-1oaryl, or said Cs.isheterocyclyl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH, COOH, OC1-6alkyl, CH2OH, SO2H, S(=0), C2-6alkenyl, C1-6alkyl-Ra, OC1-6alkyl-Ra, C(=O)C1-6alkyl-Ra, C(=O)OC1-6alkyl-Ra, C(=0)NH2, C(=O)NHC1-6alkyl-Ra, C(=O)N(C1-6alkyl-Ra)2, S(=O)Ci-6alkyl-Ra, S(=O)NHC1-6alkyl-Ra, S(=O)N(C1.6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(Ci-6alkyl-Ra)2, NHC(=O)Ci-6alkyl, C6-i0aryl-Ra, OC6-10aryl-Ra, C(=O)C6-10aryl-Ra, Ceθ)OC6-ioaryl-Ra, C(=O)NHC6.10aryl-Ra, C(-O)N(C6-i0aryl-Ra)2, S(=O)C6-10aryl-Ra, S(=O)NHC6-10aryl-Ra, S(=O)N(C6-10aryl-Ra)2, SO2C6-10aryl-Ra, SO2NHC6-10aryl-Ra, S02N(C6-ioaryl-Ra)2, NH(C6-10aryl)-Ra, N(C6-10aryl-Ra)2, NC(=O)C6-10aryl, C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(=0)C5-6heterocyclyl-Ra, C(=0)OC5.6heterocyclyl-Ra, C(=0)NHC5-6heterocyclyl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl-Ra), N(C5.6heterocyclyl-Ra)2, NHC(=O)C5-6heterocyclyl, SO2Ra, S(=O)Ra, N(C1-6alkyl-Ra)(C6-i0aryl-Ra), N(C1-6alkyl-Ra)(C6-1oheteroaryl-Ra), N(C6-1oaryl-Ra)(C6-10heteroaryl-Ra), C(=0)(C1-6alkyl-Ra)(C6-1oaryl-Ra), C(=0)(C1-6alkyl-Ra)(C6-10heteroaryl-Ra), C(=0)(C6-10aryl-Ra)(C6.1oheteroaryl-Ra), C(=0)0(C1.6alkyl-Ra)(C6-1oaryl-Ra)5 C(=O)O(C1-6alkyl-Ra)(C6-10heteroaryl-Ra), C(=O)O(C6-10aryl-Ra)(C6-10heteroaryl-Ra), Seθ)(C1-6alkyl-Ra)(C6-10aryl-Ra), S(=O)(C1-6alkyl-Ra)(C6.10heteroaryl-Ra)5 S(=O)(C6-10aryl-Ra)(C6-10heteroaryl-Ra), SO2(C1-6alkyl-Ra)(C6-10aryl-Ra), SO2(C1-6alkyl-Ra)(C6-10heteroaryl-Ra), or SO2(C6-10aryl-Ra)(C6-10heteroaryl-Ra); each Ra is, independently, selected from H, halogen, CN, NH2, OH, C^alkyl, OC1-6alkyl, C(=O)Ci.6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, SOC1-6alkyl, SONHC 1-6alkyl, SON(C1-6alkyl)2, SO2C1-6alkyl, SO2NHC1-6alkyl, SO2N(C1-6alkyl)2, NH(Ci.6alkyl), N(Cwa]kyl)2,
Figure imgf000007_0001
C5-6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=O)NH2, C(=O)NHC5-6aryl, Ceθ)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5.6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, C5-6heterocyclyl, OC5-6heterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=O)NH2, C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, S(=O)C5-6heterocyclyl, S(=O)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2> SO2NHC5-6heterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHC1-6alkylC5-6aryl, NRbRb, C(=O)Rb, C(=O)NRbRb, OC(=O)NRbRb, S(=O)Rb, S(=O)NRbRb, or SO2NRbRb; each Rb is, independently, selected from H, C1-6alkyl, C5-6aryl, or C5-6heterocyclyl; each V is, independently, selected from NH, O, S, S(=0), SO2, NHS(=O), NHSO2, S(=O)NH, SO2NH, NHC(=O), Q=O)NH, NRaSO2, NRaS(=O), NRaC(O), C(O)NR3, S(O)2NR3, S(=O)NRa, OC1-6alkylenyl, C2-6alkenylenyl or C1-6alkylenyl, wherein said OC1-6alkylenyl, C2-6alkenylenyl, and Ci-6alkylenyl is optionally substituted by 1, 2, or 3 substitutents independently selected from Ra;
X, Y, and Z are, independently, selected from NH, O, S, S(=0), SO2, NHS(=O), NHSO2, S(=O)NH, SO2NH, NHC(=O), C(=0)NH, NR2SO2, NRaS(=O), NRaC(0), C(0)NRa, S(O)2NR3, S(=O)NRa, or C1-6alkyl wherein said C1-6alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from Ra; m is O, 1, 2 or 3; n, q, r, s, and u are each, independently, O or 1 ;
R2 is selected from H, halogen, C1-6alkyl, C3-12cycloalkyl, C6-loaryl, C1-6alkyl-C6-10aryl, C5-10heterocyclyl, or C1-6alkyl-C5-10heterocyclyl wherein said Ci-6alkyl, C3-12cycloalkyl, C6-1OaTyI, C^alkyl-Ce^oaryl, Cs-ioheterocyclyl, and C1-6alkyl-C5-10heterocyclyl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH, C1-6alkyl-Ra, OCi-6alkyl-Ra, C(=O)Ci-6alkyl-Ra, C(=O)OC1-6alkyl-Ra, C(=O)NH2, C(=O)NHC1-6alkyl-Ra, C(=O)N(C1-6alkyl-Ra)2 S(=O)C1-6alkyl-Ra, S(=O)NHC1-6alkyl-Ra, S(=O)N(C1-6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2, NHC(=O)C1-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5-6aryl-Ra, C(=O)OC5-6aryl-Ra, C(=O)NH2, C(=O)NHC5-6aryl-Ra, C(=O)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)23 SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2, NH(C5-6aryl)-Ra, N(C5-6aryl- Ra)2, NHC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OCs-eheterocyclyl-R3,
Figure imgf000008_0001
C(=O)OC5-6heterocyclyl-Ra, C(=0)NH2, C(=O)NHC5-6heterocycryl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5.6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2 S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, or NHC(=O)C5-6heterocyclyl;
R3 is selected from R1, C1-6alkylRc, C1-6alkylNRcRc, C1-6alkylORc, C1-6alkylSRc, Ci.ealkylNHCi.ealkylCs-earylR'3, C1-6alkylNHC6-10arylRd, C1-6alkylNHC(O)C6-10arylRd, C1-6alkyl0C1-6alkylC5-6arylRd, C1-6alkylSC1-6alkylC5-6arylRd, C1-6aIkylC5-9heterocyclylRd, C1-6alkylC3-9cycloalkylRd, C1-6alkylNHC1-6alkylC5-9heterocyclylRd, C1-6alkylNHC5-9heterocyclyl(Rd)t, C1-6alkylNHC(O)C5-9heterocyclylRd, C1-6alkylOC1-6alkylC5-9heterocyclylRd, C1-6alkylSC1-6alkylC5-9heterocyclylRd, C1-6alkylNHC1-6alkylC3-9cycloallcylRd, C1-6alkylOC1-6alkylC3-9cycloalkylRd, or C1-6alkylSC1-6alkylC3-9cycloalkylRd; t is O, 1, 2, 3, 4 or 5; each Rc is, independently, selected from H, C(=O)C1-4alkyl, C(=O)Ci-4alkylOC1-4alkyl,
Figure imgf000008_0002
C5-6arylRd, Cs.gheterocyclylR*1, C3-9cycloalkylRd, C(=O)C5-6arylRd, C(=O)C5-9heterocyclylRd, C(=O)C3-9cycloalkylRd, C1-4alkyl-C5-6arylRd, C1-4alkyl-C5-9heterocyclylRd, or C1-4alkyl-C3-9cycloalkylRd; and
Rd is selected from H, C1-3alkyl, NH2, OH, COOH, OC^alkyl, or 0C1-3alkyl0H.
The present invention further provides compositions comprising a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, and and at least one pharmaceutically acceptable carrier, diluent or excipient.
The present invention further provides methods of modulating activity of BACE comprising contacting the BACE with a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
The present invention further provides methods of treating or preventing an Aβ-related pathology in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof. The present invention further provides a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for use as a medicament.
The present invention further provides a compound of formula Ia or fomula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for the manufacture of a medicament.
Detailed Description of the Invention
Provided herein are novel compounds of structural formula Ia or formula Ib:
Figure imgf000009_0001
Ia
Figure imgf000009_0002
Ib or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, wherein:
W is C or N;
Q is selected from C3-12CyClOaIlCyI, C3-12cycloalkenyl, C6-14aryl, or C5-15heterocyclyl; each R1 is, independently, selected from H, halogen, C2-6alkenyl, C1-6alkyl, C3.12cycloalkyl, C6-10aryl, C1-6alkyl-C6-10aryl, or C5-15heterocyclyl wherein said C1-6alkyl, said C3.12cycloalkyl, said C6-10aryl, said C1-6alkyl-C6-1oaryl, or said C5-15heterocyclyl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH, COOH, OC1-6alkyl, CH2OH, SO2H, S(=0), C2-6alkenyl, C1-6alkyl-Ra, OC1-6alkyl-Ra, C(=O)C1-6alkyl-Ra, C(=O)OC1-6alkyl-Ra, C(=0)NH2, C(=O)NHC1-6alkyl-Ra, C(=O)N(Ci-6alkyl-Ra)2, S(=O)C1-6allcyl-Ra, S(=O)NHC1-6alkyl-Ra, S(=O)N(C1-6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2; NHC(=O)C1-6alkyl, C6-i0aryl-Ra, OC6-10aryl-Ra, C(=O)C6-i0aryl-Ra, C(=O)OC6-10aryl-Ra, C(=O)NHC6-i0aryl-Ra, C(=O)N(C6-i0aryl-Ra)2, S(=O)C6-10aryl-Ra, S(=O)NHC6-i0aryl-Ra, S(=O)N(C6-10aryl-Ra)2, SO2C6-10aryl-Ra, SO2NHC6-10aryl-Ra, SO2N(C6-10aryl-Ra)2, NH(C6-10aryl)-Ra, N(C6-10aryl-Ra)2, NC(=O)C6-10aryl, C5-6heterocyclyl-Ra, OC^heterocyclyl-R3, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, C(=O)NHC5-6heterocyclyl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6lieterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5.6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl-Ra), N(C5-6heterocyclyl-Ra)2, NHC(=O)C5-6heterocyclyl, SO2Ra, S(=O)Ra, N(C1-6alkyl-Ra)(C6-10aryl-Ra), N(C1-6alkyl-Ra)(C6-10heteroaryl-Ra), N(C6-10aryl-Ra)(C6-1oheteroaryl-Ra), C(=0)(Ci-6alkyl-Ra)(C6-ioaryl-Ra), C(=0)(C1-6alkyl-Ra)(C6-10lieteroaryl-Ra), C(=O)(C6-10aryl-Ra)(C6.10heteroaryl-Ra), C(=O)O(C1-6alkyl-Ra)(C6-i0aryl-Ra), C(=0)0(C1-6alkyl-Ra)(C6-ioheteroaryl-Ra), C(=0)0(C6-10aryl-Ra)(C6-10heteroaryl-Ra), S(=0)(C1-6alkyl-Ra)(C6-1oaryl-Ra), S(=0)(Ci-6alkyl-Ra)(C6-i0heteroaryl-Ra), S(=O)(C6-i0aryl-Ra)(C6-10heteroaryl-Ra), SO2(C1-6alkyl-Ra)(C6-10aryl-Ra), SO2(C1-6alkyl-Ra)(C6-10lieteroaryl-Ra), or SO2(C6-10aryl-Ra)(C6-10lieteroaryl-Ra); each Ra is, independently, selected from H, halogen, CN, NH2, OH, Q-βalkyl, OC1-6alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, C(=O)NHC1-6aUcyl, C(=O)N(C1-6alkyl)2, SOC1-6alkyl, SONHCi-6alkyl, SON(C1-6alkyl)2j SO2C1-6alkyl, SO2NHC1-6alkyl, SO2N(d-6alkyl)2, NH(Ci.6alkyl), N(C1-6alkyl)2, NC(=O)C1-6alkyl, C5-6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, C5-6heterocyclyl, OCs-eheterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=O)NH2, C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, S(=O)C5-6heterocyclyl, S(=O)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2) SO2NHC5-6heterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHC1-6alkylC5-6aryl, NRbRb, C(=O)Rb, C(=O)NRbRb, 0C(=0)NRbRb, S(=O)Rb, S(=O)NRbRb, or SO2NRbRb; each Rb is, independently, selected from H, C1-6alkyl, C5-6aryl, or Cs-βheterocyclyl; each V is, independently, selected from NH, O, S, S(=O), SO2, NHS(=O), NHSO2, S(=O)NH, SO2NH, NHC(=0), C(=0)NH, NR3SO2, NRaS(=O), NRaC(O), C(O)NRa, S(O)2NRa, S(=O)NRa, OCϊ-δalkylenyl, C2-6alkenylenyl or C1-6alkylenyl, wherein said OQ-βatkylenyl, C2-6alkenylenyl, and C1-6alkylenyl is optionally substituted by 1, 2, or 3 substitutents independently selected from Ra;
X, Y, and Z are, independently, selected from NH, O, S, S(O), SO2, NHS(O), NHSO2, S(O)NH, SO2NH5 NHC(O), C(O)NH5 NR2SO2, NRaS(O), NRaC(O), C(O)NRa, S(O)2NRa, S(O)NRa, or C1-6alkyl wherein said
Figure imgf000011_0001
is optionally substituted by 1, 2, or 3 substituents independently selected from Ra; m is O, 1, 2 or 3; n, q, r, s, and u are each, independently, O or 1 ;
R2 is selected from H5 halogen, C1-6alkyl, C3-12cycloalkyl, C6-1oaryl, C1-6alkyl-C6-10aryl, C5-1oheterocyclyl5 or C1-6alkyl-C5-10heterocyclyl wherein said Ci-6alkyl, C3-12cycloalkyl, C6-1oaryl, Ci-βalkyl-Ce-ioaryl, Cs-ioheterocyclyl, and C1-6alkyl-C5-10heterocycryl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH5 C1-6alkyl-Ra, OC1-6alkyl-Ra, C(=O)C1-6alkyl-Ra, C(0)OC1-6alkyl-Ra, C(O)NH2, C(O)NHC1-6alkyl-Ra 5 C(=O)N(C1-6aUcyl-Ra)2 S(O)C1-6alkyl-Ra; S(O)NHC1-6alkyl-Ra, S(O)N(C1-6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra 5 N(Ci-6alkyl-Ra)2, NHC(=O)Ci-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(O)C5-6aryl-Ra, C(=O)OC5-6aryl-Ra, C(O)NH2, C(O)NHC5-6aryl-Ra, C(O)N(C5-6aryl-Ra)2, S(O)C5-6aryl-Ra, S(O)NHC5-6aryl-Ra, S(O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2, NH(C5-6aryl)-Ra, N(C5-6aryl- Ra)2, NHC(O)C5--6aryl, C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(0)C5-6heterocyclyl-Ra, C(0)OC5-6heterocyclyl-Ra, C(O)NH2, C(=O)NHC5-6heterocyclyl-Ra, C(0)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2 S(0)C5-6heterocyclyl-Ra, S(0)NHC5-6heterocyclyl-Ra, S(0)N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, or NHC(0)C5.6heterocyclyl;
R3 is selected from R1, C1-6alkylR°, C1-6alkylNRcRc, C1-6alkyl0Rc, C1-6alkylSRc,
Figure imgf000011_0002
C1-6alkylNHC(0)C6-1oarylRd, C1-6alkyl0C1-6al]iylC5-6arylRd, C1-6alkylSC1-6all^lC5-6arylRd, C1-6aUcylC5.9heterocyclylRd, C1-6alkylC3.9cycloalkylRd, C1-6alkylNHC1-6alkylC5-9heterocyclylRd, C1-6alkylNHC5-9heterocyclyl(Rd)t5 C1.6alkylNHC(O)C5-9heterocyclylRd 5 C1-6alkylOC1-6alkylC5-9heterocyclylRd, C1-6alkylSC1-6alkylC5-9heterocyclylRd, C1-6alkylNHC1-6alkylC3-9cycloalkylRd, C1-6alkylOC1-6alkylC3.9cycloalkylRd, or C1-6alkylSC1-6alkylC3-9cycloalkylRd; t is O5 1, 2, 3, 4 or 5; each Rc is, independently, selected from H, C(=O)C1-4alkyl, C(=O)C1-4alkylOC1-4alkyl, C(-O)Ci-4alkylC(=O)OCi-4alkyl, C(=O)C1-4alkylC(=O)OH, C(=O)C1-4alkylOC(=O)C1-4alkyl, C5-6arylRd, Cs.gheterocyclylR'1, C3-9cycloaIkylRd, C(=O)C5-6arylRd, C(=O)C5-9heterocyclylRd, C(=O)C3-9cycloalkylRd, C1-4alkyl-C5-6arylRd, C1-4alkyl-C5-9heterocyclylRd, or C1-4alkyl-C3-9cycloalkylRd; and
Rd is selected from H, Ci-3alkyl, NH2, OH, COOH, OC1-3alkyl, or OC1-3alkylOH.
In some embodiments, when the compound has formula Ia, W is N, R2 is C1-4alkyl, q is O, r is O, and s is 0, then [R1KV)n] m-Q is other than phenyl.
In some embodiments, when the compound has formula Ia, W is N, R2 is C1-4alkyl, q is 0, r is 0, s is 0, Q is phenyl, and m is 1, then R1^V)n- is other than bromo, pyridyl, or methoxyphenyl.
In some embodiments, when the compound has formula Ib, W is N5 and — [X]q— [Y]r— [Z]s— is -CH2- then [R^(V)n] m-Q is other than phenyl.
In some embodiments, when the compound has formula Ib, W is N5 — [X]q-[Y]r-[Z]s- is -CH2- or -CH(CH3)-, Q is phenyl, and m is 2, then at least one of RJ-(V)n- is other than fluoro.
In some embodiments, when the compound has formula Ib, W is N, -[X]q-[Y]r-[Z]s- is - NH-, Q is phenyl, and m is 2, then at least one of R^(V)n- is other than C1-4alkyl.
In some embodiments, when the compound has formula Ib, W is N, and -[X]q-[Y]r-[Z]s- is -O- then [R^(V)n] m-Q is other than phenyl.
In some embodiments, compounds of the present invention have the structure of formula Ia.
In some embodiments, compounds of the present invention have the structure of formula Ib.
In some embodiments, W is N.
In some embodiments, R3 is selected from H, C1-6alkyl, C1-6alkylNRcRc, C1-6alkylORc,
Figure imgf000012_0001
C1-6alkylC6.10arylRd, C1-6alkylC5-9heterocyclylRd, or C1-6alkylC3-9cycloalkylRd.
In some embodiments, R3 is selected from H, C1-6alkyl, C1-6alkylNRcRc, or C1-6alkyl-C5-9heterocyclylRd.
In some embodiments, R3 is C1-3alkyl.
In some embodiments, Q is C6-10aryl, C3-10cycloalkyl or C3-10cycloalkenyl.
In some embodiments, Q is C6aryl or C3-10cycloalkenyl.
In some embodiments, Q is C6aryl. hi some embodiments, Q is C^iocycloalkenyl. In some embodiments, -[X]q-[Y]r-[Z]s- is OC1-3alkyl, N(C1-3alkyl)C1-3alkyl, C1-3alkyl0C1-3alkyl, C1-3alkylN(H)C1-3alkyl or C1-3alkyl optionally substituted by OH.
In some embodiments, -[X]q-[Y]r-[Z]s- is OC1-3alkyl or C1-3alkyl0C1-3alkyl.
In some embodiments, -[X]q-[Y]r-[Z]s- is OC1-3aIkyl.
In some embodiments, q is 0, r is 0 and s is 0 (i.e., -[X]q-[Y]r-[Z]s- is absent).
In some embodiments, each R1 is independently C6-1oaryl or Cs-isheterocyclyl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-ioaryl, OH, NHC(=O)C1-4alkyl and -C6aryl-Ra.
In some embodiments, each R1 is independently C6-10aryl or Cs-isheterocyclyl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -C6aryl- OC1-4alkyl.
In some embodiments: each R1 is, independently, selected from C6-10aryl or C5-10heterocyclyl, each optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OC1-4alkyl, C5-6heterocyclyl or -C6arylRa; and
Ra is H5 OH, C1-6alkyl or OC1-6alkyl.
In some embodiments, m is 1, V is S, n is O or 1, and R1 is C6-10aryl or Cs.^heterocyclyl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -Cearyl-OC^alkyl.
In some embodiments, m is 1, n is O, and R1 is C6-1oaryl, wherein said aryl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -Cearyl-OCMalkyl.
In some embodiments:
R1 is, independently, selected from H, halogen, C6aryl, or C5-6heterocyclyl wherein said C6aryl, or C5-6heterocyclyl is optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OH, NH2, CN, C(=0)NH2, C^alkyl, OC1-6alkyl, C1-4alkyl0H, C1-4alkyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2C1-6alkyl, SO2NHC 1-6alkyl, OC1-3alkylOC1-3alkyl, 0C1-3alkyl0H, OC1-3alkylOC(=O)C1-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=0)NH2, C5-6heterocyclyl, OC5-6aryl, -C6aryl-OC1-4alkyl or OC1-6alkyl-C5-6aryl; and R2 is H or C1-6alkyl; and
R3 is H or C^aUcyl.
In some embodiments:
Q is C6aryl or Cs.gheterocyclyl;
W is N;
R1 is, independently, selected from H, halogen, C6aryl, or C5-6heterocyclyl wherein said C6aryl, or C5-6heterocyclyl is optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OH, NH2, CN, C(=O)NH2, C1-6alkyl, OC1-6alkyl, C1-4alkylOH, Ci-4aUcyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2Ci-6alkyl, SO2NHC1-6alkyl, OCμsalkylOd.salkyl, 0C1-3alkyl0H, OC1-3alkylOC(=O)C1-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, Cs.eheterocyclyl, OC5-6aryl, -C6aryl-OC1-4alkyl or OC1-6alkyl-C5-6aryl; and
R2 is C1-3alkyl.
In some embodiments: compounds of the invention have formula Ib;
Q is C6-10aryl;
W is N;
-[XJq-[Y] -[Z]s- is OCi.3alkyl; m is 1; n is 0; and
R1 is C6-1oaryl optionally substituted by 1 or 2 substituents independently selected from: OC1-4alkyl and -C6aryl-OC1-4alkyl.
In some embodiments: compounds of the invention have formula Ib;
Q is C3-10cycloalkenyl;
W is N
-[X]q-[Y]r-[Z]s- is absent; m is 1; n is 0; and
R1 is C6-10aryl optionally substituted by 1 or 2 substituents independently selected from: OC1-4alkyl and -C6aryl-OC1-4alkyl.
In some embodiments: compounds of the invention have formula Ia;
Q is Cβ-ioaryl, C3-10cycloalkyl or C3-10cycloalkenyl; W is N;
-[X]q-[Y] -[Z]s- is OCi-3alkyl, N(C1-3alkyl)Ci-3alkyl, C1-3alkyl0C1-3alicyl, C1-3alkylN(H)C1-3alkyl or C1-3alkyl optionally substituted by OH; m is 1;
V is S; n is 0 or 1; and
R1 is Cβ-ioaryl or Cs-^heterocyclyl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -C6aryl-OCMalkyl.
In some emboments, the present invention provides compounds of formula Ia or formula Ib selected from the following:
2-ammo-6-[[3-(3-methoxyphenyl)phenoxy]methyl]-3-methyl-3H-pyrimidin-4-one; and
2-amino-6-[2-[3-(3-methoxyphenyl)phenyl]-3-bicyclo[2.2.1]hept-5-enyl]-3-methyl-3H-p yrimidin-4-one, or a pharmaceutically acceptable salt, tautomer, or in vzvo-hydrolysable precursor thereof.
In another aspect, provided herein are novel compounds of structural formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof:
Figure imgf000015_0001
Ha
Figure imgf000015_0002
lib wherein
W is selected from C or N;
Q is selected from C3-12cycloalkyl, C3-12cycloalkenyl, C5-14aryl or Cs-uheterocyclyl;
R1 is independently selected from H, halogen, optionally substituted C1-6alkyl, optionally substituted C3-12cycloalkyl, optionally substituted C5-1oaryl, optionally substituted Ci-6alkyl-C5-10aryl, or optionally substituted Cs.ioheterocyclyl wherein such substituent are independently selected from: halogen, CN, NH2, OH, COOH, OC1-6alkyl, CH2OH, SO2H, S(O), Ci-6alkyl-Ra, OC1-6alkyl-Ra, C(=O)C1-6alkyl-Ra, C(=O)OC1-6alkyl-Ra, C(=0)NH2,
Figure imgf000016_0001
S(O)C1 -6alkyl-Ra, S(=O)NHCi-6alkyl-Ra, S(O)N(C1-6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(Ci-6alkyl-Ra)2j NHC(=O)C1-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5-6aryl-Ra, C(=O)OC5-6aryl-Ra, C(=O)NHC5-6aryl-Ra, Ceθ)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2 NH(C5-6aryl)-Ra, N(C5-6aryl)2-Ra, NC(=O)C5-6aryl3 C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(=O)C5-6heterocyclyl-Ra, C(=0)OC5-6heterocyclyl-Ra, C(=O)NHC5-6heterocyclyl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, NC(=O)C5-6heterocyclyl, SO2Ra, S(=O)Ra, N(Ci-6alkyl-Ra)(C1-6aryl-Ra), N(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), N(Ci-6aryl-Ra)(C1-6heteroaryl-Ra), C(=O)(C1-6alkyl-Ra)(Ci-6aryl-Ra)3 C(=O)(Cj-6alkyl-Ra)(C1-6heteroaryl-Ra), C(=O)(C1-6aryl-Ra)(C1-6heteroaryl-Ra), C(=O)O(C1-6alkyl-Ra)(C1-6aryl-Ra), C(=O)O(C1-6alkyl-Ra)(Ci-6heteroaryl-Ra), C(=O)O(C1-6aryl-Ra)(C1-6heteroaryl-Ra)3 S(=O)(C1-6alkyl-Ra)(C1-6aryl-Ra), S(=O)(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), S(=O)(C1-6aryl-Ra)(Ci-6heteroaryl-Ra), SO2(C1-6alkyl-Ra)(C1-6aryl-Ra), SO2(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), SO2(C1-6aryl-Ra)(C1-6heteroaryl-Ra):
Ra is selected from H, halogen, CN, NH2, OH, C1-6alkyl, OC1-6alkyl, C(=O)C1.6alkyl, C(=O)OC1-6alkyl, C(=0)NH2, C(=O)NHC1-6alkyl, CC=O)N(C1 -6alkyl)2, SOC1-6alkyl, SONHCLβaUcyl, SON(C1-6alkyl)2, SO2C1-6alkyl, SO2NHC1-6alkyl, SO2N(C1-6alkyl)2, NHCd^alkyl), N(C1-6alkyl)2, NC(=O)C1-6alkyl, C5.6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=0)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5.6aryl, C5-6heterocyclyl, OCs-eheterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5.6heterocyclyl, C(=0)NH2, C(=O)NHC5-6heterocyclyl-, C(=O)N(C5-6heterocyclyl)2, S(0)C5-6heterocyclyl, S(=0)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2j SO2NHC5-6heterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl)3 N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHC1-6alkylC5-6aryl, NRbRb, C(O)Rb, C(O)NRbRb, CO2NRbRb, S(O)Rb, S(=O)NRbRb, SO2NRbRb;
Rb is independently selected from H, C1-6alkyl, C5-6aryl, or C5-6heterocyclyl;
V is selected from N, O, S5 S(O), SO2, NHS(O), NHSO2, S(O)NH, SO2NH, NHC(O), C(O)NH, NRaSO2, NR3S(O), NRaC(O), C(O)NRa, S(O)2NRa, S(O)NRa or optionally substituted C1-6alkyl wherein such substituent is/are independently selected from Ra;
X is selected from N, O, S, S(O), SO2, NHS(O), NHSO2, S(O)NH, SO2NH, NHC(O), C(O)NH, NR3SO2, NR3S(O), NR3C(O), C(O)NR3, S(O)2NR3, S(O)NR3 or optionally substituted C1-6alkyl wherein such substituent is/are independently selected from Ra;
Y is selected from N, O, S, S(O), SO2, NHS(O), NHSO2, S(O)NH, SO2NH, NHC(O), C(O)NH, NR3SO2, NR3S(O), NR3C(O), C(O)NR3, S(O)2NR3, S(O)NR3 or optionally substituted Q-βalkyl wherein such substituent is/are independently selected from R3;
Z is selected from N, O, S, S(O), SO2, NHS(O), NHSO2, S(O)NH, SO2NH, NHC(O), C(O)NH, NR3SO2, NRaS(O), NR3C(O), C(O)NR3, S(O)2NR3, S(O)NR3 or optionally substituted Q^alkyl wherein such substituent is/are independently selected from R3; • m is O, 1, 2 or 3; n is O or 1; p is O or 1; q is O or 1; r is O or 1; s is O or 1; t is O or 1; u is O or 1; with the proviso that m, n, p, q, r, s, t, and u cannot all be O simultaneously.
R2 is independently selected from H, halogen, optionally substituted C1-6alkyl, optionally substituted C3-12cycloalkyl, optionally substituted C5-10aryl, optionally substituted C1-6alkyl-C5-1oaryl, optionally substituted C5.10heterocyclyl or optionally substituted Q-όalkyl-Cs-iQheterocyclyl wherein such substituent are independently selected from: halogen, CN, NH2, OH, C1-6alkyl-Ra, OCi-6alkyl-Ra, C(O)C1-6alkyl-Ra, C(O)0C1-6alkyl-Ra, C(O)NH2, C(O)NHCi-6alkyl-Ra, C(O)N(C1-6alkyl-R3)2 S(O)C1-6alkyl-Ra, S(O)NHCi-6alkyl-Ra, S(O)N(Ci-6alkyl-Ra)2, SO2Ci-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(Ci-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2, NC(=O)C1-6alkyl, C5-6aryl-Ra, OC5.6aryl-Ra, C(=O)C5-6aryl-Ra, C(=O)OC5-6aryl-Ra, C(=O)NH2, C(=O)NHC5-6aryl-Ra, C(=O)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2, NH(C5-6aryl)-Ra, N(C5-6aryl- Ra)2, NC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OCs-eheterocyclyl-R1, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, C(=O)NH2, C(=O)NHC5-6heterocyclyl-Ra 3 C(=O)N(C5-6heterocyclyl- Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl- Ra)2 S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl- Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, NC(=O)C5-6heterocyclyl;
R3 is independently selected from Rl5 H, C1-6alkyl, C1-6alkylRcRc, C1-6alkylNRQRc, C1-6alkylORcRc, C1-6alkylSRcRc, C1-6alkylNC1-6alkylC5-6arylRd, or C1-6alkyl0C1-6alkylC5-6arylRd, C1-6alkylSC1-6alkylC5-6arylRd, C1-6alkylC5-9lieterocyclylRd, C1-6alkylNC1-6alkylC5-9heterocyclylRd, C1-6alkylOC1-6alkylC5-9lieferocyclylRd, C1-6alkylSC1-6alkylC5-9lieterocyclylRd, C1-6alkylNC1-6alkylC3-9cycloalkylRd, Ci.ealkylOCi.ealkylCs.gcycloalky^, C1-6alkylSC1-6attylC3-9cycloalkylRd;
Rc is independently selected from H, CC=O)C1 -4alkyl, C(=O)C1-4alkylOC1-4alkyl, C(=0)C1-4alkylC(=O)OC1-4aliyl, C(=0)C1-4alkylC(=O)OH, C(=0)C1-4all^l0C(=O)C1-4alkyl, C5-6arylRd, C5-9heterocyclylRd, C3-9cycloalkylRd, C(=O)C5-6arylRd, C(=O)C5-9heterocyclylRd, C(=O)C3-9cycloalkylRd, C1-4alkyl-C5-6arylRd, C1-4alkyl-C5-9heterocyclylRd, C1-4alkyl-C3-9cycloalkylRd;
Rd is independently selected from H, C1-3alkyl, NH2, OH, COOH, OC1.3alkyl, OC^alkylOH.
One embodiment of the present invention provides a compound of formula IIa or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein Q is C5-6aryl and W, R1, R\ Rb, V, X, Y, Z, m, n, o, p, q, r, s, t, u, R2, R3, Rc and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein Q is Qaryl and W, R1, Ra, Rb, V, X, Y, Z, m, n, o, p, q, r, s, t, u, R2, R3, Rc and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides compounds of formula Ha or formula Eb, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein R2 is C1-3alkyl and Q, W3 R1, Ra, Rb, V, X, Y, Z, m, n, o, p, q, r, s, t, u, R3, Rc and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein R3 is C1-3alkyl and Q, W, R1, Ra, Rb, V, X, Y, Z, m, n, o, p, q, τ, s, t, u, R2, R0 and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides compounds of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzVo-hydrolysable precursors wherein Q is Cgheterocyclyl and W, R1, Ra, Rb, V, X, Y, Z, m, n, o, p, q, r, s, t, u, R2, R3, Rc and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides compounds of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
Q is C6-1oaryl or C5-9heterocyclyl;
X is C1-3alkyl; q is 0 or 1 ; m is 0 or 1 or 2;
R1 is independently selected from H, halogen, optionally substituted C5-1oaryl, optionally substituted OC5-10aryl or optionally substituted C5-10heterocyclyl wherein such substituent(s) are independently selected from: halogen, OH, NH2, CN, C(=O)NH2, C1-6alkyl, OC1-6alkyl, C1-4alkylOH, C1-4alkyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2C1-6alkyl, SO2NHC1-6alkyl, OC1-3alkylOC1-3alkyl, OC^alkylOH, OC1-3alkylOC(=O)C1-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, Q=O)NH2, Cs-eheterocyclyl, OC5-6aryl, OC1-6alkyl-C5-6aryl,
R2 is H, C1-6alkyL t is O or 1;
R3 is independently selected from H, C1-3alkyl.
One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
W is N;
Q is C6aryl or Cgheterocyclyl;
X is C1-3alkyl; q is O or 1; m is O or 1 or 2; R1 is independently selected from H, halogen, optionally substituted C6aryl, or optionally substituted C5-6heterocyclyl wherein such substituent(s) are independently selected from: halogen, OH3 NH2, CN, C(O)NH2, C1-6alkyl, OCi.6alkyl, C1-4alkyl0H, C1-4alkyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2Ci-6alkyl, SO2NHC1-6alkyl, OC1-3alkylOC1-3alkyl, 0C1-3alkyl0H, OC1-3alkylOC(=O)C1-3alkyl, C(=O)Ci-6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, C5-6heterocyclyl, OC5-6aryl, OC1-6alkyl-C5-6aryl;
R2 is C1-3alkyl; t is O or 1; and V, Y, Z, n, o,p, r, s, u, R3, Rc and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
W is N;
Q is C6aryl or Cgheterocyclyl;
X is C1-3alkyl; q is O or l; m is O or 1 or 2;
R1 is independently selected from H, halogen, optionally substituted C6aryl, or optionally substituted C5.6heterocyclyl wherein such substituent(s) are independently selected from: halogen, OH, NH2, CN, C(=0)NH2, C^alkyl, OCi-6alkyl, C1-4alkyl0H, C1-4alkyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2Ci-6alkyl, SO2NHC1-6alkyl, OC1-3alkylOC1-3alkyl, 0C1-3alkyl0H, OC1.3alkylOC(=O)C1-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, Q=O)NH2, C5-6heterocyclyl, OC5-6aryl, OCi-6alkyl-C5-6aryl;
R2 is C1-3alkyl; t is O orl;
R3 is H, C1-6alkyl, C1-6alkylNRcRc, C1-6alkyl-C5-9heterocyclylRd; and V, Y, Z, n, o,p, r, s, u, Rc, and Rd have any of the meanings as defined hereinabove.
One embodiment of the present invention provides a compound of formula Ha or formula lib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein:
Q is C6aryl or Cgheterocyclyl;
X is C1-3alkyl; q is O or l; m is 0 or 1 or 2;
R is independently selected from H, halogen, optionally substituted C6aryl, or optionally substituted C5-6heterocyclyl wherein such substituent(s) are independently selected from: halogen, OH, NH2, CN, C(=0)NH2, Ci-6alkyl, OC1-6alkyl, C1-4alkylOH, C1-4alkyl0Ci-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2C1-6alkyl, SO2NHC1-6alkyl, OC1-3alkylOC1-3alkyl, OC1-3alkylOH, 0C1-3alkyl0C(==0)Ci-3alkyl, C(=O)Ci.6alkyl, C(O)0Ci-6alkyl, C(=O)NH2, C5-6heterocyclyl, OC5-6aryl, OC1-6alkyl-C5-6aryl;
R2 is C1-3alkyl; t is O or 1;
R3 is C1-3alkyl; and u is 1.
Compounds of the present invention also include pharmaceutically acceptable salts, tautomers and in vzvo-hydrolysable precursors of the compounds of formula Ia and/or formula Ib. Compounds of the invention further include hydrates and solvates.
Compounds of the invention can be used as medicaments. In some embodiments, the present invention provides compounds of formula Ia or formula Ib, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, for use as medicaments. In some embodiments, the present invention provides compounds described herein for use as as medicaments for treating or preventing an Aβ-related pathology. In some further embodiments, the Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
In some embodiments, the present invention provides compounds of formula Ia or formula Ib, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, in the manufacture of a medicament for the treatment or prophylaxis of Aβ-related pathologies. In some further embodiments, the Aβ-related pathologies include such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
In some embodiments, the present invention provides a method of inhibiting activity of BACE comprising contacting the BACE with a compound of the present invention. BACE is thought to represent the major β-secretase activity, and is considered to be the rate-limiting step in the production of amyloid-β-protein (Aβ). Thus, inhibiting BACE through inhibitors such as the compounds provided herein would be useful to inhibit the deposition of Aβ and portions thereof. Because the deposition of Aβ and portions thereof is linked to diseases such as Alzheimer Disease, BACE is an important candidate for the development of drugs as a treatment and/or prophylaxis of Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
In some embodiments, the present invention provides a method for the treatment of Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, comprising administering to a mammal (including human) a therapeutically effective amount of a compound of formula Ia or formula Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
In some embodiments, the present invention provides a method for the prophylaxis of Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration comprising administering to a mammal (including human) a therapeutically effective amount of a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydroly sable precursors.
In some embodiments, the present invention provides a method of treating or preventing Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration by administering to a mammal (including human) a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors and a cognitive and/or memory enhancing agent.
In some embodiments, the present invention provides a method of treating or prevenitng Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration by administering to a mammal (including human) a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursors thereof wherein constituent members are provided herein, and a choline esterase inhibitor or anti-inflammatory agent.
In some embodiments, the present invention provides a method of treating or prevenitng Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, or any other disease, disorder, or condition described herein, by administering to a mammal (including human) a compound of the present inventionand an atypical antipsychotic agent. Atypical antipsychotic agents includes, but not limited to, Olanzapine (marketed as Zyprexa), Aripiprazole (marketed as Ability), Risperidone (marketed as Risperdal), Quetiapine (marketed as Seroquel), Clozapine (marketed as Clozaril), Ziprasidone (marketed as Geodon) and Olanzapine/Fluoxetine (marketed as Symbyax).
In some embodiments, the mammal or human being treated with a compound of the invention has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the mammal or human being treated is in need of such treatment. Diagnosis, however, need not be previously performed.
The present invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention herein together with at least one pharmaceutically acceptable carrier, diluent or excipent.
When used for pharmaceutical compositions, medicaments, manufacture of medicaments, inhibiting activities of BACE, or treating or preventing Aβ-related pathologies, compounds of the present invention include the compounds of formula Ia and/or formula Ib, and pharmaceutically acceptable salts, tautomers and in vivo-hydrolysable precursors thereof. Compounds of the present invention further include hydrates and solvates.
The definitions set forth in this application are intended to clarify terms used throughout this application. The term "herein" means the entire application.
As used in this application, the term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. In the event a substitution is desired then such substitution means that any number of hydrogens on the designated atom or moiety is replaced with a selection from the indicated group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, then 3 hydrogens on the carbon atom can be replaced. For another example, when a substituent is oxo (i.e., =0), then 2 hydrogens of the atom or moiety where the substitution occurs are replaced. For example if V is O and n is 1 then m cannot be greater than 1. Examples of suitable substituents include, but are not limited to: halogen, CN, NH2, OH, SO, SO2, COOH, OC1-6alkyl, CH2OH, SO2H, C1-6alkyl, OC1-6alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=0)NH2, CC=O)NHC1.6alkyl, C(=O)N(C1-6alkyl)2, SO2C1-6alkyl, SO2NHC1-6alkyl, SO2N(Ci-6alkyl)2, NH(C1-6alkyl), N(C1-6alkyl)2, NHC(=O)Ci-6alkyl, NC(=O)(C1-6alkyl)2, C5-6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, NC(=O)(C5-6aryl)2, C5-6heterocyclyl, OCs-eheterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, SO2C5-6heterocyclyl, SO^HCs-eheterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, NC(=O)(C5-6heterocyclyl)2.
A variety of compounds in the present invention may exist in particular geometric or stereoisomer^ forms. The present invention takes into account all such compounds, including cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. AU such isomers, as well as mixtures thereof, are intended to be included in this invention. 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. When required, separation of the racemic material can be achieved by methods known in the art. 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.
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", "alkylenyl" or "alkylene" used alone or as a suffix or prefix, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "C1-6alkyl" 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. As used herein, "C1-3alkyl", whether a terminal substituent or an alkylene (or atkylenyl) group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylenyl" refers to a divalent linking alkenyl group.
As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent linking alkynyl group.
As used herein, "aromatic" refers to hydrocarbyl groups having one or more polyunsaturated carbon rings having aromatic characters, (e.g., 4ri + 2 delocalized electrons) and comprising up to about 14 carbon atoms.
As used herein, the term "aryl" refers to an aromatic ring structure made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be a polycyclic moiety in which at least one carbon is common to any two adjoining rings therein (for example, the rings are "fused rings"), for example naphthyl. The aromatic ring can be substituted at one or more ring positions with such substituents as described above. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls or cycloalkynyls. The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups, having the specified number of carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or bridged rings) groups. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene, cyclohexane, and the like. The term "cycloalkyl" further includes saturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure. For example, "C3-6 cycloalkyl" denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, "cycloalkenyl" refers to ring-containing hydrocarbyl groups having at least one carbon-carbon double bond in the ring, and having from 3 to 12 carbons atoms.
As used herein, "cycloalkynyl" refers to ring-containing hydrocarbyl groups having at least one carbon-carbon triple bond in the ring, and having from 7 to 12 carbons atoms.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
"Counterion" is used to represent a small, negatively or positively charged species such as chloride (CV), bromide (Br'), hydroxide (OH"), acetate (CH3COO") , sulfate (SO42"), tosylate (CH3-phenyl-SO3 "), benezensulfonate (phenyl-SO3 "), sodium ion (Na+), potassium (K+), ammonium (NH4 +), and the like.
As used herein, the term "heterocyclyl" or "heterocyclic" or "heterocycle" refers to a ring-containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising from 3 to 20 atoms in the rings, more preferably 3- to 7- membered rings. The number of ring-forming atoms in heterocyclyl are given in ranges herein. For example, C5-10 heterocyclyl refers to a ring strcture comprising from 5 to 10 ring-forming atoms wherein at least one of the ring-forming atoms is N, O or S. Heterocyclic groups may be saturated or partially saturated or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring as in the case of polycyclic systems. The heterocyclic rings described herein may be substituted on carbon or on a heteroatom atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocyclyl may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another.
Examples of heterocyclyls include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H- 1, 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, diazepane, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dioxolane, furyl, 2,3-dihydrofliran, 2,5-dihydrofuran, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, lH-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, oxirane, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidinyl, pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl dione, pyrrolinyl, pyrrolyl, pyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetramethylpiperidinyl, tetrahydroquinoline, tetrahydroisoquinoliήyl, thiophane, thiotetrahydroquinolinyl, 6H-l,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, thiopheneyl, thiirane, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazoryL 1,3,4-triazolyl, xanthenyl.
As used herein, "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, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, the term "carbonyl" is art recognized and includes such moieties as can be represented by the general formula:
Figure imgf000028_0001
wherein X is a bond or represents an oxygen or sulfur, and R represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-RJ ' or a pharmaceutically acceptable salt, R' represents a hydrogen, an alkyl, an alkenyl or -(CH2)Hi-R", where m is an integer less than or equal to ten, and R" is alkyl, cycloalkyl, alkenyl, aryl, or heteroaryl. Where X is an oxygen and R and R' is not hydrogen, the formula represents an "ester". Where X is an oxygen, and R is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R' is a hydrogen, the formula represents a "carboxylic acid." Where X is oxygen, and R' is a hydrogen, the formula represents a "formate." In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and R and R' is not hydrogen, the formula represents a "thiolester." Where X is sulfur and R is hydrogen, the formula represents a "thiolcarboxylic acid." Where X is sulfur and R' is hydrogen, the formula represents a "thiolformate." On the other hand, where X is a bond, and R is not a hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R is hydrogen, the above formula is represents an "aldehyde" group.
As used herein, the term "sulfonyl" refers to a moiety that can be represented by the general formula:
O Il
— S-R Il O wherein R is represented by but not limited to hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
As used herein, some substituents are discribled in a combination of two or more groups. For example, the expression of "C(=O)C3-9cycloalkylRd" is meant to refer to a structure:
Figure imgf000029_0001
wherein p is 1, 2, 3, 4, 5, 6 or 7 (a Ca.gcycloalkyl); the C3-9cycloalkyl is substituted by Rd; and the point of attachment of the "C(=O)C3-9cycloalkylRd" is through the carbon atom of the carbonyl group, which is on the left of the expression.
As used herein some substitutents can occur at multiple times. For example, the expression of "C1-6alkylNHC5.9heterocyclyl(Rd)t" is meant to ferer to Rd can can occur on the heterocyclyl moiety portion t times and Rd can be a different substituent in its definition at each occurence.
As used herein, the phrase "protecting group" means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999). As used herein, "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 (i.e., also include counterions). 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, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that 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 used.
As used herein, "in vivo hydrolysable precursors" means an in vivo hydroysable (or cleavable) ester of a compound of formula Ia or formula Ib that contains a carboxy or a hydroxy group. For example amino acid esters, C1-6 alkoxymethyl esters like methoxymethyl; C1-6alkanoyloxymethyl esters like pivaloyloxymethyl; C3.8cycloalkoxycarbonyloxy C1-6alkyl esters like 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, or phosphoramidic cyclic esters.
As used herein, "tautomer" means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, keto-enol tautomerism where the resulting compound has the porperties of both a ketone and an unsturated alchol.
As used herein "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.
Compounds of the invention further include hydrates and solvates. The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to H (also written as D for deuterium), H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36Cl3 82Br, 75Br, 76Br, 77Br, 123I3 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3H3 14C3 82Br3 1251 , 1311, 35S or will generally be most useful. For radio-imaging applications 11C, 18F3 1251, 123I3 124I3 131I, 75Br3 76Br or 77Br will generally be most useful.
It is understood that a "radio-labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting Of 3H3 14C3 1251 , 35S and 82Br.
The anti-dementia treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional chemotherapy. Such chemotherapy may include one or more of the following categories of agents:
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention.
Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
An effective amount of a compound of the present invention for use in therapy of dementia is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of dementia, to slow the progression of dementia, or to reduce in patients with symptoms of dementia the risk of getting worse. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, trifluoroacetate and the like.
In some embodiments, the present invention provides a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The term composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.
The compounds of the invention may be derivatised in various ways. As used herein "derivatives" of the compounds includes salts (e.g. pharmaceutically acceptable salts), any complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination complexes with metal ions such as Mn2+ and Zn2+), esters such as in vivo hydrolysable esters, free acids or bases, polymorphic forms of the compounds, solvates (e.g. hydrates), prodrugs or lipids, coupling partners and protecting groups. By "prodrugs" is meant for example any compound that is converted in vivo into a biologically active compound.
Salts of the compounds of the invention are preferably physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art. All such salts are within the scope of this invention, and references to compounds include the salt forms of the compounds.
Compounds having acidic groups, such as carboxylate, phosphates or sulfates, can form salts with alkaline or alkaline earth metals such as Na5 K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds having both acidic and basic groups can form internal salts.
Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +.
Where the compounds contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the invention.
Compounds containing an amine function may also form N-oxides. A reference herein to a compound that contains an amine function also includes the N-oxide.
Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art. Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a Cs-20 aryl group, preferably a C1-7 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(^O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, wherein R is an acyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OQ=O)CH2Ph.
Derivatives which are prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it. Some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Examples of such metabolically labile esters include those of the formula -C(=O)OR wherein R is: C1-7alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C1-7aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1 -( 1 -methoxy- 1 -methyl)ethyl-carbonyloxyethyl; 1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1 -isopropoxy-carbonyloxy ethyl; cyclohexyl-carbonyloxymethyl; 1 -cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; l-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and l-(4-tetrahydropyranyl)carbonyloxyethyl).
Also, some prodrugs are activated enzymatically to yield the active compound, or a - compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Other derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it. Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody or an inhibitor. Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group. Other derivatives include formulating the compounds with liposomes.
Where the compounds contain chiral centres, all individual optical forms such as enantiomers, epimers and diastereoisomers, as well as racemic mixtures of the compounds are within the scope of the invention.
Compounds may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by the scope of this invention.
The quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 pg/kg to 10 mg/kg per day. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
Compounds of the present invention have been shown to inhibit beta secretase (including BACE) activity in vitro. Inhibitors of beta secretase have been shown to be useful in blocking formation or aggregation of Aβ peptide and therefore have a beneficial effects in treatment of Alzheimer's Disease and other neurodegenerative diseases associated with elevated levels and/or deposition of Aβ peptide. Therefore it is believed that the compounds of the present invention may be used for the treatment of Alzheimer disease and disease associated with dementia Hence compounds of the present invention and their salts are expected to be active against age-related diseases such as Alzheimer, as well as other Aβ related pathologies such as Downs syndrome and b-amyloid angiopathy. It is expected that the compounds of the present invention would most likely be used in combination with a broad range of cognition deficit enhancement agents but could also be used as a single agent.
Generally, the compounds of the present invention have been identified in one or both assays described below as having an IC50 value of 100 micromolar or less. For example the compound of example number 34 has an IC5O value of 36nM.
IGEN Assay
Enzyme is diluted 1:30 in 4OmM MES pH 5.0. Stock substrate is diluted to 12uM in 4OmM MES pH 5.0. PALMEB solution is added to the substrate solution (1:100 dilution). DMSO stock solutions of compounds or DMSO alone are diluted to the desired concentration in 4OmM MES pH 5.0. The assay is done in a 96 well PCR plate from Nunc. Compound in DMSO (3 μL) is added to the plate then enzyme is added (27 μL) and pre-incubated with compound for 5 minutes. Then the reaction is started with substrate (30 μL). The final dilution of enzyme is 1:60; the final concentration of substrate is 6 uM (Km is 150 μM). After a 20 minute reaction at room temperature, the reaction is stopped by removing 10 μl of the reaction mix and diluting it 1 :25 in 0.20M Tris pH 8.0. The compounds are added to the plate by hand then all the rest of the liquid handling is done on the CyBi- well instrument.
AU antibodies and the streptavidin coated beads are diluted into PBS containing 0.5% BSA and 0.5% Tween20. The product is quantified by adding 50 μL of a 1:5000 dilution of the neoepitope antibody to 50 μL of the 1:25 dilution of the reaction mix. Then, 100 μL of PBS (0.5% BSA, 0.5% Tween20) containing 0.2mg/ml IGEN beads and a 1:5000 dilution of ruthinylated goat anti-rabbit (Ru-Gar) antibody is added. The final dilution of neoepitope antibody is 1:20,000, the final dilution of Ru-GAR is 1:10,000 and the final concentration of beads is 0.1 mg/ml. The mixture is read on the IGEN instrument with the Cindy AB40 program after a 2-hour incubation at room temperature. Addition of DMSO alone is used to define the 100% activity. 2OuM control inhibitor is used to define 0% of control activity and 10OnM inhibitor defines 50% control of control activity in single-poke assays. Control inhibitor is also used in dose response assays with an IC50 of 10OnM.
Fluorescent Assay
Enzyme is diluted 1 :30 in 4OmM MES pH 5.0. Stock substrate is diluted to 30 uM in 4OmM MES pH 5.0. PALMEB solution is added to the substrate solution (1:100 dilution). Enzyme and substrate stock solutions are kept on ice until the placed in the stock plates. The Platemate-plus instrument is used to do all liquid handling. Enzyme (9 μL) is added to the plate then 1 μL of compound in DMSO is added and pre-incubated for 5 minutes. When a dose response curve is being tested for a compound, the dilutions are done in neat DMSO and the DMSO stocks are added as described above. Substrate (10 μL) is added and the reaction proceeds in the dark for 1 hour at room temperature. The assay is done in a Corning 384 well round bottom, low volume, non-binding surface (Corning #3676). The final dilution of enzyme is 1:60; the final concentration of substrate is 15uM (Km of 25 μM). The fluorescence of the product is measured on a Victor II plate reader with an excitation wavelength of 360nm and an emission wavelength of 485nm using the protocol labeled Edans peptide. The DMSO control defines the 100% activity level and 0% activity is defined by using 5OuM of the control inhibitor, which completely blocks enzyme function. The control inhibitor is also used in dose response assays and has an IC50 of 95nM.
Beta-Secretase Whole Cell Assay
Generation of HEK-Fc33-1:
The cDNA encoding full length BACE was fused in frame with a three amino acid linker (Ala-Val-Thr) to the Fc portion of the human IgGl starting at amino acid 104. The BACE-Fc construct was then cloned into a GFP/pGEN-IRES-neoK vector (a proprietary vector of AstraZeneca) for protein expression in mammalian cells. The expression vector was stably transfected into HEK-293 cells using a calcium phosphate method. Colonies were selected with 250 μg/mL of G-418. Limited dilution cloning was performed to generate homogeneous cell lines. Clones were characterized by levels of APP expression and Aβ secreted in the conditioned media using an ELISA assay developed in-house. Aβ secretion of BACE/Fc clone Fc33-1 was moderate.
Cell Culture:
HEK293 cells stably expressing human BACE (HEK-Fc33) were grown at 37 0C in DMEM containing 10% heat-inhibited FBS, 0.5mg/mL antibiotic-antimycotic solution, and 0.05 mg/mL of the selection antibiotic G-418.
Aβ40 Release Assay:
Cells were harvested when between 80 to 90% confluent. 100 μL of cells at a cell density of 1.5 million/mL were added to a white 96- well cell culture plate with clear flat bottom (Costar 3610), or a clear, flat bottom 96-well cell culture plate (Costar 3595), containing 100 μL of inhibitor in cell culture medium with DMSO at a final concentration of 1%. After the plate was incubated at 37 0C for 24 h, 100 μL cell medium was transferred to a round bottom 96-well plate (Costar 3365) to quantify Aβ40 levels. The cell culture plates were saved for ATP assay as described in ATP assay below. To each well of the round bottomplate, 50 μL of detection solution containing 0.2 μg/mL of the RαAβ40 antibody and 0.25 μg/mL of a biotinylated 4G8 antibody (prepared in DPBS with 0.5%BSA and 0.5% Tween-20) was added and incubated at 4 0C for at least 7 h. Then a 50μL solution (prepared in the same buffer as above) containing 0.062 μg/mL of a ruthenylated goat anti-rabbit antibody and 0.125 mg/mL of streptavidin coated Dynabeads was added per well. The plate was shaken at 22 0C on a plate shaker for 1 h, and then the plates were then measured for ECL counts in an IGEN M8 Analyzer. Aβ standard curves were obtained with 2-fold serial dilution of an Aβ stock solution of known concentration in the same cell culture medium used in cell-based assays.
ATP Assay:
As indicated above, after transferring 100 μL medium from cell culture plates for Aβ40 detection, the plates, which still contained cells, were saved for cytotoxicity assays by using the assay kit (ViaLight™ Plus) from Cambrex BioScience that measures total cellular ATP. Briefly, to each well of the plates, 50 μL cell lysis reagent was added. The plates were incubated at room temperature for 10 min. Two min following addition of 100 μL reconstituted ViaLight™ Plus reagent for ATP measurement, the luminescence of each well was measured in an LJL plate reader or Wallac Topcount. BACE Biacore Protocol Sensor Chip Preparation:
BACE was assayed on a Biacore3000 instrument by attaching either a peptidic transition state isostere (TSI) or a scrambled version of the peptidic TSI to the surface of a Biacore CM5 sensor chip. The surface of a CM5 sensor chip has 4 distinct channels that can be used to couple the peptides. The scrambled peptide KFES-statine-ETIAEVENV was coupled to channel 1 and the TSI inhibitor KTEEISEVN-statine-V AEF was couple to channel 2 of the same chip. The two peptides were dissolved at 0.2 mg/ml in 20 mM Na Acetate pH 4.5, and then the solutions were centrifuged at 14K rpm to remove any particulates. Carboxyl groups on the dextran layer were activated by injecting a one to one mixture of O.5M N-ethyl-N' (3-dimethylaminopropyl)-carbodiimide (EDC) and 0.5M N-hydroxysuccinimide (NHS) at 5 μL/minute for 7 minutes. Then the stock solution of the control peptide was injected in channel
1 for 7 minutes at 5 μL/min.5 and then the remaining activated carboxyl groups were blocked by injecting IM ethanolamine for 7 minutes at 5 μL/minute.
Assay Protocol:
The BACE Biacore assay was done by diluting BACE to 0.5μM in Na Acetate buffer at pH 4.5 (running buffer minus DMSO). The diluted BACE was mixed with DMSO or compound diluted in DMSO at a final concentration of 5% DMSO. The BACE/inhibitor mixture was incubated for 1 hour at 40C then injected over channel 1 and 2 of the CM5 Biacore chip at a rate of 20 μL/minute. As BACE bound to the chip the signal was measured in response units (RU). BACE binding to the TSI inhibitor on channel 2 gave a certain signal. The presence of a BACE inhibitor reduced the signal by binding to BACE and inhibiting the interaction with the peptidic TSI on the chip. Any binding to channel 1 was non-specific and was subtracted from the channel
2 responses. The DMSO control was defined as 100% and the effect of the compound was reported as percent inhibition of the DMSO control. 2-Amino-3-methyl-6-(2-naphthalen-2-yl- ethyl)-3H-pyrimidin-4-one, AZ12066871, inhibited BACE binding in the BACE Biacore assay by 69% when tested at a concentration of ImM.
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. Such methods include, but are not limited to, those described below. AU references cited herein are hereby incorporated in their entirety by reference. The novel compounds of this invention may be prepared using the reactions and techniques described herein. The reactions are performed in solvents appropriate to the reagents and materials employed and 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 workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are not compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used.
The starting materials for the examples contained herein are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some of the starting materials and examples used herein.
General procedures for making the compounds of the invention is as follows: The invention will now be illustrated by the following non-limiting examples, in which, unless stated otherwise:
I. temperatures are given in degrees Celsius (°C); unless otherwise stated, operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-250C;
II. organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60°C; πi. chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates; IV. in general, the course of reactions was followed by TLC or HPLC and reaction times are given for illustration only;
V. melting points are uncorrected and (dec) indicates decomposition; VI. final products had satisfactory proton nuclear magnetic resonance (NMR) spectra; VII. when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using deuterated chloroform (CDCl3), dimethylsulphoxide (d6-DMSO) or dimethylsulphoxide/TFA (de-DMSO/TFA) as solvent; conventional abbreviations for signal shape are used; for AB spectra the directly observed shifts are reported; coupling constants (J) are given in Hz; Ar designates an aromatic proton when such an assignment is made;
VIII. reduced pressures are given as absolute pressures in pascals (Pa); elevated pressures are given as gauge pressures in bars;
IX. non-aqueous reactions were run under a nitrogen atmosphere X. solvent ratios are given in volume:volume (v/v) terms; and XL Mass spectra (MS) were run using an automated system with atmospheric pressure chemical (APCI) or electrospry (+ES) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). XII. Commercial reagents were used without further purification".
XIII. The ketone starting materials for compounds prepared according to schemes 1 or 2, unless otherwise noted, were either commercially available or prepared according to the procedures in the following references: Example 14, Chemical Abstracts, CAN 123:115721, AN 2000:718846; Example 10, Broxton et al, J. Chem. Soc. Perkin Trans. 1, 1974, 1769-1771; Example 12 Boatman et al., J. Org. Chem., 1965, 30, 3321-3324.
XTV. Phosphonoacetate used to prepare olefins such as that in (Scheme 1, A), may be either trimethylphosphonoacetate, ethyl dimethylphosphonoacetate, tert-butyl dimethylphosphonoacetate, triethylphosphonoacetate, methyl diethylphosphonoacetate, or tert-butyl diethylphosphonoacetate.
XV. Mass spectra were recorded using either a Hewlett Packard 5988A or a MicroMass Quattro-1 Mass Spectrometer and are reported as m/z for the parent molecular ion.
XVI. Room temperature refers to 20-25°C. XVII. LC-MS HPLC conditions: Column: Agilent Zorbax SB-C8 2mm ID X 50mm Flow: 1.4 mL/minGradient: 95% A to 90% B over 3 min. hold 1 minute ramp down to 95% A over 1 minute and hold 1 minute. Where A = 2% acetonitrile in water with 0.1% formic acid and B = 2% water in acetonitrile with 0.1% formic acid. UV-DAD 210-400 nm XVIII. Preparative reverse phase HPLC conditions (A): Compounds were purified on a
Phenomenex Luna C18 reverse phase column (250 X 21mm, 10 micron particle size) using an Agilent system. The crude compounds were solubilized in acetonitrile:water:TFA (75:25:0.1). An elution gradient (0-50% acetonitrile over 12 mins, hold at 50% acetonitrile for 3 mins, 50-100% acetonitrile over 7 mins, flow rate at 40 ml/min, 220 nm) yielded the purified title compounds. Retention time (tR) = mins. This method was used for Examples 1-28. XIX. Preparative reverse phase HPLC conditions (B): Compounds were purified on a
Phenomenex Luna C18(2) reverse phase column (60 X 21.2 mm, 10 micron particle size) using a Gilson system. Gradient elution performed with aqueous 0.1% trifluoroacetic acid in water and acetonitrile (typically 25-75% acetonitrile over 15 min.) with flow rate of 50 mL/min, UV collection at 220 nm. This method was used for Examples 29-87. XX. Preparative reverse phase HPLC conditions (C): Gilson instrumentation (215 Injector, 333 Pumps and 155 UV/Vis Detector): Varian C8 reverse phase column (60 Angstrom irregular load in 8 mm particle size, 21 mm ID x 25 cm). The crude compounds were solubilized in dimethyl sulfoxide: methanol (-1:1). Gradient elution performed with aqueous 0.1% trifluoroacetic acid / acetonitrile (typically 25-75% acetonitrile over 30 min., 95% acetonitrile over 7 min.) flow rate at 22 mL/min, UV collection at 254nm. Retention time ^R) = mins. This method was used for Examples 88-94.
XXI. Normal phase chromatography conditions: Flash chromatography employed as a method for purification for selected intermediates. Isco CombiFlash Sq 16x instrument: pre-packaged disposable RediSep SiO2 stationary phase columns (4, 12, 40, 120 gram sizes) with gradient elution at 5-125 mL/min of selected bi-solvent mixture, UV detection (190-760nm range) or timed collection, 0.1mm flow cell path length.
XXII. Microwave heating instrumentation: A Personal Chemistry Smith Synthesizer unit
(monomodal, 2.45 GHz, 300W max) was utilized for microwave heating of reactions.
XXπi. Terms and abbreviations: Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex; only diagnostic signals are reported, arm: atmospheric pressure; Boc: t-butoxycarbonyl; Cbz: benzyloxycarbonyl; DCM: methylene chloride; DIPEA: diisopropylethylamine; DMF: N;N-dimethyl form- amide; DMSO: dimethyl sulfoxide; Et2O: diethyl ether; EtOAc: ethyl acetate; h: hour(s); HPLC: high pressure liquid chromatography; minute(s): min.; NMR: nuclear magnetic resonance; psi: pounds per square inch; TFA: trifluoroacetic acid; THF: tetrahydrofuran; ACN: acetonitrile.
Figure imgf000043_0001
(EtO)2P(O)CH2COOtBu
Figure imgf000044_0002
Figure imgf000044_0001
4-MeOBnNH,
Figure imgf000044_0003
Figure imgf000044_0004
Figure imgf000044_0005
Scheme 2
Example 1: 2-Amino-6-(3-bromo-phenyl)-6-metliyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 1, B)
Figure imgf000044_0006
To a solution of guanidine HCl salt (0.35 g, 3.72 mmol) and sodium methoxide (0.16 g, 4.09 mmol) in NMP (2 mL) was added (E)-3-(3-bromo-phenyl)-but-2-enoic acid ethyl ester (Scheme 1, A) (0.5 g, 1.86 mmol) and the reaction was subjected to microwaves at 200 0C for 15 min. The NMP was removed under reduced pressure to yield a dark amber syrup. To this was added acetonitrile-.water. TFA (75:25:0.1, 10 ml) and the resulting precipitate was removed. The filtrate was purified using RP-HPLC (tR = 8.33). The combined purified fractions were lyophilized to give the title compound as a light tan powder (0.21g, 40%). 1H NMR (300 MHz, DMSOd6): δ 1.64 (s, 3H); 3.14 (d, IH, J = 16.5 Hz); 3.34 (d, IH, J = 16.5 Hz); 7.44 (m, 2H); 7.55 (m, IH); 7.64 (s, IH). m/z (ES) 282 M+. To one skilled in the art, it is appreciated that the olefin used in the cyclization may be one of a diverse set of esters, for example methyl, ethyl, isopropyl or t-butyl. However, t-butyl esters are sometimes less efficient in the cyclization reaction. In these cases, the t-butyl ester can be converted to a methyl ester via Fisher ester synthesis, i.e. by treatment with concentrated sulfuric acid in methanol (1:10 V: V).
(E)-3-(3-Bromo-phenyl)-but-2-enoic acid ethyl ester (Scheme 1, A) was prepared as follows.
(E)-3-(3-bromo-phenyl)-but-2-enoic acid ethyl ester (Scheme 1, A)
Figure imgf000045_0001
To a -78°C stirred solution of triethyl phosphonoacetate (6.19 g, 27.63 mmol) in THF (70 mL) was added n-BuLi in hexanes (1.6 N, 18.06 mL, 28.89 mmol) and the reaction was stirred at -78 0C for 30 min. To this mixture was added 3'-bromoacetophenone (3.34 mL, 25.12 rαmole) and the reaction stirred at -780C for 30 min. The mixture was warmed to room temperature and stirred for 18 hours. The THF was removed under reduced pressure to yield a cloudy yellow oil. To this was added hexanes (250 mL) and the reaction stirred for 10 min. The resulting precipitate was removed and the filtrate collected and concentrated under reduced pressure. The crude compound was purified using flash chromatography (silica gel, 5:95 ethyl acetate: hexanes) to give the title compound as a pale, clear yellow oil (5.63 g, 83%). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (t, 3H, J = 7.2 Hz); 2.44 (s, 3H); 4.10 (q, 2H, J = 7.2 Hz); 6.17 (s, IH); 7.35 (t, IH3 J = 7.8 Hz); 7.56 (m, 2H); 7.68 (s, IH). m/z (ES) 269 M+.
Example 2:
2-Amino-6-(3'-methoxy-biphenyl-3-yl)-3,6-dimethyl-536-dihydro-3H-pyrimidin-4-one (Scheme 2, 1)
Figure imgf000045_0002
General Suzuki Conditions Method A: To a solution of
2-amino-6-(3-bromo-phenyl)-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 2, H) (47 mg, 0.132 mmol) in 1.5 mL 7:3:2 1,2-dimethoxyethane: water: ethanol was added was added cesium carbonate (129 mg, 0.396 mmol), 3-methoxyphenylboronic acid (26mg, 0.172 mmol), and dichlorobis(triphenylphosphine)palladmm(II) (4.6mg, 0.0065 mmol). The reaction was subjected to microwaves for 15 min. at 150 0C after which the solvents were removed under a stream of nitrogen. To this brown gum was added ACN: water: TFA (75:25:0.1, 2.0 ml) and the resulting precipitate removed. The filtrate was purified using RP-HPLC (Ret. time: 14.2 mins). The combined purified fractions were lyophilized to give the title compound as a white powder (25mg g, 43%). 1H NMR (300 MHz, DMSO-d6/TFA-d): δ 1.71 (s, 3H); 3.13 (s, 3H); 3.21 (d, IH, J = 16.5 Hz); 3.59 (d, IH, J = 16.2 Hz); 3.85 (s, 3H); 6.98 (d, IH, J - 3.9 Hz); 7.23 (m, 2H); 7.41 (m, 2H); 7.51 (t, IH, J = 7.8 Hz); 7.64 (d, IH, J = 7.5 Hz); 7.71 (s, IH); m/z (APCI+) M+l (324.17); LCMS tR 1.97 min.
Example 3: 6-(3'-methoxy-l,r-biphenyl-3-yl)-6-methyl-2-(methylamino)-5,6-dihydropyrimidin-4(3H)-one
Figure imgf000046_0001
The HPLC purification of Example 2 resulted in isolation of the title compound as a white powder (4.7 mg, 10%). IHNMR (300.132 MHz, DMSO) d 1.77 (s, 3H), 3.04 (s, 3H), 3.13 (d, J = 16.6 Hz, IH), 3.48 (d, J = 16.6 Hz, IH), 3.85 (s, 3H), 6.99 (dd, J = 10.0 Hz, J = 2.4 Hz, IH) 7.23 (m, 2H), 7.42 (m, 2H), 7.52 (t, J = 7.7 Hz, IH), 7.65 (d, J = 7.5 Hz, IH), 7.73 (s, IH); m/z (ES+) M+l= 324; LCMS tR = 1.7 min.
2-Amino-6-(3-bromo-phenyl)-3,6-dimethyl-556-dihydro-3H-pyrimidin-4-one (Example 4, Scheme 2, H) was prepared as follows.
(E)-3-(3-Bromo-phenyl)-but-2-enoic acid tert-butyl ester (Scheme 2, C)
Figure imgf000046_0002
To a -78°C stirred solution of tert-butyldimethylphosphonoacetate (21.9 mL, 0.111 mol) in THF (150 mL) was added n-BuLi in hexanes (1.6 N, 72.0 mL, 0.116 mol) and the reaction stirred at -78 0C for 10 min. To this mixture was added 3'-bromoacetophenone (13.4 mL, 0.100 mole) and the reaction allowed to warm to room temperature and was stirred for 18 hours. The THF was removed under reduced pressure to yield a yellow solid. To this was added hexanes (300 mL) and the solids triturated for one hour. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give the title compound as a crude oil (28.9 g). This was carried directly into the next reaction. 1H NMR (300 MHz, DMSOd6): δ 1.47 (s, 9H); 2.44 (s, 3H); 6.05 (s, IH); 7.36 (t, IH, J = 7.8 Hz); 7.53 (m, 2H); 7.71 (s, IH).
(E)-3-(3-Bromo-phenyl)-but-2-enoic acid (Scheme 2, D)
Figure imgf000047_0001
A solution of crude (E)-3-(3-Bromo-phenyl)-but-2-enoic acid tert-butyl ester C (28.9g) in trifluroracetic acid: methylene chloride (1:1, 300 mL) was stirred at room temperature for 15 min. and the solvents removed under reduced pressure. The crude yellow solidwas triturated in hexanes (400 mL), filtered, and dried under vacuum to give the title compound as a white solid (8.87g, 38%). 1H NMR (300 MHz, DMSO-d6): δ 2.46 (s, 3H); 6.11 (s, IH); 7.37 (t, IH, J = 7.8 Hz); 7.53 (m, 2H); 7.72 (t, IH, J = 1.5 Hz).
(E)-3-(3-Bromo-phenyl)-but-2-enoyl chloride (Scheme 2, E)
Figure imgf000047_0002
To a suspension of (E)-3-(3-Bromo-phenyl)-but-2-enoic acid (Scheme 2, D) (1.00 g, 4.148 mmol) in 10 mL methylene chloride was added oxalyl chloride (434 μL, 4.98 mmol) followed by DMF (15 μL, 0.207 mmol) and the reaction stirred at room temperature. After two hours the solvent was removed under reduced pressure to give the title compound as a yellow oil that solidified to an off white solid. 1H NMR (300 MHz, DMSO-d6): δ 2.51 (s, 3H); 6.44 (s, IH); 7.29 (t, IH, J = 7.8 Hz); 7.43 (d, IH, J = 7.8 Hz); 7.57 (d, IH, J = 8.7 Hz); 7.63 (t, IH5 J = 1.8 Hz).
(E)-3-(3-bromo-phenyl)-N-cyano-N-methyl-but-2-enamide (Scheme 2, F)
Figure imgf000048_0001
To a -60°C stirred solution of cyanogen bromide (4.24 g, 40.00 mmol) in 100 roL THF was added sodium carbonate (6.36 g, 60.00 mmol) followed by drop wise addition of a solution of 2.0 M methyl amine solution in THF (20.0 mL 40.00 mmol). The bath temperature was kept below -2O0C for two hours. The reaction was filtered cold under a blanket of nitrogen through Celite and a solution (E)-3-(3-Bromo-phenyl)-but-2-enoyl chloride (Scheme 2, E) (5.19g, 20.00 mmol) in 100 mL THF was added to the filtrate. To this mixture was added N,N-diisopropylethylamine (4.2 mL, 24.00 mmol) and the reaction stirred at room temperature for two hours. The solvent was removed under reduced pressure and the resulting oil put under high vacuum over night. The crude compound was purified using flash chromatography on silica gel eluting with DCM to give the title compound as an off white solid (4.29 g, 75%). 1H NMR (300 MHz, DMSOd6): δ 2.44 (s, 3H); 3.22 (s, 3H); 6.65 (s, IH); 7.42 (t, IH, J = 7.8 Hz); 7.58 (d, IH, J = 8.4 Hz); 7.65 (d, IH, J = 7.8 Hz); 7.76 (t, IH, J - 1.8 Hz).
6-(3-Bromo-phenyl)-l-(4-methoxy-benzylamino)-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 2, G)
Figure imgf000048_0002
To a solution of (E)-3-(3-bromo-ρhenyl)-N-cyano-N-methyl-but-2-enamide (Scheme 2, F) (12.11 g, 45.75 mmol) in 50 mL DMF was added 4-methoxybenzyl amine (44.9 mL, 114.38 mmol). After four hours the solvent was removed under reduced pressure and the resulting viscous oil put under high vacuum over night. The crude compound was purified using sequential flash chromatography. The first purification was on silica gel eluting with DCM, 2.5:97.5 MeOH: DCM, 5:95 MeOH: DCM to give 18.96 g crude product. The second purification was done on silica gel eluting Et2O, EtOAc, 5:95 MeOH: EtOAc, 10:90 MeOH: EtOAc to give clean title compound as an off white solid (15.48g, 81%). 1H NMR (300 MHz, DMSO-de/TFA-d): δ 1.65 (s, 3H); 3.20 (s, 3H); 3.30 (d, IH, J = 16.5 Hz); 3.58 (d, IH, J = 16.8 Hz); 3.78 (s, 3H); 4.97 (dd, 2H, J = 4.8 Hz); 6.96 (d, 2H, J = 8.7 Hz); 7.34 (m, 4H); 7.57 (m, 2H); m/z (APCI+) M+l (416.08); LCMS tR 1.80 min. Example 4: 2-Amino-6-(3-bromo-plienyl)-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 2, H).
Figure imgf000049_0001
To a solution of 6-(3-Bromo-phenyl)-l-(4-methoxy-benzylamino)-3,6-dimethyl-5,6 -dihydro-3H-pyrimidin-4-one (Scheme 2, G) (15.48 g, 37.18 mmol) in 150 mL ACN was added 50 mL water followed by ammonium cerium nitrate (61.15 g, 111.55 mmol) and the reaction stirred for 18 hours. Celite (32 g) was added followed by sodium bicarbonate (31.23 g, 371.8 mmol) and reaction stirred for two hours. Additional Celite (15 g) was added at the halfway point. The reaction was filtered through Celite and filtrate concentrated under reduced pressure. The resulting orange solid was put under high vacuum. A crude purification was done using silica gel eluting with 15:85:0.1 MeOH: DCM: acetic acid. The resulting orange solid was triturated with methanol to give the first batch of the title compound. The solvents were removed from the filtrate under reduced pressure and the resulting orange solid was triturated with ethanol to give a second batch of the title compound. The batches were combined to give the title compound (8.75 g, 79%) as an off white solid. 1H NMR (300 MHz, DMSO-d6/TFA-d): δ 1.64 (s, 3H); 3.14 (s, 3H); 3.19 (d, IH, J = 16.5 Hz); 3.49 (d, IH, J = 16.2 Hz); 7.39 (m, 2H); 7.55 (m, IH); 7.67 (s, IH); m/z (APCI+) M+l (296.0); LCMS tR 1.30 min.
In some examples, the l-(4-metholxy-benzylamino) group can be replaced with a 1-benzylamino group. In this case cleavage of the benzyl group can be accomplished by catalytic transfer hydrogenation 10% Pd/C in 5% formic acid/methonal. (e.g. Example 5, Table
1).
Example 6:
2-Amino-6-[3-(5-chloro-thioρhen-2-yl)-phenyl]-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one.
Figure imgf000049_0002
General Suzuki Conditions Method B: To the solid product from Example 4 (47 mg, 0.13 mmol) in a vial was added tripotassium phosphate (83mg, 0.39 mmol), 5-chlorothiophene-2-boronic acid (55mg, 0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.016 mmol), and 2.0 mL 7:3:2 1,2-dimethoxy ethane: water: ethanol. The reaction was sealed and placed in a 100°C bath for 15 min. after which the solvents were removed under vacuum. To this brown gum was added acetonitrile: water: TFA (75:25:0.1, 2.0 ml) and the resulting precipitate removed. The filtrate was purified using RP-HPLC (Ret. time: 15.0 mins). The combined purified fractions were lyophilized to give the title compound as a white powder (46mg, 61%). 1H NMR (300 MHz, DMSO-d6/TFA-d): δ 1.68 (s, 3H); 3.12 (s, 3H); 3.21 (d, IH, J = 16.5 Hz); 3.54 (d, IH, J = 16.2 Hz); 7.16 (d, IH, J = 3.9 Hz); 7.43 (m, 3H); 7.57 (d, IH, J = 7.8 Hz); 7.66 (s, IH); m/z (APCI+) M+l (334.0); LCMS tR 1.91 min.
The following compounds were synthesized using methods analogous to those previously described for Examples 1 or 4 employing the appropriate commercially available boronic acid. The column "Method" contains three rows: the first is the scheme used; the second is the Suzuki method described in Example 2 (A) or Example 6 (B); and the third is the arylbromide used in the Suzuki. NA denotes that the Suzuki coupling with an arylbromide was not used.
Table 1
Figure imgf000050_0001
1.33
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0003
Figure imgf000055_0001
K
Figure imgf000055_0002
M N
Scheme 3 Example 27: 2-Amino-6-(3,4-dichloro-phenyl)-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 3, N)
Figure imgf000056_0001
To a solution of N'-[4-(3,4-Dichloro-phenyl)-l,4-dimethyl-6-oxo-l,4,5,6-tetrahydro -pyrimidin-2-yl]-N,N-dimethyl-formamidine (Scheme 3, M) (0.16 g, 0.47 mmol) in MeOH (15 mL) was added 7 N methanolic ammonia (3 mL, 21.0 mmol) and the reaction was heated to 60° C for 3 hrs. The MeOH was removed under reduced pressure to yield an amber syrup. To this was added acetonitrile:water.TFA (75:25:0.1, 4 ml) and the resulting precipitate was removed. The filtrate was purified using RP-HPLC (Ret. time: 13.03 mins). The combined purified fractions were lyophilized to give the title compound as a white powder (0.03g, 22%). 1H NMR (300 MHz, DMSO-d6): δ 1.65 (s, 3H); 3.12 (s, 3H); 3.19 (d, IH, J = 16.5 Hz); 3.50 (d, IH, J - 16.5 Hz); 7.41 (d, IH, J = 8.4 Hz); 7.67 (d, IH, J = 8.4 Hz); 7.72 (s, IH). m/z MS (ES) 286 M+.
N'-[4-(3,4-Dichloro-phenyl)-l,4-dimethyl-6-oxo-l,4,5,6-tetrahydro-pyrimidin-2-yl]-N,N-dimeth yl-formamidine (Scheme 3, M) was prepared as follows.
(E)-3-(3,4-Dichloro-phenyl)-but-2-enoic acid ethyl ester (Scheme 3, J)
Figure imgf000056_0002
To a -78 0C stirred solution of triethylphosphonoacetate (11.5 mL, 58.2 mmol) in THF (100 mL) was added n-BuLi in hexanes (1.6 N, 38 mL, 61 mmol) and the reaction stirred at -78 0C for 10 min. To this mixture was added a solution of 3,4-dichloroacetophenone (10.Og, 52.9 mmol) in THF (10 mL) and the reaction allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure to yield a yellow solid. To this was added 400 mL 1:3 Et2O: hexanes and the solids triturated for one hour. The resulting precipitate was removed by filtering through Celite and the filtrate collected, concentrated under reduced pressure, and put under high vacuum to give the title compound as a crude oil (12.14 g). This was carried directly into the next reaction. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (t, 3H, J = 6.9); 2.48 (s, 3H); 6.22 (s, IH); 7.50 (d, IH, J = 2.4 Hz); 7.84 (d, 2H, J = 2.1 Hz). Example 28: 2-Amino-6-(3,4-dichloro-phenyl)-6-methyl-5,6-dihydro-3H-pyrimidin-4-one (Scheme 3, K)
Figure imgf000057_0001
To a solution of (E)-3-(3,4-Dichloro-phenyl)-but-2-enoic acid ethyl ester (Scheme 3, J) (100 mg, 0.386 mmol) in 2.0 mL NMP was added guanidine hydrochloride (147 mg, 1.54 mmol), sodium methoxide (62 mg, 1.62 mmol), and the reaction was subjected to microwaves at 200 0C for 10 min. The solids were filtered from the reaction and the filtrate used directly for purification using RP-HPLC (Ret. time: 12.6 mins). The combined purified fractions were lyophilized to give the title compound as white solid (49mg, 33%). 1H NMR (300 MHz, DMSO-d6/TFA-d): δ 1.65 (s, 3H); 3.17 (m, IH); 3.36 (d, IH, J = 16.5 Hz); 7.42 (d, IH3 J = 8.4 Hz); 7.70 (m, 2H); m/z (+ES) M+l (271.98); LCMS tR 1.35 min. -
N ' - [4-(3 ,4-Dichloro-phenyl)-4-methyl-6-oxo- 1 ,4,5 ,6-tetrahydro-pyrimidin-2-yl] -N,N-dimethyl-f ormamidine (Scheme 3, L)
Figure imgf000057_0002
To an ambient stirred solution of Example 28 (0.25 g, 0.94 mmol) in DMF (5 mL) was added dimethylformamide dimethylacetal (0.16 mL, 1.17 mmol) and the reaction was stirred for 2 hrs. The DMF was removed under reduced pressure to yield a pale yellow oil. The oil was purified by ether tritruation (2 X 20 mL) to give the title compound as a clear, colorless oil (0.30 g, 99%). 1HNMR (300 MHz, DMSO-d6): δ 1.67 (s, 3H); 3.11-3.17 (br s, 4H); 3.20-3.29 (br s, 4H); 7.47 (d, IH, J = 8.4 Hz); 7.69 (d, IH, J = 8.4 Hz); 7.76 (s, IH); 8.56 (s, IH). m/z (ES) 327 M+.
N'-[4-(3,4-Dichloro-phenyl)-l,4-dimethyl-6-oxo-l,4,5,6-tetrahydro-pyrimidin-2-yl]-N,N-dimeth yl-formamidine (Scheme 3, M)
Figure imgf000057_0003
To an ambient stirred solution of N'-[4-(3,4-Dichloro-phenyl)-4-methyl-6-oxo-l,4,5,6-tetrahydro -pyrimidin-2-yl]-N,N-dimethyl-formamidine (Scheme 3, L) (0.31 g, 0.94 mmol) and potassium carbonate (0.14 g, 1.03 mmol) in DMF (70 mL) was added iodomethane (0.06 mL, 1.03 mmol) and the reaction was stirred for 18 hrs. To this mixture was added additional potassium carbonate (0.14g, 1.03 mmole) and iodomethane (0.06 mL, 1.03 mmole) and the reaction stirred an additional 18 hrs at ambient temperature. The THF was removed under reduced pressure to yield a cloudy yellow oil. To this was added hexanes (250 mL) and the reaction stirred for 10 min. The resulting precipitate was removed and the filtrate collected and concentrated under reduced pressure. The crude compound was purified using flash chromatography (silica gel, 5:95 ethyl acetate:hexanes) to give the title compound as a pale, clear yellow oil (5.63 g, 83%). 1H NMR (300 MHz, DMSO-d6): δ 1.67 (s, 3H); 3.11 (s, 3H); 3.19 (s, 3H); 3.22 (d, IH, J = 16.5 Hz); 3.36 (s, 3H); 3.57 (d, IH, J = 16.5 Hz); 7.49 (d, IH, J = 8.3 Hz); 7.65 (d, IH, J = 8.4 Hz); 7.82 (s, IH); 8.65 (s, IH). m/z (ES) 341 M+.
Figure imgf000058_0001
B
Figure imgf000058_0002
Scheme 4
Figure imgf000058_0003
B
Scheme 5
Figure imgf000059_0001
Scheme 6
Example 29: 2-Amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one (Scheme 4, D)
Figure imgf000059_0002
This material was prepared according to Scheme 4. To a stirred solution of 2-amino-6-[2-(3-bromophenyl)ethyl]pyrimidin-4(3H)-one (6.7 g, 23 mmol) (Scheme 4, C) in DMF (410 mL) was added potassium carbonate (2.8 g, 20 mmol) and iodomethane (1.3 mL, 20 mmol). The reaction was allowed to stir 3 days, then another portion of potassium carbonate (0.94 g, 7 mmol) and iodomethane (0.43 mL, 7 mmol) was added. The reaction was allowed to stir overnight, then another portion of potassium carbonate (0.94 g, 7 mmol) and iodomethane (0.43 mL, 7 mmol) was added. The reaction was again allowed to stir overnight then added to a large volume of water (approximately 8 L). The material was extracted into diethyl ether (6 x 200 mL) and the resulting solution was concentrated under reduced pressure. A portion of the resulting solid (3.0 g) was stirred in methylene chloride (260 mL) then filtered to give the desired product as a white solid (2.2 g, 92%). 1H NMR (300MHz3 DMSO-d6): δ 7.43 (s, IH), 7.37 (mult, IH), 7.24 (mult, 2H), 7.07 (s, 2H), 5.50 (s, IH), 3.22 (s, 3H), 2.87 (t, 2H3 J = 7.7Hz)3 2.54 (t, 2H3 J = 8.5 Hz); m/z (APCI) 308 (MH+), HRMS (ES) M+, found 308.0348; C13H14BrN3O requires 308.0398.
2-Amino-6-[2-(3-bromophenyl)ethyl]pyrimidin-4(3H)-one (Scheme 4, C) was prepared as follows.
Ethyl 5-(3-bromophenyl)-3-oxopentanoate (Scheme 4, B)
Figure imgf000060_0001
To a round bottom flask was added magnesium chloride (10.4 g, 109 mmol), acetonitrile (580 mL), potassium malonate (15.6 g, 92 mmol), and triethlamine (19.5 mL, 140 mmol). Separately, 3-(3-bromophenyl)propionic acid (10 g, 44 mmol) (Scheme 4, A) was dissolved in acetonitrile (200 mL) and to this was added l3l'-carbonyldiimidazole (CDI) (7.8 g, 48 mmol). Both were allowed to stir for approximately 2.5 hours then the 3-(3-bromophenyl)propionic acid/CDI solution was added dropwise to the mixture OfMgCl2, potassium ethyl malonate and Et3N. The reaction was stirred overnight, then was heated at 90 °C for 3 h. It was then allowed to cool to room temperature, filtered and rinsed with acetonitrile (3x100 mL). The combined filtrates were concentrated under reduced pressure then partitioned between methylene chloride and water. The product was extracted into the methylene chloride layer which was then washed 10% aqueous citric acid solution, dried over sodium sulfate and concentrated under reduced pressure to give the desired product (9.72 g, 75%). This material was used without purification.
2-Amino-6-[2-(3-bromophenyl)ethyl]pyrimidin-4(3H)-one (Scheme 4, C)
Figure imgf000060_0002
To a solution of ethyl 5-(3-bromophenyl)-3-oxopentanoate (9.72 g, 32 mmol) in ethanol (120 mL) was added guanidine carbonate (2.9 g, 16 mmol) and the reaction was heated under reflux overnight. The reaction was allowed to cool then the resulting solid collected by filtration and rinsed with ethanol (20 mL). The solid was dried under high- vacuum to give the desired product as a white solid (6.8g, 71%). 1HNMR (300 MHz, DMSO-d6) δ 10.58 (s, IH), 7.42 (s, IH)5 7.37 (mult, IH)5 7.23 (mult, 2H), 6.46 (s, 2H), 5.39 (s, IH)5 2.86 (t, J = 7.8 Hz5 2H)5 2.53 (t, J = 8.1 Hz, 2H); m/z (APCI) 294 (MH+).
Example 30: 2-Amino-6-[2-(2-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one
Figure imgf000061_0001
This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 3-(2-bromophenyl)propionic acid was used in place of 3-(3-bromophenyl)propionic acid. 1H NMR (300 MHz, DMSO-d6) δ 7.58 (d, J = 7.7 Hz5 IH), 7.31 (mult, 2H), 7.15 (mult, IH)5 7.07 (s, 2H)5 5.50 (s, IH), 3.22 (s, 3H)5 2.97 (t, J = 8.0 Hz, 2H), 2.54 (t, J = 8.4 Hz, 2H); m/z (APCI) 308.2 (MH+), HRMS (ES) M+, found 308.037; C13H14BrN3O requires 308.0398.
Example 31 : 2-Amino-6-[2-(4-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one
Figure imgf000061_0002
This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 3-(4-bromophenyl)propionic acid was used in place of 3-(3-bromophenyl)propionic acid. 1H NMR (300 MHz5 DMSOd6) δ 7.45 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H)5 7.05 (s, 2H), 5.48 (s, IH), 3.21 (s, 3H)5 2.84 (t, J = 7.8 Hz, 2H)5 2.53 (t, J = 8.4 Hz5 2H); m/z (APCI) 294 (MH+), HRMS (ES) M+, found 308.0388; C13H14BrN3O requires 308.0398. Example 32: 2-Amino-6-[2-(lH-indol-6-yl)etliyl]-3-methylpyrimidm-4(3H)-one
Figure imgf000062_0001
This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except 2-amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one was used in place of 2-ammo-6-[2-(3-bromophenyl)ethyl]pyrimidin-4(3H)-one. 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, IH), 8.40 (bs, IH), 7.46 (d, J = 8.5 Hz, IH), 7.26 (mult, 2H), 6.90 (d, J = 8.5 Hz, IH), 6.37 (s, IH), 5.82 (s, IH), 3.95 (bs, IH), 3.27 (s, 3H), 2.96 (t, J = 9.0 Hz, 2H), 2.75 (t, J = 9.0 Hz, 2H); ); m/z (APCI) 269 (MH+).
Example 33: 2-Amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one
Figure imgf000062_0002
Ethyl 5-(lH-indol-6-yl)-3-oxopentanoate (approximately 65% pure with over-reduced product as the major contaminant), (20 g, 77 mmol) was dissolved ethanol (160 mL) under argon and to this was added guanidine carbonate (9.Og, 50 mmol). The reaction was heated under reflux overnight then concentrated until approximately 50 mL of ethanol remained. To this was added water (50 mL) and the mixture was stirred for 3 h. The resulting solid was collected by filtration and rinsed with water (approximately 50 mL) then dried under high vacuum at 60 0C overnight to give the desired product as a yellow solid (7.9 g, 62%). Another batch (2.4 g, 19%) slowly crystallized from the filtrate. 1H NMR (300.132 MHz, DMSO-d6) δ 10.90 (s, IH), 7.41 (d, J = 8.1 Hz, IH), 7.23 (d, J = 3.1 Hz, IH), 7.18 (s, IH), 6.85 (d, J = 8.0 Hz, IH), 6.62 (s, 2H), 6.34 (d, J = 2.9 Hz5 IH), 5.36 (s, IH), 2.93 (t, J = 7.9 Hz, 2H), 2.56 (t, J = 7.9 Hz, 2H); m/z (APCI) 255 (MH+). Ethyl 5-(lH-indol-6-yl)-3-oxopentanoate (Scheme 5, C) was prepared as follows.
Ethyl (4E)-5-(lH-indol-6-yl)-3-oxopent-4-enoate (Scheme 5, B)
Figure imgf000063_0001
6-Formylindole (15 g, 103 mmol) (Scheme 5, A) was dissolved in dry THF (410 mL) under argon and to this was added [3-(ethoxycarbonyl)-2-oxopropyl]triphenylphosphoniurn chloride (66 g, 155 mmol) and the reaction cooled to 5 0C. Sodium hydride (60%, 6.5 g, 412 mmol) was then added in portions over 10 min., the cooling bath removed, and the reaction was allowed to stir overnight. Another portion of sodium hydride (60%, 4.1 g, 102 mmol) was added, the reaction allowed to stir for 2 hours, then another portion of the
[3-(ethoxycarbonyl)-2-oxopropyl]triphenylphosphonium chloride (22 g, 51 mmol) was added. The reaction was again allowed to stir overnight, cooled to 5 °C, and to this was added saturated aqueous ammonium chloride (200 mL) and water (100 mL). Ethyl acetate (100 mL) was added and the product extracted into the organic phase. It was then dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel chromatography (30% ethyl acetate/ hexanes) to give the desired product as an oil which later solidified (20.6 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ 11.38 (s, IH), 7.79 (d, J = 16.1 Hz, IH), 7.72 (s, IH), 7.59 (d, J = 8.3 Hz, IH), 7.49 (mult, IH), 7.39 (d, J = 8.3 Hz, IH), 6.83 (d, J = 16.1 Hz, IH), 6.49 (s, IH), 4.12 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H); m/z (ES) 256 (M-H) \
Ethyl 5-(lH-indol-6-yl)-3-oxopentanoate (Scheme 5, C)
Figure imgf000063_0002
Ethyl (4E)-5-(lH-indol-6-yl)-3-oxopent-4-enoate (20.6 g, 80 mmol) (Scheme 5, B) was dissolved in ethanol (160 mL) under argon. The solvent was degassed with argon then 10% Pd/C (4.25 g, 4.0 mmol) was added. The mixture was placed under 1 atmosphere of hydrogen and stirred vigorously for 2 hours. It was then filtered through celite rinsing with ethanol, then concentrated under reduced pressure to give desired product (20 g, 65% pure with the remainder being the over-reduced material); m/z (ES) 258 (M-H) ". Example 34: 2-Amino-3-methyl-6-[2-(2-naphthyl)ethyl]pyrimidin-4(3H)-one
Figure imgf000064_0001
This compound was prepared according to the method described for 2-amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one except ethyl 5-(2-naphthyl)-3-oxopentanoate was used in place of ethyl 5-(3-bromophenyl)-3-oxopentanoate 1H NMR (300 MHz, DMSOd6) δ 8.46 (s, 2H), 7.86 (mult, 3H), 7.76 (s, IH), 7.48 (mult, 3H)5 5.82 (s, IH), 3.26 (s, 3H), 3.07 (t, J = 7.8 Hz, 2H), 2.81 (t, J = 7.7 Hz, 2H); m/z (APCI) 280 (MH+), HRMS (ES) M+, found 280.1417; C17H17N3O requires 280.145.
Ethyl 5-(2-naphthyl)-3-oxopentanoate was prepared as follows.
Figure imgf000064_0002
Diisopropylamine (8.7 mL, 62 mmol) was dissolved in THF (100 mL) under nitrogen, cooled to O0C, and to this was added N-butlyllithim (1.6 M, 3.8 mL, 65 mmol). The resulting solution was then added to ethyl acetoacetate (3.8 mL, 30 mmol) and allowed to stir at 0 0C for approximately 25 min. Next, a solution of of 2-(bromomethyl)naphthalene (6.6 g, 30 mmol) in THF (90 mL) was added over approximately 45 min. The reaction was allowed to stir for 3 h at 0 0C then quenched with a mixture of concentrated HCl (5.2 mL), water (14 mL), and diethyl ether (40 mL). The mixture was stirred 20 min. then partitioned between diethyl ether (300 mL) and water (150 mL). The layers were separated and the aqueous again extracted with diethyl ether (150 mL). The combined organics were washed approximately 10 times with water (10x100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography using methylene chloride/hexanes as the eluant to afford the desired product as a light yellow liquid (2.83 g, 36%). 1H NMR (300 MHz, CDCl3) δ 7.78 (mult, 3H), 7.62 (s, IH), 7.44 (mult, 2H), 7.31 (mult, IH), 4.17 (q, J = 7.1 Hz, 2H), 3.43 (s, 2H), 3.08 (mult, 2H), 2.97 (mult, 2H), 1.24 (t, J = 7.1 Hz, 3H); m/z (APCI) 293 (MNa+). Example 35: 2-amino-3-(l,3-dioxolan-2-ylmethyl)-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one
Figure imgf000065_0001
To a stirred solution of 2-amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one (1.0 g, 3.9 mmol) in DMF (20 mL) was added potassium carbonate (0.82 g, 5.91 mmol) and 2-bromomethyl-l,3-dioxolane (0.57 mL, 5.51 mmol). The reaction was heated at 90 °C for 2 h, sodium iodide was added (0.03 g, 0.2 mmol), then the mixture was heated at 100°C overnight. The temperature was increased to 11O0C for 2 h, then to 120 0C for another 2 h. The temperature was then lowered to 100 0C and additional portions of 2-bromomethy 1-1,3 -dioxolane (0.08 mL, 0.8 mmol) and potassium carbonate (0.11 g, 0.8 mmol) were added. The reaction was stirred 8 h, cooled, then concentrated under reduced pressure. It was diluted with ethyl acetate, washed with water, and again concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (60-100% ethyl acetate/hexanes, 1% methanol/ethyl acetate) to afford the desired product as a solid (370 mg, 28%). 1H NMR (300 MHz, MeOH-dt) δ 7.42 (d, J = 8.1 Hz, IH), 7.19 (s, IH), 7.13 (d, J = 3.1 Hz, IH), 6.87 (mult, IH), 6.35 (mult, IH), 5.66 (s, IH), 5.09 (t, J = 4.1 Hz, IH), 4.18 (d, J = 4.0 Hz, 2H), 3.93 (mult, 4H), 3.00 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H); m/z (APCI) 341 (MH+), HRMS (ES) M+, found 341.1595; C18H20N4O3 requires 341.1613.
Example 36: 2-Amino-3-methyl-6- {2-[3-(2-thienyl)phenyl]ethyl}pyrimidin-4(3H)-one
Figure imgf000065_0002
2-Amino-6-[2-(3-bromophenyl)ethyl]-3-methylpyrimidin-4(3H)-one (0.15 g, 0.49 mmol) was combined with a solution of dimethoxyethane/water/ethanol (7:3:2 ratio, 4 mL). Next, thiophene-2- boronic acid (0.081 g, 0.63 mmol), cesium carbonate (0.32 g, 0.97 mmol), and dichkorbis(triphenylphosohine)palladium(II) (0.017 g, 0.024 mmol) were added and the mixture was heated by microwave at 150 °C for 15 min. Insoluble materials were then removed by filtration and the solution purified by reverse phase HPLC (CH3CN/H2O/0.1% TFA) to afford the desired product as a white solid (70 mg, 45%). 1H NMR (300 MHz5 DMSO) δ 8.30 (s, 2H), 7.52 (mult, 4H), 7.34 (t, J = 7.6 Hz, IH), 7.20 (d, J = 7.5 Hz, IH), 7.14 (mult, IH), 5.81 (s, IH), 3.26 (s, 3H)5 2.94 (t, J = 7.8 Hz, 2H), 2.74 (t, J = 7.8 Hz5 2H); m/z (APCI) 312 (MH+).
The following compounds were synthesized using methods analogous to those previously described for Example 36 employing the appropriate boronic acid with the precursor aryl bromide as indicated.
Table 2
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0002
Example 71:
N-{2-[2-Ammo-4-{2-[3-(2-furyl)phenyl]ethyl}-6-oxopyrimidin-l(6H)-yl]ethyl}acetamide (Scheme 6, 1).
Figure imgf000074_0001
This material was prepared according to Scheme 6. To a stirred solution of 2-amino-3-(2-ammoethyl)-6-{2-[3-(2-furyl)phenyl]ethyl}pyrimidin-4(3H)-one (40 mg, 0.072 mmol as the bis-TFA salt) in CH2Cl2 (1 mL) and DMF (0.5 mL) was added triethylamine (33 μL, 0.24 mmol), then acetyl chloride (5.7 μL, 0.080 mmol). The reaction was allowed to stir for 15 min., then concentrated to remove the CH2Cl2. EtOH (0.5 mL) and H2O (0.5 mL) were then added and the material purified by reverse phase HPLC (CH3CN/ H2O/ 0.1% TFA) to afford the desired product as a white solid (20 mg, 77%). 1H NMR (300 MHz, d3-MeOD) δ 7.60 (s, IH), 7.55 (mult, 2H)3 7.33 (t, J = 7.7 Hz, IH), 7.17 (d, J = 7.6 Hz, IH), 6.75 (d, J = 3.3 Hz, IH), 6.50 (mult, IH), 5.85 (s, IH), 4.09 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 1.91 (s, 3H); m/z (APCI) 367 (MH+).
2-Amino-3-(2-amino-ethyl)-6-[2-(3-furan-2-yl-phenyl)-ethyl]-3H-pyrimidin-4-one (Scheme 6, H) was prepared as follows. 3-(3-Bromo-phenyl)-propionic acid ethyl ester (Scheme 6, A)
Figure imgf000075_0001
To a solution of 3-(3-bromophenyl)-propionic acid (25.0 g, 109 mmol) in DCM (300.0 mL) was added oxalyl chloride (11.9 mL, 136 mmol) and 2 drops of DMF. After stirring for 2 h the solution was concentrated under reduced pressure, dissolved in DCM (80 mL), and cooled to -10 0C. To this solution, ethanol (80 mL) was added dropwise and stirred at room temperature for 4 h. The solution was concentrated under reduced pressure and dried under vacuum to afford the product in quantitative yield. 1H NMR (300.132 MHz, DMSO) δ 7.45 (s, IH), 7.38 (mult IH), 7.24 (d, J = 20.8 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H); m/z (APCI) 258 (MH+).
3-(3-Furan-2-yl-phenyl)-propionic acid ethyl ester (Scheme 6, B)
Figure imgf000075_0002
To a solution of 3-(3-bromo-phenyl)-propionic acid ethyl ester (13.0 g, 50.5 mmol) in dioxane (338 mL) was added 2-(tributylstannyl)furan (9.5 mL, 30.3 mmol, 0.6 eq.), and dichloro-bis-(triphenylphosphine) palladium (2.48 g, 3.53 mmol, 0.07 eq.). The mixture was headed at 100 °C for 20 min. then portions of 2-(tributylstannyl)furan (9.5 mL, 30.3 mmol, 0.6 eq.) were added at 20 min. intervals until the starting material was consumed. The solution was concentrated under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (hexanes, hexanes:DCM; 9.5/0.5 DCM, hexanes:DCM; 4/1, hexanes:DCM; 1/1) to afford the desired product (11.16 g, 45.68 mmol, 90%) as a yellow/brown solid. 1H NMR (300.132 MHz, DMSO) δ 7.73 (s, IH), 7.54 (t, J = 8.3 Hz, 2H), 7.33 (mult IH), 7.14 (d, J = 12.0 Hz, IH), 6.91 (s, IH), 6.58 (d, J = 5.1 Hz, IH), 4.05 (q, J = 7.1 Hz, 2H), 2.89 (t, J = 7.4 Hz5 2H), 2.65 (t, J - 7.4 Hz, 2H), 1.15 (t, J = 8.0 Hz, 3H); m/z (APCI) 245 (MH+).
3-(3-Furan-2-yl-phenyl)-propionic acid ester (Scheme 6, C)
Figure imgf000076_0001
To a solution of 3-(3-furan-2-yl-phenyl)-propionic acid ethyl ester (23.23 g, 95.09 mmol) in THF (438 mL) and water (218 mL) was added a solution of LiOH (4.38 g, 104 mmol) in water (40 mL) by dropwise addition. After stirring overnight, the mixture was concentrated under reduced pressure to remove THF. The resulting solution was washed with diethyl ether and the aqueous phase was acidified by addition of HCl and washed with DCM. The DCM solution was dried (Na2SO4), concentrated under reduced pressure, and dried under vacuum to afford the desired product (18.32 g, 84.72 mmol, 90%) as a yellow solid. 1H NMR (300.132 MHz, DMSO) δ 12.09 (s, IH), 7.73 (s, IH), 7.54 (t, J = 9.1 Hz3 2H)5 7.33 (t, J = 7.7 Hz, IH), 7.16 (d, J = 7.5 Hz, IH), 6.92 (d, J = 3.2 Hz, IH), 6.58 (s, IH), 2.87 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H); m/z (APCI) 217 (MH+)
5-(3-Furan-2-yl-phenyl)-3-oxo-pentanoic acid ethyl ester (Scheme 6, D)
Figure imgf000076_0002
This material was prepared according to the procedure described for ethyl 5-(3-bromophenyl)-3-oxopentanoate, except 3-(3-furan-2-yl-phenyl)-propionic acid ester was used in place of 3-(3-bromophenyl)propionic acid to afford the desired product (11.69 g, 40.83 mmol, 48%). 1H NMR (300. MHz, DMSO) δ 7.73 (s, IH), 7.52 (t, J = 7.1 Hz, 2H), 7.32 (t, J = 7.6 Hz, IH), 7.13 (d, J = 7.5 Hz, IH), 6.91 (d, J = 3.3 Hz, IH), 6.58 (mult, IH), 4.08 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 2.87 (mult, 4H), 1.17 (t, J = 7.1 Hz, 3H); m/z (APCI) 287 (MH+).
2-Amino-6-[2-(3-furan-2-yl-phenyl)-ethyl]-3H-pyrimidin-4-one (Scheme 6, E)
Figure imgf000076_0003
This material was prepared according to the procedure described for 2-ammo-6-[2-(3-bromophenyl)ethyl]pyrimidm-4(3H)-one, except 5-(3-furan-2-yl-phenyl)-3-oxo-pentanoic acid ethyl ester was used in place of ethyl 5-(3-bromophenyl)-3-oxopentanoate to give the desired product as a light brown solid (8.86 g, 31.4 mmoL 77%). 1H NMR (300. MHz, DMSO) δ 7.73 (s, IH), 7.52 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.6 Hz, IH), 7.13 (d, J = 7.5 Hz, IH), 6.91 (d, J = 3.3 Hz, IH), 6.56 (mult, 4H), 5.40 (s, IH), 2.90 (t, J = 7.9 Hz, 2H), 2.58 (t, J = 7.9 Hz3 2H); m/z (APCI) 282 (MH+).
N'-(4-{2-[3-(2-Furyl)phenyl]ethyl}-6-oxo-l,6-dihydropyrimidin-2-yl)-N,N-dimethylimidoforma mide (Scheme 6, F)
Figure imgf000077_0001
To a stirred solution of 2-amino-6-{2-[3-(2-furyl)phenyl]ethyl}pyrimidin-4(3H)-one (5.0 g, 17.8 mmol) in DMF (54 mL) under nitrogen was added DMF dimethyl acetal (3.5 mL, 26.7 mmol). The reaction was allowed to stir overnight, then H2O (0.5 mL) was added and solution concentrated under reduced pressure. The resulting material was then dissolved in CH3CN and again concentrated under reduced pressure to afford desired product as a gum (quantitative yield). 1HNMR (300 MHz, d3-MeOD) δ 8.58 (s, IH), 7.52 (mult, 3H), 7.28 (t, J = 7.7 Hz, IH)5 7.11 (d, J = 7.6 Hz, IH)5 6.72 (d, J = 2.8 Hz, IH), 6.49 (mult, IH)5 5.78 (s, IH), 3.17 (s, 3H), 3.11 (s, 3H), 3.00 (mult, 2H), 2.78 (mult, 2H); m/z (APCI) 337 (MH+).
Benzyl
{2- [2- { [( 1 E)-(dimethylamino)methylene] amino } -4- {2- [3 -(2-furyl)phenyl] ethyl} -6-oxopyrimidin
-l(6H)-yl]ethyl}carbamate (Scheme 6, G)
Figure imgf000078_0001
To a stirred solution of N'-(4-{2-[3-(2-furyl)phenyl]ethyl}-6-oxo-l,6-dihydropyrimidin-2-yl) -N,N-dimemylimidoformamide (4.0 g, 11.9 mmol) in THF (60 mL) under nitrogen atmosphere was added benzyl N-(2-hydroxyethyl)carbamate (4.6 g, 23.8 mmol) and triphenylphosphine (6.2 g, 23.8 mmol). The solution was allowed to stir for 10 min., then diethyl azodicarboxylate (DEAD) (3.7 mL, 238 mmol) was added and reaction allowed to stir for 0.5 h. A moderate exotherm occurred after the addition. This material was used without purification, m/z (APCI) 514 (MH+).
2-Amino-3-(2-aminoethyl)-6-{2-[3-(2-furyl)phenyl]ethyl}ρyrimidin-4(3H)-one (Scheme 6, H)
Figure imgf000078_0002
Benzyl {2-[2-{[(lE)-(dimethylamino)methylene]amino}-4-{2-[3-(2-furyl)phenyl]ethyl} -6-oxopyrimidin-l(6H)-yl]ethyl} carbamate (11.9 mmol) was dissolved in EtOH under nitrogen atmosphere. The solution was degassed with nitrogen, then Pd/C (10%, 4.0 g) was added and the mixture placed under 1 atmosphere of hydrogen. The reaction was stirred vigorously for 2.5 h, the catalyst removed by filtration, and the remaining solution concentrated under reduced pressure. The residue was then dissolved in CH3CN (50 mL) and to this was added aqueous NH4OH (50 mL) and the reaction heated in a sealed container at 70°C for 6 h. It was then cooled, concentrated under reduced pressure, and partitioned between DCM and aqueous 1 N HCl. The layers were separated and the aqueous washed again with DCM. The aqueous was then basified with 50% aqueous sodium hydroxide solution and extracted with EtOAc (2x). The organic solution was then dried over Na2SO4, filtered, concentrated and purified by reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to give the desired product as a white solid (2.7 g of the bis-TFA salt, 3 steps; 40 %). 1HNMR (300 MHz, d3-Me0D) δ 7.61 (s, IH), 7.54 (mult, 2H), 7.32 (t, J = 7.7 Hz, IH), 7.18 (d, J = 7.7 Hz, IH), 6.74 (d, J = 3.4 Hz, IH), 6.50 (mult, IH), 5.89 (s, IH), 4.29 (mult, 2H)3 3.25 (mult, 2H), 3.01 (mult, 2H), 2.83 (mult, 2H); m/z (APCI) 325 (MH+).
The compounds below were prepared by reaction of
2-amino-3-(2-aminoethyl)-6-{2-[3-(2-furyl)phenyl]ethyl}pyrimidin-4(3H)-one (Scheme 6, H) with the appropriate acid chloride according to the procedure described for Example 71.
Table 3
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0002
Example 79: 2-Amino-3-[2-(ben2ylamino)e%l]-6-{2-[3-(2-furyl)phenyl]e%l}pyrimidin-4(3H)-one.
Figure imgf000081_0001
To a solution of 2-amino-3-(2-aminoeώyl)-6-{2-[3-(2-fuiyl)phenyl]ethyl}pyrimidin-4(3H)-one (Scheme 6, H) (40 mg, 0.073 mmol) in MeOH (800 mL) was added benzaldehyde (7.7 mg, 0.073 mmol) and Et3N (14.7 mg 0.145 mmol). After stirring for 30 min., a solution of NaBH3CN (6.9 mg, 0.109 mmol) in MeOH (200 mL) was added and stirred for 30 min. The solution was concentrated under reduced pressure and purified by reverse phase HPLC using water/acetonitrile with 0.1% TFA to afford the desired product (6.0 mg, 0.015 mmol, 20%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.73 (s, IH), 7.50 (mult, 9H), 7.33 (t, J = 7.6 Hz, IH), 7.16 (d, J = 7.8 Hz, IH), 6.92 (d, J = 3.3 Hz, IH), 6.59 (mult, IH), 5.69 (s, IH), 4.18 (mult, 5H), 3.17 (mult, 2H), 2.92 (t, J = 7.9 Hz, 2H), 2.65 (t, J = 8.1 Hz, 2H); m/z (APCI) 415 (MH+).
Figure imgf000082_0002
Example 81:
2-( {3 '-[2-(2-Amino- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin-4-yl)ethyl]- 1 , 1 '-biphenyl-3-yl} oxy)et hyl acetate
Figure imgf000082_0001
To a solution of 2-amino-6-[2-(3'-hydroxybiphenyl-3-yl)ethyl]-3-methylpyrimidin-4(3H)-one (Example 45) (80 mg, 0.249 mmol), in DMF (2.60 mL) was added K2CO3 (0.0344g, 0.2489 mmol), 2-bromoethyl acetate (0.42 mg, 0.25 mmol) and stirred overnight. Additional K2CO3 and 2-bromoethyl acetate (one additional equivalent) were added every 6 h until the starting material was consumed. The mixture was purified by reverse phase HPLC using water/acetonitrile with 0.1% TFA to afford the desired product (24 mg, 0.059 mmol, 24%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.48 (mult, 2H), 7.36 (mult, 2H), 7.20 (mult, 3H), 7.06 (s, 2H), 6.95 (mult, IH), 5.54 (s, IH), 4.36 (mult, 2H), 4.27 (mult, 2H), 3.23 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H), 2.05 (s, 3H); m/z (APCI) 408 (MH+).
Example 82:
2-Amino-6- {2-[3 '-(2-hydroxyethoxy)- 1 , 1 '-biphenyl-3 -yl] ethyl} -3-methylpyrimidin-4(3H)-one
Figure imgf000083_0001
To a solution of
2-({3'-[2-(2-amino-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)ethyl]-l,r-biphenyl-3-yl}oxy)eth yl acetate (Example 81) (10 mg, 0.025 mmol), in CH3CN (0.200 mL), H2O (0.200 mL), was added IN NaOH (0.0246 mL). After 4 h, additional IN NaOH (0.0140 mL) was added. The mixture was neutralized by addition of IN AcOH (0.0386 mL), and purified by reverse phase HPLC using water/acetonitrile with 0.1% TFA to afford the desired product (7 mg,0.019 mmol, 78%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.47 (d, J = 11.7 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.18 (mult, 3H), 7.05 (s, 2H), 6.93 (mult, IH), 5.53 (s, IH), 4.84 (s, IH)5 4r06 (t, J = 5.0 Hz, 2H), 3.74 (s, 2H), 3.22 (s, 3H), 2.94 (t, J - 7.8 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H); m/z (APCI) 366 (MH+).
Example 83:
2-Amino-6- {2-[3'-(2-methoxyethoxy)-l ,l'-biphenyl-3-yl]ethyl} -3-methylpyrimidin-4(3H)-one
Figure imgf000083_0002
This compound was prepared according to the method described for
2-({3'-[2-(2-amino-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)ethyl]-l,r-biphenyl-3-yl}oxy)eth yl acetate (Example 81) except 2-bromoethyl methyl ether was used in place of 2-bromoethyl acetate to give the desired product (30 mg, 0.079 mmol, 32%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.47 (mult, 2H), 7.35 (t, J- = 7.9 Hz, 2H), 7.18 (mult, 3H), 7.05 (s, 2H), 6.93 (mult, IH), 5.54 (s, IH), 4.17 (t, J = 4.6 Hz, 2H), 3.69 (t, J = 4.6 Hz, 2H), 3.33 (s, 3H), 3.33 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H); m/z (APCI) 380 (MH+).
Example 84:
2-( {3 '-[2-(2-Amino- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin-4-yl)ethyl]- 1 , 1 '-biphenyl-4-yl} oxy)et hyl acetate
Figure imgf000084_0001
To a solution of 2-amino-6-[2-(4'-hydroxybiphenyl-3-yl)ethyl]-3-methylpyrimidin-4(3H)-one (Example 54) (0.80g, 0.249 mmol), in DMF (2.60 mL) was added K2CO3 (0.0344g, 0.2489 mmol), 2-bromoethylacetate (0.0416g, 0.2489 mmol) and stirred overnight. More K2CO3 and 2- bromoethyl acetate (1 equiv. every 6 h) were added until the starting material was consumed. The mixture was purified by reverse phase HPLC using water/acetonitrile with 0.1% TFA to afford the desired product (34.0 mg, 0.084 mmol, 34%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.57 (d, J = 8.6 Hz, 2H), 7.42 (mult, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.15 (d, J = 7.4 Hz, IH), 7.03 (d, J = 8.7 Hz, 3H), 5.53 (s, IH), 4.35 (mult, 2H), 4.23 (mult, 2H), 3.22 (s, 3H), 2.92 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 7.8 Hz3 2H), 2.05 (s, 3H); m/z (APCI) 408 (MH+).
Example 85: 2-Amino-6-{2-[4'-(2-methoxyethoxy)-l,r-biphenyl-3-yl]ethyl}-3-methylρyrimidin-4(3H)-one
Figure imgf000084_0002
This compound was prepared according to the method described for
2-( {3 '-[2-(2-amino- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin-4-yl)ethyl]- 1 , 1 '-biphenyl-4-yl} oxy)eth yl acetate (Example 84) except 2-bromoethyl methyl ether was used in place of 2-bromoethyl acetate to give the desired product (16.0 mg, 0.042 mmol, 17%) as a white solid. 1H NMR (300. MHz, DMSO) δ 7.56 (d, J = 8.6 Hz, 2H), 7.42 (mult, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.14 (d, J = 7.4 Hz, IH), 7.03 (t, J = 7.9 Hz, 3H), 5.53 (s, IH), 4.13 (t, J = 4.5 Hz, 2H), 3.68 (t, J = 4.5 Hz, 2H), 3.32 (s, 3H), 3.22 (s, 3H), 2.92 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H); m/z (APCI) 380 (MH+).
Example 86: 2-Amino-3-[2-(>enzyloxy)ethyl]-6-{2-[3-(2-furyl)phenyl]ethyl}pyrimidm-4(3H)-one
Figure imgf000085_0001
To a solution of 2-amino-6-{2-[3-(2-furyl)phenyl]ethyl}pyrirnidin-4(3H)-one (Scheme 6, E) (60 mg, 0.21 mmol) in DMF (2.0 mL), was added K2CO3 (30 mg, 0.21 mmol), benzyl-2-bromoethyl ether (46 mg, 0.21 mmol) and the mixture was stirred at room temperature. Additional K2CO3 (30 mg, 0.21 mmol), benzyl-2-bromoethyl ether (46 mg, 0.21 mmol) were added and stirring was continued until the starting material was consumed. The mixture was purified by reverse phase HPLC using water/acetonitrile with 0.1% TFA to afford the desired product (14 mg, 0.034 mmol 16%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 8.05 (s, 2H), 7.73 (s, IH), 7.59 (s, IH), 7.53 (d, J = 7.9 Hz, IH), 7.31 (mult, 6H), 7.17 (d, J = 7.6 Hz, IH), 6.91 (d, J = 3.3 Hz, IH), 6.59 (s, IH), 5.76 (s, IH), 4.48 (s, 2H), 4.15 (t, J = 5.4 Hz, 2H), 3.62 (t, J = 5.3 Hz, 2H), 2.93 (t, J = 7.8 Hz, 2H), 2.71 (t, J = 7.8 Hz, 2H); m/z (APCI) 416 (MH+), HRMS (ES) M+, found 416.1959; C25H25N3O3 requires 416.1974.
Figure imgf000086_0001
Figure imgf000086_0002
Scheme 7
Example: 87: 2-Amino-3-methyl-6-(3'-methyl-biphenyl-3-ylmethyl)-3H-pyrimidin-4-one (Scheme 7, D)
Figure imgf000086_0003
A thick-walled glass vial was charged with a stir bar,
2-Amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 7, C) (60 mg, 0.2 mmol), 3-methylphenylboronic acid (26 mg, 0.19 mmol), dichlorobis(triphenylphosphine)-palladium (II) (2.7 mg, 0.003 mmol), Cs2CO3 (123 mg, 0.38 mmol) and DMEZH2CVEtOH (7:3:2 - ca. 5 mL). Crimp sealed and subject to microwave radiation for 5 min. at 150 0C. The resultant black slurry was filtered through Celite and a 0.7μm GMF filter, washing with MeOH (3 x 3 mL) then concentrated in vacuo. The resultant residue was subject to RP-HPLC purification (tR = 11.1 min). Appropriate fractions were concentrated via centrifugal evaporation to afford the white trifluoroacetic acid salt of the title compound (62 mg, 78%). 1H NMR (300 MHz, MeOH-dO δ 2.40 (s, 3H), 3.39 (s, 3H), 3.91 (s, 2H), 5.83 (s, IH), 7.17 (d, J = 7.4 Hz, IH), 7.26 - 7.33 (m, 2H), 7.38 - 7.46 (m, 3H), 7.52 - 7.57 (m, 2H); m/z (APCI+) M+l = 306.2; LCMS tR = 1.81 min.
2-Amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 7, C) was prepared as follows.
4-(3-Brornophenyi)-3-oxo-butyric acid ethyl ester (Scheme 7, A)
Figure imgf000086_0004
To a stirring suspension of potassium malonate (7.42 g, 43.6 mmol) in anhydrous acetonitrile (100 mL) at ambient temperature was added triethylamine (9.0 mL, 64.4 mmol) and magnesium chloride (4.94 g, 51.9 mmol) under an argon atmosphere. Stirring was continued for 3 hours before the rapid addition of the 2-(3-bromophenyl) ethanoic imidazolide in the same solvent (60 mL), prepared 20 min. prior by reaction between 3-bromophenylacetic acid (4.47 g, 20.8mmol) and l,l'-carbonyldiimidazole (4.04 g, 24.9 mmol) in dry acetonitrile (60 mL). The reaction mixture was allowed to stir for 17 hours at room temperature, followed by heating to reflux for 1.5hrsbefore quenching by the slow addition of ca. 13% aqueous HCl (100 mL) at 5 0C. The clear biphasic mixture was separated, wherein the organic layer was concentrated by rotary evaporation to a residue and treated with ethyl acetate (80 mL) while the aqueous remains were further extracted into ethyl acetate (2 x 50 mL). The combined organic extracts were washed with a saturated sodium carbonate aqueous solution (2 x 80 mL) and brine (1 x 50 mL), dried over MgSO4, then concentrated in vacuo to afford the desired 4-(3-bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 7, A) as a clear yellow oil (5.93 g, quant). 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H), 3.53 (s, 2H), 3.88 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 7.13 - 7.26 (m, 2H), 7.37 - 7.44 (m, 2H); m/z (ES+) M+l = 285.0; LCMS tR = 2.52 min.
2-Amino-6-(3-bromo-benzyl)-3H-pyrimidin-4-one (Scheme 7, B)
Figure imgf000087_0001
To a solution of 4-(3-bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 7, A) (5.93 g, 20.8 mmol) in ethanol (60 mL) was added guanidine carbonate (2.06 g, 11.4 mmol) and the reaction heated under reflux for 16 hours. Upon concentration by rotary evaporation to ca. 1A volume and cooling, the resulting solid was collected by filtration and washed with cold ethanol (3 x 10 mL). The precipitate was dried under high vacuum, at 30 0C over night to afford the title compound as a white solid (4.8 g, 83 %). 1H NMR (300 MHz, DMSOd6) δ 3.63 (s, 2H), 5.49 (s, IH), 6.47 (s, 2H), 7.25 - 7.29 (m, 2H), 7.40 - 7.43 (m, IH), 7.45 (s, IH), 10.61 (s, IH); m/z (ES+) M+l = 280.0 LCMS tR = 1.28 min.
Amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 7, C)
Figure imgf000087_0002
To a suspension of 2-Amino-6-(3-bromo-benzyl)-3H-pyrimidin-4-one (Scheme 7, B) (1.63 g, 5.83 mmol) in absolute ethanol (35 mL) was added solid potassium hydroxide (589 mg, 10.5 mmol), which was stirred until a homogeneous solution was achieved. Iodomethane (1.31 mL, 20.9 mmol) was added in one portion and the reaction heated in a sealed tube to 78 0C for 17 hours. Upon completion, was concentrated in vacuo to a pale yellow residue and subject to flash chromatography (SiO2 - 40 g; gradient elution: 0.5% MeOH/CH2Cl2 for 3min, then 0.5-5% MeOHZCH2Cl2 over 24min at 60 mL/min) to provide the
2-Amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 7, C) as a white solid (1.3 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 3.20 (s, 3H), 3.58 (s, 2H), 5.52 (s, IH), 7.07 (s, 2H), 7.26 (m, 2H), 7.41 (m, IH), 7.46 (s, IH); m/z (ES+) M+l = 294.0 LCMS tR = 1.39 min.
The following compounds were synthesized using methods analogous to those previously described for Example 87 employing the appropriate boronic acid with the precursor aryl bromide; Scheme 7, C.
Table 5
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Example 94:
2-amino-6-[2-[3-(3-methoxyphenyl)phenyl]ethyl]-3-methyl-6-phenyl-5,6-dihydro-3H-pyrimidin-
4-one
Figure imgf000090_0002
Prepared according to scheme 2 using the ketone prepared using standard Weinreb amide displacements with the appropriate organometallic according to Nahm, et al, Tet. Lett., 1981, 22, 3815-3818. IH NMR (300 MHz, DMSO-d6/TFA-d) δ 2.27 (m, 2H), 2.47 (m, IH), 2.65 (m, IH), 3.09 (s, 3H), 3.43 (dd, J= 36.4, 16.3 Hz, 2H), 3.83 (s, 3H), 6.94 (dd, J= 8.0, 2.2 Hz, IH), 7.18 (m, 3H), 7.36 (m, 3H), 7.47 (m, 6H); m/z (APCI+) M+l (414); LCMS tR = 2.37 min.
Example 95:
2-amino-6-[3-(3-methoxyphenyl)phenyl]-3-methyl-6-(trifluoromethyl)-5,6-dihydro-3H-pyrimidi n-4-one
Figure imgf000090_0003
Prepared according to scheme 2 using the ketone prepared according to the method of Kogon et al, Leibigs Ann. Chem., 1992, 8, 879-882 using NBS as the brominating agent. IH NMR (300 MHz, DMSO-d6/TFA-d) 5 3.18 (s, 3H), 3.75 (d, J = 16.6 Hz, IH), 3.85 (s, 3H), 4.02 (d, J = 16.6 Hz, IH), 7.01 (dd, J = 7.9, 2.1 Hz, IH), 7.24 - 7.30 (m, 2H), 7.43 (t, J = 7.9 Hz, IH), 7.61 - 7.67 (m, 2H)3 7.80 - 7.87 (m, IH), 7.93 (s, IH); va/z (APCI+) M+l (378); LCMS tR = 2.05 min.
Example 96:
(R)-2-Amino-6-[2-(3'-methoxy-biphenyl-3-yl)-ethyl]-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4- one
Figure imgf000091_0001
Racemic
2-Amino-6-[2-(3'-methoxy-biphenyl-3-yl)-ethyl]-3,6-dimethyl-5,6-dihydro-3H-pyrimidin-4-one, (the title compound for Example 25), 165mg, prepared according to Scheme 2, was dissolved in methanol and enantiomers separated on a preparative supercritical fluid chromatography (prep SFC) system (Ret. time: 3.78 mins) using the following conditions: 21X250mm ChiralPak AS-H 5 micron column, 50.0 mL/min, 15:85 (methanol containing 0.5% dimethylethylamine): supercritical carbon dioxide, UV-260nm. The solvent was removed from the product fractions on a Genevac evaporator to give a waxy solid. This solid was then purified on an Agilent RP-HPLC (Ret. time: 15.58 mins). The combined purified fractions were lyophilized to give the title compound as a white powder (0.036g, 22%). 1U NMR (300 MHz, DMSO) δ 1.36 (s, 3H), 1.93 (t, J= 8.5 Hz, 2H), 2.71 (t, J= 14.7 Hz, 2H), 2.82 (d, J= 16.4 Hz, IH), 2.97 (d, J= 16.4 Hz, IH), 3.20 (s, 3H), 3.84 (s, 3H), 6.95 (dd, J= 8.1, 2.0 Hz, IH), 7.18 (d, J= 2.2 Hz, IH), 7.23 (t, J= 6.9 Hz, 2H), 7.38 (t, J= 7.9 Hz, 2H), 7.51 (t, J= 7.7 Hz, 2H), w/z (APCI+) M+l (352); LC RT 1.98 min, analytical chiral SCF RT 4.36 min >99%ee conditions: 4.6X250mm ChiralPak AS-H 5 micron column, 2.20 mL/min, 15:85 (methanol containing 0.5% dimethylethylamine): supercritical carbon dioxide, UV-260nm.
The following compounds were synthesized using the methods analogous to those previously described for Examples 94 and 95 employing the appropriate starting matereials. Table 6
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Scheme 8
Example 113: 2-Amino-6-(4'-ethylbiphenyl-3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3f/)-one
Figure imgf000096_0002
The title compound was prepared according to the method shown in Scheme 8. A solution of 2-amino-6-(3-bromophenyl)-3,6-dimethyl-5,6-dihydropyrimidin-4(5/i)-one (50 mg, 0.169 mmol) in 2 mL of 1,2-dimethoxyethane/water/ethanol (7:3:2 v/v) was added to a mixture of 4-ethylphenylboronic acid (51 mg, 0.338 mmol), potassium phosphate (90 mg, 0.39 mmol) and bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol). The resulting mixture was heated for 15 minutes at 1000C then allowed to cool to room temperature. Si-TAAcOH resin, (Silicycle, 100 mg) was added as a palladium scavenger and the resulting mixture stirred for 1 hour then filtered. The volatiles were evaporated on a Genevac HT-4 and the residue purified by mass-directed LCMS. [Waters Exterra column, 30x100 mm, 5μ, eluting with 12-88% acetonitrile/water buffered with 2.5 mM ammonium carbonate at 52 mL/min] to yield the title compound as a off-white solid. (23 mg, 43%). 1H NMR (500.132 MHz, DMSOd6) δ 7.66 (s, IH), 7.62 - 7.56 (m, 3H), 7.49 (t, J= 7.7 Hz, IH), 7.37 - 7.31 (m, 3H), 3.55 (d, J= 16.3 Hz, IH)3 3.19 (d, J= 16.3 Hz5 IH), 3.09 (s, 3H), 2.66 (q, J= 7.6 Hz, 2H), 1.67 (s, 3H), 1.21 (t, J= 7.6 Hz, 3H).
The following compounds in Table 7 were synthesized using the method analogous to that previously described for Example 113 employing the appropriate available boronic acid. Table 7
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
The following compounds in Table were synthesized using methods analogous to those previously described for Example 36 employing the appropriate boronic acid with the precursor aryl bromide of the title compound in Example 29.
Table 8
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Example 246: 2-Amino-3-(cyclohexylmethyl)-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidin-4-one
Figure imgf000126_0002
A solution of N'-(4-{2-[3-(2-furyl)phenyl]ethyl}-6-oxo-l,6-diliydropyrimidin-2-yl) -N,N-dimethylimidoformamide (Scheme 6, F) (40 mg) was dissolved in DMF (300 μL). The mixture was heated to 55 0C and to this was added potassium bicarbonate (100 mg) and cyclohexylmethyl bromide (100 μL) in portions over 24 h. To the cooled mixture was added acetonitrile (100 μL) and concentrated aqueous ammonium hydroxide (300 μL). This mixture was heated in a sealed tube at 800C. The cooled solution was neutralized by addition of HCl and purified by preparative reverse phase HPLC to afford the desired product (6.7 mg) as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO) δ 8.23 (s, 4H), 7.73 (s, 5H), 7.58 - 7.52 (m, 12H), 7.33 (t, J= 7.7 Hz5 7H), 7.16 (d, J= 7.6 Hz, 6H), 6.90 (s, 6H), 6.60 - 6.58 (m, 6H), 5.73 (s, 5H), 3.74 (d, J= 7.6 Hz, 23H), 2.94 (t, J= 7.8 Hz, 14H), 2.71 (t, J= 7.7 Hz, 13H), 1.65 - 1.51 (m, 36H), 1.11 (s, 16H), 1.01 - 0.93 (m, 16H); m/z 378.2.
Example 247: 2-Amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(tetrahydrofuran-2-ylmetliyl)-3H-pyrimidin-4-one
Figure imgf000127_0001
This material was prepared according to the procedure described for Example 246 with the exception that tetrahydrofurfuryl bromide was used in place of cyclohexylmethyl bromide. Following purification by preparative reverse phase chromatography, the desired product was contaminated with approximately 10% of the corresponding isocytosine 4-oxo ether. 1H NMR (300 MHz, DMSO) δ 7.73 (s, IH), 7.58 - 7.52 (m, 3H), 7.38 - 7.32 (m, IH), 7.18 - 7.15 (m, IH), 6.90 (s, IH), 6.58 (s, IH)5 5.74 (s, IH), 4.16 - 3.59 (m, 4H), 2.93 (t, J= 8.0 Hz, 2H), 2.70 (t, J= 7.7 Hz, 2H), 1.97 - 1.53 (m, 4H); m/z 366.1.
Example 248: 2-Ammo-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(3-hydroxypropyl)-3H-pyrimidin-4-one
Figure imgf000127_0002
This material was prepared according to the procedure described for Example 246 with the exception that l-bromo-3-(tetrahydropyranyloxy)propane was used in place of cyclohexylmethyl bromide. After deprotection of the DMF dimethyl acetal (with ammonium hydroxide, as described) the mixture was diluted with 6M HCl and incubated until the tetrahydropyran deprotection was complete. The mixture was neutralized and purified by preparative reverse phase HPLC to afford the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO) δ 8.02 (s, IH), 7.74 (s, IH), 7.58 - 7.53 (m, 2H), 7.34 (t, J= 7.7 Hz, IH), 7.17 (d, J= 7.9 Hz, IH)5 6.91 (d5 J= 3.1 Hz5 IH), 6.60 - 6.58 (m, IH)5 5.75 (s, IH)5 3.90 (t, J= 7.1 Hz, 2H)5 3.44 (t, J= 6.3 Hz5 2H)5 2.93 (t, J= 7.8 Hz5 2H), 2.70 (t, J= 7.7 Hz5 2H)5 1.74 - 1.65 (m5 2H); m/z 340.1. Example 249: 2-Amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[(3-inethoxyphenyl)methyl]-3H-pyrimidm-4-one
Figure imgf000128_0001
This material was prepared according to the procedure described for Example 246 with the exception that 3-methoxybenzyl bromide was used in place of cyclohexylmethyl bromide. 1H NMR (300 MHz, DMSO) δ 7.87 (s, IH), 7.73 (s, IH), 7.59 - 7.53 (m, 2H), 7.34 (t, J= 7.8 Hz, IH), 7.23 (t, J= 7.9 Hz, IH), 7.16 (d, J= 7.6 Hz, IH), 6.91 (d, J= 3.3 Hz, IH), 6.86 - 6.81 (m, 2H), 6.72 (d, J= 7.6 Hz, IH), 6.60 - 6.58 (m, IH), 5.77 (s, IH), 5.11 (s, 2H), 3.73 (s, 3H), 2.95 (t, J= 7.8 Hz, 2H), 2.72 (t, J= 7.7 Hz, 2H); m/z 402.2.
Example 250:
2-ammo-6-[243-(2-furyl)phenyl]ethyl]-3-[[3-(lH-tetrazol-5-yl)phenyl]methyl]-3H-pyrimidin-4- one
Figure imgf000128_0002
To a reaction tube was added
3 - [[2-amino-4- [2-(3-furan-2-yl-phenyl)-ethyl] -6-oxo-6H-pyrimidin- 1 -ylmethyl] -benzonitrile (56.6 mg, 0.126 mmol), DMF (1.4 mL), NaN3 (131 mg, 2.007 mmol), NH4C1 128 mg, 2.383 mmol) and heated in a 1000 oil bath for 2 h. The cooled reaction was filtered and purified by preparative reverse phase chromatography to afford product as the trifluoroacetate salt (15 mg, 0.034 mmol, 27%). 1H NMR (300 MHz, DMSO) δ 7.95 - 7.92 (m, 4H), 7.73 (s, IH), 7.60 (s, IH), 7.56 (d, J = 4.7 Hz3 2H), 7.53 (d, J = 6.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, IH), 7.34 (t, J = 7.9 Hz, IH), 7.18 (d, J = 7.2 Hz, IH), 6.91 (d, J = 2.9 Hz, IH), 6.58 (s, IH), 5.24 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.73 (t, J = 8.0 Hz, 2H). m/z (APCI+) M+l (440.0); tR 2.17 min.
3-[[2-Amino-4-[2-(3-furan-2-yl-ρhenyl)-emyl]-6-oxo-6H-pyriniidin-l-ymiethyl]-benzonitrile was prepared as follows.
Example 251: 3-[[2-amino-4-[2-(3-furan-2-yl-ρhenyl)-ethyl]-6-oxo-6H-pyrimidm-l-ylmethyl]-benzonitrile
Figure imgf000129_0001
This material was prepared according to the procedure described for Example 252 below with the exception that 3-bromomethyl-benzonitrile (58.2 mg, 0.297 mmol) was used in place of 3-bromomethyl-benzoic acid methyl ester. Purification by preparative reverse phase HPLC afforded product as the trifluoroacetate salt (67.6 mg, 0.171 mmol, 58%). 1H NMR (300 MHz, DMSO) δ 7.77 - 7.73 (m, 3H), 7.68 (s, 2H), 7.59 - 7.48 (m, 4H)3 7.34 (t, J = 7.6 Hz, IH), 7.16 (d, J = 7.4 Hz, IH), 6.91 (d, J = 3.2 Hz, IH), 6.59 (t, J = 2.2 Hz, IH), 5.75 (s, IH), 5.17 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.7 Hz, 2H).m/z (APCI) M (396.9); tR 2.36 min.
Example 252: 3-[[2-Ainino-4-[2-[3-(2-furyl)phenyl]emyl]-6-oxo-lH-pyrimidin-l-yl]methyl]benzoic acid
Figure imgf000129_0002
To a reaction tube was added
3-[[2-Ammo-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-6H-pyrimidin-l-yl]methyl]benzoic acid methyl ester (43 mg, 0.100 mmol), THF (0.46 mL), water (0.23 mL), LiOH (4.6 mg, 0.110 mmol) and stirred at room temperature. After 1 h., additional LiOH (4.6 mg, 0.110 mmol) was added and reaction allowed to stir overnight. Mixture was brought to pH 1-2 using IN-HCl and purified by preparative reverse phase chromatography to afford product as the trifluoroacetate salt (7 mg, 0.017 mmol, 17%). 1H NMR (300 MHz, DMSO) d 7.83 (s, 2H), 7.73 (d, J = 1.3 Hz, IH), 7.59 (s, 2H), 7.53 (d, J = 7.7 Hz, 2H), 7.48 - 7.42 (m, 3H), 7.33 (t, J = 7.7 Hz5 IH), 7.15 (d, J = 7.5 Hz, IH), 6.91 (d, J = 3.2 Hz, IH), 6.59 (d, J = 5.2 Hz, IH), 5.72 (s, IH), 5.19 (s, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H); m/z (APCI+) M+l(416.1); tR 2.17 min.
3-[[2-Amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-6H-pyrimidiri-l-yl]methyl]berizoic acid methyl ester was prepared as follows.
Example 253:
3-[[2-Amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-6H-pyrimidin-l-yl]methyl]berizoic acid methyl ester
Figure imgf000130_0001
To a solution of
N'-(4-{2-[3-(2-furyl)phenyl]ethyl}-6-oxo-l,6-dihydropyrimidin-2-yl)-N,Ndime1±ιylimidoforma mide(100 mg, 0.297 mmol) in DMF (2 mL) in a reaction tube was added potassium carbonate ( 41 mg, 0.297 mmol), 3-bromomethyl-benzoic acid methyl ester (68 mg, 0.297 mmol) and allowed to stir at room temperature overnight.To the reaction mixture was added acetonitrile (0.30 mL) and concentrated ammonium hydroxide (0.90 mL) and heated in a 80° oil bath for 4 h. The cooled solution was neutralized by addition of HCl and purified by preparative reverse phase HPLC to afford product as the trifluoroacetate salt (50 mg, 0.117 mmol, 39%). 1H NMR (300 MHz, DMSO) δ 7.86 (s, 2H), 7.73 (d, J= 1.1 Hz3 IH), 7.58 - 7.46 (m, 6H)3 7.34 (t, J= 9.7 Hz, IH), 7.15 (d, J= 7.3 Hz, IH)3 6.91 (d, J= 3.0 Hz, IH)3 6.58 (d3 J= 2.9 Hz3 IH)3 5.68 (s, IH)3 5.19 (s, 2H)3 3.85 (s, 3H)3 2.94 (t, J= 8.0 Hz3 2H)3 2.70 (t, J= 10.1 Hz3 2H)3 m/z (APCI+) M+l (430.0); tR 2.44 min.
Example 254:
3 -[2- [2- Amino-4- [2- [3-(2-furyl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl] ethylamino] -3 -oxo-prop anoic acid
Figure imgf000130_0002
To a stirring solution of
2-amino-3-(2-aminoethyl)-6-{2-[3-(2-furyl)phenyl]ethyl}pyrimidin-4(3i?)-one (30 mg of the bis TFA salt, 0.054 mmol) in DMF (0.5 mL) was added Et3N (0.023 mL, 0.17 mmol), then methyl-3-chloro-3-oxopropionate (0.006 mL, 0.054 mmol). The reaction was stirred 30 min. during which more Et3N and methyl-3-chloro-3-oxopropionate were added to drive the reaction to completion. Aqueous IN NaOH (1 mL) was then added and reaction allowed to stir 1 hour after which it was neutralized with 1 N HCl and purified by reverse phase HPLC to give the desired product as a white solid (10 mg as the TFA salt, 35%). (300 MHz, MeOH) δ 7.59 - 7.53 (m, 3H)3 7.33 (t, J = 7.7 Hz, IH), 7.16 (d, J = 7.6 Hz, IH), 6.75 (d, J = 3.4 Hz3 IH), 6.51 - 6.49 (m, IH), 5.84 (s, IH)3 4.12 (t, J = 6.6 Hz, 2H), 3.48 (t, J = 6.6 Hz3 2H), 3.25 (s, 2H)3 3.03 - 2.98 (m, 2H). 2.84; TO/* 411.2 Examρle 255:
2-[2-[2-Ammo-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethylcarbamoyl]benzoic acid
Figure imgf000131_0001
2-Amino-3-(2-aminoethyl)-6-{2-[3-(2-fι^l)phenyl]ethyl}pyτimidin-4(3iϊ)-one (30 mg of the bis TFA salt, 0.054 mmol), methyl hydrogen phthalate (11 mg, 0.060 mmol), and HOBt (8 mg, 0.060 mmol) were combined in a reaction tube and dissolved in DMF (1 mL). Triethylamine (0.024 mL, 0.18 mmol) was added next, then EDCLHCl (12 mg, 0.065 mmol) and reaction allowed to stir overnight. Aqueous 1 N NaOH (0.5 mL) was added and reaction allowed to stir over the weekend. It was then neutralized to slightly basic using cone. HCl and purified by reverse phase HPLC to give the desired product as a solid (12 mg.as the TFA salt, 38%). (300 MHz, MeOH) δ 7.99 - 7.96 (m, IH), 7.64 - 7.52 (m, 5H), 7.44 - 7.41 (m, IH), 7.30 (t, J = 7.7 Hz, IH), 7.15 (d, J = 7.8 Hz, IH), 6.75 (d, J = 3.3 Hz, IH), 6.51 - 6.49 (m, IH)3 5.88 (s, IH), 4.25 (t, J = 6.6 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H); m/z 473.2.
Figure imgf000131_0002
Figure imgf000131_0003
Figure imgf000131_0004
Scheme 9 The precursor compounds in Scheme 9 were prepared as follows. 4-(3-Bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 9, A)
Figure imgf000132_0001
To a stirring suspension of potassium malonate (7.42 g, 43.6 mmol) in anhydrous acetonitrile (100 mL) at ambient temperature was added triethylamine (9.0 mL, 64.4 mmol) and magnesium chloride (4.94 g, 51.9 mmol) under an argon atmosphere. Stirring was continued for 3 h before the rapid addition of the 2-(3-bromophenyl) ethanoic imidazolide in the same solvent (60 mL), prepared 20 min prior by reaction between 3-bromophenylacetic acid (4.47 g, 20.8mmol) and l,r-carbonyldiimidazole (4.04 g, 24.9 mmol) in dry acetonitrile (60 mL). The reaction mixture was allowed to stir for 17 h at room temperature, followed by heating to reflux for 1.5 h, before quenching by the slow addition of approximately 13% aqueous HCl (100 mL) at 5 0C. The clear biphasic mixture was separated, wherein the organic layer was concentrated by rotary evaporation to a residue and treated with ethyl acetate (80 mL) while the aqueous remains were further extracted into ethyl acetate (2 x 50 mL). The combined organic extracts were washed with a saturated sodium carbonate aqueous solution (2 x 80 mL) and brine (1 x 50 mL), dried over MgSO4 and concentrated in vacuo to afford the desired 4-(3-bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 100, A) as a clear yellow oil (5.93 g, quantitative). 1HNMR (300 MHz, CDCl3) δ 1.28 (t, J= 7.1 Hz, 3H), 3.53 (s, 2H), 3.88 (s, 2H), 4.19 (q, J= 7.1 Hz, 2H), 7.13 - 7.26 (m, 2H), 7.37 - 7.44 (m, 2H); m/z (ES+) M+l = 285.0; tR = 2.52 min.
2-Amino-6-(3-bromo-benzyl)-3H-pyrimidin-4-one (Scheme 9, B)
Figure imgf000132_0002
To a solution of 4-(3-bromophenyl)-3-oxo-butyric acid ethyl ester (Scheme 9, A) (5.93 g, 20.8 mmol) in ethanol (60 mL) was added guanidine carbonate (2.06 g, 11.4 mmol) and the reaction heated under reflux for 16 h. Upon concentration by rotary evaporation to about half the original volume, and cooling, the resulting solid was collected by filtration and washed with cold ethanol (3 x 10 mL). The precipitate was dried under high vacuum at 30 0C overnight to afford the title compound as a white solid (4.8 g, 83 %). 1H NMR (300 MHz, DMSO-^6) δ 3.63 (s, 2H)5 5.49 (s, IH), 6.47 (s, 2H), 7.25 - 7.29 (m, 2H), 7.40 - 7.43 (m, IH), 7.45 (s, IH), 10.61 (s, IH); m/z (ES+) M+ = 280.0; HPLC tR = 2.28 min.
Amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, C)
Figure imgf000133_0001
To a suspension of 2-amino-6-(3-bromo-benzyl)-3H-pyrimidin-4-one (Scheme 9, B) (1.63 g, 5.83 mmol) in absolute ethanol (35 mL) was added solid potassium hydroxide (589 mg, 10.5 mmol), which was stirred until a homogeneous solution achieved. Iodomethane (1.31 mL, 20.9 mmol) was added in one portion and the reaction heated in a sealed tube to 78 0C for 17 h. Upon completion, was concentrated in vacuo to a pale yellow residue and subject to flash chromatography eluting with 0.5 to 5% MeOH in DCM to provide the 2-amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 100, C) as a white solid (1.3 g, 76%). 1H NMR (300 MHz, DMSO-J6) δ 3.20 (s, 3H), 3.58 (s, 2H), 5.52 (s, IH), 7.07 (s, 2H), 7.26 (m, 2H), 7.41 (m, IH), 7.46 (s, IH); m/z (ES+) M+ = 294.0; HPLC tR = 1.39 min.
2-Amino-3-methyl-6-(3'-vinyl-biphenyl-3-ylmethyl)-3H-pyrimidin-4-one (Scheme 9, D)
Figure imgf000133_0002
A thick-walled glass vial was charged with a stir bar, 2-amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, C) (120 mg, 0.2 mmol), 3-vinylphenylboronic acid (46 mg, 0.39 mmol), dichlorobis(triphenylphosphine)-palladium (II) (approximately 6 mg, 0.006 mmol), Cs2CO3 (246 mg, 0.76 mmol) and DME/H2O/EtOH (7:3:2; 5 mL). The vial was crimp sealed and subjected to microwave radiation for 5 min at 150 0C. The resultant black slurry was filtered, washed with methanol (3 x 3 mL) then concentrated in vacuo. The resultant residue was then purified by reverse phase HPLC. Appropriate fractions were concentrated via centrifugal evaporation to afford the white trifluoroacetic acid salt of the title compound (62 mg, 35%). 1H NMR (300 MHz, DMSO- J6ZTFA-J) δ 3.27 (s, 3H), 3.93 (s, 2H), 5.33 (d, J = 11.0 Hz, IH), 5.93 (d, J = 17.7 Hz5 IH), 5.98 (s, IH), 6.83 (dd, J = 17.7, 11.0 Hz, IH), 7.36 - 7.52 (m, 4H), 7.59 (d, J = 16.8 Hz, IH), 7.62 (d, J = 17.2 Hz, IH), 7.72 - 7.73 (m, 2H); m/z (APCI+) M+l = 318.2; tR = 2.17 min.
Example 257: 2-Amino-6-(3'-ethyl-biphenyl-3-ylmethyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, E)
Figure imgf000134_0001
A glass reaction vessel was charged with palladium (10% on activated carbon, approximately 5 mg, -25% w/w) and 2-amino-3-methyl-6-(3'-vinyl-biplienyl-3-ylmethyl)-3H-pyrimidin-4-one (Scheme 9, D) (21 mg, 0.07 mmol) in ethanol (1 mL) then subjected to hydrigen (40psi) for 5 min at 27°C. The resultant black slurry was filtered, washed with ethanol (3 x 3 mL) then concentrated in vacuo overnight to afford the title compound as a colorless film (18 mg, 82%). 1H NMR (300 MHz, MeOH-J4) δ 1.25 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.6 Hz, 2H), 2.88 (s, 3H)3 3.73 (s, 2H), 4.80 (s, 2H), 5.67 (s, IH), 7.14 - 7.22 (m, 2H), 7.28 - 7.48 (m, 6H); m/z (ES+) M+l = 320.2; tR = 1.88 min.
Example 258:
2- Amino-6- { 3 - [(E)-2-(3 -methoxy-phenyl)-vinyl] -benzyl} -3 -methyl-3H-pyrimidin-4-one (Scheme 9, F)
Figure imgf000134_0002
A thick-walled glass vial was charged with a stir bar, 2-amino-6-(3-bromo-benzyl)-3-methyl-3H-pyrimidin-4-one (Scheme 9, C) (130 mg, 0.44 mmol), 3-vinylanisole (89 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol),
Figure imgf000134_0003
tetrafluoroborate (10 mg, 0.035 mmol), iV.N-dicyclohexyhnethylamine (104 mg, 0.53 mmol) and anhydrous 1,4-dioxane (2 mL). The reaction vial was sealed and subject to microwave radiation for 1 h at 150 0C. The resultant slurry was filtered, washed with methanol (3 x 3 mL) then concentrated in vacuo. The resultant residue was subject to reverse phase purification (13-50% acetonitrile over 35 min). Appropriate fractions were concentrated via centrifugal evaporation to afford the white trifiuoroacetic acid salt of the title compound (148 mg, 73%). 1H NMR (300 MHz, DMSCWTFA-d) δ 3.29 (s, 3H), 3.81 (s, 3H), 3.89 (s, 2H), 5.95 (s, IH), 6.87 (d, J= 9.3 Hz, IH), 7.16 - 7.19 (m, 2H), 7.24 - 7.30 (m, 3H), 7.36 (d, J = 15.4 Hz, IH), 7.38 (d, J= 15.4 Hz, IH), 7.54 (d, J= 7.8 Hz, IH), 7.61 (s, IH); m/z (ES+) M+l = 348.2; tR = 1.87 min. Example 259:
2-Amino-6-{3-[2-(3-methoxy-phenyl)-ethyl]-benzyl}-3-methyl-3H-pyrimidin-4-one (Scheme
9,G)
Figure imgf000135_0001
A glass Endeavor® reaction vessel was charged palladium (10% on activated carbon, approximately 9 mg, ~10% w/w), and 2-amino-6-{3-[(E)-2-(3-methoxy-phenyl)-vinyl]-benzyl} -3-methyl-3H-pyrimidin-4-one (Example 258, Scheme 9, F) (98 mg, 0.28 mmol) in ethyl acetate/ethanol (1:4, 5 mL) then subjected to hydrogen (40psi) for 20 min at 27 0C. The resultant black slurry was filtered, washed with ethanol (3 x 3 mL) then concentrated in vacuo. The resultant residue was subjected to reverse phase HPLC purification (13-55% acetonitrile over 35 min). Appropriate fractions were concentrated via centrifugal evaporation giving rise to the white trifluoroacetic acid salt of the title compound (48 mg, 37%). 1H NMR (300 MHz, OMSO-d6/TFA-d) δ 2.52 (t, J= 1.8 Hz, 2H), 2.87 (app s, 2H), 3.29 (s, 3H), 3.72 (s, 3H), 3.81 (s, 2H), 5.84 (s, IH), 6.72 - 6.79 (m, 3H), 7.14 - 7.30 (m, 5H); m/z (ES+) M+l = 350.1; tR = 2.18 min.
The following compounds in Table 10 were synthesized using methods analogous to those previously described for Example 258 (Scheme 9, F), employing the appropriate aryl olefin with the precursor aryl bromide of Scheme 9, C.
Table 10
Figure imgf000135_0002
(ES+)
298.1
Figure imgf000136_0001
The following compounds in Table 11 were synthesized using methods analogous to those previously described for Example 259 (Scheme 9, G), employing the appropriate previously described benzyl styryl analogs as precursor (see e.g., Table 10).
Table 11
Figure imgf000136_0002
(ES+)
Figure imgf000137_0001
The following compounds in Table 12 were synthesized using methods analogous to those previously described for Examples 1 or 4 employing the appropriate commercially available boronic acid. The column "Method" contains three rows: the first is the scheme used; the second is the Suzuki method described in Example 2 (A) or Example 6 (B); and the third is the arylbromide used in the Suzuki. NA denotes that the Suzuki coupling with an arylbromide was not used. Table 12
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
The following compounds in Table 13 were also prepared and demonstrated a max affinity value of between 0.001 to 100 μM.
Table 13
IUPAC Name
2-amino-3-methyl-6-[2-[3-(2-thienyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-ammo-6-[2-[3-(3-memoxyphenyl)phenyl]ethyl]-3,6-dimethyl-5,6-dihydro-3H-pyrimidin -4-one
2-amino-3-methyl-6-phenyl-5,6-dihydro-3H-pyrimidin-4-one
3-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethylcarbamoyl] benzoic acid j-aniino-6-[2-[3-(2-furyl)ρhenyl]ethyl]-3-[2-(lH-imidazol-l-yl)e%l]-3H-pyrimidin-4-one
2-aniino-3-[2-[bis(3-fuiylmethyl)ammo]e%l]-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidm
-4-one N-[2-[2-ammo-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-ρyrimidin-l-yl]ethyl]-2 -( 1 H-tetrazol-5-yl)acetamide
5 - [2- [2-amino-4- [2- [3 -(2-furyl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl] ethy lamino]- 5-oxo-pentanoic acid acetic acid 2- [2-amino-4- [2- [3 -(2-fiιryl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl] ethylcarbamoylmethyl ester
N-[2-[2-amino-4-[2-[3-(2-furyl)ρhenyl]ethyl]-6-oxo- lH-ρyrimidin- 1 -yl]ethyl] -3 -hydroxy-benzamide
N-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl] -4-hydroxy-benzamide
4-amino-N-[2- [2-amino-4- [2- [3 -(2-furyl)phenyl] ethyl]-6-oxo- 1 H-pyrimidin- 1 -yl] ethyl]benzamide
N-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl] piperidine-4-carboxamide
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(2-phenethylaminoethyl)-3H-pyrimidm-4-one
4-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethylaminomethyl] benzoic acid
2-ammo-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-[(3-hydroxyphenyl)methylamino]ethyl] -3H-pyrimidin-4-one
2-amino-6- [2- [3 -(2-furyl)phenyl] ethyl]-3 - [2- [[4-(2-hydroxy ethoxy)phenyl]methylarnino] ethyl]-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(2-isobutylaminoethyl)-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-(lH-indol-5-yhnethylamino)ethyl] -3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-[(4-hydroxyphenyl)methylamino]ethyl] -3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-(3-pyridylmethylamino)ethyl]-3H-pyrimidin-4-one
2-amino-3-benzyl-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-foryl)phenyl]ethyl]-3-(2-hydroxyethyl)-3H-pyrimidin-4-one
2-amino-6- [2- [3 -(2-furyl)phenyl] ethyl] -3 -isopentyl-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-[(l-hydroxy-2,236,6-tetramethyl-4-piperidyl) amino]ethyl]-3H-pyrimidm-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[2-[(l-hydroxy-2,2,6,6-tetramethyl-4-piperidyl) amino] ethyl] -3H-pyrimidin-4-one
2-amino-3-[2-(l,3-dioxan-2-yl)ethyl]-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidm-4-one
4- [[2-amino-4-[2- [3 -(2-furyl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl]methyl]benzonitrile
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-[[4-(lH-tetrazol-5-yl)phenyl]methyl] -3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(2-morpholinoethyl)-3H-pyrimidin-4-one
2-[[2-amino-4- [2- [3 -(2-fiiryl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl]methyl]benzonitrile
2-amino-6-[2-[3-(2-flιryl)phenyl]ethyl]-3-[2-(l-piperidyl)ethyl]-3H-pyrimidm-4-one
The following compounds in Table 14 were prepared and demonstrated a max affinity value of 100 μM or greater. Table 14
HJPAC Name
2-amino-6-[3-(4-hydroxyphenyl)phenyl]-6-methyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-3-benzyl-6-phenyl-5,6-dihydro-3H-pyriniidin-4-one
2-amino-6-methyl-6-phenyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-(3,4-dichlorophenyl)-6-isopropyl-5,6-dihydro-3H-ρyrimidin-4-one
2-amino-6-(3,4-dichlorophenyl)-3-methyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-(3-furyl)-6-phenyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-(3,4-dichlorophenyl)-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-methyl-6-(3 -pyridyl)-5 ,6-dihydro-3H-pyrimidin-4-one
2-amino-6-benzyl-6-methyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-[3-(4-hydroxyphenyl)phenyl]-6-methyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-3-benzyl-6-phenyl-5,6-dihydro-3H-pyrimidin-4-one
2-amino-3-methyl-6-(o-tolyl)-5,6-dihydro-3H-pyrimidin-4-one
2-ammo-6-(3-bromophenyl)-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-(o-tolyl)-5,6-dihydro-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-hydroxyphenyl)phenyl]ethyl]-3-methyl-3H-pyrimidin-4-one
2-amino-6-[[3-[2-(4-methoxyplienyl)ethyl]phenyl]metb.yl]-3-metb.yl-3H-pyriinidm-4-o ne
2-amino-3-methyl-6-[[3-[2-(4-methyltliiazol-5-yl)ethyl]phenyl]methyl]-3H-pyrimidm- 4-one
2-amino-3-methyl-6-[[3-[2-(4-pyridyl)vinyl]phenyl]methyl]-3H-pyrimidin-4-one
2-amino-6-[2-(4-bromophenyl)ethyl]-3H-pyrimidin-4-one
2-amino-6-[2-[4-[2-(2-methoxyethoxy)ethoxy]phenyl]ethyl]-3-metliyl-3H-pyrimidin-4 -one
2-amino-3-methyl-6-[2-[3-(8-quinolyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-amino-6- [2- [3 -(3 ,4-dimethoxyphenyl)phenyl] ethyl] -3 -methyl-3H-pyrirnidin-4-one
2-amino-6-[2-[4-(2-methoxyethoxy)phenyl]ethyl]-3-methyl-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2-furyl)phenyl]ethyl]-3-(2-phenoxyethyl)-3H-pyrimidin-4-one
2-amino-6-[2-[3-(2,6-dioxabicyclo[5.4.0]undeca-7,9,ll-trien-9-yl)phenyl]ethyl]-3-met hyl-3H-pyrimidin-4-one
2-amino-3-methyl-6-phenethyl-3H-pyrimidin-4-one
2-ammo-3-(2-aminoethyl)-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-amino-6-[2-(4-hydroxyphenyl)ethyl]-3-metb.yl-3H-pyrimidin-4-one
2-amino-6-[2-(3-bromophenyl)ethyl]-3H-pyrimidin-4-one
2-amino-6-[2-[3-(4-dimethylaminophenyl)phenyl]ethyl]-3-methyl-3H-pyrimidin-4-one
2-amino-3-[(3-aminophenyl)methyl]-6-[2-(3-tetraliydrofuran-2-ylphenyl)ethyl]-3H-pyr imidin-4-one
2-amino-3-methyl-6-[[3-[2-(2-pyridyl)vinyl]phenyl]methyl]-3H-pyrimidin-4-one 2-amino-6-[2-[3-(3-pyridyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-amino-6-(4-benzyloxyphenyl)-3H-pyrimidin-4-one 2-amino-6-phenethyl-3-(lH-tetrazol-5-ylmethyl)-3H-pyrimidin-4-one
2-amino-6-[[3-[3-(methoxymethyl)phenyl]phenyl]methyl]-3-methyl-3H-pyrimidin-4-o ne 2-amino-6-[3-(3-methoxyphenyl)phenyl]-3-metliyl-3H-pyrimidin-4-one
2-amino-6-[2-(4-benzyloxyphenyl)ethyl]-3-methyl-3H-pyrimidin-4-one
2-amino-6-[2-(4-benzyloxyphenyl)ethyl]-3H-pyrimidin-4-one
2-amino-3 -methyl-6- [2- [3 - [3 -(trifluoromethoxy)phenyl]pheny 1] ethyl] -3H-pyrimidin-4- one
2-amino-6- [2- [3 -(3 -isopropylphenyl)pheny 1] ethyl] -3 -methyl-3H-pyrimidin-4-one acetic acid 2-[2-amino-4-[2-(lH-indol-6-yl)ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl ester
2-amino-3-methyl-6-(3-phenylphenyl)-3H-pyrimidin-4-one
2-ammo-3-[2-(3-furylmethylamko)e%l]-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidin -4-one
2-amino-6-[[5-(3-methoxyphenyl)-3-pyridyl]methyl]-3-methyl-3H-pyrimidin-4-one
2-amino-6- [2- [2-(3 -methoxypheny l)phenyl] ethyl] -3 -methyl-3H-pyrimidin-4-one
2-amino-3-methyl-6-(l-methyl-2-phenyl-ethyl)-3H-pyrimidin-4-one
2-amino-6-[2-[3-[4-(aminomethyl)phenyl]phenyl]ethyl]-3-methyl-3H-pyrimidin-4-one
2-amino-6-[[3-[2-[4-(dimethylaminomethyl)phenyl]vinyl]phenyl]methyl]-3-methyl-3H -pyrimidin-4-one
2-amino-6- [(3 -bromophenyl)methyl] -3 -methyl-3 H-pyrimidin-4-one
2-[3-[2-(2-amino-l-methyl-6-oxo-lH-pyrimidin-4-yl)ethyl]phenyl]benzoic acid
2-amino-6-[(3-bromophenyl)methyl]-3H-pyrimidin-4-one
2-amino-6- [(5 -bromo-3 -pyridyl)methyl] -3 H-pyrimidin-4-one
N-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl]-3-cyano -benzamide
N-[2-[2-ammo-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl]-3-pheny 1-propanamide
N-[2-[2-ammo-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidm-l-yl]ethyl]benzarni de
2-amino-3-(2-diben2ylaminoethyl)-6-[2-[3-(2-furyl)phenyl]ethyl]-3H-pyrimidin-4-one
2-ammo-3-methyl-6-[[3-[2-(2-pyridyl)ethyl]phenyl]methyl]-3H-pyrimidm-4-one
2-amino-6-[[3-[3-(hydroxymethyl)phenyl]phenyl]methyl]-3-methyl-3H-pyrirnidin-4-o ne
3 - [2- [2-amino-4-[2-[3 -(2-furyl)phenyl] ethyl] -6-oxo- 1 H-pyrimidin- 1 -yl] ethoxy]benzoic acid
2-arrήno-3-methyl-6-[[3-[2-(4-methylthiazol-5-yl)vinyl]phenyl]methyl]-3H-pyrirnidin- 4-one
2-amino-6-(3-bromophenyl)-3H-pyrimidm-4-one
2-ammo-6-(3-bromophenyl)-3-methyl-3H-pyrimidin-4-one
2-amino-3-methyl-6-phenyl-3H-pyrimidin-4-one
N-[2-[2-amino-4-[2-[3-(2-ruryl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl]-3-rnetho xy-benzamide
N-[2-[2-amino-4-[2-[3-(2-furyl)phenyl]ethyl]-6-oxo-lH-pyrimidin-l-yl]ethyl]-2-(4-me thoxyphenyl)-acetamide
2-amino-6-(2-bromophenyl)-3H-pyrimidin-4-one
2-amino-6-(2-bromophenyl)-3-methyl-3H-pyrimidin-4-one
2-amino-3-methyl-6-(2-phenylphenyl)-3H-pyrimidin-4-one
2-amino-6-[2-(3-methoxyphenyl)phenyl]-3-methyl-3H-pyrimidin-4-one
2-ammo-6-[2-[3K2-furyl)phenyl]ethyl]-3-[[2-(lH-tetrazol-5-yl)phenyl]methyl]-3H-pyr
Figure imgf000145_0001
The following compounds in Table 15 were also prepared and demonstrated a max affinity value of between 0.001 to 100 μM.
Table 15
Figure imgf000145_0002
Figure imgf000146_0001
The following compounds in Table 16 were prepared and demonstrated a max affinity value of 100 μM or greater.
Table 16
Figure imgf000146_0002
thyl-3H-pyrimid
[2. 2.2]oct-5-enyl]-3-metnyl-3H-pyrimidin-4-one
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001

Claims

What is claimed is:
1. A compound of formula Ia or formula Ib :
Figure imgf000151_0001
Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein:
W is C or N;
Q is selected from C3-12cycloalkyl, C3-12cycloaIkenyl, C6-14aryl, or C5.15heterocyclyl; each R1 is, independently, selected from H, halogen, C2-6alkenyl, C1-6alkyl, C3.12cycloalkyl, C6-10aryl, C1-6alkyl-C6-1oaryl, or Cs-isheterocyclyl wherein said C1-6alkyl, said C3-12cycloalkyl, said C6-1oaryl, said C1-6alkyl-C6-10aryl, or said Cs-isheterocyclyl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH, COOH, OC1-6alkyl, CH2OH, SO2H, S(=0), C2-6alkenyl, C1-6alkyl-Ra, OC1-6allcyl-Ra,
Figure imgf000151_0002
C(=O)N(C1-6alkyl-Ra)2, S(=O)C1-6alkyl-Ra, S(=O)NHC1-6alkyl-Ra, S(O)N(C1 -6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra 5 SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2> NHC(=O)C1-6alkyl, C6-10aryl-Ra, OC6-10aryl-Ra, C(=O)C6-10aryl-Ra, C(0)OC6-1oaryl-Ra, C(=O)NHC6-10aryl-Ra, C(=O)N(C6-i0aryl-Ra)2, S(O)C6.10aryl-Ra, S(=O)NHC6-10aryl-Ra, S(=O)N(C6-10aryl-Ra)2, SO2C6.10aryl-Ra, SO2NHC6-10aryl-Ra, SO2N(C6-10aryl-Ra)2, NH(C6-10aryl)-Ra, N(C6-10aryl-Ra)2,
Figure imgf000151_0003
Cs-eheterocyclyl-R", OCs-eheterocyclyl-R3, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, C(=O)NHC5-6heterocyclyl-Ra, C(=0)N(C5-6heterocyclyl-Ra)2, S(=0)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra,
S(=0)N(C5-6heterocyclyl-Ra)2, S02C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra,
SO2N(C5-6heterocyclyl-Ra)2, NH(C5-6lieterocyclyl-Ra), N(C5-6heterocyclyl-Ra)2,
NHC(=O)C5-6heterocyclyl, SO2Ra, S(=O)Ra, N(C1-6alkyl-Ra)(C6-10aryl-Ra),
N(C1-6alkyl-Ra)(C6-10heteroaryl-Ra), N(C6-10aryl-Ra)(C6-1olieteroaryl-Ra),
C(=O)(C1-6alkyl-Ra)(C6-10aryl-Ra), C(=O)(C1-6alkyl-Ra)(C6,10heteroaryl-Ra),
CeO)(C6-10aryl-Ra)(C6-10heteroaryl-Ra), C(=0)0(C1-6alkyl-Ra)(C6-1oaryl-Ra),
C(=0)0(C1-6alkyl-Ra)(C6-ioheteroaryl-Ra), C(=0)0(C6-10aryl-Ra)(C6-10heteroaryl-Ra),
S(=0)(C1-6alkyl-Ra)(C6-1oaryl-Ra), S(=0)(C1-6alkyl-Ra)(C6-10heteroaryl-Ra),
S(-0)(C6-ioaryl-Ra)(C6-ioheteroaryl-Ra), S02(Ci-6alkyl-Ra)(C6-1oaryl-Ra),
S02(C1-6alkyl-Ra)(C6-10heteroaryl-Ra)5 or S02(C6-1oaryl-Ra)(C6-1oheteroaryl-Ra); each Ra is, independently, selected from H, halogen, CN, NH2, OH, C1-6alkyl, OC1-6alkyl, C(=O)C1-6alkyl, C(=O)OCi-6alkyl, C(=O)NH2, C(=O)NHC1-6alkyl, C(=O)N(Ci-6alkyl)2, SOC1-6alkyl, SONHC1-6alkyl, SON(C1-6alkyl)2, SO2Ci-6alkyl, SO2NHC1-6alkyl, SO2N(C1-6alkyl)2, NH(C1-6allcyl), N(C1-6alkyl)2, NC(=O)C1-6alkyl, C5.6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, Cs^heterocycryl, OCs-eheterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=0)NH2, C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, S(=O)C5-6heterocyclyl, S(=O)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2) SO2NHC5-6heterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl,
Figure imgf000152_0001
S(-O)NRbRb, or SO2NRbRb; each Rb is, independently, selected from H, C1-6alkyl, C5-6aryl, or Cs-δheterocyclyl; each V is, independently, selected from NH, O, S, S(=O), SO2, NHS(=O), NHSO2, S(=O)NH, SO2NH, NHC(=0), C(=O)NH, NR2SO2, NRaS(=O), NR3C(O), C(O)NRa, S(O)2NR3, S(=O)NRa, OCi-βalkylenyl, C2-6aIkenylenyl or C1-6alkylenyl, wherein said OC1-6alkylenyl, C2-6alkenylenyl, and C1-6alkylenyl is optionally substituted by 1, 2, or 3 substitutents independently selected from Ra;
X, Y, and Z are, independently, selected from NH, O, S, S(=0), SO2, NHS(=O), NHSO2, S(=O)NH, SO2NH, NHC(=O), C(=O)NH, NR3SO2, NRaS(=O), NR3C(O), C(O)NR3, S(O)2NR3, S(=O)NRa, or Ct-βalkyl wherein said C1-6alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from Ra; m is 0, 1, 2 or 3; n, q, r, s, and u are each, independently, 0 or 1 ;
R2 is selected from H, halogen, C1-6alkyl, C3-12cycloalkyl, C6-10aryl, C1-6alkyl-C6-10aryl, Cs.ioheterocyclyl, or C1-6alkyl-C5-10heterocyclyl wherein said C1-6alkyl, C3-12cycloalkyl, C6-10aryl, Ci-6alkyl-C6-10aryl, C5-10heterocyclyl, and C1-6alkyl-C5-1oheterocyclyl is optionally substituted by 1, 2, or 3 substitutents independently selected from: halogen, CN, NH2, OH, Ci-6alkyl-Ra, OC1-6alkyl-Ra,
Figure imgf000153_0001
C(=O)NHC1-6alkyl-Ra, C(=O)N(Ci-6alkyl-Ra)2 S(=O)C1-6alkyl-Ra,
Figure imgf000153_0002
S(=O)N(C1-6alkyl-Ra)2, SO2Ci-6alkyl-Ra, SO2NHCi-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(Ci-6alkyl-Ra)2, NHC(=O)Ci-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5-6aryl-Ra, C(=O)OC5-6aryl-Ra, C(=O)NH2, C(=O)NHC5-6aryl-Ra, C(=O)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2, NH(C5-6aryl)-Ra, N(C5-6aryl- Ra)2, NHC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, Q=O)NH2, C(=O)NHC5-6heterocyclyl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2 S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, or NHC(=O)C5-6heterocyclyl;
R3 is selected from R1, C1-6alkylRc, C1-6alkylNRcRc, Ci-6alkylORc, C1-6alkylSRc, C1-6alkylNHC1-6a%lC5-6arylR^ C1-6alkylNHC6-10arylRd, Ci-6alkylNHC(O)C6-10arylRd, Ci-6alkylOC1-6alkylC5-6arylRd, C1-6alkylSC1-6all^lC5-6a]ylRd, C1-6alkylC5-9heterocyclylR^ C1-6alkylC3-9cycloalkylRd, C1-6alkylNHC1-6alkylC5-9heterocyclylRd, C1-6alkylNHC5-9heterocyclyl(Rd)t, C1.6alkylNHC(O)C5-9heterocyclylRd, C1-6alkylOC1-6alkylC5-9heterocyclylRd, CuealkylSCi-ealkylCs-gheterocyclylR^ C1-6alkylNHC1-6alkylC3-9cycloalkylRd, C1-6alkylOC1-6alkylC3-9cycloalkylRd, or CLealkylSd-ealkylCs.gcycloalkylR'1; t is O, 1, 2, 3, 4 or 5; each Rc is, independently, selected from H, C(=O)C1-4alkyl, C(=O)C1-4alkylOC1-4alkyl, C(=O)C1-4alkylC(=O)OC1-4allψl, C(=O)C1-4all^lC(=O)OH, C(=O)C1-4a%lOC(=O)CMalky^^ C5-6arylRd, C5-9heterocyclylRd, C3-9cycloalkylRd, C(=O)C5-6arylRd, C(=O)C5.9heterocyclylRd, C(=O)C3-9cycloalkylRd, C1-4alkyl-C5-6arylRd, C1-4alkyl-C5.9heterocyclylRd, or C1-4alkyl-C3-9cycloaUcylRd; and
Rd is selected from H, C1-3allcyl, NH2, OH, COOH, OC1-3alkyl, or 0C1-3alkyl0H; provided that: a) when the compound has formula Ia, W is N, R2 is
Figure imgf000154_0001
q is 0, r is 0, and s is 0, then [R1HV)n] m-Q is other than phenyl; b) when the compound has formula Ia, W is N, R2 is C1-4alkyl, q is 0, r is 0, s is 0, Q is phenyl, and m is 1, then R^(V)n- is other than bromo, pyridyl, or methoxyphenyl; c) when the compound has formula Ib, W is N, and -[X]q-[Y]r-[Z]s- is -CH2-, then [R1- (V)n] m-Q is other than phenyl; d) when the compound has formula Ib, W is N, -[X]q-[Y]r-[Z]s- is -CH2- or - CH(CH3)-, Q is phenyl, and m is 2, then at least one of R1^V)n- is other than fluoro; e) when the compound has formula Ib, W is N, -[X]q-[Y]r-[Z]s- is -NH-, Q is phenyl, and m is 2, then at least one of R^(V)n- is other than C1-4alkyl; and f) when the compound has formula Ib, W is N, and -[X]q-[Y]r-[Z]s- is -O-, then [R1- (V)n] m-Q is other than phenyl.
2. A compound of claim 1, or a pharmaceutically acceptable 'salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein said compound has the structure of said formula Ia.
3. A compound of claim 1, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein said compound has the structure of said formula Ib.
4. A compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein W is N.
5. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein R3 is selected from H, C^alkyl, Ci-6alkylNRcRc, Ci-6alkylORc, C1-6alkylNHC1-6alkylC6-10arylRd, Ci-6alkylNHC(O)C6-10arylRd 3 C1-6alkyl0C1-6allcylC5-6arylRd, C1-6alkylC6-10arylRd, C1-6alkylC5-9heterocyclylRd, or C1-6alkylC3-9cycloalkylRd.
6. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein R3 is selected from H, C1-6alkyl, C1-6alkylNRcRc, or C1-6alkyl-C5-9heterocyclylRd.
7. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein R3 is Ci-3alkyl.
8. A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein Q is C6-1oaryl, C3.10cycloalkyl or C3-iocycloalkenyl.
9. A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein Q is C6aryl or Cs-iocycloalkenyl.
10. A compound of any one of claims 1-9, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein — [X]q— [Y]r-[Z]S— is OCi-3alkyl, N(C1-3alkyl)C1-3alkyl, C1-3alkyl0C1-3alkyl, C1-3alkylN(H)C1-3alkyl or C1-3alkyl optionally substituted by OH.
11. A compound of any one of claims 1-9, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein q is 0, r is 0 and s is 0.
12. A compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein m is 1, V is S, n is 0 or 1, and R1 is C6-1oaryl or Cs-isheterocyclyl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, Ci-4haloalkyl, OC1-4alkyl, OCi-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6.10aryl, OH,
Figure imgf000155_0001
and -C6aryl-OC1-4alkyl.
13. A compound of any one of claims 1-12, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein m is 1, n is 0, and R1 is C6-1oaryl, wherein said aryl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -C6aryl-OC1-4alkyl.
14. A compound of claim 1, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein:
R1 is, independently, selected from H, halogen, C6aryl, or Cs-βheterocyclyl wherein said C6aryl, or Cs-βheterocyclyl is optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OH, NH2, CN, C(=0)NH2, C1-6alkyl, OC1-6alkyl, C1-4alkyl0H, C1-4allcyl0C1-3alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2C1-6alkyl, SO2NHC1-6alkyl, OC1-3alkylOC1-3alkyl, OC1-3alkylOH, OC1-3alkylOC(=O)Ci-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, C5-6heterocyclyl, OC5-6aryl, -C6aryl-OC1-4alkyl or OC1-6alkyl-C5-6aryl; and
R2 is H or C1-6alkyl; and
R3 is H or C1-3alkyl.
15. A compound of claim 1 , or a pharmaceutically acceptable salt, tautomer or in vzVo-hydrolysable precursor thereof, wherein:
Q is C6aryl or Cs^heterocyclyl;
W is N;
R1 is, independently, selected from H, halogen, C6aryl, or Cs-6heterocyclyl wherein said C6aryl, or C5-6heterocyclyl is optionally substituted by 1, 2, or 3 substituents, independently, selected from: halogen, OH, NH2, CN, C(=O)NH2, C1-6alkyl, OC1-6alkyl, C1-4alkylOH, CMalkylOC^alkyl, CH2OH, SO2H, SO2NHC(CH3)3, SO2Cj-6alkyl, SO2NHCi-6alkyl, OC1-3alkylOC1-3alkyl, OC1-3alkylOH, OC1-3alkylOC(=O)C1-3alkyl, C(=O)C1-6alkyl, C(=O)OC1-6alkyl, C(=0)NH2, C^heterocyclyl, OC5-6aryl, -C6aryl-OC1-4aIkyl or OC1-6alkyl-C5-6aryl; and
R2 is C1-3alkyl.
16. A compound of claim 3, or a pharmaceutically acceptable salt, tautomer or in vzVo-hydrolysable precursor thereof, wherein:
Q is C6-ioaryl; W is N;
-[X]q-[Y]r-[Z]s- is OC1-3alkyl; m is 1; n is 0; and
R1 is C6-1oaryl optionally substituted by 1 or 2 substituents independently selected from: OC^alkyl and -Cearyl-OC^aUcyl.
17. A compound of claim 3, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein:
Q is Cs-iocycloalkenyl;
W is N
-[X]q-[Y]r-[Z]s- is absent; m is 1; n is 0; and
R1 is C6-10aryl optionally substituted by 1 or 2 substituents independently selected from: OC1-4alkyl and -C6aryl-OC1-4alkyl.
18. A compound of claim 2, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, wherein:
Q is C6-10aryl, C3-1ocycloalkyl or C3-i0cycloalkenyl;
W is N;
-[X]q-[Y] -[Z]s- is OCi.3alkyl, N(Ci-3alkyl)C1-3alkyl, Ci-3alkyl0C1-3alkyl, C^alkylNOHQC^alkyl or C1-3alkyl optionally substituted by OH; m is 1;
V is S; n is O or l; and
R1 is C6-10aryl or C5-15heterocycryl, wherein each said aryl and heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from: halogen, CN, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, -C(O)H, COOH, OC1-4alkyl-C6-10aryl, OH, NHC(=O)C1-4alkyl and -C6aryl-OC1-4alkyl.
19. A compound of claim 1 selected from:
2-amino-6- [ [3 -(3 -methoxyphenyl)phenoxy]methyl] -3 -methyl-3H-pyrimidin-4-one; and 2-amino-6-[2-[3-(3-methoxyphenyl)phenyl]-3-bicyclo[2.2.1]hept-5-enyl]-3-methyl-3H-p yrimidin-4-one, or a pharmaceutically acceptable salt, tautomer, or in vzvo-hydrolysable precursor thereof.
20. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, as a medicament.
21. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, as a medicament for treating or preventing an Aβ-related pathology.
22. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, as a medicament for treating or preventing an Aβ-related pathology, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration
23. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology.
24. Use of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
25. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
26. A method of treating or preventing an Aβ-related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
27. The method of claim 26, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
28. The method of claim 26, wherein said mammal is a human.
29. A method of treating or preventing an Aβ-related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
30. The method of claim 29, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
31. The method of claim 29, wherein said mammal is a human.
32. A pharmaceutical composition comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or in v/vo-hydrolysable precursor thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
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