WO2007145569A1 - Amino-imidazolones and their use as a medicament for treating cognitive impairment, alzheimer disease, neurodegeneration and dementia - Google Patents

Amino-imidazolones and their use as a medicament for treating cognitive impairment, alzheimer disease, neurodegeneration and dementia Download PDF

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Publication number
WO2007145569A1
WO2007145569A1 PCT/SE2007/000572 SE2007000572W WO2007145569A1 WO 2007145569 A1 WO2007145569 A1 WO 2007145569A1 SE 2007000572 W SE2007000572 W SE 2007000572W WO 2007145569 A1 WO2007145569 A1 WO 2007145569A1
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Prior art keywords
pyrimidin
tetrahydroimidazo
acetate
amino
phenyl
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PCT/SE2007/000572
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French (fr)
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WO2007145569A9 (en
Inventor
Stefan Berg
Jörg Holenz
Katharina HÖGDIN
Jacob KIHLSTRÖM
Karin Kolmodin
Johan LINDSTRÖM
Niklas Plobeck
Didier Rotticci
Fernando Sehgelmeble
Maria Ek
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Astrazeneca Ab
Astex Therapeutics Ltd
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Priority to JP2009515345A priority Critical patent/JP2009539974A/en
Priority to EP07748235A priority patent/EP2035424A1/en
Publication of WO2007145569A1 publication Critical patent/WO2007145569A1/en
Publication of WO2007145569A9 publication Critical patent/WO2007145569A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel compounds, their pharmaceutical compositions.
  • the present invention relates to therapeutic methods for the treatment and/or prevention 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 o 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"),
  • ⁇ -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 Cleaving Enzyme (BACE) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 0 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 30 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
  • the compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved hERG selectivity.
  • A is independently selected from a 5, 6 or 7 membered heterocyclic ring optionally substituted with one or more R 1 ;
  • B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one or more R 2 ;
  • R 1 is independently selected from halogen, cyano, nitro, OR 6 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylaryl, Co- ⁇ alkylheteroaryl, Co-6alkylC 3-6 cycloalkyl, C 0-6 alkylC 3- ecycloalkenyl, C 0- 6alkylC 3-6 cycloalkynyl, C 0-6 alkylC 3-6 heterocyclyl, NR 6 R 7 , CONR 6 R 7 , NR 6 (CO)R 7 , O(CO)R 6 , CO 2 R 6 , COR 6 , (SO 2 )NR 6 R 7 , NR 6 (SO 2 )R 7 , SO 2 R 6 , SOR 6 , OSO 2 R 6 and SO 3 R 6 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkyla
  • R 2 , R 3 and R 4 are independently selected from halogen, cyano, nitro, OR 6 , C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylCs.gcycloalkyl, Co- 6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 3-6 cycloalkynyl, Co- 6 alkylC 3-6 heterocyclyl, NR 6 R 7 , CONR 6 R 7 , NR 6 (CO)R 7 , 0(CO)R 6 , CO 2 R 6 , COR 6 , (SO 2 )NR 6 R 7 , NR 6 (SO 2 )R 7 , SO 2 R 6 , SOR 6 , OSO 2 R 6 and SO 3 R 6 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • R 5 is independently selected from hydrogen, cyano, OR 6 , C 1-6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, Co -6 alkylaryl, C 0-6 alkylheteroaryl, Co-ealkylQ-gcycloalkyl, Co- 6 alkylC 3- ecycloalkenyl, C 0-6 alkylC 3-6 cycloalkynyl, C 0-6 alkylC 3 , 6 heterocyclyl, CONR 6 R 7 , CO 2 R 6 , COR 6 , SO 2 R 6 and SO 3 R 6 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylaryl, C 0- 6 alkylheteroaryl, Co -6 alkylC 3-6 cycloalkyl, Co -6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 3-
  • C 0-6 alkylC 3-6 heterocyclyl may be optionally substituted with one or more C;
  • C is independently selected from halogen, nitro, CN, OR 6 , C 1-6 alkyl, C 2-6 alkenyL C 2-6 alkynyl, C 0 . 6 alkylaryl, Co -6 alkylheteroaryl, Co -6 alkylC 3-6 cycloalkyl, Co- 6 alkylC 3- gcycloalkenyl, Co- 6 alkylC 3-6 cycloalkynyl, Co- ⁇ alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifiuoromethoxy, NR 6 R 7 , CONR 6 R 7 , NR 6 (CO)R 7 , 0(CO)R 6 , CO 2 R 6 , COR 6 , (SO 2 )NR 6 R 7 , NR 6 SO 2 R 7 , SO 2 R 6 , SOR 6 , OSO 2 R 6 and SO 3 R 6
  • 6 alkylC 3- 6 cycloalkynyl or Co- ⁇ alkylheterocyclyl may be optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR 6 , C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;
  • R 6 and R 7 are independently selected.from hydrogen, C ⁇ aUcyl, Co -6 alkylaryl, heteroaryl, C 0-6 alkylC 3-6 cycloalkyl, Co -6 alkylC3 -6 cycloalkenyl, Co -6 alkylC 3 -6cycloalkynyl, Co- 6 alkylheterocyclyl, fluoromethyl, difluoromethyl and trifluoromethyl; or R 6 and R 7 may together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S;
  • n 0, 1, 2 or 3
  • p 0, 1, 2 or 3
  • q 0, 1, 2 or 3; as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
  • the present invention further provides pharmaceutical compositions comprising as active ingredient a therapeutically effective amount of a compound of formula I in association with pharmaceutically acceptable excipients, carriers or diluents.
  • the present invention further provides methods of modulating activity of BACE comprising contacting the BACE enzyme with a compound of formula I.
  • 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 I.
  • the present invention further provides a compound described herein for use as a medicament.
  • a compound according to formula I wherein R 5 is hydrogen.
  • a compound according to formula I wherein m is 1 or 2, wherein R 1 is independently selected from halogen, cyano ⁇ OR 6 , NR 6 (CO)R 7 , CO 2 R 6 , NR 6 (SO 2 )R 7 and SO 2 R 6 .
  • R 6 and R 7 are independently selected from hydrogen, C 1- ealkyl and trifluoromethyl.
  • B is phenyl substituted with one R 2 .
  • B is phenyl substituted with one R 2 selected from OR 6 and OSO 2 R 6 .
  • B is phenyl substituted with one R 2 selected from OR 6 and OSO 2 R 6 and R 6 is Ci -6 alkyl.
  • R 2 selected from OR 6 and OSO 2 R 6 and R 6 is Ci -6 alkyl.
  • R 2 is C 1-6 alkyl.
  • R 3 is selected from halogen, cyano, nitro, OR 6 , C ⁇ alkyl, SO 2 R 6 and OSO 2 R 6 and wherein said C ⁇ alkyl, is optionally substituted with one or more C.
  • C is halogen
  • R 6 is C ⁇ alkyl or trifluoromethyl.
  • B is independently selected from phenyl or a 6 membered heteroaromatic ring optionally substituted with one R 2 ;
  • R 2 and R 3 are independently selected from halogen, cyano, nitro, OR 6 , C 1-6 alkyl, SO 2 R 6 and OSO 2 R 6 , wherein said C 1-6 alkyl, may be optionally substituted with one or more C;
  • R 5 is hydrogen;
  • C is halogen
  • A is independently selected from a 5 or 6 membered heterocyclic ring optionally substituted with one or more R 1 ;
  • B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one R 2 ;
  • R 1 is independently selected from halogen, cyano, OR 6 , NR 6 (CO)R 7 , CO 2 R 6 , NR 6 (SO 2 )R 7 and SO 2 R 6 ;
  • R 2 and R 3 are independently selected from halogen, OR 6 , C 1-6 alkyl and OSO 2 R 6 ;
  • R 5 is hydrogen;
  • A is a 6 membered heterocyclic ring substituted with two R 1 ;
  • B is a 6 membered heteroaromatic ring;
  • R 1 is halogen
  • R 3 is independently selected from halogen and OR 6 ;
  • R 4 is halogen
  • a compound according to formula I selected from: 8-(3'-Methoxybiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5- ⁇ ]pyrimidin-6-amine hydrochloride;
  • 6-amine hydrochloride 0 ⁇ -CS'jS'-Dichlorobiphenyl-S-y ⁇ -S-phenyl ⁇ j ⁇ -tetrahydroimidazofljS- ⁇ Jpyrimidin- ⁇ - amine hydrochloride; 3'-(6-Amino-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5- ⁇ ]pyriniidin-8-yl)-5- methoxybiphenyl-3-yl methanesulfonate hydrochloride;
  • Some compounds of formula I may have stereogenic centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical isomers, enantiomers, diastereoisomers, atropisomers and geometric isomers.
  • the present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • the present invention provides compounds of formula I, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, for use as medicaments.
  • the present invention provides compounds described here in 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 use of compounds of formula I or pharmaceutically acceptable salts, tautomers or in vzv ⁇ -hydroly sable 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 0 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 0 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,
  • 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 I, or a pharmaceutically acceptable salt, tautomer or in vzv ⁇ -hydrolysable precursor thereof.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angi
  • 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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in v/vo-hydrolysable precursors.
  • a ⁇ -related pathologies such as Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy,
  • 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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in vzv ⁇ -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 amyloid angiopathy
  • Cognitive enhancing agents, memory enhancing agents and choline esterase inhibitors includes, but not limited to, onepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine (Namenda, Axura or Ebixa).
  • 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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in v/vo-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 ⁇ -amyloid angiopathy, such
  • 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 mammal including human
  • 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 0 active ingredient, one or more of the compounds of the invention herein together with at least one pharmaceutically acceptable carrier, diluent or excipent.
  • a variety of compounds in the present invention may exist in particular geometric or stereoisomeric 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 0 the scope of this invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All 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, by synthesis from optically active starting materials, or synthesis using optically active reagents.
  • 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 o separated isomeric forms. AU chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • substitution means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted.
  • substitution means that any number of hydrogens on the designated atom or moiety is replaced with a selection from the indicated 5 group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound.
  • a substituent is methyl (i.e., CH 3 )
  • 3 hydrogens on the carbon atom can be replaced.
  • alkyl 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 0 - 6 alkyl denotes alkyl having 0, 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, penryl, and hexyl.
  • a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group s may be absent, i.e. there is a direct bond between the groups.
  • alkenyl used alone or as a suffix or prefix is intended to include both branched and straight-chain alkene or olefin containing aliphatic hydrocarbon groups 0 having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 2-6 alkenyl denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut- 1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. 5
  • alkynyl used alone or as a suffix or prefix is intended to include both branched and straight-chain alkyne containing aliphatic hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 2-6 alkynyl denotes alkynyl having 2, 3, 4, 5 or 0 6 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2- ⁇ ro ⁇ ynyl, 3-butynyl, -pentynyl, hexynyl and l-methylpent-2-ynyl.
  • aromatic refers to hydrocarbonyl groups having one or more unsaturated carbon ring(s) having aromatic characters, (e.g. 4n + 2 delocalized electrons) and comprising up to about 14 carbon atoms.
  • heteromatic refers to groups having one or more unsaturated rings containing carbon and one or more heteroatoms such as nitrogen, oxygen or sulphur having aromatic character (e.g. 4n + 2 delocalized electrons).
  • 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 polycyclic, 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 5 one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • 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 is intended to include 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. 5
  • cycloalkenyl refers to ring-containing hydrocarbyl groups having at least one carbon-carbon double bond in the ring, and having from 4 to 12 carbons atoms.
  • cycloalkynyl refers to ring-containing hydrocarbyl groups having at least 0 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 charged species such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, and the like.
  • heterocyclyl or “heterocyclic” or “heterocycle” refers to a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 3 to 20 atoms of which 1, 2, 3, 4 or 5 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s) or a ring nitrogen is optionally quarternized; wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo.
  • heterocyclyl group is bi- or tricyclic then at least one of the rings may optionally be a heteroaromatic or aromatic ring provided that at least one of the rings is non-heteroaromatic. If the said heterocyclyl group is monocyclic then it must not be aromatic.
  • heterocyclyls include, but are not limited to, piperidinyl, N- acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, JV-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl and 2,5-dioxoimidazolidinyl.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e.
  • furanyl quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, fluorenonyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl or heteroaromatic group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl or heteroaromatic 5 group has 1 heteroatom.
  • 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 o 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 s compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the 5 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 acid.
  • 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 diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • 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 properties of both a ketone and an unsaturated alcohol.
  • 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. 5
  • 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 0 occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 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, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radiolabeled compounds will depend on the specific application of that radio-labeled compound. 5 For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful. For radio- imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 I, 75 Br, 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, 14 C, 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: acetyl cholinesterase inhibitors, anti-inflammatory agents, cognitive and/or memory enhancing agents or atypical antipsychotic 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.
  • the present invention provides a compound of formula I 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 o 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. s
  • 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 0 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 5 for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral
  • compositions 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+ ), 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. AU such salts are within the scope of this invention, and references to compounds include the salt forms of the compounds. 5
  • 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 iV-oxides.
  • a reference herein to a compound that contains an amine function also includes the iV-oxide.
  • one or more than one nitrogen atom may be oxidised to form an iV-oxide.
  • Particular examples of iV-oxides are the iV-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
  • 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 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 ⁇ -amyloid angiopathy. It is expected that the compounds of the present invention would most likely be used as single agents but could also be used in combination with a broad range of cognition deficit enhancement agents.
  • the present invention also relates to processes for preparing the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof.
  • suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis.
  • Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Protective Groups in Organic Synthesis by T.W. Greene, P.G.M Wutz, 3 rd Edition, Wiley-Interscience, New York, 1999. It is understood that microwaves can be used for the heating of reaction mixtures.
  • the reaction may be carried out by treating the compound of formula III with an appropriate tiolate or an appropriate thiol together with a suitable base such as sodium hydride, triethylamine or sodium hydroxide.
  • a suitable base such as sodium hydride, triethylamine or sodium hydroxide.
  • the reactions may be preformed in a suitable solvent such as ethanol, N,N-dimethylformamide or tetrahydrofuran at a temperature between O 0 C and reflux.
  • the reaction may be carried out by oxidation using an appropriate oxidizing agent such as 3-chloroperoxybenzoic acid or hydrogen peroxide.
  • the reactions may be preformed in a suitable solvent such as dicholormethane, N,N-dimethylformamide or acetic acid, at a temperature between 0 °C and reflux.
  • the reaction may be carried out by treating the compound of formula VI with a suitable acylating reagent such as an anhydride e.g. acetic anhydride or an acyl chloride e.g. acetyl chloride, in a suitable solvent such as diethylether, dichloromethane, ethyl acetate or 25 toluene at a temperature between -20 °C and reflux.
  • a suitable acylating reagent such as an anhydride e.g. acetic anhydride or an acyl chloride e.g. acetyl chloride
  • a suitable solvent such as diethylether, dichloromethane, ethyl acetate or 25 toluene at a temperature between -20 °C and reflux.
  • a suitable base may be pyridine, potassium carbonate or potassium hydroxide.
  • the reaction may be carried out by treating the compound of formula IX with an appropriate sulfonylchloride such as a compound of formula VIII together with a suitable o base such as triethylamine, pyridine or sodium hydroxide.
  • a suitable o base such as triethylamine, pyridine or sodium hydroxide.
  • the reactions may be preformed in a suitable solvent such as diethylether, tetrahydrofuran or dichloromethane at a temperature between - 50 °C and reflux.
  • the reaction may be carried out by treating an appropriate amine with nitrous acid followed by treating the formed diazonium salt with an appropriate cuprous halide such as copper(I) bromide or copper(I) chloride, or with copper and hydrobromic acid or hydrochloric acid.
  • the reactions may be preformed in a suitable solvent such as water at a temperature between —20 °C and reflux.
  • the reaction may be carried out by: a) an alkyllithium such as butyllithium, or magnesium, and a suitable boron compound such as trimethyl borate or triisopropyl borate.
  • the reaction may be performed in a suitable solvent such as tetrahydrofuran, hexane or dichloromethane in a temperature range between -78 0 C and +20 0 C; or, b) a suitable boron species such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1,3,2- dioxaborolane, biscatecholatodiboron, or pinacolborane in the presence of a suitable palladium catalyst such as tris(dibenzylideneacetonedipalladium)(O), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, palladium(O) tetrakistripheny
  • the reaction may be performed in a solvent such as dioxane, toluene, acetonitrile, water, ethanol or 1,2- dimethoxyethane, or mixtures thereof, at temperatures between 20 0 C and +160 0 C.
  • a solvent such as dioxane, toluene, acetonitrile, water, ethanol or 1,2- dimethoxyethane, or mixtures thereof, at temperatures between 20 0 C and +160 0 C.
  • the reaction may be carried out by treating the compound of formula XIV with an alkyllithium, such as butyllithium, or magnesium followed by addition of a compound of formula XV.
  • the reaction may be preformed in a suitable solvent such as diethyl ether or tetrahydrofuran at a temperature between -78 °C and reflux.
  • the reaction may be carried out by reduction using an appropriate reducing agent such as sodium borohydride, cyanoborohydride or lithium aluminium hydride.
  • the reaction may be preformed in a suitable solvent such as methanol, ethanol, diethyl ether or tetrahydrofuran at a temperature between -78 0 C and reflux.
  • the reaction may be carried out by treating a compound of formula XVII with a suitable thiocarbonyl transfer reagent such as 0,Odipyridine-2-yl thiocarbonate or thiophosgene.
  • a suitable thiocarbonyl transfer reagent such as 0,Odipyridine-2-yl thiocarbonate or thiophosgene.
  • the reaction may be preformed in a suitable solvent such as dichloromethane or chloroform at a temperature between -78 °C and reflux.
  • the reaction may be carried out by treating the appropriate isothiocyanate such as a compound of formula XVIII and carbon disulfide with a suitable base such as potassium fert-butoxide in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature between -78 0 C and reflux.
  • a suitable base such as potassium fert-butoxide
  • a suitable solvent such as tetrahydrofuran or diethyl ether
  • the reaction may be carried out by treating a compound of formula XIX with an appropriate diamine such as diamines described in Tetrahedron 1994, 50(29), 8617 and 1995, 51(10), 2875 or diamines such as compounds of formula V, VII and X.
  • the reaction may be preformed in a suitable solvent such as ethanol or methanol at a temperature between 0 °C and reflux.
  • the reaction may be carried out by treating the appropriate thione such as a compound of formula XX with an appropriate oxidazing agent such as tert-butyl hydroperoxide and aqueous ammonia.
  • an appropriate oxidazing agent such as tert-butyl hydroperoxide and aqueous ammonia.
  • the reaction may be performed in a suitable solvent such as methanol at a temperature between 0 0 C and reflux.
  • the reaction may be carried out by treating the methyl ether with a suitable Lewis acid such as boron tribromide in a suitable solvent such as dichloromethane at a temperature between -78 °C and reflux.
  • a suitable Lewis acid such as boron tribromide
  • a suitable solvent such as dichloromethane
  • the reaction may be carried out by treating the appropriate alcohol with a suitable sulfonyl s chloride or anhydride such as methanesulfonyl chloride, 1-propanesulfonyl chloride, cyclopropanesulfonyl chloride or methanesulfonic anhydride in the presence of a suitable base such as triethylamine.
  • a suitable sulfonyl s chloride or anhydride such as methanesulfonyl chloride, 1-propanesulfonyl chloride, cyclopropanesulfonyl chloride or methanesulfonic anhydride in the presence of a suitable base such as triethylamine.
  • a suitable solvent such as dichloromethane at a temperature between 0 °C and reflux.
  • reaction may be carried out by treating the appropriate alcohol with 1,1,1-trifluoro- iV-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide in the presence of a suitable base such as potassium carbonate, triethylamine or N-ethyldiisopropylamine.
  • a suitable base such as potassium carbonate, triethylamine or N-ethyldiisopropylamine.
  • the reaction may be carried out in a suitable solvent such as dichloromethane or tetrahydrofuran at a temperature between 0 0 C and +160 0 C.
  • the reaction may be carried out by treating the appropriate alcohol with a suitable base such as sodium hydride followed by addition of a suitable alkyl halide such as s iodomethane.
  • a suitable base such as sodium hydride
  • a suitable alkyl halide such as s iodomethane.
  • the reaction may be preformed in a suitable solvent such as tetrahydrofuran at a temperature between —78 °C and reflux.
  • Another obj ect of the invention is the process a for the preparation of compounds of general Formula I, wherein A, B, C, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 unless otherwise specified, are defined as hereinbefore, and salts thereof.
  • the free base may be treated with an acid such as a hydrogen halide such as hydrogen chloride in a suitable solvent such as tetrahydrofuran, diethyl ether, methanol, 5 ethanol, chloroform or dichloromethane or mixtures thereof and the reaction may occur between -30 0 C to +50 0 C.
  • the reaction may be carried out by coupling of a suitable compound such as a compound of formula XXVII with an appropriate aryl boronic acid or ester of formula XIII wherein R 9 represents hydrogen, alkyl, aryl or two R 9 may form a cyclic boronic ester.
  • the reaction may be carried out using a suitable palladium catalyst such as, [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, 0 tetrakis(triphenylphosphine)palladium(0), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0), together with, or without, a suitable ligand such as triphenylphosphine, tri-Ztert-butylphosphine or 2- (dicyclohexylphosphino)biphenyl, or using a nickel catalyst such as nickel on charcoal or l,2-bis(diphenylphosphino)ethanenickel dichloride together with zinc and sodium s triphenylphosphinetrimetasulfonate.
  • a suitable palladium catalyst such as, [1,1'- bis(
  • a suitable base such as cesium fluoride, an alkyl amine such as triethyl amine, or an alkali metal or alkaline earth metal carbonate or hydroxide such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydroxide may be used in the reaction, which may be performed in a temperature range between +20 0 C and +160 0 C, in a suitable solvent such as toluene, tetrahydrofuran, 0 dioxane, dimethoxyethane, water, ethanol or ⁇ N-dimethylformamide, or mixtures thereof.
  • a suitable solvent such as toluene, tetrahydrofuran, 0 dioxane, dimethoxyethane, water, ethanol or ⁇ N-dimethylformamide, or mixtures thereof.
  • LC-MS analyses were performed on an LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZMD single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode.
  • the capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively.
  • the mass spectrometer was scanned between m/z 100-600 by a scan time of 0.7s.
  • the diode array detector was scanned from 200-400 nm.
  • the temperature of the ELS detector was adjusted to 40 °C and the pressure was set to 1.9 bar.
  • LC-MS analyses were performed on a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode.
  • the capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively.
  • the mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3s.
  • the diode array detector scanned from 200-400 nm.
  • the temperature of the ELS detector was adjusted to 40 0 C and the pressure was set to 1.9 bar.
  • LC-MS analyses were performed on a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 85 ELS detector and a ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode.
  • the capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively.
  • the mass spectrometer scanned between m/z 100-700 with a scan time of 0.3s.
  • the diode array detector scanned from 200-400 nm.
  • the temperature of the ELS detector was adjusted to 40 °C and the pressure was set to 1.9 bar.
  • LC-MS analyses were preformed on a Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; Acquity UPLCTM BEH C 8 1.7 ⁇ m 2.1 x 50mm. The column temperature was set to 65 0 C. A linear 2 min gradient from 100% A (A: 95% 0.0 IM ammonium acetate in MiUiQ water and 5% acetonitrile) to 100% B (5% 0.01 M ammonium acetate in MiUiQ water and 95% acetonitrile) was applied for LC-separation at flow rate 1.2 mL/min. The PDA was scanned from 210-350nm and 254nm was extracted for purity determination.
  • the ZQ mass spectrometer was run with ES in pos/neg switching mode.
  • the Capillary Voltage was 3kV and the Cone Voltage was 30V, or LC-MS analyses were preformed on a Waters LCMS consisting of an Alliance 2690 o Separations Module, Waters 2487 Dual 1 Absorbance Detector (220 and 254 nm) and a Waters ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and cone voltage was 30 V.
  • the mass spectrometer was scanned between m/z 97-800 with a scan time of 0.3 or 0.8 s. Separations were performed 5 on a Chromolith Performance RP-18e (100 x 4.6 mm). A linear gradient was applied starting at 95% A (A: 0.1% formic acid (aqueous)) ending at 100% B (acetonitrile) in 5 minutes. Flow rate: 2.0 mL/min or
  • LC-MS analyses were performed on a LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 ⁇ binary pump, a Waters 1500 column oven, a Waters ZQ single 0 quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector.
  • the mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device.
  • APCI atmospheric pressure chemical ionisation
  • APPI atmospheric pressure photo ionisation
  • the mass spectrometer scanned in the positive mode, switching between APCI and APPI mode.
  • the mass range was set to m/z 120-800 using a scan time of 0.3 s.
  • the APPI repeller and the APCI corona were set to 0.86 kV and
  • desolvation temperature 300 0 C
  • desolvation gas 400 L/Hr
  • cone gas 5 L/Hr
  • desolvation temperature 300 0 C
  • desolvation gas 400 L/Hr
  • cone gas 5 L/Hr
  • Separation was performed using a Gemini column C18, 3.0 mm x 50 mm, 3 ⁇ m, (Phenomenex) and run at a flow rate of 1 ml/min.
  • a linear gradient was used starting at 100 % A (A: 10 mM ammonium acetate in 5% methanol) and ending at 100% B (methanol).
  • the column oven o temperature was set to 40 0 C.
  • GC-MS Compound identification was performed on a GC-MS system (GC 6890, 5973N MSD) supplied by Agilent Technologies. The column used was a VF-5 MS, ID 0.25 mm x 15m, 0.25 ⁇ m (Varian Inc.). A linear temperature gradient was applied starting at 40 °C s (hold 1 min) and ending at 300 0 C (hold 1 min), 25 °C/minute.
  • the mass spectrometer was equipped with a chemial ionisation (CI) ion source and the reactant gas was methane.
  • the mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV.
  • CI chemial ionisation
  • EI electron impact
  • the mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.25 scan/s, or 0 Compound identification was performed on a GC-MS system (GC 6890, 5973N MSD) supplied by Agilent Technologies.
  • the mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH.
  • the mass spectrometer was configured with a chemical ionisation (CI) ion source and the reactant gas was methane.
  • the mass spectrometer was equipped with an electron impact (EI) ion source and the 5 electron voltage was set to 70 eV.
  • the mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.25 scan/s.
  • a linear temperature gradient was applied starting at 40 °C (hold 1 min) and ending at 300 0 C (hold 1 min), 25 °C/minute.
  • the column used was a VF-5 MS, ID 0.25 mm x 30m, 0.25 ⁇ m (Varian Inc.).
  • Preparative-HPLC Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 ⁇ m. Gradient with acetonitrile/0.1 M ammonium acetate in 5 % acetonitrile in MiIIiQ Water. Flow rate: 20 mL/min.
  • purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV-vis.-detector equipped with a Waters Symmetry ® column (C18, 5 ⁇ m, 100 mm x 19 mm). Gradient with acetonitrile/0.1% trifluoroacetic acid in MiIIiQ Water. Flow rate: 10 mL/min.
  • Microwave heating was performed in a Creator or Initiaror or Smith Synthesizer Single- mode microwave cavity producing continuous irradiation at 2450 MHz.
  • TLC Thin layer chromatography
  • Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0 C in an ice bath.
  • the resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 0 C.
  • Methanesulfonyl chloride (122 ⁇ L, 0.79 mmol) was added dropwise at 0 °C to a mixture of 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.79 mmol) and triethylamine (0.4 mL, 3.14 mmol) in dry dichloromethane (1.5 mL).
  • 3-Bromobenzonitrile (10.92 g, 60 mmol) was added to a solution of bromo(phenyl)magnesium (24 mL, 72 mmol) in dry tetrahydrofuran (25 mL) at ambient 25 temperature under an atmosphere of argon. The resulting mixture was stirred at 60 °C for 4 h, then cooled to 0 °C and dry methanol (60 mL) was added. Sodium borohydride (5.68 g, 150 mmol) was added in three portions at 0 °C under an atmosphere of argon and the resulting mixture was allowed to reach ambient temperature and stirred for 1.5 h.
  • Butyllithium (2.5 M in hexanes, 10.20 mL, 25.40 mmol) was added to a cooled (-78 °C) solution of 1,3-dibromo-benzene (6 g, 25.40 mmol) in dry diethyl ether (60 mL), under an atmosphere of argon. The obtained mixture was stirred for 1 h at -78 °C. 4-Cyanopyridine (2.64 g, 25.40 mmol) in dry diethyl ether (45 mL) was added and the stirring was continued for 20 min at -78 °C.
  • the reaction mixture was allowed to attain the ambient temperature and dry methanol (30 mL) was added and the resulting mixture was stirred for another 45 min.
  • the solution was cooled to 0 °C, sodium borohydride (1.3 g, 34.0 mmol) was added and the reaction stirred overnight at ambient temperature.
  • Saturated aqueous ammonium chloride 40 mL was carefully added and the mixture was concentrated.
  • the aqueous phase was extracted twice with dichloromethane (40 mL), the organic phase was dried over sodium sulfate and concentrated in vacuo.
  • Examples 33-59 were synthesised as described for Example 32 in similar yields as seen in the table below.
  • Examples 60-66 were synthesised as described for Example 32 in similar yields as seen in 5 the table below.
  • Examples 68-86 were synthesised as described for Method A (Example 32) or Method B in similar yields as seen in the table below.
  • Example IPS Di-tert-butyl ⁇ -(methvlsulfonyppropane- 1 ,3 -diyllbiscarbamate Oc " SS ' .
  • Trifluoroacetic acid (5 mL) was added to a solution of di-tert-butyl [2- (methylsulfonyl)propane-l,3-diyl]biscarbamate (100 mg, 0.28 mmol) in dichloromethane (5 mL). The obtained mixture was stirred for 30 min and then concentrated in vacuo and co-evaporated twice with ethanol to give 107 mg (100 % yield) of the title compound. MS (ES) m/z 153 [M+l] + .
  • Triethylamine (15.5 mL) was added in one portion.
  • the reaction mixture was heated to 70 0 C with an oil bath and stirred for 16 h, allowed to cool to room temperature and the solvent was evaporated.
  • the residue was re-dissolved in ethyl acetate and water, and the phases separated.
  • the organic phase was washed with water.
  • the combined aqueous layers were extracted with ethyl acetate, the organic fractions were combined, dried over o magnesium sulfate, filtered and evaporated in vacuo.
  • Aqueous fer/-butyl hydroperoxide (70 %, 0.5 mL, 3.6 mmol) was added to a solution of 8- (3-bromophenyl)-8-(4-methoxyphenyl)-3-(methylsulfonyl)-3,4,7,8-tetrahydroimidazo[l,5- a]pyrimidine-6(2H)-thione (120 mg, 0.24 mmol) and aqueous ammonia (30 %, 0.97 mL) in methanol (3 mL). The resulting mixture was stirred at room temperature overnight.
  • Aqueous tert-butyl hydroperoxide (70 %, 5 mL) was added to a mixture of 8-(3- bromophenyl)-3,3-difluoro-8-pyridm-4-yl-3,4,7,8-tetrahydroimidazo[l,5- ⁇ ]pyrimidine- 6(2H)-thione (1.41 g, 3.33 mmole), methanol (20 mL) and aqueous ammonia (25 %, 10 mL). The reaction was stirred at room temperature 21 h then evaporated in vacuo.
  • the title compound was synthesized in 72 % yield as described in example 124, starting from 8-(3-bromo-phenyl)-3,3-difluoro-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5- a]pyrimidin-6-ylamine and (2-fluoro-5-methoxyphenyl)boronic acid.
  • reaction vessel was sealed and heated to 65 0 C and stirred for 48 h.
  • the reaction mixture was diluted with water and dichloromethane and the phases were separated.
  • the organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo followed by purification by prep HPLC to give 26.7 mg (23 % yield).
  • 1,3-Dibromobenzene (1.314 mL, 10.86 mmol) was dissolved in dry diehtylether (25 niL) and cooled to -78 0 C.
  • n-Butyl lithium (4.53 mL, 10.86 mmol, 2.5 M in hexane) was added drop wise and the mixture was stirred for 30 min.
  • 3-Furonitrile (1.0 g, 10.86 mmol) in dry diethyl ether (10 mL) was added and the mixture was slowly warmed to 0 °C over 2 h. Dry methanol (30 mL) was added and after 30 min at 0 0 C was sodium borohydride (0.83 g, 21.7 mmol) added.
  • Example 141 8-(3-BromophenylV8-( ' 3-furvl)-2,3,4,8-tetrahvdroimidazori,5- ⁇ 1pvrimidin-6-aniine
  • the title compound was synthesized as described for example 141 in 80 % yield starting from 8-(3-bromophenyl)-8-(3-thienyl)-3,4,7,8-tetrahydroimidazo[l,5- ⁇ ]pyrimidine-6(2H)- thione.
  • Examples 178-192 were synthesised as described for example 176 (method C) or example 177 (method D) in similar yields as seen in the table below.
  • tert-Butyl hydroperoxide 70 % aqueous solution, 0.9 mL, 5.6 mmol
  • a solution of 3,3-difluoro-3,4,7,8-tetrahydroimidazo[l ,5- ⁇ ]pyrimidine-6(2H)-thione-4-(3- bromo-4-fluorobenzyl)pyridine (0.167 g, 0.38 mmol) and ammonia (30 % aqueous solution, 1.7 mL) in methanol (10 mL).
  • ammonia 30 % aqueous solution, 1.7 mL
  • the soluble part of the human ⁇ -Secretase (AA 1 — AA 460) was cloned into the ASP2- FcI 0-1 -IRES-GFP -neoK mammalian expression vector.
  • the gene was fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
  • Purified sB ACE-Fc is stored in Tris buffer, pH 9.2 and has a purity of 95%.
  • the enzyme was diluted to 43 ⁇ g/ml in 40 mM MES pH 5.0.
  • the IGEN substrate was diluted to 12 ⁇ M in 40 mM MES pH 5.0.
  • Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is
  • the assay was performed in a 96 well PCR plate from Greiner (#650201). Compound in dimethyl sulfoxide (3 ⁇ L) and enzyme (27 ⁇ L) were added to the plate, and pre- incubated for 10 min. The reaction was started with substrate (30 ⁇ L). The final dilution of enzyme was 20 ⁇ g/ml and the final concentration of substrate was 6 ⁇ M. After 20 minutes reaction at room temperature (RT), the reaction was stopped by removing 10 ⁇ L of the reaction mix and diluting it 1:25 in 0.2 M Trizma-HCl, pH 8.0.
  • the product was 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 (all antibodies and the streptavidin coated beads were diluted in PBS containing 0.5% BSA and 0.5% Tween20). Then, 100 ⁇ L of 0.2 mg/mL streptavidin coated beads (Dynabeads M-280) and a 1:5000 dilution of ruthenylated goat anti-rabbit (Ru-GaR) antibody was added. The mixture was measured for electro- chemiluminescence in a BioVeris M8 Analyzer after 2 hours of incubation with shaking at RT. The dimethyl sulfoxide control defined 100% activity level and 0% activity was defined by exclusion of the enzyme (using 40 mM MES pH 5.0 buffer instead).
  • the enzyme was diluted to 52 ⁇ g/ml in 40 mM MES pH 5.0.
  • the substrate (Dabcyl-Edans) was diluted to 30 ⁇ M in 40 mM MES pH 5.0.
  • Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is 5%).
  • the assay is done in a Corning 384 well round bottom, low volume, non-binding surface plate (Corning #3676).
  • Enzyme (9 ⁇ L) together with 1 ⁇ L of compound in dimethyl sulfoxide were added to the plate and pre-incubated for 10 min.
  • Substrate (10 ⁇ L) was added and the reaction proceeded in the dark at RT for 25 min.
  • the final dilution of enzyme was 23 ⁇ g/ml, and the final concentration of substrate was 15 ⁇ M (Km of 25 ⁇ M).
  • the fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 360 nm and an emission wavelength of 485 nm using a protocol for labelled Edans peptide.
  • the dimethyl sulfoxide control defined 100% activity level and 0% activity was defined by exclusion of the enzyme (using 40 mM MES pH 5.0 buffer instead).
  • Enzyme was diluted to 6 ⁇ g/mL and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM in reaction buffer (NaAcetate, chaps, triton x-100, EDTA pH 4.5). Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is 5%). The assay was done in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676). Enzyme (9 ⁇ L) and 1 ⁇ L of compound in dimethyl sulfoxide was added to the plate, mixed and pre-incubated for 10 min.
  • 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-VAEF was coupled to channel 2 of the same chip.
  • the two peptides were dissolved at 0.2 mg/mL in 20 mM sodium 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 0.5 M N-ethyl-N' (3-dimethylaminopropyl)-carbodiimide and 0.5 M N- hydroxysuccinimide at 5 ⁇ L/min for 7 min. Then the stock solution of the control peptide was injected in channel 1 for 7 min at 5 ⁇ L/min., and then the remaining activated carboxyl groups were blocked by injecting 1 M ethanolamine for 7 min at 5 ⁇ L/min.
  • the BACE Biacore assay was done by diluting BACE to 0.5 ⁇ M in sodium acetate buffer at pH 4.5 (running buffer minus dimethyl sulfoxide). The diluted BACE was mixed with dimethyl sulfoxide or compound diluted in dimethyl sulfoxide at a final concentration of 5% dimethyl sulfoxide. The BACE/inhibitor mixture was incubated for 30 minutes at RT before being injected over channel 1 and 2 of the CM5 Biacore chip at a rate of 20 ⁇ L/min. 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.
  • RU response units
  • 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 dimethyl sulfoxide control was defined as 100% and the effect of the compound was reported as percent inhibition of the dimethyl sulfoxide control.
  • the pcDNA3.1 plasmid encoding the cDNA of human full-length APP695 was stably transfected into HEK-293 cells using the Lipofectamine transfection reagent according to manufacture's protocol (Invitrogen). Colonies were selected with 0.1-0.5 mg/mL of zeocin. 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.
  • HEK293 cells stably expressing human wild-type APP were grown at 37 0 C, 5% CO 2 in DMEM containing 4500 g/L glucose, GlutaMAX and sodium pyruvate supplemented with 10% FBS, 1% non-essential amino acids and 0.1 mg/mL of the selection antibiotic zeocin.
  • a ⁇ 40 release assay HEK293-APP695 cells were harvested at 80-90% confluence and seeded at a concentration of 0.2x10 6 cells/mL, 100 mL cell suspension/well, onto a black clear bottom 96-well poly-D-lysine coated plate. After over night incubation at 37 0 C, 5% CO 2 , the cell medium was replaced with cell culture medium with penicillin and streptomycin (100 U/mL, 100 ⁇ g/mL, respectively) containing test compounds in a final dimethyl sulfoxide concentration of 1%. Cells were exposed to the test compounds for 24 h at 37 0 C, 5% CO 2 .
  • test plate 100 ⁇ L cell medium was transferred to a round bottom polypropylene 96-well plate (assay plate). The cell plate was saved for the ATP assay, as described below.
  • 50 ⁇ L of primary detection solution containing 0.5 ⁇ g/mL of the rabbit anti-A ⁇ 40 antibody and 0.5 ⁇ g/mL of the biotinylated monoclonal mouse 6E10 antibody in DPBS with 0.5 %BSA and 0.5% Tween-20 was added per well and incubated over night at 4 0 C.
  • SH-SY5Y cells were grown 37 0 C with 5% CO 2 in DMEM/F-12 1:1 containing GlutaMAX supplemented with 1 mM HEPES, 10% FBS and 1% non-essential amino acids.
  • SH-SY5Y cells were harvested at 80-90% confluence and seeded at a concentration of 1.5x10 6 cells/mL, 100 mL cell suspension/well, onto a black clear flat bottom 96-well tissue culture plate. After 7 hours of incubation at 37 0 C, 5% CO 2 , the cell medium was replaced with 90 ⁇ l cell culture medium with penicillin and streptomycin (100 U/mL, 100 ⁇ g/mL, respectively) containing test compounds in a final dimethyl sulfoxide concentration of 1%. Cells were exposed to the test compounds for 18 h at 37 0 C, 5% CO 2 .
  • sAPP ⁇ microplates from Meso Scale Discovery were used and the assay was performed according to the manufacture's protocol. Briefly, 25 ⁇ L cell medium was transferred to a previously blocked MSD sAPP ⁇ microplate. The cell plate was saved for the ATP assay, as described below. The sAPP ⁇ was captured during shaking at RT for 1 hour, by antibodies spotted in the wells of the microplate. After multiple washes, SULFO-TAG labeled detection antibody was added (25 ⁇ L/well, final concentration InM) to the assay plate and the plate was incubated with shaking at RT for 1 hour. Following multiple washes, 150 ⁇ l/well of Read Buffer T was added to the plate. After 10 minutes at RT the plate was read in the SECTORTM Imager for electro-chemiluminescence.
  • MSD Meso Scale Discovery
  • the plate was used to analyze cytotoxicity using the ViaLightTM Plus cell 30 proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP.
  • the assay was performed according to the manufacture's protocol. Briefly, 50 ⁇ L cell lysis reagent was added per well. The plates were incubated at RT for 10 min. Two min after addition of 100 ⁇ L reconstituted ViaLightTM Plus ATP reagent, the luminescence was measured in a Wallac Victor 2 1420 multilabel counter.
  • the hERG-expressing Chinese hamster ovary Kl (CHO) cells described by (Persson, Carlsson, Duker, & Jacobson, 2005) were grown to semi-confluence at 37 °C in a humidified environment (5% CO 2 ) in F- 12 Ham medium containing L-glutamine, 10% foetal calf serum (FCS) and 0.6 mg/ml hygromycin (all Sigma- Aldrich). Prior to use, the monolayer was washed using a pre-warmed (37°C) 3 ml aliquot of Versene 1:5,000 (Invitrogen).
  • CHO-KvI.5 cells which were used to adjust the voltage offset on IonWorksTM HT, were maintained and prepared for use in the same way.

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Abstract

This invention relates to novel compounds having the structural formula (I) and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

Description

NEW COMPOUNDS 318
The present invention relates to novel compounds, their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention 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 o 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.
s 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 Cleaving Enzyme (BACE) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 0 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 5 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. 0
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 30 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 identity 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, WO05/058311 , WO05/097767,
WO06/041404, WO06/041405, WO06/0065204, WO06/0065277, US2006287294, WO06/138265, US20050282826, US20050282825, US20060281729, WO06/138217, WO06/138230, WO06/138264, WO06/138265, WO06/138266, WO06/099379, WO06/076284, US20070004786, US20070004730, WO07/011833, WO07/011810, US20070099875, US20070099898, WO07/049532).
The compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved hERG selectivity.
Disclosure of the invention
Provided herein are novel compounds of structural formula I:
/(R1L
HN f
[T -N I
Il V ^) N-,
/■ — s
Λ B )-(R2)π
^- — ^
Figure imgf000005_0001
I
(R4)c
A is independently selected from a 5, 6 or 7 membered heterocyclic ring optionally substituted with one or more R1;
B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one or more R2;
R1 is independently selected from halogen, cyano, nitro, OR6, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co-βalkylheteroaryl, Co-6alkylC3-6cycloalkyl, C0-6alkylC3- ecycloalkenyl, C0-6alkylC3-6cycloalkynyl, C0-6alkylC3-6heterocyclyl, NR6R7, CONR6R7, NR6(CO)R7, O(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6(SO2)R7, SO2R6, SOR6, OSO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co- όalkylheteroaryl, C0-6alkylC3-6cycloalkyl, Co-ealkylCs-όCycloalkenyl, Co-6alkylC3- 6cycloalkynyl, and C0-6alkylC3-6heterocyclyl may be optionally substituted with one or more C; or two R1 substituents may together with the atom to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more C;
R2, R3 and R4 are independently selected from halogen, cyano, nitro, OR6, C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylCs.gcycloalkyl, Co- 6alkylC3-6cycloalkenyl, C0-6alkylC3-6cycloalkynyl, Co-6alkylC3-6heterocyclyl, NR6R7, CONR6R7, NR6(CO)R7, 0(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6(SO2)R7, SO2R6, SOR6, OSO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-<;alkylC3-6cycloalkyl, Co-6alky IC3-6Cy cloalkenyl, Co-6alkylC3- 6cycloalkynyl and Co-6alkylC3-6heterocyclyl may be optionally substituted with one or more C; or two R2, R3 or R4 substituents may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more C;
R5 is independently selected from hydrogen, cyano, OR6, C1-6alkyl, C2.6alkenyl, C2-6alkynyl, Co-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylQ-gcycloalkyl, Co-6alkylC3- ecycloalkenyl, C0-6alkylC3-6cycloalkynyl, C0-6alkylC3,6heterocyclyl, CONR6R7, CO2R6, COR6, SO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylaryl, C0- 6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, C0-6alkylC3-
6cycloalkynyl, C0-6alkylC3-6heterocyclyl may be optionally substituted with one or more C;
C is independently selected from halogen, nitro, CN, OR6, C1-6alkyl, C2-6alkenyL C2-6alkynyl, C0.6alkylaryl, Co-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3- gcycloalkenyl, Co-6alkylC3-6cycloalkynyl, Co-όalkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifiuoromethoxy, NR6R7, CONR6R7, NR6(CO)R7, 0(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6SO2R7, SO2R6, SOR6, OSO2R6 and SO3R6, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0- galkylaryl, Co-βheteroaryl, Co-6alkylC3-6cycloalkyl, C0-6alkylC3-6cycloalkenyl, Co.6alkylC3- 6cycloalkynyl or Co-βalkylheterocyclyl may be optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR6, C1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;
R6 and R7 are independently selected.from hydrogen, C^aUcyl, Co-6alkylaryl, heteroaryl, C0-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC3-6cycloalkynyl, Co- 6alkylheterocyclyl, fluoromethyl, difluoromethyl and trifluoromethyl; or R6 and R7 may together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S;
m = 0, 1, 2 or 3; n = 0, 1, 2 or 3; p = 0, 1, 2 or 3; q= 0, 1, 2 or 3; as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
The present invention further provides pharmaceutical compositions comprising as active ingredient a therapeutically effective amount of a compound of formula I in association with pharmaceutically acceptable excipients, carriers or diluents.
The present invention further provides methods of modulating activity of BACE comprising contacting the BACE enzyme with a compound of formula I.
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 I.
The present invention further provides a compound described herein for use as a medicament. In one aspect of the present invention, there is provided a compound according to formula I, wherein R5 is hydrogen.
In another aspect of the present invention, there is provided a compound according to formula I, wherein A is selected from a 5 or 6 membered heterocyclic ring.
In another aspect of the present invention, there is provided a compound according to formula I, wherein m is 0.
In another aspect of the present invention, there is provided a compound according to formula I, wherein m is 1 or 2, wherein R1 is independently selected from halogen, cyano^ OR6, NR6(CO)R7, CO2R6, NR6(SO2)R7 and SO2R6.
In one embodiment of this aspect, R6 and R7 are independently selected from hydrogen, C1- ealkyl and trifluoromethyl.
In another aspect of the present invention, there is provided a compound according to formula I, wherein q is 0.
In another aspect of the present invention, there is provided a compound according to formula I, wherein B is selected from phenyl or pyridyl optionally substituted with one or more R2.
In one embodiment of this aspect, B is phenyl substituted with one R2.
In another embodiment of this aspect, B is phenyl substituted with one R2 selected from OR6 and OSO2R6.
In another embodiment of this aspect, B is phenyl substituted with one R2 selected from OR6 and OSO2R6 and R6 is Ci-6alkyl. In another aspect of the present invention, there is provided a compound according to formula I, wherein B is a 5 membered heteroaromatic ring optionally substituted with one R2.
In one embodiment of this aspect, R2 is C1-6alkyl.
In another aspect of the present invention, there is provided a compound according to formula I, wherein p is 1 or 2.
In one embodiment of this aspect, R3 is selected from halogen, cyano, nitro, OR6, C^alkyl, SO2R6 and OSO2R6 and wherein said C^alkyl, is optionally substituted with one or more C.
In another embodiment of this aspect, C is halogen.
In another embodiment of this aspect, R6 is C^alkyl or trifluoromethyl.
In another aspect of the present invention, there is provided a compound according to formula I, wherein A is independently selected from a 5 or 6 membered heterocyclic ring;
B is independently selected from phenyl or a 6 membered heteroaromatic ring optionally substituted with one R2;
R2 and R3 are independently selected from halogen, cyano, nitro, OR6, C1-6alkyl, SO2R6 and OSO2R6, wherein said C1-6alkyl, may be optionally substituted with one or more C; R5 is hydrogen;
C is halogen;
R6 is selected from, C1-6alkyl and trifluoromethyl; m = 0; n = 0 or 1; 0 p = 1 or 2; q = 0. In another aspect of the present invention, there is provided a compound according to formula I, wherein
A is independently selected from a 5 or 6 membered heterocyclic ring optionally substituted with one or more R1; B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one R2;
R1 is independently selected from halogen, cyano, OR6, NR6(CO)R7, CO2R6, NR6(SO2)R7 and SO2R6;
R2 and R3 are independently selected from halogen, OR6, C1-6alkyl and OSO2R6; R5 is hydrogen;
R6 and R7 are independently selected from hydrogen, Ci-βalkyl, and trifluoromethyl; m= 0, l or 2; n = 0 or 1; p = 1 or 2; q= 0.
In another aspect of the present invention, there is provided a compound according to formula I, wherein
A is a 6 membered heterocyclic ring substituted with two R1; B is a 6 membered heteroaromatic ring;
R1 is halogen;
R3 is independently selected from halogen and OR6;
R4 is halogen;
R5 is hydrogen; R6 is C1-6alkyl; m = 2; n = 0; p = 2; and q= l. 0
In another aspect of the present invention, there is provided a compound according to formula I, selected from: 8-(3'-Methoxybiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine hydrochloride;
8-(3'-Chlorobiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine hydrochloride; 4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate;
4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl propane- 1 -sulfonate 0.5 acetate;
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-{6-Amino-8-[3'-(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl}phenyl propane- 1 -sulfonate 0.5 acetate; 4-[6-Amino-8-(4'-fluoro-3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- o]pyrimidin-8-yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chloro-2'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(2',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3J4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropane sulfonate 0.75 acetate;
4-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropanesulfonate 0.75 acetate; 4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropane sulfonate 0.75 acetate;
4-{6-Amino-8-[31-(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl}phenyl cyclopropane sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chloro-2'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl cyclopropane sulfonate 0.75 acetate;
4-[6-Amino-8-(2',5'-dichlorobiphenyl-3-yl)-2,334,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropane sulfonate 0.5 acetate; 4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate acetate;
4-[6-Amino-8-(3'-cyanobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimiciin-8- yl]phenyl methanesulfonate acetate; 4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-a]pyrimidin-8- yl]phenyl methanesulfonate 0.25 acetate;
4-{6-Amino-8-[3'-(trifluoromethoxy)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl}phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(2'-fluoro-3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(2'-fluoro-5'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.25 acetate;
4-[6-Amino-8-(3l-ethoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate 0.5 acetate; 4-[6-Amino-8-(3'-nitrobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(2',5'-dimethoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-
8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(3'-cyano-4'-fluorobiphenyl-3-yl)-2:,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(5'-cyano-2'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.75 acetate;
4-[6-Amino-8-(3',51-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate acetate; 3l-[6-Amino-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]-5- methoxybiphenyl-3-yl methanesulfonate acetate;
3'-[6-Amino-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-(3]pyrimidm-8-yl]-5- chlorobiphenyl-3-yl methanesulfonate acetate;
4-[5-Amino-7-(3'-methoxybiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.25 acetate;
4-[5-Amino-7-(3',5'-dichlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.25 acetate; 4-[5-Ammo-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.5 acetate;
4-[5-Amino-7-(3'-methoxybiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl propane-2-sulfonate 0.5 acetate; 4-[5-Amino-7-(3',5'-dichlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl propane-2-sulfonate 0.5 acetate;
4-[5-Ammo-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H'-imidazo[l,5-«]imidazol-7- yl]phenyl propane-2-sulfonate 0.5 acetate;
3!-[5-Amino-7-(4-methoxyphenyl)-2,7-dihydro-3//-imidazo[l,5-«]imidazol-7-yl]-5- methoxybiphenyl-3-yl methanesulfonate acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5-a]pyrimidin-8-yl)-biphenyl-3- carbonitrile hydrochloride;
8-(3'-Methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine 0.25 acetate; 8-(3'-Chlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidm-6- amine 0.25 acetate;
8-(2'-Fluoro-3'-methoxybiphenyl-3-yl)-8-pyridm-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
8-(2'-Fluoro-5t-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2J3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-terrahydroimidazo[l,5-α]pyrimidm-8-yl)-6- fluorobiphenyl-3 -carbonitrile 0.25 acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-5- chlorobiphenyl-3-yl methanesulfonate 0.5 acetate; 3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-4- fluorobiphenyl-3-carbonitrile 0.25 acetate;
8-(3'-Chloro-2'-fiuorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
8-Pyridin-4-yl-8-[3'-(trifiuoromethyl)biphenyl-3-yl]-2,354,8-tetrahydroimidazo[l,5- a]pyrimidin-6-amine 0.25 acetate;
8-[3'-(Methylsulfonyl)biphenyl-3-yl]-8-ρyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate; 8-(3^5'-Dichlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-β]pyrimidin-
6-amine 0.25 acetate;
8-(3'-Chloro-5'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- fl]pyrimidin-6-amine 0.25 acetate; 8-(2',3f-Dichlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-
6-amine 0.25 acetate;
8-(3'-Ethoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-(5r]pyrimidin-6- amine 0.5 acetate;
8-(5I-Chloro-2'-fluorobiphenyl-3-yl)-8-pyridm-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
8-(4'-Fluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-fl]pyrimidin-8-yl)-5- methoxybiρhenyl-3-yl methanesulfonate 0.25 acetate; 8-(2'J5t-Dichlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3J4,8-tetrahydroimidazo[l,5-α]pyrimidin-
6-amine 0.25 acetate; and
8-(3'-Chloro-4'-fluorobiρhenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate.
In another aspect of the present invention, there is provided a compound according to formula I, selected from:
4-[5-Amino-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl trifluoromethanesulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- 5 yl]phenyl trifluoromethanesulfonate acetate;
8-(2'-Fluoro-5'-methoxybiphenyl-3-yl)-8-ρhenyl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine hydrochloride;
S-CS'-Chloro^'-fluorobiphenyl-S-y^-S-phenyl^^^jS-tetrahydroimidazotl^-^pyrimidin-
6-amine hydrochloride; 0 δ-CS'jS'-Dichlorobiphenyl-S-y^-S-phenyl^^^jδ-tetrahydroimidazofljS-αJpyrimidin-β- amine hydrochloride; 3'-(6-Amino-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyriniidin-8-yl)-5- methoxybiphenyl-3-yl methanesulfonate hydrochloride;
8-(3',5'-Dichlorobiρhenyl-3-yl)-8-(4-methoxyphenyl)-3-(methylsulfonyl)-2,3,458- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 2.0 acetate; 6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-3-ol;
8-(3',5'-Dichlorobiρhenyl-3-yl)-3-methoxy-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine;
6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- o tetrahydroimidazo[l ,5-α]pyrimidine-3-carbonitrile;
6-Amino-8-(3l J5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l ,5-α]pyrimidine-3-carboxylic acid;
N-[6-Ammo-8-(3l,5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-3-yl]acetamide; 5 N-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo [1 , 5-α]pyrimidin-3 -yl]methanesulfonamide ;
(41S)-6-Amino-8-(3',5'-dichlorobiρhenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l ,5-α]pyrimidine-4-carboxylic acid;
8-(3',5'-Dichlorobiρhenyl-3-yl)-3,3-difluoro-8-(4-methoxyphenyl)-2,3,4,8- 0 tetrahydroimidazo[l35-α]pyrimidin-6-amine 0.75 acetate;
3,3-Difluoro-8-(2l-fluoro-5'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 0.25 acetate;
3,3-Difluoro-8-(2'-fluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 0.75 acetate; 5 3,3-Difluoro-8-(3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 1.25 acetate;
8-(3',5'-Dichlorobiρhenyl-3-yl)-3-fluoro-8-(4-methoxyρhenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 1.5 acetate;
8r(3^5'-Dichlorobiρhenyl-3-yl)-8-(3-furyl)-2,3,4,8-tetrahydroimidazo[l,5-fl]pyrirnidin-6- 0 amine acetate;
8-(3^5'-Dichlorobiphenyl-3-yl)-8-(2-furyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine acetate; 8-(2-Furyl)-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine acetate;
8-(3',5'-Dichlorobiρhenyl-3-yl)-8-(2-methyl-l,3-thiazol-4-yl)-2,3,458- tetrahydroimidazo[l,5-α]pyrimidm-6-amine acetate; 8-(3',5'-Dichlorobiphenyl-3-yl)-8-(3-thienyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine acetate;
3-{6-Amino-8-[3',5'-bis(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidm-8-yl}phenyl methanesulfonate;
3-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl trifluoromethanesulfonate; δ-CS^'-Dichlorobiphenyl-S-yO-δ^B-methoxyphenyO^^^jδ-tetrahydroimidazotljS- α]pyrimidin-6-amine ; δ-CS'-Chlorobiphenyl-S-y^-δ^S-methoxyphenylJ^^^jδ-tetrahydroimidazofl^- α]pyrimidin-6-amine; 8-(3'-Methoxybiphenyl-3-yl)-8-(3-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine;
3-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate;
3-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate;
3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate;
3-[6-Amino-8-(3'55'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate; 3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl propane- 1 -sulfonate;
3-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropanesulfonate;
S-tβ-Amino-S-CS'-methoxybiphenyl-S-yO^^^^-tetrahydroimidazofljS-αJpyrimidin-δ- yljphenyl cyclopropanesulfonate;
S-tβ-Amino-δ-CS'^'-dichlorobiphenyl-S-y^^^^jS-tetrahydroimidazotljS-αjpyrimidin-δ- yljphenyl trifluoromethanesulfonate; 3-[6-Amino-8-(3'-niethoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl trifluoromethanesulfonate;
3'-[6-Amino-8-(3-methoxyphenyl)-2,354,8-tetrahydroimidazo[l,5-α]pyrimidm-8-yl]-5- methoxybiphenyl-3-yl methanesulfonate; S-Cβ-Amino-δ-CS'^'-dimethylbiphenyl-S-y^^^^^-tetrahydroimidazotl^-^pyrimidm-δ- yljphenyl methanesulfonate; and
8-(3',5'-Dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- σ]pyrimidin-6-amine.
In another aspect of the present invention, there is provided a compound according to formula I, said compound being:
3,3-Difluoro-8-(2',6-difluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l ,5-α]pyrimidin-6-amine acetate.
Some compounds of formula I may have stereogenic centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical isomers, enantiomers, diastereoisomers, atropisomers and geometric isomers.
The present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
It is to be understood that the present invention relates to any and all tautomeric forms of the compounds of formula I.
Compounds of the invention can be used as medicaments. In some embodiments, the present invention provides compounds of formula I, or pharmaceutically acceptable salts, tautomers or in vzvo-hydrolysable precursors thereof, for use as medicaments. In some embodiments, the present invention provides compounds described here in 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 use of compounds of formula I or pharmaceutically acceptable salts, tautomers or in vzvø-hydroly sable 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 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 0 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 I, or a pharmaceutically acceptable salt, tautomer or in vzvø-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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in v/vo-hydrolysable 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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in vzvø-hydrolysable precursors and a cognitive and/or memory enhancing agent. Cognitive enhancing agents, memory enhancing agents and choline esterase inhibitors includes, but not limited to, onepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine (Namenda, Axura or Ebixa).
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, presenile 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 I or a pharmaceutically acceptable salt, tautomer or in v/vo-hydrolysable precursors thereof wherein constituent members are provided herein, and a choline esterase inhibitor or anti-inflammatory agent.
0 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 0 active ingredient, one or more of the compounds of the invention herein together with at least one pharmaceutically acceptable carrier, diluent or excipent.
The definitions set forth in this application are intended to clarify terms used throughout this application. The term "herein" means the entire application. 5
A variety of compounds in the present invention may exist in particular geometric or stereoisomeric 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 0 the scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All 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, by synthesis from optically active starting materials, or synthesis using optically active reagents. 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 o separated isomeric forms. AU 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 s 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, positions of substituents and/or variables are permissible only if such combinations result in stable compounds. 0
As used in this application, the term "optionally substituted," 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 5 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 when a substituent is methyl (i.e., CH3), then 3 hydrogens on the carbon atom can be replaced. Examples of such substituents include, but are not limited to: halogen, CN, NH2, OH, SO, SO2, COOH, OCi- βalkyl, CH2OH, SO2H, C1-6alkyl, Od.6alkyl, C(=O)C1-6alkyl, C(=O)OCi-6aIkyl, o C(=O)NH2, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, SO2C1-6alkyl, SO2NHCi -6alkyl,
SO2N(C1-6alkyl)25 NH(Ci-6alkyl), N(C1-6alkyl)2, NHC(=O)C1-6alkyl, NC(=O)(C1-6alkyl)2, C5-6aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=O)NHC5-6aryl, Q=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- eheterocyclyl, C(=0)OC5-6heterocyclyl, C(=O)NHC5-6heterocyclyl, C(O)N(C5- 6heterocyclyl)2, SO2C5-6heterocyclyl, SO2NHC5.6heterocyclyl, S02N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, NC(=0)(C5. 6heterocyclyl)2.
As used herein, "alkyl", 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 "C0-6 alkyl" denotes alkyl having 0, 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, penryl, and hexyl. In the case where a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group s may be absent, i.e. there is a direct bond between the groups.
As used herein, "alkenyl" used alone or as a suffix or prefix is intended to include both branched and straight-chain alkene or olefin containing aliphatic hydrocarbon groups 0 having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "C2-6alkenyl" denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut- 1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. 5
As used herein, "alkynyl" used alone or as a suffix or prefix is intended to include both branched and straight-chain alkyne containing aliphatic hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "C2-6alkynyl" denotes alkynyl having 2, 3, 4, 5 or 0 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-ρroρynyl, 3-butynyl, -pentynyl, hexynyl and l-methylpent-2-ynyl. As used herein, "aromatic" refers to hydrocarbonyl groups having one or more unsaturated carbon ring(s) having aromatic characters, (e.g. 4n + 2 delocalized electrons) and comprising up to about 14 carbon atoms. In addition "heteroaromatic" refers to groups having one or more unsaturated rings containing carbon and one or more heteroatoms such as nitrogen, oxygen or sulphur having aromatic character (e.g. 4n + 2 delocalized electrons).
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 polycyclic, 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 5 one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. 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.
0 As used herein, the term "cycloalkyl" is intended to include 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. 5
As used herein, "cycloalkenyl" refers to ring-containing hydrocarbyl groups having at least one carbon-carbon double bond in the ring, and having from 4 to 12 carbons atoms.
As used herein, "cycloalkynyl" refers to ring-containing hydrocarbyl groups having at least 0 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 charged species such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, and the like.
As used herein, the term "heterocyclyl" or "heterocyclic" or "heterocycle" refers to a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 3 to 20 atoms of which 1, 2, 3, 4 or 5 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s) or a ring nitrogen is optionally quarternized; wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo. 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. If the said heterocyclyl group is bi- or tricyclic then at least one of the rings may optionally be a heteroaromatic or aromatic ring provided that at least one of the rings is non-heteroaromatic. If the said heterocyclyl group is monocyclic then it must not be aromatic. Examples of heterocyclyls include, but are not limited to, piperidinyl, N- acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, JV-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl and 2,5-dioxoimidazolidinyl.
As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, fluorenonyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl or heteroaromatic group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl or heteroaromatic 5 group has 1 heteroatom.
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 o 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 s 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.
o As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the 5 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 acid.
0 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 diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
5 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 properties of both a ketone and an unsaturated alcohol.
o 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. 5
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 0 occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 1231, 1241, 125I and 131I. The radionuclide that is incorporated in the instant radiolabeled compounds will depend on the specific application of that radio-labeled compound. 5 For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio- imaging applications 11C, 18F, 1251, 1231, 1241, 131I, 75Br, 76Br or 77Br will generally be most useful.
0 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 3H, 14C, 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: acetyl cholinesterase inhibitors, anti-inflammatory agents, cognitive and/or memory enhancing agents or atypical antipsychotic 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.
In some embodiments, the present invention provides a compound of formula I 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 o 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. s
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 0 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 5 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.
0 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+), 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. AU such salts are within the scope of this invention, and references to compounds include the salt forms of the compounds. 5
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. 0
Compounds containing an amine function may also form iV-oxides. A reference herein to a compound that contains an amine function also includes the iV-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an iV-oxide. Particular examples of iV-oxides are the iV-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.
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 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 β-amyloid angiopathy. It is expected that the compounds of the present invention would most likely be used as single agents but could also be used in combination with a broad range of cognition deficit enhancement agents.
Methods of Preparation
The present invention also relates to processes for preparing the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Protective Groups in Organic Synthesis by T.W. Greene, P.G.M Wutz, 3rd Edition, Wiley-Interscience, New York, 1999. It is understood that microwaves can be used for the heating of reaction mixtures.
Preparation of Intermediates The process, wherein A, B, C, R1, R2, R3, R4, R5, R6 and R7 unless otherwise specified, are as hereinbefore defined, comprises,
(i) reaction of a compound of formula II and a compound of formula III, to obtain a compound of formula IV, wherein R8 is hydrogen or a suitable protecting group such as fert-butoxycarbonyl. Rf + H ^ H H S H
O=S=O I
II III IV
The reaction may be carried out by treating the compound of formula III with an appropriate tiolate or an appropriate thiol together with a suitable base such as sodium hydride, triethylamine or sodium hydroxide. The reactions may be preformed in a suitable solvent such as ethanol, N,N-dimethylformamide or tetrahydrofuran at a temperature between O 0C and reflux.
(ii) oxidation of a compound of formula IV to obtain a compound of formula V, wherein R8 is defined as in (i) above.
R8-N^^N-R8 R8-N^^N-R8
R6 R6
IV V
The reaction may be carried out by oxidation using an appropriate oxidizing agent such as 3-chloroperoxybenzoic acid or hydrogen peroxide. The reactions may be preformed in a suitable solvent such as dicholormethane, N,N-dimethylformamide or acetic acid, at a temperature between 0 °C and reflux.
(iii) reaction of a compound of formula VI to obtain a compound of formula VII, wherein R8 is defined as in (i) above
RV IN,/\ T^ IM,/R8 RV u,^ T^^ . N LJ,/R8
L R6 R6 T R7
VI VII
The reaction may be carried out by treating the compound of formula VI with a suitable acylating reagent such as an anhydride e.g. acetic anhydride or an acyl chloride e.g. acetyl chloride, in a suitable solvent such as diethylether, dichloromethane, ethyl acetate or 25 toluene at a temperature between -20 °C and reflux. The reaction is advantageously effected by the precense of a base. A suitable base may be pyridine, potassium carbonate or potassium hydroxide.
(iv) reaction of a compound of formula VIII and a compound of formula IX, to obtain a compound of formula X wherein R8 is defined as in (i) above
R7—s-CI + H I H H J H
Re O \R7
VIII IX X
The reaction may be carried out by treating the compound of formula IX with an appropriate sulfonylchloride such as a compound of formula VIII together with a suitable o base such as triethylamine, pyridine or sodium hydroxide. The reactions may be preformed in a suitable solvent such as diethylether, tetrahydrofuran or dichloromethane at a temperature between - 50 °C and reflux.
(v) diazotization of a compound of formula XI to obtain a compound of formula XII, s wherein halo represents bromine or chloride.
-NH2 *■ L C -}— halo
(R3); "
Figure imgf000035_0001
XI XII
0 The reaction may be carried out by treating an appropriate amine with nitrous acid followed by treating the formed diazonium salt with an appropriate cuprous halide such as copper(I) bromide or copper(I) chloride, or with copper and hydrobromic acid or hydrochloric acid. The reactions may be preformed in a suitable solvent such as water at a temperature between —20 °C and reflux. S
(vi) borylation of a compound of formula XII, wherein halo represents halogen such as bromine or chlorine, to obtain a compound of formula XIII, wherein R9 represents hydrogen, alkyl, aryl or two R9 may form a cyclic boronic ester. O— R9 halo
Figure imgf000036_0002
O— R9
Figure imgf000036_0001
(R3),
XII XIII
The reaction may be carried out by: a) an alkyllithium such as butyllithium, or magnesium, and a suitable boron compound such as trimethyl borate or triisopropyl borate. The reaction may be performed in a suitable solvent such as tetrahydrofuran, hexane or dichloromethane in a temperature range between -78 0C and +200C; or, b) a suitable boron species such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1,3,2- dioxaborolane, biscatecholatodiboron, or pinacolborane in the presence of a suitable palladium catalyst such as tris(dibenzylideneacetonedipalladium)(O), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, palladium(O) tetrakistriphenylphosphine, palladium diphenylphosphineferrocene dichloride or palladium acetate, with or without a suitable ligand such as tricyclohexylphosphine or 2- (dicyclohexylphosphino)biphenyl, and a suitable base, such as a tertiary amine, such as trietylamine or diisopropylethylamine, or potassium acetate may be used. The reaction may be performed in a solvent such as dioxane, toluene, acetonitrile, water, ethanol or 1,2- dimethoxyethane, or mixtures thereof, at temperatures between 20 0C and +1600C.
(vii) reaction of a compound of formula XIV wherein halo represents halogen e.g. bromide, R10 is aryl or heteroaryl, and a compound of formula XV wherein R11 is aryl or heteroaryl, to obtain a compound of formula XVI.
RIO y Halo ' Z?
R11' B -HR2)n
Figure imgf000036_0003
XIV XV XVI The reaction may be carried out by treating the compound of formula XIV with an alkyllithium, such as butyllithium, or magnesium followed by addition of a compound of formula XV. The reaction may be preformed in a suitable solvent such as diethyl ether or tetrahydrofuran at a temperature between -78 °C and reflux.
(viii) reaction of a compound of formula XVI to obtain a compound of formula XVII
B t-(R2)π (R2)n
Figure imgf000037_0001
Figure imgf000037_0002
XVI XVII
The reaction may be carried out by reduction using an appropriate reducing agent such as sodium borohydride, cyanoborohydride or lithium aluminium hydride. The reaction may be preformed in a suitable solvent such as methanol, ethanol, diethyl ether or tetrahydrofuran at a temperature between -78 0C and reflux.
(ix) reaction of a compound of formula XVII to obtain a compound of formula XVIII
-^s
B -HR2)n B -MR2)n
Figure imgf000037_0003
Figure imgf000037_0004
XVII XVIII
The reaction may be carried out by treating a compound of formula XVII with a suitable thiocarbonyl transfer reagent such as 0,Odipyridine-2-yl thiocarbonate or thiophosgene. The reaction may be preformed in a suitable solvent such as dichloromethane or chloroform at a temperature between -78 °C and reflux.
(x) reaction of a compound of formula XVIII to obtain a compound of formula XIX.
Figure imgf000038_0001
Figure imgf000038_0002
XVIII XIX
The reaction may be carried out by treating the appropriate isothiocyanate such as a compound of formula XVIII and carbon disulfide with a suitable base such as potassium fert-butoxide in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature between -78 0C and reflux.
(xi) reaction of a compound of formula XIX to obtain a compound of formula XX
Figure imgf000038_0003
Figure imgf000038_0004
XIX XX
The reaction may be carried out by treating a compound of formula XIX with an appropriate diamine such as diamines described in Tetrahedron 1994, 50(29), 8617 and 1995, 51(10), 2875 or diamines such as compounds of formula V, VII and X. The reaction may be preformed in a suitable solvent such as ethanol or methanol at a temperature between 0 °C and reflux.
(xii) reaction of a compound of formula XX to obtain a compound of formula XXI.
(R2)π
Figure imgf000038_0005
Figure imgf000038_0006
XX XXI
The reaction may be carried out by treating the appropriate thione such as a compound of formula XX with an appropriate oxidazing agent such as tert-butyl hydroperoxide and aqueous ammonia. The reaction may be performed in a suitable solvent such as methanol at a temperature between 0 0C and reflux.
(xiii) reaction of a compound of formula XXII wherein D is ring B or a phenyl in formula I, to a compound of formula XXIII.
f D VoCH3 ^ C D V-C
xxπ XXIIi
The reaction may be carried out by treating the methyl ether with a suitable Lewis acid such as boron tribromide in a suitable solvent such as dichloromethane at a temperature between -78 °C and reflux.
(xiv) reaction of a compound of formula XXIII, wherein D is ring B or a phenyl in formula I5 to a compoud of formula XXIV, wherein R11 is alkyl. 0
(D^-OH Q)-o^\
XXIII XXIV
The reaction may be carried out by treating the appropriate alcohol with a suitable sulfonyl s chloride or anhydride such as methanesulfonyl chloride, 1-propanesulfonyl chloride, cyclopropanesulfonyl chloride or methanesulfonic anhydride in the presence of a suitable base such as triethylamine. The reaction may be carried out in a suitable solvent such as dichloromethane at a temperature between 0 °C and reflux. Or the reaction may be carried out by treating the appropriate alcohol with 1,1,1-trifluoro- iV-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide in the presence of a suitable base such as potassium carbonate, triethylamine or N-ethyldiisopropylamine. The reaction may be carried out in a suitable solvent such as dichloromethane or tetrahydrofuran at a temperature between 0 0C and +160 0C.
(xv) reaction of a compound of formula XXV, wherein D is ring B or a phenyl in formula I, to a compoud of formula XXVT.
( D VOH ( D j-OCH3
XXV XXVI
The reaction may be carried out by treating the appropriate alcohol with a suitable base such as sodium hydride followed by addition of a suitable alkyl halide such as s iodomethane. The reaction may be preformed in a suitable solvent such as tetrahydrofuran at a temperature between —78 °C and reflux.
Methods of Preparation of End products 0 Another obj ect of the invention is the process a for the preparation of compounds of general Formula I, wherein A, B, C, R1, R2, R3, R4, R5, R6 and R7 unless otherwise specified, are defined as hereinbefore, and salts thereof. When it is desired to obtain the acid salt, the free base may be treated with an acid such as a hydrogen halide such as hydrogen chloride in a suitable solvent such as tetrahydrofuran, diethyl ether, methanol, 5 ethanol, chloroform or dichloromethane or mixtures thereof and the reaction may occur between -30 0C to +50 0C.
reaction of a compound of formula XXVTI, wherein halo represents a halogen such as bromine, to obtain a compound of formula I.
30 H2N.
(R2)π
(R3)P
Figure imgf000041_0001
Figure imgf000041_0002
XXVII XIII
The reaction may be carried out by coupling of a suitable compound such as a compound of formula XXVII with an appropriate aryl boronic acid or ester of formula XIII wherein R9 represents hydrogen, alkyl, aryl or two R9 may form a cyclic boronic ester. The reaction may be carried out using a suitable palladium catalyst such as, [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, 0 tetrakis(triphenylphosphine)palladium(0), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0), together with, or without, a suitable ligand such as triphenylphosphine, tri-Ztert-butylphosphine or 2- (dicyclohexylphosphino)biphenyl, or using a nickel catalyst such as nickel on charcoal or l,2-bis(diphenylphosphino)ethanenickel dichloride together with zinc and sodium s triphenylphosphinetrimetasulfonate. A suitable base such as cesium fluoride, an alkyl amine such as triethyl amine, or an alkali metal or alkaline earth metal carbonate or hydroxide such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydroxide may be used in the reaction, which may be performed in a temperature range between +20 0C and +160 0C, in a suitable solvent such as toluene, tetrahydrofuran, 0 dioxane, dimethoxyethane, water, ethanol or ^N-dimethylformamide, or mixtures thereof.
General Methods
Starting materials used were available from commercial sources, or prepared according to literature procedures. 5
1H NMR spectra were recorded in the indicated deuterated solvent, using a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1H equipped with a 4-nucleus probehead with Z-gradients or a Bruker av400 NMR spectrometer operating at 400 MHz 1H equipped with a 3mm flow injection SEI 1HTD-13C probehead with Z-gradients, using a BEST 215 liquid handler for sample injection. Chemical shifts are given in ppm. Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet, and broad respectively.
LC-MS analyses were performed on an LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZMD single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer was scanned between m/z 100-600 by a scan time of 0.7s. The diode array detector was scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 °C and the pressure was set to 1.9 bar. For separation a linear gradient was applied starting at 100% A (A: 10 mM ammonium acetate in 5% acetonitrile) and ending at 100% B (B: acetonitrile). The column used was an X-Terra MS C8, 3.0 mm x 50 mm, 3.5 μm (Waters) run at a flow rate of 1.0 mL/min. The column oven temperature was set to 40 °C, or
LC-MS analyses were performed on a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3s. The diode array detector scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 0C and the pressure was set to 1.9 bar. Separation was performed on an X-Terra MS C8, 3.0 mm x 50 mm, 3.5 μm (Waters) run at a flow rate of 1 mL/min. A linear gradient was applied starting at 100% A (A: 10 mM ammonium acetate in 5% acetonitrile or 8 mM formic acid in 5% acetonitrile) ending at 100% B (B: acetonitrile). The column oven temperature was set to 40 °C, or
30 LC-MS analyses were performed on a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 85 ELS detector and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer scanned between m/z 100-700 with a scan time of 0.3s. The diode array detector scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 °C and the pressure was set to 1.9 bar. Separation was performed on an X-Terra MS C8, 3.0 mm x 50 mm, 3.5 μm (Waters) run at a flow rate of 1 rnL/min. A linear gradient was applied starting at 100% A (A: 1OmM ammonium acetate in 5% acetonitrile, or 8 mM formic acid in 5% acetonitrile) ending at 100% B (B: acetonitrile). The column oven temperature was set to 40 °C, or
LC-MS analyses were preformed on a Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; Acquity UPLC™ BEH C8 1.7μm 2.1 x 50mm. The column temperature was set to 650C. A linear 2 min gradient from 100% A (A: 95% 0.0 IM ammonium acetate in MiUiQ water and 5% acetonitrile) to 100% B (5% 0.01 M ammonium acetate in MiUiQ water and 95% acetonitrile) was applied for LC-separation at flow rate 1.2 mL/min. The PDA was scanned from 210-350nm and 254nm was extracted for purity determination. The ZQ mass spectrometer was run with ES in pos/neg switching mode. The Capillary Voltage was 3kV and the Cone Voltage was 30V, or LC-MS analyses were preformed on a Waters LCMS consisting of an Alliance 2690 o Separations Module, Waters 2487 Dual 1 Absorbance Detector (220 and 254 nm) and a Waters ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and cone voltage was 30 V. The mass spectrometer was scanned between m/z 97-800 with a scan time of 0.3 or 0.8 s. Separations were performed 5 on a Chromolith Performance RP-18e (100 x 4.6 mm). A linear gradient was applied starting at 95% A (A: 0.1% formic acid (aqueous)) ending at 100% B (acetonitrile) in 5 minutes. Flow rate: 2.0 mL/min or
LC-MS analyses were performed on a LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single 0 quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device. The mass spectrometer scanned in the positive mode, switching between APCI and APPI mode. The mass range was set to m/z 120-800 using a scan time of 0.3 s. The APPI repeller and the APCI corona were set to 0.86 kV and
5 0.80 μA, respectively. In addition, the desolvation temperature (3000C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode. Separation was performed using a Gemini column C18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) and run at a flow rate of 1 ml/min. A linear gradient was used starting at 100 % A (A: 10 mM ammonium acetate in 5% methanol) and ending at 100% B (methanol). The column oven o temperature was set to 40 0C.
GC-MS: Compound identification was performed on a GC-MS system (GC 6890, 5973N MSD) supplied by Agilent Technologies. The column used was a VF-5 MS, ID 0.25 mm x 15m, 0.25 μm (Varian Inc.). A linear temperature gradient was applied starting at 40 °C s (hold 1 min) and ending at 300 0C (hold 1 min), 25 °C/minute. The mass spectrometer was equipped with a chemial ionisation (CI) ion source and the reactant gas was methane. The mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV. The mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.25 scan/s, or 0 Compound identification was performed on a GC-MS system (GC 6890, 5973N MSD) supplied by Agilent Technologies. The mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH. The mass spectrometer was configured with a chemical ionisation (CI) ion source and the reactant gas was methane. The mass spectrometer was equipped with an electron impact (EI) ion source and the 5 electron voltage was set to 70 eV. The mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.25 scan/s. A linear temperature gradient was applied starting at 40 °C (hold 1 min) and ending at 300 0C (hold 1 min), 25 °C/minute. The column used was a VF-5 MS, ID 0.25 mm x 30m, 0.25 μm (Varian Inc.).
30 Preparative-HPLC: Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 μm. Gradient with acetonitrile/0.1 M ammonium acetate in 5 % acetonitrile in MiIIiQ Water. Flow rate: 20 mL/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV-vis.-detector equipped with a Waters Symmetry® column (C18, 5 μm, 100 mm x 19 mm). Gradient with acetonitrile/0.1% trifluoroacetic acid in MiIIiQ Water. Flow rate: 10 mL/min.
Alternatively, another column was used; Atlantis C18 19 x 100 mm, 5 μm column. Gradient with acetonitrile/0.1 M ammonium acetate in 5% acetonitrile in MiIIiQ Water. Flow rate: 15 mL/min, or Preparative-HPLC was run on a Waters FractionLynx system with a Autosampler combined Automated Fraction Collector (Waters 2767), Gradient Pump (Waters 2525), Regeneration Pump (Waters 600), Make Up Pump (Waters 515), Waters Active Splitter, Column Switch (Waters CFO), PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; XBridge™ Prep C8 5μm OBD™ 19 x 100mm, with guard column; XTerra ® Prep MS C8 10μm 19 x 10 mm Cartridge. A gradient from 100% A (95% 0.1 M ammonium acetate in MiIIiQ water and 5% acetonitrile) to 100% B (100% acetonitrile) was applied for LC-separation at flow rate 25 mL/min. The PDA was scanned from 210- 350 nm. The ZQ mass spectrometer was run with ES in positive mode. The Capillary Voltage was 3kV and the Cone Voltage was 30V. Mixed triggering, UV and MS signal, determined the fraction collection.
Microwave heating was performed in a Creator or Initiaror or Smith Synthesizer Single- mode microwave cavity producing continuous irradiation at 2450 MHz.
Thin layer chromatography (TLC) was performed on Merch TLC-plates (Silica gel 60 F254) and UV visualized the spots. Column chromatography was performed on a Combi Flash® Companion™ using RediSep™ normal-phase flash columns or using Merck Silica gel 60 (0.040-0.063 mm).
Compounds have been named using ACD/Name, version 8.0 or 9.0, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON5 Canada, www.acdlabs.com, 2004 and 2005. EXAMPLES
Below follows a number of non-limiting examples of compounds of the invention.
Example 1
4-Bromo- 1 -fluoro-2-methoxvbenzene
Figure imgf000046_0001
F
Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0 - 5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 0C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d«j): δ 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) 0 >«/z 204, 206 [M+»].
Example 2 2-(4-Fluoro-3-methoxvphenvlV4,4,5.5-tetramethvl-1.3,2-dioxaborolane
Figure imgf000046_0002
Anhydrous 1,2-dimethoxy ethane (12 mL) was added to 4-bromo-l-fluoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol) and 5 the resulting mixture was irradiated in a microwave at 150 °C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+*].
Example 3 o 3-Methoxv-5-f4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-vl)phenol
Figure imgf000047_0001
^O ^^ OH
The title compound was synthesized as described for example 2 in 48% yield starting from 3-chloro-5-methoxyphenol. Purified by column chromatography, using a gradient of dichloromethane/acetonitrile (100/0 to 90/10) as the eluent: 1H-NMR (DMSOd6): δ 9.36 s (s, 1 H), 6.69 (d, J = 2.3 Hz, 1 H), 6.61 (d, J = 2.0 Hz, 1 H), 6.41 (t, J = 2.4 Hz, 1 H)5 3.69 (s, 3 H), 1.27 (s, 12 H); MS (ES) m/z 251 [M+lf.
Example 4 3-methoxv-5-(4.4,5,5-tetramethvl-l,3,2-dioxaborolan-2-yl')phenvl methanesulfonate
0
Figure imgf000047_0002
To a stirred solution of 3-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (0.12 g, 0.48 mmol) in dichloromethane (3 mL) was added triethylamine (0.058 g, 0.58 mmol) followed by methanesulfonyl chloride (0.071 g, 0.62 mmol) at 0 °C under an atmosphere of argon. The reaction mixture was allowed to reach ambient temperature and stirred for 18 h and the resulting mixture was concentrated to dryness in vacuo. Purified by column chromatography, using a gradient of dichloromethane/acetonitrile (100/0 to 90/10) as the eluent, to give 0.050 g (32% yield) of the title compound: 1H-NMR (CDCl3): δ 7.30 (d, J = 2.3 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 6.96 (t, J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.16 (s, 3 H), 1.35 (s, 12 H); MS (ES) m/z 329 [M+l]+.
Example 5 3-Chloro-5-f4.4.5.5-tetramethvl-1.3.2-dioxaborolan-2-vDphenol
/ \
Figure imgf000048_0001
cr ^ OH
3-Bromo-5-chlorophenol (5 g, 19.9 mmol, described in: Maleczka R. E. et. al. J. Am.
Chem. Soc. 2003, 125, 7792-7793), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi~l,3,2- dioxaborolane (6.06 g, 23.9 mmol), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (487 mg, 0.6 mmol), potassium acetate (5.86 g, 59.7 mmol), 1,2-dimethoxyethane (60 mL) and water (4 mL) were divided into four microwave vials and irradiated in a microwave at 150 °C for 15 min each. When cooled to ambient temperature the mixtures were pooled, diluted with brine and extracted with diethyl ether.
The combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Purified by column chromatography, using a gradient with 0-5% acetonitrile in dichloromethane as the eluent, to give 1.43 g (28% yield) of the title compound: 1H NMR
(DMSO-J6) δ 9.89 (s, 1 H), 7.02 (s, 2 H), 6.91 (s, 1 H), 1.28 (s, 12 H); MS (ES) m/z 253
[M-I]-.
Example 6 3 -Chloro-5 -(4,4,5,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-vDρhenvl methanesulfonate / T
cr
Figure imgf000049_0001
Methanesulfonyl chloride (122 μL, 0.79 mmol) was added dropwise at 0 °C to a mixture of 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.79 mmol) and triethylamine (0.4 mL, 3.14 mmol) in dry dichloromethane (1.5 mL). The reaction mixture was stirred for 1 h at ambient temperature after which it was diluted with dichloromethane (10 mL), washed with water, dried over sodium sulfate and concentrated in vacuo to give 0.200 g (86% yield) of the crude title compound: 1H NMR (CDCl3) δ 7.75 (d, J= 1.52 Hz, 1 H), 7.57 (d, J= 1.77 Hz, 1 H), 7.41 (t, J= 2.15 Hz, 1 H), 3.18 (s, 3 H), 1.35 (s, 12 H); MS (EI) m/z 332 [M+*].
Example 7 2-(3-Chloro-5-methoxvphenvl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane
^ /
Figure imgf000049_0002
3-Chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.79 mmol) in 5 dry tetrahydrofuran (1.5 mL) was added dropwise to a slurry of sodium hydride in dry tetrahydrofuran (0.5 mL). The mixture was stirred for 10 min and iodomethane (147 μL, 2.36 mmol) was added. The obtained mixture was stirred overnight. Saturated aqueous ammonium chloride (1 mL) was added and the product was extracted with dichloromethane (20 mL). The organic phase was washed with brine, dried over sodium 0 sulfate and concentrated in vacuo to give 0.170 g (90% yield) of the crude title compound: 1H NMR (CDCl3) δ 7.38 (d, J= 1.26 Hz, 1 H), 7.20 (d, J= 2.02 Hz, 1 H), 7.02 - 6.98 (m, 1 H), 3.83 (s, 3 H), 1.35 (s, 12 H); MS (EI) m/z 268 [M+.]. Example 8
1 -(3 -Bromophenyl)- 1 -(4-methoxyphenvl)methanamine
Figure imgf000050_0001
4-Bromoanisole (5.3 g, 28.4 mmol) in dry tetrahydrofuran (25 mL) was added dropwise to a mixture of magnesium (0.69 g, 28.4 mmol) and a crystal of iodide in dry tetrahydrofuran (25 mL) at 50 °C. The mixture was stirred for 5 h and then cooled to room temperature. 3- Bromobenzonitrile (3.5 g, 19 mmol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min and the mixture was heated at 60 °C for 16 h. The mixture was cooled to room temperature and dry methanol (25 mL) was added and the mixture was stirred for another 45 min. The mixture was cooled to 0 0C and sodium borohydride (1.4 g, 38 mmol) was added in portions over 15 min, the mixture was then allowed to reach room temperature and stirred for 4 h. Saturated aqueous ammonium chloride was added and most of the organic solvents were removed in vacuo. The residue was extracted with dichloromethane. The organics were dried over sodium sulfate, filtrated and evaporated. Purification by column chromatography, using ethyl acetate from 10 - 35 % in n-heptane as the eluent, afforded 4.5 g (81% yield) of the title compound: 1H NMR (DMSO-J6) 5 7.59 - 7.57 (m, 1 H), 7.37 - 7.33 (m, 2 H), 7.30 - 7.26 (m, 2 H), 7.25 - 7.20 (m, 1 H), 6.86 - 6.82 (m, 2 H), 5.03 (s, 1 H), 3.70 (s, 3 H), 2.31 (br s, 2 H); MS m/z (CI) 291, 293 [M+l]+.
Example 9 l-(3-Bromophenyl)-l-phenylmethanamine NH,
Figure imgf000050_0002
Br
3-Bromobenzonitrile (10.92 g, 60 mmol) was added to a solution of bromo(phenyl)magnesium (24 mL, 72 mmol) in dry tetrahydrofuran (25 mL) at ambient 25 temperature under an atmosphere of argon. The resulting mixture was stirred at 60 °C for 4 h, then cooled to 0 °C and dry methanol (60 mL) was added. Sodium borohydride (5.68 g, 150 mmol) was added in three portions at 0 °C under an atmosphere of argon and the resulting mixture was allowed to reach ambient temperature and stirred for 1.5 h. The reaction was quenched by addition of a saturated aqueous solution of ammonium chloride. The mixture was diluted with dichloromethane and the organic phase separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were concentrated to give 17.1 g (quantitative yield) of the title compound: MS (EI) m/z 261, 263 [M+lf.
Example 10 l-(3-Bromophenvl)-l-pvridin-4-vlmethanamine
■M
Figure imgf000051_0001
Br
Butyllithium (2.5 M in hexanes, 10.20 mL, 25.40 mmol) was added to a cooled (-78 °C) solution of 1,3-dibromo-benzene (6 g, 25.40 mmol) in dry diethyl ether (60 mL), under an atmosphere of argon. The obtained mixture was stirred for 1 h at -78 °C. 4-Cyanopyridine (2.64 g, 25.40 mmol) in dry diethyl ether (45 mL) was added and the stirring was continued for 20 min at -78 °C. The reaction mixture was allowed to attain the ambient temperature and dry methanol (30 mL) was added and the resulting mixture was stirred for another 45 min. The solution was cooled to 0 °C, sodium borohydride (1.3 g, 34.0 mmol) was added and the reaction stirred overnight at ambient temperature. Saturated aqueous ammonium chloride (40 mL) was carefully added and the mixture was concentrated. The aqueous phase was extracted twice with dichloromethane (40 mL), the organic phase was dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography, using chloroform: methanol 0-10% gradient as the eluent, to give 4.22 g (63% yield) of the title compound: 1R NMR (CDCl3) δ 8.56 (add, J= 4.55, 1.52 Hz, 2 H), 7.54 (t, J= 1.77 Hz, 1 H), 7.40 (dt, J= 7.83, 1.52 Hz, 1 H), 7.33 - 7.24 (m, 3 H), 7.20 (t, J = 7.83 Hz, 1 H), 5.15 (s, 1 H), 1.78 (br s, 2 H); MS (ES) m/z 264, 266 [M+lf.
Example 11 l-Bromo-3-fisothiocvanato(4-methoxvτ3henyl)methyl1benzene s^
Figure imgf000052_0001
Thiophosgene (1.3 mL, 17 mmol) was added in portions to a stirred solution of l-(3- bromophenyl)-l-(4-methoxyphenyl)methanamine (4.5 g, 15.4 mmol) in dichloromethane (70 mL) and saturated aqueous sodium bicarbonate (40 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The organics were collected and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtrated and concentrated in vacuo to give 5.02 g (98% yield) of the title compound: 1H NMR (DMSO-^6) δ 7.57 - 7.52 (m, 2 H), 7.41 - 7.37 (m, 2 H), 7.34 - 7.30 (m, 2 H), 6.99 - 6.95 (m, 2 H), 6.48 (s, 1 H), 3.75 (s, 3 H).
Example 12 l-Bromo-3-ri'sothiocyanato(phenvDmethvllbenzene
Figure imgf000052_0002
The title compound was prepared as described for Example 11 in quantitative yield starting from l-(3-bromophenyl)-l-phenylmethanamine: MS (ESI) m/z 302, 304 [M-I]'.
Example 13
4-[(3-Bromophenyl)('isothiocvanato)methvl1pyridine S-.
Figure imgf000052_0003
20 O,O-Dipyridin-2-yl thiocarbonate (183 mg, 0.79 mmol; described in: Kim S. et al.
Tetrahedron Lett. 1985, 26(13), 1661-1664) was added, in one portion, to a solution of 1- (3-bromophenyl)-l-pyridin-4-ylmethanamine (100 mg, 0.38 mmol) in dichloromethane (2 mL). The mixture was stirred for 30 min and was then diluted with dichloromethane (15 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo to give 0.100 g (86% yield) of the crude product: MS (ES) m/z 305, 307 [M+l]+.
Example 14 4-r3-Bromophenvl)-4-(4-methoxvphenvl)-l,3-thiazolidine-2,5-dithione
Figure imgf000053_0001
l-Bromo-3-[isothiocyanato(4-methoxyphenyl)methyl]benzene (8.7 g, 26 mmol) and carbon disulfide (3.1 mL, 52 mmol) in dry tetrahydrofuran (30 mL) was added dropwise to a stirred mixture of potassium tert-butoxide (4.2 g, 37 mmol) in dry tetrahydrofuran (80 mL) at -78 °C. After the addition the mixture was allowed to reach room temperature overnight. Water, brine and ethyl acetate was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 10.5 g (98% yield) of the title product: 1H NMR (DMSO-J6) δ 7.48 - 7.43 (m, 1 H), 7.41 - 7.39 (m, 1 H), 7.31 - 7.24 (m, 2 H), 7.22 - 7.18 (m, 2 H), 6.89 - 6.85 (m, 2 H), 3.74 (s, 3 H).
Example 15 4-(3-BromophenylV4-phenyl-l,3-thiazolidine-2,5-dithione S.
Figure imgf000053_0002
Br
The title compound was prepared as described for Example 14 in quantitative yield starting from l-bromo-3-[isothiocyanato(phenyl)methyl]benzene: MS (ES) m/z 380, 382 [M+l]+. Example 16 4-r3-Bromo-phenvlV4-pyridin-4-vl-thiazolidine-2.5-dithione
Figure imgf000054_0001
Br 4-[(3-Bromophenyl)(isothiocyanato)methyl]pyridine (4.63 g, 15.19 mmol) and carbon disulfide (1.82 mL, 30.38 mmol) in dry tetrahydrofuran (30 mL) was added dropwise, at - 78 °C, to a stirred solution of potassium fert-butoxide (2.56 g, 22.79 mmol) in dry tetrahydrofuran (60 mL). The mixture was allowed to attain ambient temperature while stirring overnight. The solvent was evaporated and the residue dissolved in ethyl acetate (100 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography, using chloroform: methanol 0-10% gradient as the eluent, gave 4.95 g (85% yield) of the title compound: MS (ES) m/z 382, 383 [MH-I]+.
Example 17 δ-rS-BromophenvD-S-^-methoxvphenyD-S^J.δ-tetrahvdroimidazofLS-αipyrimidine- 6(2HVthione
Figure imgf000054_0002
A solution of 4-(3-bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (7 g, 15 mmol) and 1,3-diaminopropane (3.3 g, 44 mmol) in ethanol (70 mL) was heated at 70 0C for 1.5 h. The mixture was cooled to room temperature and concentrated, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. Purification by column chromatography, using ethyl acetate from 5 - 25 % in rø-heptane as the eluent, afforded 5.1 g (83% yield) of the title compound: 1HNMR (DMSO-J6) δ 10.82 (s, 1 H), 7.54 - 7.51 (m, 2 H), 7.44 - 7.41 (m, 1 H), 7.37 - 7.33 (m, 1 H), 7.27 - 7.23 (m, 2 H), 6.96 - 6.92 (m, 2 H), 3.74 (s, 3 H), 3.74 - 3.70 (m, 2 H), 3.49 - 3.44 (m, 2 H), 1.80 - 1.73 (m, 2 H).
Example 18 5 S-fS-BromophenvD-S-phenyl-S^J^-tetrahydroimidazorLS-glpyrimidine-ό^Hl-thione
Figure imgf000055_0001
Br
The title compound prepared as described for Example 17 in 90% yield starting from 4-(3- bromoρhenyl)-4-phenyl-l,3-miazolidώe-2,5-dithione: MS (ES) m/z 386, 388 [M+l]+.
o Example 19
8-(3-Bromorjhenvl)-8-pvridin-4-vl-3,4J,8-tetrahvdroimidazori,5-αlρyrimidine-6(2H)-
Figure imgf000055_0002
Br A mixture of 4-(3-bromo-phenyl)-4-pyridin-4-yl-thiazoIidine-2,5-dithione (1.99 g, 5.22 s mmol) and 1,3-diaminopropane (1.31 mL, 15.66 mmol) in ethanol (40 mL) was heated overnight at 70 0C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography, using chloroform: methanol 0-10% gradient as the eluent, gave 1.59 g 0 (79% yield) of the title compound: 1H NMR (CDCl3) δ 8.89 (s, 1 H), 8.64 (dd, J= 4.55, 1.77 Hz, 2 H), 7.58 - 7.50 (m, 2 H), 7.38 - 7.31 (m, 3 H), 7.29 - 7.25 (m, 1 H), 3.92 (t, J- 6.06 Hz, 2 H), 3.65 (q, J= 5.64 Hz, 2 H), 2.01 - 1.90 (m, 2 H); MS (ES) m/z 387, 389 [M+l]+. Example 20
8-("3-BromophenvlV8-(4-hvdroxvphenvl)-3,4.7.8-tetrahydroimidazori,5-αlpyrimidine-
6f2HVthione
Figure imgf000056_0001
OΗ 8-(3-Bromophenyl)-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine- 6(2H)-thione (4.5 g, 10.9 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 °C. Boron tribromide (1.5 mL, 16 mmol) was added and the mixture was warmed to room temperature and stirred 2 h. The mixture was cooled again to 0 °C and additional boron tribromide (1.5 mL, 16 mmol) was added, and the mixture was allowed to reach room temperature and stirred for 1 h. Water, brine and ethyl acetate were added and the organics were collected. The aqueous phase was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to give 3.6 g (82 % yield) of the title compound: 1H NMR (DMSO-J6) δ 10.77 (s, 1 Η), 9.58 (s, 1 Η), 7.55 - 7.51 (m, 2 Η), 7.44 - 7.40 (m, 1 Η), 7.38 - 7.32 (m, 1 Η), 7.13 - 7.09 (m, 2 Η), 6.76 - 6.72 (m, 2 Η), 3.74 - 3.69 (m, 2 Η), 3.48 - 3.43 (m, 2 Η), 1.80 - 1.73 (m, 2 Η).
Example 21
4-[8-(3-Bromophenvl)-6-thioxo-23,4,6J,8-hexahvdroimidazo|'1.5-α1pvrimidin-8- o yllphenvl methanesulfonate
Figure imgf000056_0002
To a mixture of 8-(3-bromophenyl)-8-(4-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]pyrimidine-6(2H)-thione (3.6 g, 8.9 mmol) and triethylamine (1.7 mL, 12 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.78 mL, 10 mmol) and the mixture was stirred overnight. Additional triethylamine (0.85 mL, 6 mmol) was added and the mixture was heated at 30 °C for 4 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organics were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography, using ethyl acetate in n-heptane from 10 — 50 % as the eluent, afforded 2.4 g (56% yield) of the title compound: 1H NMR (DMSO-J6) δ 10.93 (br s, 1 H), 7.59 - 7.51 (m, 2 H), 7.48 - 7.43 (m, 3 H), 7.40 - 7.35 (m, 3 H), 3.76 - 3.71 (m, 2 H), 3.51 - 3.47 (m, 2 H), 3.40 (s, 3 H), 1.82 - 1.75 (m, 2 H).
Example 22
4-r8-(3-BromophenvlV6-thioxo-2.3,4,6,7,8-hexahvdroimidazoπ.5-a1pvrimidin-8- yllphenyl propane- 1 -sulfonate
Figure imgf000057_0001
The title compound was prepared as described for example 21 in 68% yield starting from s 8-(3-bromophenyl)-8-(4-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine- 6(2H)-thione and 1-propanesulfonylchloride: 1HNMR (DMSO-J6) δ 10.93 (br s, 1 Η), 7.58 - 7.54 (m, 2 Η), 7.46 - 7.43 (m, 3 Η), 7.40 - 7.33 (m, 3 Η), 3.73 (t, J= 5.90 Hz, 2 H), 3.53 - 3.47 (m, 4 H), 1.87 - 1.81 (m, 2 H), 1.81 - 1.75 (m, 2 H), 1.03 (t, J= 7.53 Hz, 3 H).
0 Example 23
4-r8-r3-Bromophenvl')-6-thioxo-2.3,4,6.7,8-hexahvdroimidazori.5-αlpvrimidin-8- yllphenyl cyclopropanesulfonate
Figure imgf000057_0002
The title compound was prepared as described for example 21 in 65% yield starting from 8-(3-bromophenyl)-8-(4-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine- 6(2H)-thione and cyclopropanesulfonyl chloride: 1HNMR (DMSO-J6) δ 10.93 (br s, 1 H), 7.57 - 7.54 (m, 2 H), 7.48 - 7.44 (m, 2 H), 7.43 - 7.36 (m, 4 H), 3.74 (t, J= 6.15 Hz, 2 H), 3.49 (t, J= 5.27 Hz, 2 H), 3.09 - 3.02 (m, 1 H), 1.82 - 1.76 (m, 2 H), 1.20 - 1.16 (m, 2 H), 1.06 - 1.01 (m, 2 H).
Example 24
4-r6-Amino-8-(3-bromophenvlV2.3,4,8-tetrahydroimidazo[l,5-a1pvrimidin-8-vl1phenvl methanesulfonate H2N
=N
Figure imgf000058_0001
4-[8-(3-Bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate (2.4 g, 5 mmol) was dissolved in methanol (70 mL) and concentrated ammonium hydroxide (40 mL). tert-Butyl hydroperoxide (13.7 mL, 70% in water, 100 mmol) was added and the mixture was left to stir at room temperature overnight, and then heated at 30 °C for 3 h. Most of the methanol was evaporated, water and saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. Drying in a vacuum oven afforded 2.1 g (90% yield) of the title product: 1H NMR (DMSO-^6) δ 7.73 - 7.72 (m, 1 H), 7.63 - 7.57 (m, 3 H), 7.39 - 7.36 (m, 1 H), 7.26 - 7.22 (m, 3 H), 6.35 (br s, 2 H), 3.55 - 3.51 (m, 2 H), 3.43 - 3.39 (m, 2 H), 3.34 (s, 3 H), 1.71 - 1.65 (m, 2 H).
Example 25 4-r6-Amino-8-(3-bromophenvlV2,3,4,8-tetrahvdroimidazoπ,5-αlpvrimidin-8-vllphenvl propane- 1 -sulfonate H2N
Figure imgf000059_0001
The title compound was prepared as described for example 24 in 102% yield starting from 4-[8-(3-bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl propane-1-sulfonate: 1H NMR (DMSO-J6) δ 7.72 (t, J= 1.88 Hz, 1 H), 7.63 - 7.56 (m, 3 H), 7.40 - 7.36 (m, 1 H), 7.27 - 7.19 (m, 3 H), 3.53 (t, J= 5.65 Hz, 2 H), 3.49 - 3.44 (m, 2 H), 3.42 (t, J= 5.52 Hz, 2 H), 1.86 - 1.77 (m, 2 H), 1.72 - 1.65 (m, 2 H), 1.02 (t, J= 7.40 Hz, 3 H); MS (ES) m/z 489, 491 [M-I]".
Example 26
4-r6-Amino-8-(3-bromophenvlV2,3,4,8-tetrahvdroimidazori,5-α1pvrimidin-8-yllphenyl cyclopropanesulfonate H2NN
Br-
Figure imgf000059_0002
The title compound was prepared as described for example 24 in 97% yield starting from 4-[8-(3-bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl cyclopropanesulfonate: 1H NMR (DMSO-J6) δ 7.69 (t, J= 1.88 Hz, 1 H), 7.63 - 7.58 (m, 2 H), 7.57 - 7.53 (m, 1 H), 7.40 - 7.36 (m, 1 H), 7.26 - 7.23 (m, 3 H), 3.54 (t, J= 5.77 Hz, 2 H), 3.41 (t, J= 5.40 Hz, 2 H), 3.04 - 2.97 (m, 1 H), 1.73 - 1.65 (m, 2 H), 1.19 - 1.15 (m, 2 H), 1.05 - 0.98 (m, 2 H); MS (ES) m/z 487, 489 [M-I]-.
Example 27
8-(3-BromophenyD-8-('4-methoxyphenvlV2,3.4,8-tetrahvdroimidazorL5-α1pvrimidin-6- amme
Figure imgf000060_0001
The title compound was prepared as described for example 24 in 99% yield starting from 8-(3-bromophenyl)-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine- 6(2H)-thione: 1H NMR (DMSO-^6) δ 7.67 - 7.65 (m, 1 Η), 7.55 - 7.51 (m, 1 Η), 7.42 - 7.38 (m, 2 K), 7.37 - 7.33 (m, 1 Η), 7.23 - 7.19 (m, 1 Η), 6.83 - 6.79 (m, 2 Η), 3.70 (s, 3 Η), 3.54 - 3.50 (m, 2 K), 3.41 - 3.37 (m, 2 Η), 1.70 - 1.64 (m, 2 K).
Example 28 8-(3-Bromo-phenvlV8-pvridin-4-vl-23,4,8-tetrahvdro-imidazorL5-alpyrimidin-6-vlamine
Figure imgf000060_0002
o Br
8-(3-Bromophenyl)-8-pyridin-4-yl-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)- thione (2.60 g, 6.7 mmol) was dissolved in methanol (90 mL). Aqueous tert-butyl hydroperoxide (70%, 15 mL, 100.5 mmol) and aqueous ammonia (30%, 30 mL) were added and the resulting mixture was stirred overnight at ambient temperature. The mixture s was concentrated and the residue was dissolved in dichloromethane (90 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography, using chloroform (0.5% 7 M ammonia in methanol): methanol 0-10% gradient as the eluent, gave 1.97 g (80% yield) of the title compound: 1H NMR ( CDCl3) δ 8.52 (d, J= 6.06 Hz, 2 H), 7.66 (t, J= 1.77 Hz, 1 H), 7.46 - 7.36 (m, 4 H), 7.16 (t, J= 7.96 0 Hz, 1 H), 3.72 (t, J= 5.94 Hz, 2 H)5 3.61 (ddd, J= 5.43, 2.65, 2.53 Hz, 2 H), 1.92 - 1.82 (m, 2 H); MS (ES) m/z 370, 372 [M+l]+.
Example 29 8-r3-Bromophenvl)-8-phenvl-2.3.4.8-tetrahvdroimidazori,5-α]pvrimidin-6-amine
Figure imgf000061_0001
Br
The title compound was prepared as described for example 24 in 19% yield starting from 8-(3-bromophenyl)-8-phenyl-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)-thione: MS (ESI) m/z 369, 371 [M+l]+.
Example 30
8-(3'-Methoxvbipb.envl-3-vlV8-phenvl-2,3,4,8-tetrahvdroimidazori,5-a1pyrimidin-6-amine hydrochloride
ΗCI
Figure imgf000061_0002
o 8-(3-Bromophenyl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine (81 mg, 0.22 mmol), (3-methoxyphenyl)boronic acid (43 mg, 0.29 mmol), cesium carbonate (215 mg, 0.66 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (12 mg, 0.015 mmol) in 1,2-dimethoxy ethane: water: ethanol (3 mL, 6:3:1) was irradiated in a microwave at 150 °C for 15 min. When cooled to ambient s temperature the mixture was diluted with water and extracted with diethyl ether. The combined organic phases were concentrated in vacuo and the residue dissolved in dimethyl sulfoxide and purified by preparative EDPLC. The residue was diluted with 1 M sodium hydroxide and extracted with dichloromethane. Hydrochloric acid (1 M in diethyl ether, 0.5 mL) was added and the solvent was evaporated to give 40 mg (45% yield) of the title 0 compound: 1R NMR (DMSO- J6) 5 9.15 (br s, 2 H), 7.70 - 7.66 (m, 2 H), 7.52 - 7.44 (m, 2 H), 7.44 - 7.41 (m, 3 H), 7.40 - 7.36 (m, 2 H), 7.28 - 7.24 (m, 1 H), 7.19 - 7.13 (m, 2 H), 6.98 - 6.92 (m, 1 H), 3.84 - 3.78 (m, 5 H), 1.92 - 1.83 (m, 2 H); MS (ES) m/z 397 [M+l]+. Example 31
8-(3'-Chlorobiphenvl-3-ylV8-ρhenvl-23,4.8-tetrahvdroimidazori,5-α'|pyrimidin-6-amine hydrochloride
HCl
Figure imgf000062_0001
cr The title compound was prepared as described for example 30 in 57% yield starting from 8-(3-bromophenyl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-«]pyrimidin-6-amine and (3- chlorophenyl)boronic acid: 1HNMR (DMSO-J6) δ 9.17 (br s, 2 H), 7.73 - 7.68 (m, 3 H), 7.62 - 7.59 (m, 1 H), 7.53 - 7.49 (m, 3 H), 7.47 - 7.38 (m, 6 H), 3.84 - 3.77 (m, 2 H) 1.92 - 1.84 (m, 2 H); MS (ESI) m/z 401 [M+lf.
Method A:
Example 32
4-r6-Amino-8-("3'-methoxvbiphenvl-3-vl)-2,3,4,8-tetrahvdroimidazo[1.5-αlpvrimidin-8- vllphenvl methanesulfonate
Figure imgf000062_0002
4-[6-Amino-8-(3-bromophenyl)-2,3,4,8-tetrahydroimidazo[l,5-fl]pyrimidin-8-yl]phenyl methanesulfonate (70 mg, 0.15 mmol), [I5T- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (12 mg, 0.015 mmol), potassium carbonate (125 mg, 0.9 mmol), and 3-methoxyphenylboronic acid 0 (29 mg, 0.19 mmol) in dry tetrahydrofuran (3 mL) was irradicated at 130 °C for 2 h in a microwave. When cooled to ambient temperature the mixture was filtered and dimethyl sulfoxide (800 μL) was added. The solution was concentrated in vacuo to remove tetany drofuran and purified by preparative HPLC to give 19 mg (23% yield) of the title compound. 1H NMR (CDCl3) δ 7.85 - 7.82 (m, 1 H), 7.70 - 7.66 (m, 2 H), 7.58 - 7.54 (m, 1 H), 7.49 - 7.44 (m, 1 H), 7.39 - 7.32 (m, 2 H), 7.26 - 7.22 (m, 2 H), 7.11 - 7.08 (m, 1 H), 7.05 - 7.03 (m, 1 H), 6.95 - 6.91 (m, 1 H), 3.80 (s, 3 H), 3.57 - 3.52 (m, 2 H), 3.45 - 3.41 (m, 2 H), 3.34 (s, 3 H), 1.91 (s, 3 H), 1.73 - 1.66 (m, 2 H); MS (ES) m/z 491 [M+l]+.
Examples 33-59
Examples 33-59 were synthesised as described for Example 32 in similar yields as seen in the table below.
Figure imgf000063_0001
\
Figure imgf000063_0002
35 4-[6-Amino-8-(3'- CH3CH2CH2SO3 523 /525 7.86 - 7.84 (m, 1 H), 7.68 chlorobiphenyl-3- - 7.64 (m, 2 H), 7.64 - yl)-2,3,4,8- 7.61 (m, 1 H), 7.56 - 7.55 tetrahydroimidazo[l (m, 1 H), 7.52 - 7.48 (m, 3 ,5-α]pyrimidin-8- H), 7.44 - 7.40 (m, 1 H), yl]phenyl propane-
Figure imgf000064_0001
7.37 (t, J= 7.78 Hz, I H), 1-sulfonate 0.75 7.23 - 7.19 (m, 2 H), 3.55 acetate (t, J= 5.65 Hz, 2 H), 3.46 - 3.41 (m, 4 H), 1.90 (s, 2 H), 1.85 - 1.78 (m, 2 H), 1.73 - 1.67 (m, 2 H), 1.01 (t, J= 7.53 Hz, 3 H).
36 4-{6-Amino-8-[3'- CH3CH2CH2SO3 557 7.92 - 7.90 (m, 1 H), 7.88 (trifluoromethyl)bip - 7.84 (m, 1 H), 7.83 - henyl-3-yl]-2,3,4,8- 7.81 (m, I H), 7.76 - 7.71 tetrahydroimidazo[l (m, 2 H), 7.70 - 7.65 (m, 3 ,5-α]pyrimidin-8- H), 7.59 - 7.55 (m, 1 H), yl} phenyl propane-
Figure imgf000064_0002
7.42 (t, J= 7.65 Hz, I H), 1 -sulfonate 0.5 7.24 - 7.20 (m, 2 H), 3.56 acetate (t, J= 5.65 Hz, 2 H), 3.48
- 3.44 (m, 4 H), 1.92 (s, 1.5 H), 1.86 - 1.80 (m, 2 H), 1.75 - 1.68 (m, 2 H), 1.02 (t, J= 7.53 Hz, 3 H).
37 4-[6-Amino-8-(4'- CH3CH2CH2SO3 537 7.83 - 7.81 (m, I H), 7.70 fluoro-3'- - 7.66 (m, 2 H), 7.58 - methoxybiphenyl-3- 7.55 (m, 1 H), 7.51 - 7.47 yl)-2,3,4,8- (m, I H), 7.36 (t, J= 7.78 tetrahydroimidazo [ 1 Hz, 1 H), 7.32 - 7.24 (m, 2 ,5-α]pyrimidin-8- H), 7.24 - 7.20 (m, 2 H), yl]phenyl propane- 7.08 - 7.03 (m, 1 H), 3.91
Figure imgf000064_0003
1 -sulfonate 0.75 (s, 3 H), 3.56 (t, J= 5.90 acetate Hz, 2 H), 3.49 - 3.44 (m, 4 H), 1.91 (s, 2.1 H), 1.87 - 1.80 (m, 2 H), 1.75 - 1.68 (m, 2 H), 1.03 (t, J= 7.40 Hz, 3 H).
38 4-[6-Amino-8-(3'- CH3CH2CH2SO3 541 7.80 - 7.78 (m, 1 H), 7.70 chloro-2'- - 7.64 (m, 3 H), 7.62 - fluorobiphenyl-3- 7.57 (m, 1 H), 7.43 - 7.37 yl)-2,3,4,8- (m, 3 H), 7.33 (t, J= 7.65 tetrahydroimidazo [ 1 Hz, 1 H), 7.25 - 7.20 (m, 2 ,5-α]pyrimidin-8-
Figure imgf000064_0004
H), 3.57 - 3.53 (m, 2 H), yljphenyl propane- 3.47 - 3.42 (m, 4 H), 1.92 1-sulfonate 0.75 (s, 2.2 H), 1.87 - 1.80 (m, acetate 2 H), 1.74 - 1.67 (m, 2 H), 1.03 (t, J= 7.40 Hz, 3 H).
39 4-[6-Amino-8-(2',5'- CH3CH2CH2SO3 557 / 7.70 (s, 1 H), 7.67 - 7.63 dichlorobiphenyl-3 - (m, 2 H), 7.63 - 7.60 (m, 1 559 yl)-2,3,4,8- H), 7.59 - 7.56 (m, 1 H), tetrahydroimidazo [ 1
Figure imgf000064_0005
7.48 - 7.44 (m, 1 H), 7.41 ,5-α]pyrimidin-8- (d, J= 2.51 Hz, I H), 7.37 yl]phenyl propane- (t, J= 7.65 Hz, I H), 7.28 1-sulfonate 0.75 - 7.25 (m, 1 H), 7.22 - acetate 7.19 (m, 2 H), 3.53 (t, J= 5.90 Hz, 2 H), 3.47 - 3.40
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
1.73 - 1.68 (m, 2 H).
54 4-[6-Amino-8-(2',5'- CH3SO3 521 7.72 - 7.68 (m, 3 H), 7.50 dimethoxybiphenyl- - 7.46 (m, 1 H), 7.30 -
3-yl)-2,3,4,8- 7.26 (m, 2 H), 7.26 - 7.22 tetrahydroimidazo[l (m, 2 H)5 7.00 (d, J=
,5-α]pyrimidin-8-
Figure imgf000068_0001
8.78 Hz, I H), 6.88 (dd, J yl]phenyl = 9.03, 3.26 Hz, 1 H), methanesulfonate 6.76 - 6.74 (m, I H), 3.72
0.5 acetate (s, 3 H), 3.63 (s, 3 H)3 3.56 - 3.52 (m, 2 H), 3.42
- 3.39 (m, 2 H), 3.34 (s, 3 H), 1.91 (s, 1.5 H), 1.72 - 1.66 (m, 2 H).
55 4-[6-Amino-8-(3'- CH3SO3 504 8.08 (dd, J= 6.02, 2.51 cyano-4'- Hz, 1 H), 7.93 - 7.89 (m, fluorobiphenyl-3 - 1 H), 7.87 (t, J= 1.76 Hz, yl)-2,3,4,8- 1 H), 7.68 - 7.59 (m, 4 tetrahydroimidazo[l H), 7.55 - 7.51 (m, I H),
,5-α]pyrimidin-8-
Figure imgf000068_0002
7.39 (t, J= 7.78 Hz, I H), yl]ρlienyl 7.25 - 7.21 (m, 2 H), 3.56 methanesulfonate - 3.52 (m, 2 H), 3.44 -
0.5 acetate 3.41 (m, 2 H), 3.34 (s, 3 H), 1.91 (s, 1.5 H), 1.72 - 1.67 (m, 2 H).
56 4-[6-Amino-8-(5'- CH3SO3 504 7.98 (dd, J= 7.28, I H), cyano-2'- 7.95 - 7.91 (m, 1 H), 7.83 fluorobiphenyl-3 - - 7.81 (m, I H), 7.69 - yl)-2,3,4,8- 7.65 (m, 3 H), 7.57 - 7.51 tetrahydroimidazo [ 1
Figure imgf000068_0003
(m, 1 H), 7.43 - 7.39 (m, ,5-α]pyrimidin-8- 2 H), 7.25 - 7.21 (m, 2 yl]phenyl H), 3.56 - 3.52 (m, 2 H), methanesulfonate 3.43 - 3.40 (m, 2 H), 3.34 0.75 acetate (s, 3 H), 1.91 (s, 2.3 H), 1.72 - 1.67 (m, 2 H).
57 4-[6-Amino-8-(3',5'- CH3SO3 529 / 531 7.89 - 7.86 (m, 1 H), 7.70 dichlorobiphenyl-3- - 7.64 (m, 3 H), 7.62 - yl)-2,3,4,8- 7.60 (m, 1 H), 7.57 - 7.53 tetrahydroimidazo [ 1 (m, 3 H), 7.41 - 7.36 (m,
,5-α]pyrimidin-8- 1 H), 7.25 - 7.22 (m, 2 yl]phenyl H), 3.56 - 3.51 (m, 2 H), methanesulfonate 3.45 - 3.40 (m, 2 H), 3.34 acetate (s, 3 H), 1.91 (s, 3 H), 1.72 - 1.66 (m, 2 H).
58 3'-[6-Amino-8-(4- CH3O 521 7.81 - 7.79 (m, 1 H), 7.58 methoxyphenyl)- - 7.54 (m, I H), 7.51 -
2,3,4,8- 7.47 (m, 1 H), 7.45 - 7.41 tetrahydroimidazo[l
Figure imgf000068_0005
(m, 2 H), 7.38 - 7.33 (m,
,5-α]pyrimidin-8- 1 H), 7.08 - 7.04 (m, 2 yl]-5- H), 6.95 - 6.93 (m, 1 H), methoxybiphenyl-3- 6.83 - 6.79 (m, 2 H), 3.84 yl methanesulfonate (s, 3 H), 3.69 (s, 3 H), acetate 3.57 - 3.52 (m, 2 H), 3.42 (s, 3 H), 3.30 - 3.40 (m, 2 H), 1.91 (s, 3 H), 1.72 - 1.66 (m, 2 H).
Figure imgf000069_0002
Examples 60-66
Examples 60-66 were synthesised as described for Example 32 in similar yields as seen in 5 the table below.
H0N
Figure imgf000069_0001
Figure imgf000069_0003
Figure imgf000070_0001
Example 67
3'-(6-Amino-8-pvridm-4-vl-2,3.4.8-tetrahydroimidazori,5-a]pvrimidin-8-vlVbiphenvl-3- carbonitrile hydrochloride
Figure imgf000071_0001
A mixture of 8-(3-bromo-phenyl)-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5- a]pyrimidin-6-ylamine (50 mg, 135 μmol), (3-cyanophenyl)boronic acid ( 26 mg, 176 μmol), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (11 mg, 14 μmol) and cesium carbonate (132 mg, 370 μmol) in 1,2- dimethoxyethan:water:ethanol (6:3:1, 3 mL) was irradiated in a microwave at 130 °C for 15 min. When cooled to ambient temperature the mixture was diluted with water (3 mL) and extracted with dichloromethane (20 mL). The organic extract was dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC to give the title compound as the acetate salt, which was dissolved in dry methanol and treated with a hydrogen chloride solution (1 mL, 1 M in diethyl ether). The solvents were evaporated in vacuo to afford 25.6 mg (45% yield) of the title compound: 1H NMR (CDCl3) δ 8.51 (dd, J= 4.55, 1.52 Hz, 2 H), 7.87 - 7.67 (m, 1 H), 7.61 - 7.55 (m, 2 H), 7.51 - 7.40 (m, 7 H), 3.65 - 3.57 (m, 4 H), 1.92 - 1.83 (m, 2 H); MS (ES) m/z 393 [M+l]+.
0
Method B:
A mixture of 8-(3-bromo-phenyl)-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l ,5- a]pyrimidin-6-ylamine (50 mg, 135 μmol), the respective boronic acid or boronic ester (176 μmol), [l,ll-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane 25 adduct (11 mg, 14 μmol) and cesium carbonate (132 mg, 370 μmol) in 1,2- dimethoxyethan:water:ethanol (6:3:1, 3 mL) was irradiated in a microwave at 130 °C for 15 min. When cooled to ambient temperature the mixture was filtered and the solvents were removed in vacuo. The residue was dissolved in dimethyl sulfoxide (800 μL) and the product was purified using preparative-HPLC.
Examples 68-86
Examples 68-86 were synthesised as described for Method A (Example 32) or Method B in similar yields as seen in the table below.
H,N
Figure imgf000072_0001
^N
M e t m/z
Ex Chemical name R1 h [M+l 1H-NMR (DMSO-cfe) δ ppm o I+ d
68 8-(3'-Methoxybiphenyl- B 398 8.49 - 8.44 (m, 2 H), 7.88 - 7.79 (m, 1 H),
3-yl)-8-pyridin-4-yl- 7.59 - 7.48 (m, 4 H), 7.41 - 7.34 (m, 2 H),
2,3,4,8- 7.12 - 7.04 (m, 2 H), 6.94 (dd, J= 7.91, tetrahydroimidazo[l,5- 2.13 Hz, 1 H), 3.81 (s, 3 H), 3.55 (t, J= α]pyrimidin-6-amine
Figure imgf000072_0002
5.77 Hz, 2 H), 3.44 (t, J= 5.27 Hz, 2 H),
0.25 acetate 1.91 (s, 0.9 H), 1.75 - 1.67 (m, 2 H).
69 8-(3'-Chlorobiphenyl-3- B 402 8.47 - 8.43 (m, 2 H), 7.92 - 7.80 (m, 1 H), yl)-8-pyridin-4-yl- 7.63 (d, J= 7.78 Hz, 1 H), 7.59 - 7.31 (m, i 2,3,4,8- H), 3.54 (t, J= 5.77 Hz, 2 H), 3.42 (dd, J= tetrahydroimidazo[l ,5- 5.40, 2.38 Hz, 2 H), 1.91 (s, 0.9 H), 1.73 -
Figure imgf000072_0003
α]pyrimidin-6-amine 1.65 (m, 2 H). 0.25 acetate
70 8-(2'-Fluoro-3'- B 416 8.46 - 8.44 (m, 2 H), 7.74 (s, 1 H), 7.60 - methoxybiphenyl-3-yl)- 7.52 (m, 3 H), 7.39 - 7.33 (m, 2 H), 7.22 - 8-pyridin-4-yl-2,3,4,8- 7.13 (m, 2 H), 6.93 (s, 1 H), 3.86 (s, 3 H), tetrahydroimidazo[l ,5- 3.54 (t, J= 5.90 Hz, 2 H), 3.42 - 3.40 (m, 2 α]pyrimidin-6-amine H), 1.90 (s, 0.7 H), 1.68 (s, 2 H).
Figure imgf000072_0004
0.25 acetate
71 8-(2'-Fluoro-5'- B 416 8.48 - 8.43 (m, 2 H), 7.78 (s, 1 H), 7.63 - methoxybiphenyl-3-yl)- 7.56 (m, 1 H), 7.55 - 7.49 (m, 2 H), 7.38 (d,
8-pyridin-4-yl-2,3,4,8- J= 5.02 Hz, 2 H), 7.21 (dd, J= 10.42, 8.91 tetrahydroimidazo[l,5- Hz, 1 H), 6.96 - 6.89 (m, 2 H), 3.77 (s, 3 α]pyrimidin-6-amine
Figure imgf000072_0005
H), 3.54 (t, J= 5.90 Hz, 2 H), 3.41 (dd, J=
0.25 acetate 6.40, 4.64 Hz, 2 H), 1.90 (s, 0.7 H), 1.73 - 1.64 (m, 2 H). 72 3'-(6-Amino-8-pyridin-4- B 411 8.47 - 8.43 (m, 2 H), 7.99 (dd, J= 7.28, yl-2,3,4,8- 2.01 Hz, 1 H), 7.93 (ddd, J= 8.53, 4.64, tetrahydroimidazo[l ,5- 2.13 Hz, 1 H), 7.81 (s, 1 H), 7.67 (td, J= α]pyrimidin~8-yl)-6- 4.45, 1.88 Hz, 1 H), 7.58 - 7.51 (m, 3 H), fluorobiphenyl-3 -
Figure imgf000073_0001
7.45 - 7.39 (m, 2 H), 3.54 (t, J= 5.77 Hz, 2 carbonitrile 0.25 acetate H), 3.41 (d, J= 2.26 Hz, 2 H), 1.90 (s, 0.7 H), 1.73 - 1.64 (III, 2 H).
73 3'-(6-Amino-8-pyridin-4- 496 8.45 (dd, J= 4.52, 1.51 Hz, 2 H), 7.88 (s, 1 yl-2,3,4,8- H), 7.81 - 7.66 (m, 1 H), 7.66 - 7.64 (m, 1 tetrahydroimidazofl ,5- H), 7.61 (t, J= 1.63 Hz, 1 H), 7.57 (d, J= α]pyrimidin-8-yl)-5-
Figure imgf000073_0002
8.28 Hz, 1 H), 7.54 - 7.50 (m, 2 H), 7.49 - chlorobiphenyl-3-yl 7.46 (m, 1 H), 7.41 (t, J= 7.78 Hz, 1 H), methanesulfonate 0.5 3.54 (t, J= 5.90 Hz, 2 H), 3.47 (s, 3 H), acetate 3.45 - 3.39 (m, 2 H), 1.90 (s, 1.3 H), 1.73 - 1.66 (111, 2 H).
74 3'-(6-Amino-8-pyridin-4- B 411 8.49 - 8.44 (m, 2 H), 8.10 (dd, J= 6.15, yl-2,3,4,8- 2.38 Hz, 1 H), 7.96 - 7.89 (m, 1 H), 7.89 - tetrahydroimidazo[l,5- 7.85 (m, 1 H), 7.69 - 7.60 (m, 2 H), 7.58 - α]pyrimidin-8-yl)-4~ 7.53 (m, 3 H), 7.42 (t, J= 7.78 Hz, 1 H), fluorobiphenyl-3- 3.56 (t, J= 5.77 Hz, 2 H), 3.48 - 3.42 (m, 2 carbonitrile 0.25 acetate
Figure imgf000073_0003
H), 1.92 (s, 0.8 H), 1.75 - 1.67 (m, 2 H).
75 8-(3'-Chloro-2'- B 420 8.48 - 8.43 (m, 2 H), 7.78 (s, 1 H), 7.65 (td, fluorobiphenyl-3-yl)-8- J= 4.39, 1.76 Hz, 1 H), 7.62 - 7.55 (m, 1 pyridin-4-yl-2,3,4,8- H), 7.55 - 7.51 (m, 2 H), 7.43 - 7.37 (m, 3 tetrahydroimidazo[l ,5- H), 7.31 (t, J= 8.16 Hz, 1 H), 3.54 (t, J=
Figure imgf000073_0004
α]pyrimidin-6-amine 5.90 Hz, 2 H), 3.41 (dd, J= 5.40, 2.64 Hz, 0.25 acetate 2 H), 1.91 (s, 0.5 H), 1.73 - 1.65 (m, 2 H)
76 8-Pyridin-4-yl-8-[3'- B 436 8.49 - 8.43 (m, 2 H), 8.36 (br s, 2 H), 8.13 - (trifluoromethyl)bipheny 8.04 (m, 1 H), 7.91 - 7.80 (m, 3 H), 7.77 - l-3-yl]-2,3,4,8- 7.69 (m, 2 H), 7.65 (d, J= 8.03 Hz, 1 H), tetrahydroimidazo [1,5- 7.60 - 7.55 (m, 1 H), 7.54 - 7.51 (m, 1 H), fl]pyrimidin-6-amine 7.42 (t, J= 7.78 Hz, 1 H), 3.55 (t, J= 5.90 0.25 acetate
Figure imgf000073_0005
Hz, 2 H), 3.42 (dd, J= 5.40, 2.38 Hz, 2 H), 1.90 (s, 0.8 H), 1.74 - 1.66 (m, 2 H)
77 8-[3'- B 446 8.48 - 8.43 (m, 2 H), 8.07 - 8.01 (m, 1 H),
(Methylsulfonyl)bipheny 7.96 - 7.87 (m, 3 H), 7.75 (t, J= 7.78 Hz, 1 l-3-yl]-8-pyridin-4-yl- H), 7.68 (d, J= 8.03 Hz, 1 H), 7.59 (d, J=
2,3,4,8- 7.78 Hz, 1 H), 7.55 - 7.51 (m, 2 H), 7.43 (t, tetrahydroimidazo[l,5- J= 7.78 Hz, 1 H), 3.55 (t, J= 5.90 Hz, 2 α]pyrimidin-6-amine
Figure imgf000073_0006
H), 3.45 - 3.41 (m, 2 H), 3.27 (s, 3 H), 1.90
0.25 acetate (s, 0.4 H), 1.74 - 1.66 (m, 2 H).
78 8-(3',5'- B 436 8.48 - 8.43 (m, 2 H), 7.87 (s, 1 H), 7.67 (d,
Dichlorobiphenyl-3-yl)- J= 8.03 Hz, 1 H), 7.60 (t, J= 1.76 Hz, 1
8-pyridin-4-yl-2,3,4,8- H), 7.58 - 7.55 (m, 3 H), 7.53 - 7.50 (m, 2 tetrahydroimidazo[l,5- H), 7.40 (t, J= 7.65 Hz, 1 H), 3.54 (t, J=
Figure imgf000073_0007
α]pyrimidin-6-amine 5.90 Hz, 2 H), 3.46 - 3.39 (m, 2 H), 1.90 (s,
0.25 acetate 0.7 H), 1.73 - 1.66 (m, 2 H).
79 8-(3'-Chloro-5'- B 432 8.47 - 8.45 (m, 2 H), 7.85 (s, 1 H), 7.63 (d, methoxybiphenyl-3 -yl)- J= 7.78 Hz, 1 H), 7.56 - 7.52 (m, 3 H), 8-pyridin-4-yl-2,3,4,8- 7.39 (t, J= 7.78 Hz, 1 H), 7.14 (t, J= 1.51 tetrahydroimidazo[l ,5- Hz, 1 H), 7.04 (d, J= 1.25 Hz, 2 H), 3.84 α]pyrimidin~6-amine
Figure imgf000073_0008
(s, 3 H), 3.56 (t, J= 5.90 Hz, 2 H), 3.48 - 0.25 acetate 3.42 (m, 2 H), 1.92 (s, 0.9 H), 1.74 - 1.67 (m, 2 H). 80 8-(2',3'- B 436 8.47 - 8.42 (m, 2 H), 7.70 (d, J= 2.01 Hz, 1
Dichlorobiphenyl-3-yl)- H), 7.69 - 7.66 (m, 1 H), 7.61 (d, J= 7.78
8-pyridin-4-yl-2,3,4,8- Hz, 1 H), 7.54 - 7.48 (m, 3 H), 7.40 - 7.34 tetrahydroimidazo[l,5-
Figure imgf000074_0001
(m, 2 H), 7.26 (d, J= 7.78 Hz, 1 H)3 3.53 (t, α]pyrimidin-6-amine J= 5.77 Hz, 2 H), 3.43 - 3.39 (m, 2 H),
0.25 acetate 1.90 (s, 1.08 H), 1.72 - 1.64 (m, 2 H).
81 8-(3'-Ethoxybiphenyl-3- B 412 8.48 - 8.43 (m, 2 H), 7.83 (d, J= 1.51 Hz, 1 yl)-8-pyridin-4-yl- H), 7.62 - 7.44 (m, 4 H), 7.36 (t, J= 7.53 2,3,4,8- Hz, 2 H), 7.08 (d, J= 6.78 Hz, 1 H), 7.05 - tetrahydroimidazo[l ,5- 7.01 (m, J= 1.51 Hz, 1 H), 6.92 (dd, J= fl]pyrimidin-6-amine 0.5 8.03, 2.26 Hz, 1 H), 4.08 (q, J= 7.03 Hz, 2 acetate H), 3.55 (m, 2 H), 3.50 - 3.40 (m, 2 H), 1.91 (s, 1.3 H), 1.75 - 1.65 (m, 2 H), 1.35 (t, J= 6.90 Hz, 3 H).
82 8-(5'-Chloro-2'- B 420 8.46 (dd, J= 4.52, 1.51 Hz, 2 H), 7.80 (s, 1 fluorobiphenyl-3-yl)-8- H), 7.71 - 7.63 (m, 1 H), 7.56 - 7.46 (m, 4 pyridin-4-yl-2,3,4,8- H), 7.44 - 7.35 (m, 3 H), 3.55 (t, J= 5.90 tetrahydroimidazo[l ,5- Hz, 2 H), 3.46 - 3.40 (m, 2 H), 1.92 (s, 0.7
Figure imgf000074_0003
α]pyriroidin-6-amine H), 1.74 - 1.66 (m, 2 H). 0.25 acetate
83 8-(4'-Fluoro-3'- B 416 8.47 - 8.42 (m, 2 H), 7.82 (s, 1 H), 7.57 - methoxybiphenyl-3 -yl)- 7.48 (m, 4 H), 7.36 (t, J= 7.78 Hz, 1 H), 8-pyridin-4-yl-2,3,4,8- 7.31 - 7.24 (m, 2 H), 7.09 - 6.98 (m, 1 H), tetrahydroimidazo[l ,5- 3.90 (s, 3 H), 3.54 (t, J= 5.90 Hz, 2 H), α]pyrimidin-6-amine 3.46 - 3.38 (m, 2 H), 1.90 (s, 0.8 H), 1.74 - 0.25 acetate
Figure imgf000074_0004
1.66 (m, 2 H).
84 3'-(6-Amino-8-pyridin-4- A 492 8.43 (s, 2 H), 7.87 - 7.83 (m, 1 H), 7.63 - yl-2,3,4,8- 7.57 (m, 1 H), 7.52 (s, 2 H), 7.42 - 7.35 (m, tetraliydroimidazo[ 1 ,5- 1 H), 7.07 (s, 1 H), 7.07 - 7.04 (m, 1 H), α]pyrimidin-8-yl)-5-
Figure imgf000074_0005
6.98 - 6.91 (m, 1 H), 6.41 - 6.29 (m, 1 H), methoxybiphenyl-3-yl 3.84 (s, 3 H), 3.54 (s, 2 H), 3.47 - 3.38 (m, methanesulfonate 0.25 5 H), 1.94 - 1.88 (m, 0.8 H), 1.70 (s, 2 H). acetate
85 8-(2',5'- B 436 8.44 (dd, J= 4.52, 1.51 Hz, 2 H), 7.70 (s, 1
Dichlorobiphenyl-3-yl)- H), 7.65 - 7.56 (m, 2 H), 7.54 - 7.50 (m, 2 8-pyridin-4-yl-2,3,4,8- H), 7.49 - 7.44 (m, 1 H), 7.43 - 7.36 (m, 2 tetrahydroimidazo[l ,5- H), 7.32 - 7.26 (m, 1 H), 3.53 (t, J= 5.77
Figure imgf000074_0006
α]pyrimidin-6-amine Hz, 2 H), 3.44 - 3.39 (m, 2 H), 1.90 (s, 0.7 0.25 acetate H), 1.72 - 1.64 (111, 2 H).
86 8-(3'-Chloro-4'- B 420 8.48 - 8.43 (m, 2 H), 7.83 (s, 1 H), 7.71 (dd, fluorobiphenyl-3 -yl)-8- J= 7.15, 1.88 Hz, 1 H), 7.62 (d, J= 8.03 pyridin-4-yl-2,3,4,8- Hz, 1 H), 7.55 - 7.47 (m, 5 H), 7.38 (t, J= tetrahydroimidazo[l,5- 7.65 Hz, 1 H), 3.54 (t, J= 5.77 Hz, 2 H), α]pyrimidin-6-amine 3.47 - 3.39 (m, 2 H), 1.90 (s, 0.8 H), 1.73 - 0.25 acetate
Figure imgf000074_0007
1.65 (m, 2 H).
Example 87
7-('3-Bromoplienyl)-7-('4-methoxvplienvl')-2,3.6J-tetrahydro-5H-iinidazo[l,5-α1imidazole-
5-thione
Figure imgf000075_0001
The title compound was prepared as described for example 17 in 55 % yield starting from 4-(3-bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione and ethylenediamine (but heated for 36 h): 1H NMR (DMSO-J6) δ 10.62 (s, 1 H), 7.62 (t, J= 1.88 Hz, 1 H), 7.57 - 7.54 (m, 1 H), 7.49 - 7.46 (m, 1 H), 7.38 (t, J= 7.91 Hz, 1 H), 7.33 - 7.29 (m, 2 H), 6.99 - 6.95 (m, 2 H), 4.31 (t, J= 8.78 Hz, 2 H), 3.74 (s, 3 H), 3.71 (t, J= 8.78 Hz, 2 H).
Example 88 7-(3-Bromophenvl)-7-(4-hvdroxyphenvl)-2,3,6,7-tetrahvdro-5H-imidazori,5-αlimidazole- 5-thione
Figure imgf000075_0002
OH
The compound was prepared as described for example 20 in 98 % yield starting from 7-(3- bromophenyl)-7-(4-methoxyphenyl)-2,3,6,7-tetrahydro-5H-imidazo[l,5-α]imidazole-5- thione: 1R NMR (DMSO-^6) 6 10.56 (s, 1 H), 9.64 (s, 1 H), 7.63 - 7.61 (m, 1 H), 7.56 - 7.53 (m, 1 H), 7.49 - 7.45 (m, 1 H), 7.38 (t, J= 7.91 Hz, 1 H), 7.20 - 7.16 (m, 2 H), 6.79 - 6.75 (m, 2 H), 4.30 (t, J= 8.78 Hz, 2 H), 3.70 (t, J= 8.78 Hz, 2 H).
Example 89 0 4-r7-(3-BromophenvD-5-thioxo-2,5,6J-tetrahydro-3H-imidazori,5-αlimidazol-7-yl1phenvl methanesulfonate
Figure imgf000076_0001
The compound was prepared as described for example 21 in 58 % yield starting from 7-(3- bromophenyl)-7-(4-hydroxyphenyl)-2,3,6,7-tetrahydro-5H"-imidazo[l,5-«]imidazole-5- thione: 1HNMR (DMSO-J6) δ 10.74 (s, 1 H), 7.68 (t, J= 1.88 Hz, 1 H), 7.60 - 7.57 (m, 1 H), 7.56 - 7.49 (m, 3 H), 7.44 - 7.38 (m, 3 H), 4.33 (t, J= 9.03 Hz, 2 H), 3.72 (t, J= 8.91 Hz, 2 H), 3.40 (s, 3 H); MS (ES) m/z 464, 466 [M-I]".
Example 90
4-r7-(3-Bromophenyl)-5-thioxo-2,5.6,7-tetrahydro-3H-imidazo['L5-glimidazol-7-vllphenvl propane-2-sulfonate
Figure imgf000076_0002
The compound was prepared as described for example 21 in 40 % yield starting from 7-(3- bromophenyl)-7-(4-hydroxyphenyl)-2,3,6,7-tetrahydro-5H"-imidazo[l,5-«]imidazole-5- thione and isopropylsulfonyl chloride: 1HNMR (DMSO-J6) δ 10.73 (s, 1 H), 7.67 (t, J= 1.76 Hz, 1 H), 7.60 - 7.57 (m, 1 H), 7.54 - 7.49 (m, 3 H), 7.43 - 7.37 (m, 3 H), 4.36 - 4.29 (m, 2 H), 3.77 - 3.69 (m, 3 H), 1.42 (s, 3 H), 1.41 (s, 3 H).
Example 91 4-r5-Amino-7-(3-bromophenyl)-2,7-dihvdro-3H-imidazori,5-a"|imidazol-7-vllphenol
20
Figure imgf000077_0001
7-(3-Bromophenyl)-7-(4-hydroxyphenyl)-2,3,6,7-tetrahydro-5H-imidazo[l,5-a]imidazole- 5-thione (0.6 g, 1.55 mmol) was dissolved in methanol (15 mL) and ammonium hydroxide (30 %, 3 mL). tert-Butyl hydroperoxide (4.1 mL, 30 mmol, 70 % in water) was added. The mixture was stirred over night and most of the methanol was evaporated, water and saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic extracts were pooled, washed with water, brine, dried over magnesium sulfate and evaporated, drying in vacuo oven afforded 0.4 g (71 % yield) of the title product: 1R NMR (DMSO-^6) δ 10.73 (s, 2 Η), 7.70 - 7.68 (m, 1 Η), 7.55 - 7.52 (m, 1 Η), 7.38 - 7.34 (m, 1 Η), 7.31 - 7.27 (m, 2 Η), 7.23 (t, J= 7.91 Hz, 1 H), 6.68 - 6.64 (m, 2 H), 4.28 - 4.22 (m, 2 H), 3.53 - 3.46 (m, 2 H).
Example 92 7-f3-BromophenvlV7-(4-methoxyphenyl)-2,7-dihydro-3H-imidazofl,5-α1imidazol-5- amine
NH,
Figure imgf000077_0002
The title compound was prepared as described for example 21 in 97% yield starting from 7-(3-bromophenyl)-7-(4-methoxyphenyl)-2,3,6,7-tetrahydro-5H-imidazo[l,5-α]imidazole- 5-thione: 1H NMR (DMS(W6) δ 10.72 (br s, 2 H)5 7.70 (t, J= 1.76 Hz, 1 H), 7.56 - 7.52 (m, 1 H), 7.45 - 7.40 (m, 2 H), 7.39 - 7.36 (m, 1 H), 7.24 (t, J= 7.91 Hz, 1 H), 6.86 - 6.82 (m, 2 H), 4.29 - 4.22 (m, 2 H)5 3.70 (s, 3 H), 3.53 - 3.47 (m, 2 H). Example 93
4-['6-Aniino-8-('3-bromophenvlV23.4,8-tetrahvdroimidazo[l,5-alpvrimidin-8-vllphenvl methanesulfonate H2N
Figure imgf000078_0001
5 4-[8-(3-Bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate (2.4 g, 5 mmol) was dissolved in methanol (70 mL) and concentrated ammonium hydroxide (40 mL). tert-Butyl hydroperoxide (13.7 mL, 70% in water, 100 mmol) was added and the mixture was stirred at room temperature overnight, and then heated at 30 °C for 3 h. Most of the methanol was evaporated, water and saturated o aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. Drying in a vacuum oven afforded 2.1 g (90 % yield) of the title product: 1HNMR (DMSO-^6) δ 7.72 - 7.73 (m, 1 H), 7.57 - 7.63 (m, 3 H), 7.36 - 7.39 (m, 1 H), 7.22 - 7.26 (m, 3 H), 6.35 (br s, 2 H), 3.51 - 3.55 (m, 2 H), 3.39 - 3.43 (m, 2 H), 3.34 (s, 3 s H), 1.65 - 1.71 (m, 2 H).
Example 94
4-[5-Amino-7-(3-bromophenvl')-2,7-dihvdro-3H-imidazo['L5-αlimidazol-7-vl]phenvl ρropane-2-sulfonate
Q
Figure imgf000078_0002
The title compound was prepared as described for example 93 in 106 % yield starting from 4-[7-(3-bromophenyl)-5-thioxo-2,5,6,7-tetrahydro-3H"-imidazo[l,5-α]imidazol-7-yl]phenyl propane-2-sulfonate: 1H NMR (DMSO-J6) δ 7.75 (t, J= 1.88 Hz, 1 H)3 7.65 - 7.61 (m, 2 H), 7.59 - 7.56 (m, 1 H), 7.42 - 7.39 (m, 1 H), 7.29 - 7.23 (m, 3 H), 6.47 (br s, 2 H), 4.29 (t, J= 8.78 Hz5 2 H), 3.74 - 3.64 (m, 1 H)3 3.52 (t, J= 8.78 Hz, 2 H), 1.41 (s, 3 H), 1.39 (s, 3 H).
Example 95
4-r5-Amino-7-('3'-chlorobiphenvl-3-vl)-2J-dihvdro-3H-imidazo[L5-fllimidazol-7- yllphenol
Figure imgf000079_0001
4-[5-Amino-7-(3-bromophenyl)-2,7-dihydro-3H-imidazo[l,5-a]imidazol-7-yl]phenol (0.27 g, 0.73 mmol), cesium carbonate (0.71 g, 2.2 mmol), (3-chlorophenyl)boronic acid (0.16 g, 1.02 mmol) and [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (30 mg, 0.04 mmol) was dissolved in dimethoxyethane:ethanol:water (6:3:1) and heated to 130 °C for 20 min in a microwave. The mixture was filtered through celite, diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. Column chromatography, gradient elution with 0 - 10 % ammonia (7 N in methanol) in dichloromethane as solvent gave 0.115 g (39 % yield) of the title compound: 1H NMR (DMSO-J6) δ 7.85 - 7.82 (m, 1 Η), 7.61 - 7.55 (m, 2 Η), 7.52 - 7.47 (m, 3 H)3 7.45 - 7.41 (m, 1 H), 7.40 - 7.33 (m, 3 H)3 6.68 - 6.63 (m3 2 H), 4.29 - 4.22 (m, 2 H)3 3.53 - 3.46 (m, 2 H); MS (ES) m/z 401 [M-I]".
Example 96
4-[5-Ammo-7-f3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H'-imidazorL5-α]imidazol-7- vllϋhenvl trifluoromethanesulfonate 0.75 acetate Cl
Figure imgf000080_0001
4-[5-Amino-7-(3'-chlorobiphenyl-3-yl)-2s7-dihydro-3H-imidazo[l,5-«]imidazol-7- yl]phenol (115 mg, 0.285 mmol), 1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methanesulfonamide (98 mg, 0.3 mmol) and potassium carbonate (0.24 g, 1.7 mmol) was dissolved in dry tetrahydrofuran (5 mL) and heated to 120 °C for 12 min in the microwave. After cooling ethyl acetate and water was added. The organic phase was filtered and dimethyl sulfoxide (2 mL) was added. The solution was concentrated in vacuo to remove ethyl acetate and purified by preparative ΗPLC to give 36 mg (21 % yield) of the title compound: 1H ΝMR (DMSO-J6) δ 7.89 - 7.86 (m, 1 H), 7.81 - 7.77 (m, 2 H), 7.64 - 7.61 (m, 1 H), 7.58 - 7.57 (m, 1 H), 7.55 - 7.49 (m, 3 H), 7.48 - 7.40 (m, 4 H), 4.31 (t, J= 8.78 Hz, 2 H), 3.54 (t, J= 8.91 Hz, 2 H), 1.90 (s, 2 H); MS (ES) m/z 533 [M-I]'.
Example 97
4-f6-Amino-8-(3-bromophenyl')-2,3,4,8-tetrahvdroimidazori,5-α1pvrimidin-8-vllphenol H2N
Figure imgf000080_0002
The title compound was prepared as described in example 91 starting with 8-(3- bromophenyl)-8-(4-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)- thione in 98 % yield: 1HNMR (DMSO-J6) δ 10.73 (s, 2 H), 7.65 (t, J= 1.88 Hz, 1 H), 7.54 - 7.50 (m, 1 H), 7.36 - 7.32 (m, 1 H), 7.28 - 7.24 (m, 2 H), 7.20 (t, J= 7.91 Hz, 1 H), 6.65 - 6.61 (m, 2 H), 3.54 - 3.49 (m, 2 H), 3.40 - 3.36 (m, 2 H), 1.70 - 1.64 (m, 2 H). Example 98
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4.,8-tetrahydroimidazori,5-α1pvrimidin-8- ylføhenol
Figure imgf000081_0001
The title compound was prepared as described in example 95 starting with 4-[6-amino-8- (3-bromophenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]phenol hi 18 % yield: 1H NMR (DMSO-J6) δ 7.81 - 7.76 (m, 1 H), 7.59 - 7.53 (m, 2 H), 7.50 - 7.45 (m, 3 H), 7.43 - 7.39 (m, 1 H), 7.36 - 7.27 (m, 3 H), 6.65 - 6.60 (m, 2 H), 3.54 - 3.50 (m, 2 H), 3.41 - 3.36 (m, 2 H), 1.71 - 1.64 (m, 2 H); MS (ES) m/z 415 [M-I]".
Example 99
4-r6-Amino-8-β'-chlorobiphenvl-3-yl)-2,3,4,8-tetrahvdroimidazori,5-α1pyrimidin-8- yliphenyl trifluoromethanesulfonate acetate
Figure imgf000081_0002
o The title compound was prepared as described in example 96 starting with 4-[6-amino-8-
(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]phenol in 28 % yield: 1H NMR (DMSO-J6) δ 7.82 (t, J= 1.76 Hz, 1 H), 7.78 - 7.74 (m, 2 H), 7.63 - 7.59 (m, 1 H), 7.56 - 7.53 (m, 1 H), 7.52 - 7.48 (m, 3 H), 7.44 - 7.36 (m, 4 H), 3.55 (t, J= 5.77 Hz5 2 H), 3.44 - 3.42 (m, 2 H), 1.89 (s, 3 H), 1.72 - 1.67 (m, 2 H); MS (ES) m/z 547 [M-I]"
Example 100 8-r2'-Fluoro-S'-methoxvbiphenvl-3-vlV8-phenvl-2.3.4,8-tetrahvdroimidazoπ,5- α]pyrimidin-6-amine hydrochloride
HCl
Figure imgf000082_0001
The title compound was synthesized as described in example 30 in 48 % yield starting from (2-fluoro-5-methoxyphenyl)boronic acid. 1H NMR (DMSOd6) δ 9.19 (br s, 2 H), 7.61 - 7.56 (m, 2 H), 7.55 - 7.49 (m, 1 H), 7.48 - 7.38 (m, 6 H), 7.27 - 7.20 (m, 1 H), 7.04 7.00 (m, 1 H), 6.99 - 6.94 (m, 1 H), 3.84 - 3.80 (m, 2 H), 3.79 (s, 3 H), 1.92 - 1.83 (m, 2 H); MS (ES) m/z 415 [M+lf .
Example 101
8-r5'-Chloro-2'-fluorobiphenvl-3-vlV8-phenvl-2,3,4.8-tetrahvdroimidazo[L5-α]pvrimidin- 6-amine hydrochloride
HCI
Figure imgf000082_0002
The title compound was synthesized as described in example 30 in 58 % yield starting from (5-chloro-2-fiuorophenyl)boronic acid. 1H NMR (DMSO-^6) δ 9.11 (br s, 2 H), 7.62 7.55 (m, 3 H), 7.55 - 7.47 (m, 3 H), 7.44 - 7.38 (m, 6 H), 3.83 - 3.72 (m, 2 H), 1.90 - 1.83 (m, 2 H); MS (ES) m/z 419, 421 [M+l]+. Example 102
8-(3',5'-Dichlorobiphenyl-3-ylV8-phenvl-2,3.4,8-tetrahydroimidazori,5-α"]pvrimidin-6- amine hydrochloride
HCl
Figure imgf000083_0001
The title compound was synthesized as described in example 30 in 41 % yield starting from (3,5-dichlorophenyl)boronic acid. 1HNMR (DMSO-^6) δ 9.17 (br s, 2 H), 7.79 - 7.74 (m, 2 H), 7.73 - 7.71 (m, 2 H), 7.65 - 7.62 (m, 1 H), 7.55 - 7.50 (m, 2 H), 7.44 - 7.36 (m, 5 H), 3.86 - 3.74 (m, 2 H), 1.92 - 1.84 (m, 2 H); MS (ES) m/z 433, 435 [M-I]".
Example 103
3'-r6-Ammo-8-phenvl-2,3,4,8-tetrahvdroimidazo[l,5-αlpyrimidin-8-yl)-5- methoxybiphenvl-3-yl methanesulfonate hydrochloride
HCI
Figure imgf000083_0002
8-(3-Bromophenyl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine (81 mg, 0.22 mmol), potassium carbonate (0.18 g, 1.32 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl- 20 l,3,2-dioxaborolan-2-yl)phenyl methanesulfonate (100 mg, 0.31 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (18 mg, 0.02 mmol) was dissolved in tetrahydrofuran and heated to 130 °C for 4 h in a microwave. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was concentrated in vacuo and the crude was purified by preparative HPLC. The residue was diluted with 1 M sodium hydroxide and extracted with dichloromethane. Hydrochloric acid (1 M in diethyl ether, 0.5 mL) was added and the solvent was evaporated to give 28 mg (24 % yield) of the title compound: 1H NMR (DMSO-J6) δ 9.13 (br s, 2 H), 7.76 - 7.70 (m, 2 H), 7.55 - 7.47 (m, 2 H), 7.43 - 7.36 (m, 5 H), 7.23 - 7.17 (m, 2 H), 7.00 - 6.94 (m, 1 H), 3.86 (s, 3 H), 3.83 - 3.77 (m, 2 H), 3.43 (s, 3 H), 1.91 - 1.83 (m, 2 H); MS (ES) m/z 491 [M+l]+.
Example 104
Di-fert-butyl r2-(methylthio)proυane-l ,3-diyllbiscarbamate
' O O I
A solution of 2-[(fert-butoxycarbonyl)amino]-l-{[(fert- butoxycarbonyl)amino]methyl}ethyl methanesulfonate (254 mg, 0.7 mmol, described in Ramalingam, K. et al. Tetrahedron, 1995, 5i(10), 2875-2894) in N,N-dimethylformamide (50 mL) was heated to 40 0C. Sodium methylthiolate (97 mg, 1.38 mmol) was then added in one portion and the obtained mixture stirred for 1 h at this temperature. After cooling to ambient temperature the mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution, water, dried over sodium sulfate and concentrated in vacuo to yield the crude title compound 220 mg (100 % yield). MS (ES) m/z 321 [M+lf.
Example IPS Di-tert-butyl ^-(methvlsulfonyppropane- 1 ,3 -diyllbiscarbamate Oc " SS'.
Figure imgf000085_0001
Y 0 Y O
A solution di-fert-butyl [2-(methylthio)propane-l,3-diyl]biscarbamate (220 mg, 0.68 mmol) and 3-chloroperoxybenzoic acid (380 mg, 2.2 mmol) in N, N-dimethylformamide (5 mL) was heated at 50 °Cand stirred for 1 h. The mixture was then quenched by adding saturated aqueous sodium hydrogen carbonate solution (10-15 mL) and the product was extracted with toluene (50 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated to give the crude title compound 100 mg (41% yield). MS (ES) m/z 352 [M+l]+.
Example 106
2-(Methylsulfonvl")propane-l ,3-diamine bis(trifluoroacetate) » o4-
Figure imgf000085_0002
NH2 NH2
Trifluoroacetic acid (5 mL) was added to a solution of di-tert-butyl [2- (methylsulfonyl)propane-l,3-diyl]biscarbamate (100 mg, 0.28 mmol) in dichloromethane (5 mL). The obtained mixture was stirred for 30 min and then concentrated in vacuo and co-evaporated twice with ethanol to give 107 mg (100 % yield) of the title compound. MS (ES) m/z 153 [M+l]+.
Example 107 0 N-r2-amino-l-(aminomethyl)ethvnacetamide bis('trifluoroacetate)
H
HZΝJ ° Di-tert-butyl (2-aminopropane-l,3-diyl)biscarbamate (78 mg, 0.27 mmol, described in Ramalingam, K. et al. Tetrahedron, 1995, 57(10), 2875-2894) was dissolved in pyridine (1 mL) and acetic anhydride (38 μL, 0.40 mmol) was added at 0 0C. After stirring 2 h at 25 0C, the solvent was evaporated in vacuo. tert-Butoxy carbonyl deprotection was achieved by adding trifluoroacetic acid (1.5 mL) in dichloromethane (1.5 mL) and the mixture was stirred at ambient temperature for 30 min. Evaporation in vacuo gave 100 mg (quantitative yield) of the title compound which was used without further purification: MS (AP) m/z 132 IMfI]+.
Example 108
Di-tert-butyl {2-r(methylsulfonvDamino1propane- 1 ,3-divl}biscarbamate
H o
Figure imgf000086_0001
H J oA
I Hli1
Di-tert-butyl (2-aminopropane-l,3-diyl)biscarbamate (100 mg, 0.34 mmol, described in Ramalingam, K. et al. Tetrahedron, 1995, 57(10), 2875-2894) was dissolved in tetrahydrofuran (2 mL) and triethylamine (71 μL, 0.51 mmol). Methanesulphonylchloride (31 μL, 0.40 mmol) was added at 0 0C and stirring was continued for 2 h at 25 0C. Water and ethyl acetate was added and the organic phase was collected, dried over sodium sulfate and evaporation of the solvent in vacuo gave 120 mg (quantitative yield) of the title compound: MS (AP) m/z 368 [M+l]+.
Example 109
8-r3-BromophenvlV8-r4-methoxvρhenvlV3-("methvlsulfonylV3.4,7,8- tetrahydroimidazoπ,5-a1pvrimidme-6(2HVthione S; vrτs°
Figure imgf000087_0001
A mixture of 2-(methylsulfonyl)propane-l,3-diamine bis(trifluoroacetate) (107 mg, 0.28 mmol), 4-(3-bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (253 mg, 0.57 mmol) and triethylamine (0.4 mL, 2.87 mmol) in ethanol (10 mL) was stirred overnight at 70 °C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was re-dissolved in ethylacetate:water (3:1, 40 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography using an eluent with ethyl acetate in heptane (0 - 80 %) gave 120 mg (85 %) of the title compound. MS (ES) m/z 495 [M+lf. 0
Example 110
8-r3-Bromophenyl)-3-hydroxy-8-(4-methoxvphenvD-3,4,7,8-tetrahydroimidazo[l,5- fllpvrimidine-6(2H)-thione
Figure imgf000087_0002
0 4-(3-Bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (82 mg, 0.20 mmol), l,3-diaminopropan-2-ol (54 mg, 0.60 mmol) and triethylamine (139 μL, 1 mmol), was heated to 70 °C in ethanol (2 mL) for 1 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium carbonate, 0 brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using an eluent with ethyl acetate in heptane (0-100 %) to give 83 mg (96 % yield): MS (AP) m/z 433 [M+l]+. Example 111
8-(3-Bromophenvl)-3-methoxv-8-(4-methoxvphenvlV3,4J,8-tetrahvdroimidazo[1.5- alpyrimidine-6(2H)-thione 0—
Figure imgf000088_0001
O 4-(3-Bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (200 mg, 0.48 mmol), 2-methoxypropane- 1,3 -diamine (92 mg, 0.88 mmol, described in Ramalingam, K. et al. Tetrahedron, 1995, 57(10), 2875-2894) and triethylamine (0.36 mL, 2.6 mmol), was heated to 70 °C in ethanol (5 mL) for 12 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was used without further purification: MS (ES) m/z 446, 448 [M+l]+.
Example 112
8-(3-BromophenvlV8-(4-methoxvphenyl')-6-thioxo-23,4,6J,8-hexahvdroimidazori,5- αlpyrimidine-3 -carbonitrile
Figure imgf000088_0002
o
4-(3-Bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (41 mg, 0.10 mmol), 3-amino-2-(aminomethyl)propanenitrile (10 mg, 0.10 mmol, described in 0 Ramalingam, K. et al. Tetrahedron, 1995, 5i(10), 2875-2894) and triethylamine (139 μL, 1.0 mmol), was heated to 70 °C in ethanol (5 mL) for 2 days. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was used without further purification: MS (AP) m/z 442 [M+ 1]+. Example 113
Methyl 8-(3-bromophenviy8-(4-methoxvphenvlV6-thioxo-2,3A6J,8- hexahvdroimidazori,5-a1pyrimidine-3-carboxvlate
Figure imgf000089_0001
o
4-(3-Bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (100 mg, 0.24 mmol), methyl 3-amino-2-(aminomethyl)propanoate (32 mg, 0.24 mmol, described in Nanjappan, P. et al. Tetrahedron, 1994, 50(29), 8617-8632) and triethylamine (139 μL, 1 mmol), was heated to 70 °C in ethanol (5 mL) for 12 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography using an eluent with ethyl acetate in heptane (0-100 %) to give 45 mg (39 % yield): MS (AP) m/z 475 [MH]+.
Example 114 iV-[8-('3-bromophenvl)-8-(4-methoxvphenvl)-6-thioxo-2,3,4,6,7,8-hexahvdroimidazori,5- αlpyrimidin-3 -yll acetamide
Figure imgf000089_0002
O
The title compound was prepared as described in example 113 in 47 % yield starting from iV-[2-amino-l-(aminomethyl)ethyl] acetamide bis(trifluoroacetate): MS (AP) m/z All, 474 [M+l]+.
Example 115 iV-rδ-CS-bromophenvlVδ-^-methoxvphenyD-ό-thioxo^^^^J^-hexahvdroimidazorhS- alpyrimidin-3-vllmethanesulfonamide
Figure imgf000090_0001
o tert-Butoxy carbonyl deprotection was achieved by adding trifluoroacetic acid (1.5 niL) in dichloromethane (1.5 niL) to di-tert-butyl {2-[(methylsulfonyl)amino]propane-l,3- diyl}biscarbamate (122 mg, 0.33 mmol) and the mixture was stirred at room temperature for 30 min. After evaporation in vacuo the cyclization was preformed by adding 4-(3- bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (136 mg, 0.33 mmol), triethylamine (0.18 mL, 1.32 mmol) and ethanol (5 mL). The reaction mixture was heated to 70 0C for 12 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated in vacuo. The crude product (160 mg) was used without further purification: MS (AP) m/z 508, 510 [M+lf.
Example 116
(4^-8-("3-bromophenyl)-8-(4-methoxvphenvlV6-thioxo-2,3,4,6J,8-hexahvdroimidazori,5- αipyrimidine-4-carboxvlic acid
Figure imgf000090_0002
O
4-(3-Bromophenyl)-4-(4-methoxyphenyl)-l,3-thiazolidine-2,5-dithione (0.94 mg, 0.23 mmol), (25)-2-amino-4-[(fert-butoxycarbonyl)amino]butanoic acid (50 mg, 0.23 mmol) and triethylamine (32 μL, 0.23 mmol) was heated to 70 °C in ethanol (5 mL) for 12 h. The solvent was concentrated in vacuo. tert-Butoxy carbonyl deprotection was achieved by adding trifluoroacetic acid in dichloromethane (1:1, 3 mL) and the mixture was stirred at room temperature for 2 h. After evaporation in vacuo ethanol (5 mL) was added and the mixture heated to 70 °C 12 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was used without further purification: MS (AP) m/z 459, 461 [M+lf.
Example 117
8-(3-Bromophenvl)-3,3-difluoro-8-(4-methoxyphenvlV3.4,7,8-tetrahvdroimidazo[1.5- α]pyrimidine-6(2H)-thione
F
/ — — -N'
Figure imgf000091_0001
A solution of 4-(3-bromophenyl)-4-(4-methoxyρhenyl)-l,3-thiazolidine-2,5-dithione (2 g, 5 mmol), 2,2-difluoropropane- 1,3 -diamine (0.79 g, 7.2 mmol, described inNanjappan, P. et al. Tetrahedron, 1994, 50(29), 8617-8632) and triethylamine (3.5 mL, 25 mmol) in ethanol (50 mL) was heated at 70 °C and stirred overnight. The mixture was then cooled to ambient temperature, concentrated and re-dissolved in ethyl acetate: water mixture (3:1, 200 mL). The organic layer was then separated, washed with brine dried over sodium sulfate and concentrated. The product was purified with column chromatography using a gradient with 0-100 % ethyl acetate in n-heptane as eluent, to give the title compound 1.13 g (50 % yield): MS (ES) m/z 453 [M+lf.
Example 118
8-(3-Bromophenvl)-3,3-difluoro-8-pvridin-4-vl-3,4J,8-tetrahydroimidazori,5- αlpvrimidine-6C2H)-thione
Figure imgf000092_0001
Br
4-(3-Bromo-phenyl)-4-pyridin-4-yl-thiazolidine-2,5-dithione (1.76 g, 4.61 mmol) and 2,2- difluoropropane- 1,3 -diamine dihydrochloride (4.75 g, 6.84 mmol, described inNanjappan, P. et al. Tetrahedron, 1994, 50(29), 8617-8632) was dispersed in ethanol (55 mL).
5 Triethylamine (15.5 mL) was added in one portion. The reaction mixture was heated to 70 0C with an oil bath and stirred for 16 h, allowed to cool to room temperature and the solvent was evaporated. The residue was re-dissolved in ethyl acetate and water, and the phases separated. The organic phase was washed with water. The combined aqueous layers were extracted with ethyl acetate, the organic fractions were combined, dried over o magnesium sulfate, filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate, evaporated in vacuo onto 25 g of silica and then purified by column chromatography with an eluent of ethyl acetate in heptane (0- 33 %). Pure fractions were concentrated in vacuo to give 1.43 g (73 % yield) of the title compound. MS (ES) m/z 423, 425 [M+l]+ s
Example 119 δ-rS-BromophenvlVS-fluoro-S-^-methoxyphenvlVS^J^-tetrahydroimidazori.S- αlpvrimidine-6(2H)-thione
.F
Figure imgf000092_0002
0 The title compound was prepared as described in example 117 in 60 % yield starting from 2-fluoropropane- 1,3 -diamine (described in Nanjappan, P. et al. Tetrahedron, 1994, 50(29), 8617-8632): MS (ES) m/z 436 [M+l]+. Example 120
8-(3-BromophenvlV8-f4-methoxvphenvlV3-(methvlsulfonvlV2.3.4.8- tetrahvdroimidazo F 1.5-α1ρyrimidin-6-amine
Figure imgf000093_0001
Aqueous fer/-butyl hydroperoxide (70 %, 0.5 mL, 3.6 mmol) was added to a solution of 8- (3-bromophenyl)-8-(4-methoxyphenyl)-3-(methylsulfonyl)-3,4,7,8-tetrahydroimidazo[l,5- a]pyrimidine-6(2H)-thione (120 mg, 0.24 mmol) and aqueous ammonia (30 %, 0.97 mL) in methanol (3 mL). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was re-dissolved in dichloromethane, washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography, using dichloromethane with 0.05 % ammonia in methanol (7 N) and methanol from 0-10 % as eluent, gave 72 mg (62 % yield) of the title compound. MS (ES) m/z 478 [M+l]+.
Example 121 δ-fS-BromophenvD-S.S-difluoro-S-^-methoxyphenvD^^Λ.S-tetrahvdroimidazorLS- flipyrimidin-6-amine
H2N.
■Λ
Figure imgf000093_0002
> " τ
The title compound was prepared as described in example 120 in 90 % yield starting from o 8-(3-bromophenyl)-3,3-difluoro-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]pyrimidine-6(2H)-thione: MS (ES) m/z 436 [M+l]+. Example 122
8-("3-BromophenvlV33-difluoro-8-pvridin-4-vl-23,4.,8-tetrahvdroiniidazori,5- flipvrimidin-6-amine
^NV
N >
^ N
Aqueous tert-butyl hydroperoxide (70 %, 5 mL) was added to a mixture of 8-(3- bromophenyl)-3,3-difluoro-8-pyridm-4-yl-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine- 6(2H)-thione (1.41 g, 3.33 mmole), methanol (20 mL) and aqueous ammonia (25 %, 10 mL). The reaction was stirred at room temperature 21 h then evaporated in vacuo. The o residue was redissolved in dichloromethane, washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by column chromatography using a gradient with dichloromethane /methanol/ 6 M ammonium in methanol (2000:0:1 to 2000:400:1). Pure fractions were concentrated in vacuo to give 0.41 g (30 % yield) of the title compound. MS (ES) m/z 406, 408 [M+l]+ 5
Example 123
8-(3-Bromophenvl')-3-fluoro-8-(4-methoxyphenvl')-2,3,4,8-tetrahvdroimidazo[l,5- αlpvrimidin-6-amine
H2N, -F
-N
~^N
Figure imgf000094_0002
0 The title compound was prepared as described in example 120 in 89 % yield starting from 8-(3-bromophenyl)-3-fluoro-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]pyrimidine-6(2H)-thione: MS (ES) m/z 418 [M+lf. Example 124
8-(3\5'-DicMorobiphenvl-3-vlV8-r4-methoxvphenvlV3-fmethvlsulfonvlV2.3.4.8- tetrahvdroimidazorL5-αlpvrimidin-6-amme 2.0 acetate
H2N
Cl
Figure imgf000095_0001
5 A mixture of 8-(3-bromophenyl)-8-(4-memoxyphenyl)-3-(methylsulfonyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine (36 mg, 75 μmol), (3,5- dichlorophenyl)boronic acid (19 mg, 98 μmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (7 mg, 7.5 μmol) and cesium carbonate (74 mg, 226 μmol) in l,2-dimethoxyethane:water:ethanol o (6:3:1, 3 mL) was heated in a microwave at 130 °C for 15 min. When cooled to ambient temperature the mixture was diluted with water (3 mL) and extracted with dichloromethane (20 mL). The organic extract was dried over sodium sulfate, concentrated in vacuo and the product was purified by preparative HPLC, to give the title compound (25 mg, 61 % yield) as a 1:1 mixture of two diastereomers. 1H NMR (DMSO-J6) δ 7.95 - 7.87 (m, 1 H), 7.86 - 5 7.79 (m, 1 H), 7.63 - 7.53 (m, 10 H), 7.48 - 7.34 (m, 6 H), 6.94 - 6.74 (m, 4 H), 5.10 - 4.88 (m, 2 H), 3.80 (q, J= 9.50 Hz, 2 H), 3.70 (s, 6 H), 3.69 - 3.61 (m, 2 H), 3.56 - 3.36 (m, 4 H), 3.07 (s, 6 H), 1.90 (s, 6 H); MS (ES) m/z 544 [M+l]+.
Example 125 Q 6-Amino-8-("3'.5'-dichlorobiphenvl-3-vlV8-('4-methoxvphenvlV2.3.4,8- tetrahydroimidazo [1,5 -αipyrimidin-3 -ol
OH
C H,N
Figure imgf000095_0002
O
8-(3-Bromophenyl)-3-hydroxy-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]pyrimidine-6(2H)-thione (86 mg, 0.20 mmol) was dissolved in methanol: aqueous ammonia (25 %, 2:1, 6 mL) and aqueous tert-butyl hydroperoxide (70 %, 0.55 mL, 4.0 mmol). The reaction was heated at 40 0C for 12 h. Water and ethyl acetate was added and the organic phase was collected, dried over sodium sulfate and the solvent was evaporated in vacuo.
5 1,2-Dimethoxy ethane:water (2:1, 3 mL), (3,5-dichlorophenyl)boronic acid (76 mg, 0.40 mmol) and potassium carbonate (83 mg, 0.60 mmol) were added. Nitrogen was bubbled through the solution for 5 min, [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (29 mg, 0.04 mmol) added and the vial sealed. The reaction was heated in a microwave oven for 15 min at 130 °C. Water and ethyl acetate o was added and the organic phase was collected, dried over sodium sulfate and evaporation of the solvent in vacuo followed by purification by preparative HPLC gave 17 mg (15 % yield) of the title product as a 1:1 mixture of diastereomers: 1H NMR (DMSO-^) δ 7.73 - 7.61 (m, 2 H), 7.58 (m, 2 H), 7.53 - 7.46 (m, 2 H), 7.44 - 7.40 (m, 2 H), 7.36 - 7.29 (m, 2 H), 6.97 - 6.90 (m, 2 H), 4.27 (m, 1 H), 3.87 - 3.73 (m, 2 H), 3.80, 3.79 (2s, 3 H), 3.72 - s 3.65 (m, 1 H), 3.59 - 3.51 (m, 1 H); MS (AP) m/z 481 [M+l]+.
Example 126
8-f3',5'-Dichlorobiphenvl-3-vlV3-methoxv-8-(4-methoxvphenvlV2.3.4.8- tetrahydroimidazo [1,5 -αipvrimidin-6-amine
O—
Cl
Π,IN
-N
:N
Cl
Figure imgf000096_0001
' 0 U
8-(3-Bromophenyl)-3-methoxy-8-(4-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]pyrimidine-6(2H)-thione (130 mg, 0.30 mmol) was dissolved in methanol:aqueous ammonia (25 %, 2:1, 9 mL) and aqueous tert-butyl hydroperoxide (70 %, 0.83 mL, 6.0 mmol). The reaction was heated at 40 0C for 12 h. Water and ethyl acetate was added and 5 the organic phase was collected, dried over sodium sulfate and the solvent was evaporated in vacuo. Dry dioxane (3 mL), (3,5-dichlorophenyl)boronic acid (114 mg, 0.60 mmol) and potassium carbonate (248 mg, 1.80 mmol) was added. Nitrogen was bubbled through the solution for 5 min, [l,r-bis(diphenylρhosphino)ferrocene]palladium(II) chloride dichloromethane adduct (22 mg, 0.03 mmol) was added and the vial sealed. The reaction was heated at 100 ° C for 12 h. Water and ethyl acetate was added and the organic phase was collected, dried over sodium sulfate and evaporation of the solvent in vacuo followed by purification by preparative HPLC gave 2 mg (1 % yield) the title product as a 3:2 mixture of diastereomers: 1H NMR (DMSO- J6) δ 7.65 - 7.55 (m, 4 H), 7.52 - 7.42 (m, 3 H), 7.36 - 7.21 (m, 2 H), 4.01 (m, 1 H), 3.87 (m, 2 H), 3.80, 3.79 (2s, 3 H), 3.71 (m, 1 H), 3.49 - 3.43 (m, 1 H), 3.47, 3.46 (2s, 3 H); MS (ES) m/z 496 [M+l]+.
Example 127 6-Amino-8-(3',5'-dichlorobiphenvl-3-vlV8-C4-methoxvphenvlV2,3,4.8- tetrahydroimidazo f 1.5 -αlpvrimidine-3 -carbonitrile
Cl
Figure imgf000097_0001
O
The title compound was prepared as described in example 126 in 26 % yield starting from 8-(3-bromophenyl)-8-(4-methoxyphenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5- 5 α]pyrimidine-3 -carbonitrile and (3,5-dichlorophenyl)boronic acid. The reaction mixture was heated at 100 °C for 2 days to give the product as an unknown mixture of diastereomers: 1R NMR (DMSO-J6) δ 7.73 (m, 1 H), 7.68 - 7.48 (m, 5 H), 7.46 - 7.34 (m, 2 H), 6.95 (m, 2 H), 6.84 (s, 1 H), 6.73 (s, 2 H), 4.13 (m, 1 H), 3.79 (s, 3 H), 3.74 (m, 1 H), 3.61 (m, 1 H), 2.98 (m, 2 H); MS (AP) m/z 491 [M+l]+. 0
Example 128
6-Amino-8-(3',5'-dichlorobiphenvl-3-vlV8-(4-methoxvphenvlV2.3.4.8- tetrahydroimidazofl ,5-alpvrimidine-3-carboxylic acid Q
V OH
Figure imgf000098_0001
The title compound was prepared as described in example 125 in 6 % yield starting from methyl 8-(3-bromophenyl)-8-(4-methoxyphenyl)-6-thioxo-2,3,4,6,7,8- hexahydroimidazo[l,5-a]pyrimidine-3-carboxylate. The reaction mixture was heated at 80 0C for 2 days to give the product as a 1:1 mixture of diastereomers: 1H NMR (DMSO-J6) δ 7.68 - 7.59 (m, 2 H), 7.57 (m, 2 H), 7.54 - 7.45 (m, 2 H), 7.44 - 7.40 (m, 1 H), 7.32 (m, 1 H), 7.24 (m, 1 H), 6.92 (m, 2 H), 3.97 - 3.84 (m, 2 H), 3.83 - 3.68 (m, 2 H), 3.80, 3.78 (2s, 3 H), 2.88 (m, 1 H); MS (ES) m/z 510 [M+l]+.
Example 129
N-r6-amino-8-(3'.5'-dichlorobiphenvl-3-vl)-8-(4-methoxvr)henvlV2.3.4.8- tetrahvdroimidazori,5-αlpyrimidin-3-vllacetamide
Cl
Figure imgf000098_0002
The title compound was prepared as described in example 125 in 10 % yield starting from 5 N-[8-(3-bromophenyl)-8-(4-methoxyphenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5- α]pyrimidin-3-yl]acetamide. The reaction mixture was heated at 80 0C for 12 h to give the product as a 1:1 mixture of diastereomers: 1H ΝMR (DMSO-J6) δ 7.66 (m, 1 H), 7.64 - 7.60 (m, 1 H), 7.57 (m, 2 H), 7.54 - 7.50 (m, 1 H), 7.33 (m, 2 H), 6.94 (m, 2 H), 4.18 (m, 1 H), 3.96 (m, 1 H), 3.80, 3.79 (2s, 3 H), 3.78 - 3.60 (m, 3 H), 1.96, 1.89 (2s, 3 H); MS (ES) o m/z 522, 524 [M+l]+.
Example 130 JV'-r6-Ainino-8-r3\5'-dichlorobiphenvl-3-vlV8-('4-methoxvphenvlV2.3.4.8- tetrahvdroimidazori,5-αlpvrimidin-3-vnmethanesulfonamide
Cl
Figure imgf000099_0001
The title compound was prepared as described in example 125 in 5 % yield starting from N-[8-(3-bromophenyl)-8-(4-methoxyphenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5- a]pyrimidin-3-yl]methanesulfonamide and (3,5-dichlorophenyl)boronic acid to give the product as a 7:3 mixture of diastereomers: 1H ΝMR (DMSO-J6) δ 7.67 - 7.47 (m, 6 H), 7.42 (m, 1 H), 7.34 - 7.28 (m, 2 H), 6.94 (m, 2 H), 4.04 - 3.85 (m, 2 H), 3.82 - 3.69 (m, 2 H), 3.80, 3.79 (2s, 3 H), 3.55 (m, 1 H), 3.01, 2.98 (2s, 3 H); MS (ES) m/z 558, 560 [M+lf. 0
Example 131
(•4^-6-amino-8-r3'.5'-dichlorobir>henvl-3-vl)-8-(4-methoxvphenvl)-23,4,8- tetrahydroimidazo \ 1 , 5 -αipvrimidine-4-carboxvric acid
O
HO-^
Figure imgf000099_0002
5 The title compound was prepared as described in example 125 in 8 % yield starting from (4lS)-8-(3-bromophenyl)-8-(4-methoxyphenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5- α]pyrimidine-4-carboxylic acid. The reaction mixture was heated at 80 °C for 3 days to give the product as a 1:1 mixture of diastereomers: 1H ΝMR (DMSO-J6) δ 7.74, 7.69 (2m, 1 H), 7.62 - 7.50 (m, 5 H), 7.48 - 7.43 (m, 1 H), 7.41 - 7.36 (m, 1 H), 7.32 (m, 1 H), 6.98 0 (m, 1 H), 6.88 (m, 1 H), 4.61 (m, 1 H), 3.81, 3.76 (2s, 3 H), 3.66 (m, 1 H), 3.49 - 3.35 (m, 1 H), 2.45 (m, 1 H), 1.99 - 1.82 (m, 1 H). MS (ES) m/z 510 [M+lf. Example 132
8-(3',5'-Dichlorobiρhenvl-3-vlV3.3-difluoro-8-('4-methoxvphenvlV2.3.4.8- tetrahvdroimidazori.5-α1pvrimidin-6-amine 0.75 acetate F
H,N.
Cl
Figure imgf000100_0001
The title compound was prepared as described in example 124 in 47 % yield starting from 8-(3-bromophenyl)-3,3-difluoro-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine: 1H NMR (DMSO-J6) δ 7.76 (t, J= 1.61 Hz, 1 H), 7.69 - 7.49 (m, 5 H), 7.48 - 7.29 (m, 3 H), 6.96 - 6.74 (m, 2 H), 4.05 - 3.93 (m, 2 H), 3.88 - 3.76 (m, 2 H), 3.71 (s, 3 H), 1.91 (s, 2 H); MS (ES) m/z 501 [MH-I]+.
Example 133
3,3-Difluoro-8-(2'-fluoro-5'-metlioxvbiphenvl-3-vlV8-ρvridin-4-vl-23,4.8- tetrahvdroimidazofl,5-αlpvrimidin-6-amine 0.25 acetate
F H2N.
Figure imgf000100_0002
The title compound was synthesized in 72 % yield as described in example 124, starting from 8-(3-bromo-phenyl)-3,3-difluoro-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5- a]pyrimidin-6-ylamine and (2-fluoro-5-methoxyphenyl)boronic acid. 1H NMR (DMSO-J6) δ 8.49 (br s, 2 H), 7.73 (s, 1 H), 7.55 - 7.47 (m, 3 H), 7.43 - 7.38 (m, 2 H), 7.21 (dd, J= 10.23, 9.00 Hz, 1 H), 6.97 - 6.89 (m, 2 H), 3.99 (t, J= 12.29 Hz, 2 H), 3.82 (t, J= 13.33 Hz, 2 H), 3.77 (s, 3 H), 1.90 (br s, 1 H); MS (ES) m/z 452 [M+l]+.
Example 134 3.3-Difluoro-8-r2'-fluoro-3'-methoxvbiphenvl-3-vl')-8-pvridin-4-vl-2.3.4,8- tetøhydroimidazori,5-α1pvrimidm-6-amme 0.75 acetate
Figure imgf000101_0001
The title compound was synthesized in 70 % yield as described in example 124, starting rrom 8-(3-bromo-phenyl)-3,3-difluoro-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5- a]pyrimidin-6-ylamine and (2-fluoro-3-methoxyphenyl)boronic acid. 1HNMR (DMSO-J6) δ 8.48 (d, J= 5.74 Hz, 2 H), 7.70 (s, 1 H), 7.59 - 7.46 (m, 3 H), 7.42 - 7.37 (m, 2 H), 7.27 - 7.09 (m, 2 H), 7.00 - 6.86 (m, 1 H), 3.99 (t, J= 12.18 Hz, 2 H), 3.86 (s, 3 H), 3.85 - 3.78 o (m, 2 H), 1.89 (s, 2 H); MS (ESI) m/z 452 [M+lf.
Example 135
3,3-Difluoro-8-(3'-methoxvbiphenvl-3-vlV8-pvridin-4-vl-2,3,4,8-tetrahydroimidazofl.5- αipyrimidin-6-amine 1.25 acetate
F H2N
N
Figure imgf000101_0002
5
[l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 27.1 μmol) was added to a stirred and nitrogen flushed suspension of (3-methoxyphenyl)boronic acid (57 mg, 373 μmole), 8-(3-bromo-phenyl)-3,3-difluoro-8-pyridin-4-yl-2,3,4,8-tetrahydro- imidazo[l,5-a]pyrimidin-6-ylamine (110 mg, 271 μmol) and cesium carbonate (263 mg, 807 μmol) in 1,2-dimethoxy ethane (6 mL), water (3 mL) and ethanol (1 mL). The reaction vessel was sealed and heated to 65 0C and stirred for 48 h. The reaction mixture was diluted with water and dichloromethane and the phases were separated. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo followed by purification by prep HPLC to give 26.7 mg (23 % yield). 1H NMR (DMSO- J6) δ 8.48 (d, J = 4.29 Hz, 2 H), 7.78 (br s, 1 H), 7.59 - 7.43 (m, 5 H), 7.37 (t, J= 7.81 Hz, 1 H), 7.16 - 7.00 (m, 2 H), 6.93 (d, J= 8.27 Hz, 1 H), 4.01 (t, J= 12.41 Hz, 2 H), 3.89 - 3.77 (m, 5 H), 1.90 (s, 4 H); MS (ES) m/z 434 [M+l]+.
Example 136
8-(3'.5'-Dichlorobir)henvl-3-vD-3-fluoro-8-(4-methoxvphenvlV2,3,4,8- tetrahvdroimidazo[l,5-a1pyrimidin-6-amine 1.5 acetate
Cl
O
Figure imgf000102_0001
The title compound was synthesized (31 % yield; 1:1 mixture of two diastereomers) as described in example 124, starting from 8-(3-bromo-phenyl)-3-fluoro-8-(4-methoxy- phenyl)-2,3,4,8-tetrahydro-imidazo[l,5-a]pyrimidin-6-ylamine: 1H NMR (DMSO-J6) δ 7.89 - 7.82 (m, 1 H), 7.70 (t, J= 1.69 Hz, 1 H), 7.65 - 7.63 (m, 1 H), 7.63 - 7.61 (m, 1 H), 7.61 - 7.58 (m, 2 H), 7.58 - 7.56 (m, 3 H), 7.56 - 7.54 (m, 3 H), 7.48 - 7.31 (m, 6 H), 6.86 ■ 6.79 (m, 4 H), 5.28 - 5.20 (m, 1 H), 5.17 - 5.06 (m, 1 H), 4.06 - 3.72 (m, 4 H), 3.71 (s, 3 H), 3.69 (s, 3 H) 3.69 - 3.41 (m, 4 H), 1.90 (s, 5 H); MS (ES) m/z 484 [M+l]+.
Example 137 1 -Ci -Bromophenvl)- 1 -(3 -furvDmethanamine
NH, Br.
Figure imgf000102_0002
1,3-Dibromobenzene (1.314 mL, 10.86 mmol) was dissolved in dry diehtylether (25 niL) and cooled to -78 0C. n-Butyl lithium (4.53 mL, 10.86 mmol, 2.5 M in hexane) was added drop wise and the mixture was stirred for 30 min. 3-Furonitrile (1.0 g, 10.86 mmol) in dry diethyl ether (10 mL) was added and the mixture was slowly warmed to 0 °C over 2 h. Dry methanol (30 mL) was added and after 30 min at 0 0C was sodium borohydride (0.83 g, 21.7 mmol) added. The mixture was stirred over night at room temperature. Saturated aqueous ammonium chloride was added and the mixture was extracted with dichloromethane. The organic phases was pooled, dried over magnesium sulfate and concentrated. Column chromatography, gradient elution from dichloromethane to c dichloromethane: methanol 99:1 afforded 0.55 g (20 % yield) of the title compound: 1H NMR (DMSO-J6) δ 7.59 (t, J= 1.76 Hz, 1 H), 7.53 (t, J= 1.76 Hz, 1 H), 7.48 - 7.46 (m, 1 H), 7.40 - 7.36 (m, 2 H), 7.26 (t, J= 7.78 Hz, 1 H), 6.37 - 6.36 (m, 1 H), 4.95 (s, 1 H), 2.24 (br s, 2 H).
s Example 138
3-r(3-BromophenylXisothiocvanato)methvnfuran
Figure imgf000103_0001
Thiophosgene (0.20 mL, 2.6 mmol) was added in portions to a stirred solution of l-(3- bromophenyl)-l-(3-furyl)methanamine (0.55 g, 2.18 mmol) and saturated aqueous sodium 0 bicarbonate (20 mL) in dichloromethane (20 mL) at 0 °C. The mixture was stirred for 1 h at 0 0C, then at room temperature for 30 min and the organic phase were collected. The aqueos phase was extracted with dichloromethane, the organic phases were pooled, washed with brine, dried over sodium sulfate, filtrated and concentrated to give 0.65 g (quantitative yield) of the title compound: 1H NMR (DMSO-J6) δ 7.74 - 7.72 (m, 1 H), 7.69 (t, J= 1.76 5 Hz, 1 H), 7.61 - 7.56 (m, 2 H), 7.45 - 7.40 (m, 2 H), 6.53 - 6.52 (m, 1 H), 6.45 (s, 1 H).
Example 139 4-r3-BromophenvD-4-(3-furylV1.3-thiazolidine-2.5-dithione
Figure imgf000104_0001
O'
3-[(3~Bromophenyl)(isothiocyanato)memyl]furan (0.64 g, 2.18 tnmol) and carbon disulfide (0.26 mL, 4.36 mmol) in dry tetrahydrofuran (15 mL) was added drop wise to a stirred mixture of potassium fert-butoxide (0.42 g, 3.7 mmol) in dry tetrahydrofuran (8 mL) at -78 0C. After the addition was the mixture was allowed to reach room temperature overnight. Water, brine and ethyl acetate was added and the organic phase was collected. The aqueos phase was extracted with ethyl acetate, the organic extracts were pooled, washed with brine, dried over sodium sulfate and evaporated to give 0.74 g (91 %) of the title compound: 1HNMR (DMSO-J6) δ 7.75 - 7.71 (m, 1 H), 7.69 - 7.64 (m, 1 H), 7.59 - 7.54 (m, 1 H), 7.40 - 7.30 (m, 3 H), 6.50 - 6.47 (m, 1 H).
Example 140 8-β-BromophenvlV8-f3-furvlV3.4.7.8-tetrahvdroimidazori.5-α1pyrimidine-6(2H)-thione
Figure imgf000104_0002
O* s 4-(3-Bromophenyl)-4-(3-furyl)-l,3-thiazolidine-2,5-dithione (0.81 g, 2.18 mmol) and 1,3- diaminopropane (0.50 g, 6.54 mmol) was heated to 70 °C in ethanol (20 mL) for 1.5 h. The mixture was cooled to room temperature and concentrated, the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic extracts were pooled, dried over sodium sulfate and evaporated. Column 0 chromatography using ethyl acetate from 0 - 35 % in n-heptane afforded 0.50 g (61 % yield) of the title compound: 1H NMR (DMSO-J6) δ 10.75 (s, 1 H), 7.67 (t, J= 1.76 Hz, 1 H), 7.63 - 7.61 (m, 1 H), 7.55 - 7.52 (m, 2 H), 7.44 - 7.41 (m, 1 H), 7.38 - 7.34 (m, 1 H), 6.45 - 6.43 (m, 1 H), 3.74 - 3.66 (m, 2 H), 3.50 - 3.37 (m, 2 H), 1.82 - 1.69 (m, 2 H); MS (ES) m/z 376, 378 [M+l]+.
Example 141 8-(3-BromophenylV8-('3-furvl)-2,3,4,8-tetrahvdroimidazori,5-α1pvrimidin-6-aniine
Figure imgf000105_0001
o-
8-(3-Bromophenyl)-8-(3-furyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)-thione (0.50 g, 1.33 mmol) was dissolved in methanol (12 mL) and aqueous ammonia (25 %, 4 niL). tert-Butyl hydroperoxide (2.7 mL, 70 % in water, 20 mmol) was added and the mixture was heated over night at 30 °C. Most of the methanol was evaporated, water was added and the mixture was extracted with ethyl acetate. The organic extracts were pooled, washed with water, brine, dried over sodium sulfate and evaporated. The crude product was purified by column chromatography using ammonia in methanol (7 N) from 0 - 6 % in dichloromethane affording 0.38 g (79 %) of the title product: 1H NMR (DMSO-J6) δ 7.68 (t, J= 1.88 Hz, 1 H), 7.57 - 7.54 (m, 1 H), 7.51 (t5 J= 1.76 Hz, 1 H), 7.46 - 7.44 (m, 1 H), 7.39 - 7.36 (m, 1 H), 7.25 - 7.21 (m, 1 H), 6.34 - 6.33 (m, 1 H), 6.26 (br s, 2 H), 3.53 - 3.48 (m, 2 H), 3.38 - 3.35 (m, 2 H), 1.71 - 1.61 (m, 2 H); MS (ES) m/z 359, 361 [M+l]+.
Example 142 8-r3\5'-Dichlorobiphenvl-3-vlV8-r3-furvlV2,3,4,8-tetrahvdroimidazori.5-α1pvrimidin-6- amine acetate Cl
NH2
Figure imgf000105_0002
8-(3-Bromophenyl)-8-(3-furyl)-2,3,4,8-tetrahydroiniidazo[l,5-α]pyrimidin-6-amine (70 mg, 0.19 mmol), [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (8 mg, 0.01 mmol), cesium carbonate (186 mg, 0.57 mmol), and (3,5-dichlorophenyl)boronic acid (42 mg, 0.22 mmol) was dissolved in dimethoxyethane:ethanol:water (6:3:1) (4 mL) and heated at 130 °C for 20 min in a microwave. When cooled to ambient temperature the mixture was filtered and purified by preparative HPLC to give 28 mg (30 % yield) of the title compound: 1H NMR (DMSO-J6) δ 7.82 (t, J= 1.76 Hz, 1 H), 7.68 - 7.65 (m, 1 H), 7.61 - 7.59 (m, 1 H), 7.58 - 7.54 (m, 3 H), 7.52 - 7.50 (m, 1 H), 7.49 - 7.48 (m, 1 H), 7.41 - 7.37 (m, 1 H), 6.40 - 6.38 (m, 1 H), 3.55 - 3.50 (m, 4 H), 1.89 (s, 3 H), 1.71 - 1.62 (m, 2 H); MS (ES) m/z 423, 425 [M-I]".
Example 143
1 -(3 -BromophenvD- 1 -(2-furvl)methanamine
Figure imgf000106_0001
O- 5 The title compound was synthesized as described for example 137 in 47 % yield starting from 2-furonitrile: 1HNMR (DMSO-J6) δ 7.57 (t, J= 1.76 Hz, 1 H), 7.52 - 7.50 (m, 1 H), 7.44 . 7.40 (m, 1 H), 7.37 - 7.33 (m, 1 H), 7.29 - 7.25 (m, 1 H), 6.38 - 6.35 (m, 1 H), 6.23 - 6.21 (m, 1 H), 5.04 (s, 1 H), 2.34 (br s, 2 H).
o Example 144
2-r(3-Bromophenvl)(isothiocvanato)methyl1furan
Figure imgf000106_0002
U
The title compound was synthesized as described for example 138 in quantitative yield starting from l-(3-bromophenyl)-l-(2-furyl)methanamine: 1HNMR (DMSO-J6) δ 7.89 (t, 25 J= 1.63 Hz, 1 H), 7.75 - 7.74 (m, 1 H), 7.46 - 7.44 (m, 2 H), 7.30 - 7.26 (m, 2 H), 6.63 (s, 1 H), 6.50 - 6.48 (m, 1 H). Example 145 4-(3-BromophenγlV4-('2-furvlV1.3-thiazolidine-2,5-dithione
Figure imgf000107_0001
The title compound was synthesized as described for example 139 in quantitative yield starting from 2-[(3-bromophenyl)(isothiocyanato)methyl]furan: 1H NMR (DMSO- J6) δ 7.76 - 7.70 (m, 1 H), 7.62 - 7.57 (m, 1 H), 7.51 - 7.49 (m, 1 H), 7.43 - 7.35 (m, 2 H), 6.51 - 6.46 (m, 1 H), 6.37 - 6.29 (m, 1 H).
Example 146
8-(3-BromophenvlV8-(2-rurvl)-3,4J,8-tetrahvdroimidazori,5-αlpvrimidine-6C2H)-thione
Figure imgf000107_0002
The title compound was synthesized as described for example 140 in 68 % yield starting from 4-(3-bromophenyl)-4-(2-furyl)-l,3-thiazolidine-2,5-dithione. The crude product was s purified by column chromatography using ethyl acetate from 0 - 45 % in n-heptane: 1H NMR (DMSO-J6) δ 10.84 (s, 1 H), 7.71 - 7.69 (m, 1 H), 7.67 (t, J= 1.76 Hz, 1 H), 7.61 - 7.58 (m, 1 H), 7.56 - 7.53 (m, 1 H), 7.42 - 7.38 (m, 1 H), 6.44 (dd, J= 3.39, 1.88 Hz, 1 H), 6.19 - 6.17 (m, 1 H), 3.79 - 3.64 (m, 2 H), 3.49 - 3.37 (m, 2 H), 1.80 - 1.72 (m, 2 H); MS (ES) m/z 376, 378 [M+l]+. 0
Example 147 8-(3-Bromophenvl)-8-r2-furvlV2.3.4.8-tetrahvdroimidazoπ.5-αlϋvrimidin-6-amine
Figure imgf000108_0001
The title compound was synthesized as described for example 141 in 78 % yield starting from 8-(3-bromophenyl)-8-(2-furyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)- thione. The crude product was purified by column chromatography using ammonia in methanol (7 N) from 0 - 6 % in dichloromethane: 1H NMR (DMSO-J6) δ 7.76 (t, J= 1.76 Hz, 1 H), 7.64 - 7.60 (m, 1 H), 7.51 - 7.48 (m, 1 H), 7.45 - 7.41 (m, 1 H), 7.28 - 7.24 (m, 1 H), 6.32 - 6.29 (m, 1 H), 6.03 - 6.00 (m, 1 H), 3.58 - 3.45 (m, 2 H), 3.41 - 3.35 (m, 2 H), 1.70 - 1.62 (m, 2 H); MS (ES) m/z 359, 361 [M+l]+.
Example 148
8-(3'.5'-Dichlorobiphenvl-3-vl)-8-('2-furvl)-23,4,8-tetrahvdroimidazori.5-(3lpvrimidin-6- amine acetate Cl
NH2
Figure imgf000108_0002
The title compound was synthesized as described for example 142 in 52 % yield starting from 8-(3-bromophenyl)-8-(2-ftiryl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine: 1H NMR (DMSCW6) δ 7.89 (t, J= 1.76 Hz, 1 H), 7.74 - 7.70 (m, 1 H), 7.63 - 7.60 (m, 2 H), 7.58 - 7.57 (m, 2 H), 7.51 - 7.50 (m, 1 H), 7.44 - 7.40 (m, 1 H), 6.32 - 6.30 (m, 1 H), 6.05 - 6.03 (m, 1 H), 3.59 - 3.49 (m, 4 H), 1.90 (s, 3 H), 1.70 - 1.63 (m, 2 H); MS (ES) m/z 425, 427 [M+l]+.
Example 149 8-("2-FυrvlV8-(3'-metfaoxvbiphenvl-3-vlV23,4.8-tetrahvdroimidazori,5-α1pvrimidin-6- amine acetate
NH,
Figure imgf000109_0001
The title compound was synthesized as described for example 142 in 55 % yield starting 5 from 8-(3-bromophenyl)-8-(2-furyl)-2,3 ,4,8-tetrahydroimidazo[l ,5-α]pyrimidin-6-amine and (3-methoxyphenyl)boronic acid: 1HNMR (DMSO-^6) δ 7.86 (t, J= 1.76 Hz, 1 H), 7.62 - 7.59 (m, 1 H), 7.55 - 7.51 (m, 2 H), 7.40 - 7.35 (m, 2 H), 7.14 - 7.10 (m, 1 H), 7.08 7.06 (m, 1 H), 6.96 - 6.92 (m, 1 H), 6.33 - 6.31 (m, 1 H), 6.07 - 6.05 (m, 1 H), 3.81 (s, 3 H), 3.57 - 3.53 (m, 4 H)5 1.89 (s, 3 H), 1.71 - 1.63 (m, 2 H); MS (ES) m/z 387 [MfI]+. 0
Example 150
1 -(3 -BromophenvD- 1 -(2-methyl- 1 ,3 -thiazol-4-yl)methanamine NHn
S
Figure imgf000109_0002
N-
The title compound was synthesized as described for example 137 in 5 % yield starting s from 2-methylthiazole-4-carbonitrile: 1H NMR (DMSO-^6) δ 7.57 (t, J= 1.88 Hz, 1 H), 7.40 - 7.34 (m, 2 H), 7.27 - 7.23 (m, 2 H), 5.10 (s, 1 H), 2.57 (s, 3 H); MS (ES) m/z 266, 268 [M+lf.
Example 151 0 4-r(3-Bromophenyiχisothiocyanato')methvl]-2-methvl-l,3-thiazole
Figure imgf000110_0001
O,O-Dipyridin-2-ylthiocarbonate (270 ng, 1.16 mmol) was added to a stirred solution of 1- (3-bromophenyl)-l-(2-methyl-l,3-thiazol-4-yl)methanamine (165 mg, 0.58 mmol) in dichloromethane (5 mL). The mixture was stirred for 30 min, diluted with 5 dichloromethane, washed with brine, dried over sodium sulfate and concentrated to afford 0.19 g (quantitative yield) of the title compound which was used without further purification: 1H NMR (DMSO-J6) δ 7.52 - 7.38 (m, 5 H), 6.52 (s, 1 H), 2.63 (s, 3 H).
Example 152 o 4-(3-Bromophenvl)-4-r2-methyl-13-thiazol-4-vlVl,3-thiazolidine-2,5-dithione
Figure imgf000110_0002
The title compound was synthesized as described for example 139 in quantitative yield starting from 4-[(3-bromophenyl)(isothiocyanato)methyl]-2-methyl-l,3-thiazole and the crude product was used without further purification: 1H NMR (DMSO-J6) δ 7.50 - 7.46 (m, s 1 H), 7.43 - 7.37 (m, 2 H), 7.36 - 7.32 (m, 2 H), 2.63 (s, 3 H).
Example 153
8-r3-Bromoρhenvl)-8-(2-methvl-l,3-thiazol-4-vlV3,4J.8-tetrahvdroimidazon.5- fllpvrimidine-6(2H)-thione
Figure imgf000111_0001
The title compound was synthesized as described for example 140 in 42 % yield starting from 4-(3-bromophenyl)-4-(2-methyl-l,3-thiazol-4-yl)-l,3-thiazolidine-2,5-dithione. The crude product was purified by column chromatography using ethyl acetate from 0 — 40 % in n-heptane: 1H NMR (DMSO-J6) δ 10.75 (s, 1 H), 7.71 (t, J= 1.88 Hz, 1 H), 7.58 - 7.56 (m, 1 H), 7.56 - 7.54 (m, 1 H), 7.40 - 7.35 (m, 1 H), 7.17 - 7.16 (m, 1 H), 3.78 - 3.63 (m, 2 H), 3.47 - 3.39 (m, 2 H), 2.62 (s, 3 H), 1.79 - 1.71 (m, 2 H); MS (ES) m/z 405, 407 [M-I]".
Example 154 8-(3-BromophenvlV8-('2-methvl-13-thiazol-4-vlV2.3,4,8-tetrahvdroimidazofl.5- α]pyrimidin-6-amine NH0
Figure imgf000111_0002
The title compound was synthesized as described for example 141 in 57 % yield starting from 8-(3-bromophenyl)-8-(2-methyl- 1 ,3-thiazol-4-yl)-3,4,7,8-tetrahydroimidazo[l ,5- α]pyrimidine-6(2H)-thione. The crude product was purified by column chromatography using ammonia (7 N) in methanol from 0-10 % in dichloromethane: 1H NMR (DMSO-J6) δ 7.80 (br s, 1 H), 7.67 - 7.61 (m, 1 H), 7.43 - 7.39 (m, 1 H), 7.27 - 7.22 (m, 1 H), 6.96 (br s, 1 H), 6.23 (br s, 2 H), 3.58 - 3.45 (m, 2 H), 3.43 - 3.35 (m, 2 H), 2.55 (s, 3 H), 1.72 - 1.61 (m, 2 H); MS (ES) m/z 390, 392 [MH-I]+.
Example 155 8-(3',5'-Dichlorobbhenvl-3-vlV8-(2-methvl-l,3-thiazol-4-γlV2.3.4.8- tetrahydroimidazofLS-αlpvrimidm-β-amine acetate Cl
NH0
Figure imgf000112_0001
The title compound was synthesized as described for example 142 in 42 % yield starting from 8-(3-bromophenyl)-8-(2-methyl-l,3-thiazol-4-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine: 1HNMR (DMSO-J6) δ 7.96 (t, J= 1.76 Hz, 1 H), 7.76 - 7.72 (m, 1 H), 7.62 - 7.59 (m, 4 H), 7.43 - 7.39 (m, 1 H), 6.99 (s, 1 H), 3.60 - 3.55 (m, 4 H), 2.56 (s, 3 H), 1.88 (s, 3 H), 1.72 - 1.62 (m, 2 H); MS (ES) m/z 456, 458 [M+l]+.
Example 156
1 -(3 -Bromophenyl)- 1 -(3 -thienypmethanamine NH.
S
Figure imgf000112_0002
The title compound was synthesized as described for example 137 in 12 % yield starting from 3-cyanothiophene: 1HNMR (DMSO-J6) δ 7.60 (t, J= 1.76 Hz, 1 H), 7.43 - 7.40 (m, 1 H), 7.39 - 7.36 (m, 2 H), 7.31 - 7.29 (m, 1 H)5 7.27 - 7.23 (m, 1 H), 7.02 (dd, J= 5.02, 1.25 Hz, 1 H), 5.11 (s, 1 H); MS (ES) m/z 251, 253 [M+l]+.
Example 157 3-r(3-Bromophenyiyisothiocvanato)methvllthiophene
Figure imgf000112_0003
20 The title compound was synthesized as described for example 151 in quantitative yield starting from l-(3-bromophenyl)-l-(3-thienyl)methanamine: MS (ES) m/z 308, 310 [M-I]".
Example 158 4-(3 -BromophenylV4-(3 -thienyl)- 1 ,3 -thiazolidine-2, 5-dithione
Figure imgf000113_0001
s-
The title compound was synthesized as described for example 139 in quantitative yield starting from 3-[(3-bromophenyl)(isothiocyanato)methyl]thiophene: 1H NMR (DMSO-J6) δ 7.58 - 7.38 (m, 3 H), 7.37 - 7.24 (m, 3 H), 6.08 - 6.19 (m, 1 H).
Example 159
8-(3-Bromophenyl)-8-(3-thienvl)-3,4.7,8-tetrahydroimidazo[l,5-α1pyrimidine-6('2H)- thione
Figure imgf000113_0002
s- The title compound was synthesized as described for example 140 in 44 % yield starting from 4-(3-bromophenyl)-4-(3-thienyl)-l,3-thiazolidine-2,5-dithione. The crude product was purified by column chromatography using ethyl acetate from 0 - 25 % in n-heptane: 1H NMR (DMSO-J6) δ 7.58 - 7.55 (m, 1 H), 7.55 - 7.48 (m, 3 H)3 7.42 - 7.38 (m, 1 H), 7.38 - 7.33 (m, 1 H), 7.06 (dd, J= 5.14, 1.38 Hz, 1 H), 3.74 - 3.69 (m, 2 H), 3.49 - 3.42 (m, 2 H), 1.80 - 1.73 (m, 2 H); MS (ES) m/z 39O5 392 [M-I]".
Example 160 8-(3-BromophenylV8-('3-thienvl)-2,3,4,8-tetrahvdroimidazo[1.5-α1pyrimidin-6-amine
Figure imgf000114_0001
S'
The title compound was synthesized as described for example 141 in 80 % yield starting from 8-(3-bromophenyl)-8-(3-thienyl)-3,4,7,8-tetrahydroimidazo[l,5-α]pyrimidine-6(2H)- thione. The crude product was purified by column chromatography using ammonia (7 N) in methanol from 0 - 8 % in dichloromethane: 1H NMR (DMSO- 6) δ 7.68 (t, J= 1.76 Hz, 1 H), 7.57 - 7.54 (m, 1 H), 7.39 - 7.35 (m, 3 H), 7.25 - 7.20 (m, 1 H), 7.03 - 7.01 (m, 1 H)5 3.54 - 3.50 (m, 2 H), 3.39 - 3.36 (m, 2 H), 1.70 - 1.64 (m, 2 H); MS (ES) m/z 373, 375 [M- I]"-
Example 161
8-B'.5'-Dichlorobiρhenvl-3-vn-8-r3-thienvn-2,3,4,8-tetrahvdroimidazori.5-ά;lρvrimidui-6- amine acetate Cl
NH2
Figure imgf000114_0002
The title compound was synthesized as described for example 142 in 38 % yield starting from 8-(3-bromophenyl)-8-(3-thienyl)-2,3,4,8-tetrahydroimidazo[l ,5-α]pyrimidin-6- amine: 1H NMR (DMSO- J6) δ 7.84 - 7.82 (m, 1 H), 7.68 - 7.64 (m, 1 H), 7.61 - 7.59 (m, 1 H), 7.58 - 7.53 (m, 3 H), 7.41 - 7.36 (m, 3 H), 7.08 - 7.06 (m, 1 H), 3.56 - 3.52 (m, 4 H), 1.89 (s, 3 H), 1.73 - 1.64 (m, 2 H); MS (ES) m/z 439, 441 [M-I]".
Example 162
1 -("3 -BromophenvD- 1 -(3 -methoxvphenvDmethanamine
Figure imgf000115_0001
The title compound was prepared in 89 % yield as described in example 8 starting with 3- bromoanisole: 1HNMR (DMSCW6) δ 7.63 (m, 1 H), 7.38 (m, 2 H), 7.28 - 7.16 (m, 2 H), 7.01 (m, 1 H), 6.94 (m, 1 H), 6.76 (m, 1 H), 5.05 (s, 1 H), 3.73 (s, 3 H), 2.33 (br s, 2 H); MS (ES) m/z 293 [M+l]+.
Example 163 l-Bromo-S-risothiocvanatoO-methoxvphenvDmethvlibenzene
Figure imgf000115_0002
The title compound was prepared in 93 % yield as described in example 11 starting with 1- (3-bromophenyl)-l-(3-methoxyphenyl)methanamine: 1HNMR (CDCl3) δ 7.46 - 7.42 (m, 2 H), 7.32 - 7.19 (m, 3 H), 6.90 - 6.81 (m, 3 H), 5.91 (s, 1 H), 3.80 (s, 3 H).
Example 164
4-(3-BromophenvlV4-(3-methoxvr>henvl)-l,3-thiazolidine-2,5-dithione
Figure imgf000115_0003
The title compound was prepared in quantitative yield as described in example 14 starting with l-bromo-3-[isothiocyanato(3-methoxyphenyl)methyl]benzene: MS (ES) m/z 411 [M+lf.
Example 165 δ-CS-BromophenvlVδ-fS-methoxyphenylVSΛJ^-tetrahvdroimidazori.S-fllpvrimidine- 6(2HVthione
Figure imgf000116_0001
The title compound was prepared in 68 % yield as described in example 17 starting with 4- (3-bromophenyl)-4-(3-methoxyphenyl)-l,3-thiazolidine-2,5-dithione: MS (ES) m/z All [M+l]+.
Example 166 8-(3-Bromophenyl)-8-('3-hvdroxyphenvlV3,4.,7,8-tetrahydroimidazori.5-αlpvrimidine- 6(2HVthione
Figure imgf000116_0002
The title compound was prepared in quantitative yield as described in example 20 starting with 8-(3-bromophenyl)-8-(3-methoxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5- α]ρyrimidine-6(2H)-thione: MS (ES) m/z 403 [M+l]+.
Example 167
S-fS-fS-BromophenylVό-thioxo^JΛ^J^-hexahydroimidazorLS-αipvrimidin-δ- yliphenyl methanesulfonate
Figure imgf000116_0003
The title compound was prepared in 59 % yield as described in example 21 starting with 8- (3-bromophenyl)-8-(3-hydroxyphenyl)-3>4,7,8-tetrahydroimidazo[l,5-(3]pyrimidine-6(2H)- thione and methanesulfonyl chloride: MS (ES) m/z 481 [M+l]+.
Example 168
3-|"8-("3-BromophenvlV6-thioxo-2,3.4.6.7.8-hexahvdroimidazorL5-αlpyrimidin-8- yliphenyl propane- 1 -sulfonate
Figure imgf000117_0001
The title compound was prepared in 34 % yield as described in example 21 starting with 8- (3-bromophenyl)-8-(3-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l,5-<3]pyrimidine-6(2H)- thione and 1-propanesulfonylchloride: MS (ES) m/z 509 [M+l]+.
Example 169 3 - [8 -(3 -Bromophenyr)-6-thioxo-2,3 ,4,6,7,8 -hexahy droimidazo[ 1 , 5 -αipyrimidin-8- vUphenyl cyclopropanesulfonate
W N y ex
Figure imgf000117_0002
l>7
The title compound was prepared in 38 % yield as described in example 21 starting with 8- (3-bromophenyl)-8-(3-hydroxyphenyl)-3,4,7,8-tetrahydroimidazo[l;>5-α]pyrimidine-6(2H)- thione and cyclopropanesulfonyl chloride: MS (ES) m/z 507 [M+l]+.
Example 170
8-(3-Bromophenyl)-8-('3-methoxvphenvlV2,3,4,8-tetrahydroimidazori,5-α1pyrimidin-6- 2s amine H2N
Figure imgf000118_0001
The title compound was prepared in quantitative yield as described in example 27 starting with 8-(3-bromophenyl)-8-(3-methoxyphenyl)-3,4,7,8-tetrahydroimiclazo[l,5- α]pyrimidine-6(2H)-thione: MS (ES) m/z 400 [M+l]+.
Example 171 3-r6-Amino-8-('3-bromophenvl')-2.3,4,8-tetrahvdroimidazori.,5-αlpvrimidin-8-vllphenol
H2NN
-N
Figure imgf000118_0002
The title compound was prepared in quantitative yield as described in example 20 starting with 8-(3-bromophenyl)-8-(3-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin- 6-amine: MS (ES) m/z 386 [M+l]+.
Example 172
3-r6-Amino-8-(3-bromophenvlV2,3,4,8-tetrahvdroimidazori,5-a1pyrimidm-8-vl1phenvl methanesulfonate
Figure imgf000118_0003
The title compound was prepared in quantitative yield as described in example 24 starting with 3-[8-(3-bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate: MS (ES) m/z 464 [M+lf. Example 173
3-r6-Amino-8-('3-bromophenvlV2,3,4,8-tetrahydroiniidazori.5-αlρvrimidin-8-vl1phenyl propane- 1 -sulfonate
H2N
Figure imgf000119_0001
The title compound was prepared in 81 % yield as described in example 24 starting with 3- [8-(3-Bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl propane- 1 -sulfonate: MS (ES) m/z 492 [M+l]+.
Example 174
3-r6-Amino-8-("3-bromophenvlV2,3.,4,8-tetrahydroimidazori.,5-α1pvrimidin-8-vl]phenvl cyclopropanesulfonate
H2N
Figure imgf000119_0002
The title compound was prepared in 80 % yield as described in example 24 starting with 3-
[8-(3-bromophenyl)-6-thioxo-2,3,4,6,7,8-hexahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl cyclopropanesulfonate: MS (ES) m/z 490 [M+l]+.
Example 175
3-r6-Amino-8-(/3-bromophenyD-2,3,4,8-tetrahydroimidazori,5-αlpvrimidin-8-vl1phenvl trifluoromethanesulfonate H2N
Figure imgf000120_0001
3-[6-Amino-8-(3-bromophenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]phenol (0.83 g, 2.1 mmol) was mixed with 1,1,1-trifluoro-iV-phenyl-N-
[(trifluoromethyl)sulfonyl]methanesulfonamide (0.77 g, 2.1 mmol) in dichloromethane at 0 °C. Triethylamine (0.30 mL, 2.1 mmol) was added and the mixture was stirred at 25 °C for 12 h. Aqueous potassium carbonate and ethyl acetate was added and the organic phase was collected, dried over sodium sulfate and evaporation of the solvent in vacuo gave 1.5 g (138 % yield) of the title compound: MS (ES) m/z 518 [M+lf.
Method C:
Example 176
3-{6-Amino-8-r3',5'-bis('trifluoromethvnbiphenvl-3-vll-23,4,8-tetrahvdroimidazorL5- αipyrimidin-8-vUphenvl methanesulfonate
Figure imgf000120_0002
3-[6-Amino-8-(3-bromophenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl methanesulfonate (93 mg, 0.20 mmol) was dissolved in dry dioxane (3 mL) and [3,5- bis(trifluoromethyl)phenyl]boronic acid (103 mg, 0.40 mmol) and potassium carbonate (150 mg, 1.1 mmol) was added. Nitrogen was bubbled through the solution for 5 min, [1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (30 mg, 0.04 mmol) was added and the vial sealed. The reaction was heated at 100 0C for 12 h. Ethyl acetate and water was added and the aqueous phase was dried over sodium sulfate. Evaporation of the solvent in vacuo was followed by purification by reverse phase chromatography to give 6 mg (5 % yield) the title product: 1H NMR (MeOIW4) δ 8.17 (m, 2 H), 7.94 (m, 1 H), 7.71 (m, 1 H), 7.66 (m, 1 H), 7.59 - 7.53 (m, 2 H), 7.48 (m, 1 H), 7.43 - 7.26 (m, 3 H), 3.76 (m, 2 H), 3.57 (m, 2 H), 3.20 (s, 3 H), 1.96 - 1.88 (m, 2 H); MS (ES) rø/z 597 [M+l]+.
Method D:
Example 177
S-rό-Amino-δ-rS'-chlorobiphenvl-S-vD-Σ.S^^-tetrahydroimidazori.S-αlpvrimidin-δ- yllphenvl trifluoromethanesulfonate
Figure imgf000121_0001
NH.
3-[6-Amino-8-(3-bromophenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]phenyl trifluoromethanesulfonate (103 mg, 0.20 mmol) was dissolved in dry dioxane (3 mL) and (3-chlorophenyl)boronic acid (63 mg, 0.40 mmol) and potassium carbonate (150 mg, 1.1 mmol) was added. Nitrogen was bubbled through the solution for 5 min, [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (30 mg, 0.04 mmol) was added and the vial sealed. The reaction was started at room temperature and then warmed slowly up to 100 0C where the heating was continued for 2 h. Ethyl acetate and water was added and the aqueous phase was dried over sodium sulfate. Evaporation of the solvent in vacuo was followed by purification by preparative HPLC to give 3 mg (3 % yield) the title product: 1H NMR (MeOH-^) δ 7.60 (m, 1 H), 7.58 - 7.52 (m, 4 H), 7.51 - 7.45 (m, 3 H), 7.42 - 7.32 (m, 4 H), 3.76 (m, 2 H), 3.56 (m, 2 H), 1.92 (m, 2 H). MS (ES) m/z 549 [M+lf.
25 Examples 178-192 Examples 178-192 were synthesised as described for example 176 (method C) or example 177 (method D) in similar yields as seen in the table below.
H2N
Figure imgf000122_0001
Figure imgf000122_0002
3-[6-Amino-8-(3'- OH3SO3 2 days 495 182 chlorobiphenyl-3-yl)- 2,3,4,8- tetrahydroimidazo[l ,5- α]pyrimidin-8-yl]phenyl
Figure imgf000123_0001
methanesulfonate
-[6-Amino-8-(3'- CH3SO3 4 days 491 183 tnethoxybiphenyl-3-yl)- 2,3,4,8- tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate
Figure imgf000123_0002
3-[6-Amino-8-(3',5'- CH3CH2CH2SO3 12 h 557
184 dichlorobiphenyl-3-yl)-
2,3,4,8- tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl
Figure imgf000123_0003
propane-1-sulfonate
3-[6-Amino-8-(3'- CH3CH2CH2SO3C 12 h 519 185 tnethoxybiphenyl-3-yl)- 2,3,4,8- tetrahydroimidazo[l ,5- α]pyrimidin-8-yl]phenyl propane- 1-sulfonate
Figure imgf000123_0004
3-[6-Amino-8-(3',5'- cyclopropanSO; 12 h 555
186 dichlorobiρhenyl-3-yl)-
2,3,4,8- tetrahydroimidazo[l ,5- α]pyrimidin-8-yl]phenyl
Figure imgf000123_0005
cyclopropanesulfonate
3-[6-Amino-8-(3'- cyclopropanSO: 12 h 517 187 methoxybiphenyl-3-yl)- 2,3,4,8- tetrahydroimidazo[l ,5- α]pyrimidin-8-yl]phenyl cyclopropanesulfonate
Figure imgf000123_0006
3-[6-Amino-8-(3',5'- CF3SO3 D R h 583
188 dichlorobiphenyl-3-yl)-
2,3,4,8- tetrahydroimidazo [1,5- α]pyrimidin-8-yl]phenyl
Figure imgf000123_0007
trifluoromethanesulfonate 3-[6-Amino-8-(3'- 3F3SO3 D 2 h 545 189 tnethoxybiphenyl-3-yl)- |2,3,4,8-
:etrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl trifluorornethanesulfonate
Figure imgf000124_0001
3'-[6-Amino-8-(3- CH3O 4- days 521
190 methoxyphenyl)-2,3 ,4,8 tetrahy droimidazo [1,5- α]pyrimidin-8-yl]-5- metb.oxybiphenyl-3-yl
Figure imgf000124_0002
methanesulfonate
3-[6-Ammo-8-(3',5'- CH3SO3 12 h 489 7.59 - 7.54 (m, 2 H), 7.52
191 dimethylbiphenyl-3 -yl)- - 7.41 (m, 4 H), 7.39 -
2,3,4,8- 7.31 (m, 2 H), 7.16 (m, 2 tetxahy droimidazo [1,5- H), 6.98 (m, 1 H), 3.78 α]pyrimidin-8-yl]phenyl
Figure imgf000124_0003
(m, 2 H), 3.58 (m, 2 H), methanesulfonate 3.20 (s, 3 H), 2.33 (s, 6 H), 1.96 - 1.90 (m, 2 H).
8-(3',5'- CH3O 2 days 465 7.66 - 7.60 (m, 2 H), 7.56 192 Dichlorobiphenyl-3-yl)- (d, J= 2 Hz, 2 H), 7.52 - 8-(4-methoxyphenyl)- 7.49 (m, 2 H), 7.41 (m, 1 2,3,4,8- H), 7.32 - 7.28 (m, 2 H), tetrahydroimidazo[l,5-
Figure imgf000124_0004
7.96 - 7.91 (m, 2 H), 6.83 α]pyrimidin-6-amine (m, 1 H), 6.72 (d, J= 2 Hz, 2 H), 3.83 - 3.77 (m, 2 H), 3.79 (s, 3 H), 3.61 (m, 2 H), 2.00 - 1.91 (m, 2 H).
Example 193
N-tert-Butanesulfinyl 3 -bromo-4-fluorophenvl-aldimine
Figure imgf000124_0005
A mixture of 3-bromo-4-fluorophenyl-benzaldehyde (2.2 g, 11 mmol), N-tert- butanesulfinamide (2.4 g, 20 mmol) and titanium tetraethoxide (9.1 g, 40 mmol) in tetrahydrofuran (10 mL) was heated at 65 °C for 12 h. Evaporation of solvent onto silica gel and purification by chromatography using an eluent gradient of ethyl acetate in heptane (0 - 100%) afforded 3.3 g (96 %) of the title compound. MS m/z (ES) 308 [M+l]+.
10 Example 194 l-r3-Bromo-4-fluorophenvlVl-pvridin-4-vlmethanamine
Br-.
F
Figure imgf000125_0001
' tert-Butyllithium (1.5M in pentane, 5 mL, 7.45 mmol) was added to THF (25 mL) at - 105°C under argon atmosphere. 4-Iodopyridine (0.84 g, 4.09 mmol) was added over 10 minutes. A solution of N-tert-butanesulfinyl 3-bromo-4-fluorophenyl-aldimine (1.14 g, 3.72 mmol) in THF (20 mL) was added and the reaction mixture was stirred for 1 h at -100°C and then quenched by adding water (20 mL). The mixture was partitioned between water and ethyl acetate and the organic layer was dried with sodium sulfate and concentrated. The residue was re-dissolved in methanol (25 mL), hydrochloric acid (IM in diethyl ether, 3.8 mL) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium hydrogencarbonate and dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography gradient elution from methanol (0.1% 7N ammonia) in dichloromethane (0- 10%) afforded 0.321 g (31 % yield) of the title compound. MS (ESI) rø/z 282 [M+l]+.
Example 195 4-|"(3-Bromo-4-fluorophenvlVisothiocyanato')methvllpvridine
BK
Figure imgf000125_0002
-^N 0
<9,0-Dipyridin-2-yl thiocarbonate (0.285 g, 1.23 mmol) was added to a solution of l-(3- bromo-4-fluorophenyl)-l-pyridin-4-ylmethanamine (0.230 g, 0.818 mmol) in dichloromethane (18 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane (20 mL). The organic layer was washed with brine, dried 5 over sodium sulfate and concentrated in vacuo affording 0.252 g (95% yield) of the title compound. MS (ESI) m/z 324 [M+lf. Example 196
1.3-Thiazolidine-2,5-dithione - 4-(3-bromo-4-fluorobenzvl)pvridine S.
Figure imgf000126_0001
F
A mixture of 4-[(3-bromo-4-fluorophenyl)(isothiocyanato)methyl]pyridine (0.252 g, 0.77 mmol) and carbon disulfide (0.1 mL, 1.64 mmol) in dry tetrahydrofuran (6.1 mL) was added drop wise at— 78 °C to a stirred solution of potassium tert-butoxide (0.138 g, 1.23 mmol) in dry tetrahydrofuran (6 mL). The mixture was allowed to attain ambient temperature while stirring overnight. The solvent was evaporated and the residue dissolved in chloroform-ethyl acetate (1:1, 30 mL), washed with brine, dried over sodium sulfate and o concentrated in vacuo. Purification by column chromatography using methanol (0-10%) in chloroform gave 0.230 g (70% yield) of the title compound. MS (ES) m/z 400 [M+l]+.
Example 197
3,3-Difluoro-3,4,7,8-tetrahydroimidazo[l,5-α1pvrimidine-6(2H)-thione - 4-(3-bromo-4- 5 fluorobenzvDpvridine
F
Figure imgf000126_0002
HN Bi-v
F
Figure imgf000126_0003
l,3-Thiazolidine-2,5-dithione - 4-(3-bromo-4-fluorobenzyl)pyridine (0.230 g, 0.58 mmol), crude 2,2-difluoropropane- 1,3 -diamine dihydrochloride (0.63mmol, described in Nanjappan, P. et al. Tetrahedron, 1994, 50 (29), 8617-8632) and diisopropylethylamine 0 (0.84 mL, 4.9 mmol) were dissolved in ethanol (10 mL). The reaction mixture was stirred overnigt at 70 0C. After cooling to ambient temperature the mixture was concentrated, re- dissolved in dichloromethane (30 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography using ethylacetate (0- 100%) in heptane afforded 0.167 g (65% yield) of the title compound. MS (ES) m/z 442
25 [MH-I]+. Example 198
3,3-Difluoro-2,3,4,8-tetrahvdroimidazoπ.5-α1pvrimidin-6-amine-4-('3-bromo-4- fluorobenzyppyridine
H2N,
Figure imgf000127_0001
tert-Butyl hydroperoxide (70 % aqueous solution, 0.9 mL, 5.6 mmol) was added to a solution of 3,3-difluoro-3,4,7,8-tetrahydroimidazo[l ,5-α]pyrimidine-6(2H)-thione-4-(3- bromo-4-fluorobenzyl)pyridine (0.167 g, 0.38 mmol) and ammonia (30 % aqueous solution, 1.7 mL) in methanol (10 mL). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was re- dissolved in dichloromethane (30 mL), washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography using methanol (0.1% 7N ammonia) in dichloromethane (0-10%) afforded 0.086 g (54%) of the title compound. MS (ES) rή/z 425 [M+l]+.
Example 199
3.3-Difluoro-8-r2'.6-difluoro-3'-methoxvbiphenvl-3-vlV8-pvridin-4-vl-2.3.4.8- tetrahydroimidazoπ ,5-α1pvrimidin-6-amine acetate
Figure imgf000127_0002
0 A mixture of 3,3-difluoro-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine-4-(3-bromo- 4-fluorobenzyl)pyridine (0.020 g, 0.047 mmol), 2-fluoro-3-methoxy-benzeneboronic acid (0.010 g, 0.061 mmol), [l,r-bis(diphenylphosphino)ferrocene]palladiυm(II) chloride dichloromethane adduct (0.004 g, 0.005 mmol) and cesium carbonate (0.046 g, 0.141 mmol) in l,2-dimethoxyethan:water:ethanol (6:3:1, 1.5 mL) was heated in a microwave at 130 0C for 15 min. After cooled to ambient temperature the mixture was concentrated, dissolved in dichloromethane (10 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by preparative HPLC afforded 0.019 g (86%) of the title compound. 1H NMR (DMSO-J6) 58.50 (d, J=6.02 Hz, 2 H), 7.69 - 7.56 (m, 2 H), 7.48 (d, J=6.02 Hz, 2 H), 7.31 - 7.21 (m, 3 H), 6.95 - 6.80 (m, 1 H), 4.01 (t, J=12.30 Hz, 2 H), 3.88 (s, 3 H), 3.83 (t, J=13.05 Hz, 2 H), 1.90 (s, 3 H); MS (ES) m/z 470 [M+lf.
Compounds were tested in at least one of the following assays:
β-Secretase Enzyme The enzyme used in the IGEN Cleavage-, Fluorescent-, TR-FRET- and BiaCore assays is described as follows:
The soluble part of the human β-Secretase (AA 1 — AA 460) was cloned into the ASP2- FcI 0-1 -IRES-GFP -neoK mammalian expression vector. The gene was fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells. Purified sB ACE-Fc is stored in Tris buffer, pH 9.2 and has a purity of 95%.
IGEN Cleavage Assay
The enzyme was diluted to 43 μg/ml in 40 mM MES pH 5.0. The IGEN substrate was diluted to 12 μM in 40 mM MES pH 5.0. Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is
5%). The assay was performed in a 96 well PCR plate from Greiner (#650201). Compound in dimethyl sulfoxide (3 μL) and enzyme (27 μL) were added to the plate, and pre- incubated for 10 min. The reaction was started with substrate (30 μL). The final dilution of enzyme was 20 μg/ml and the final concentration of substrate was 6 μM. After 20 minutes reaction at room temperature (RT), the reaction was stopped by removing 10 μL of the reaction mix and diluting it 1:25 in 0.2 M Trizma-HCl, pH 8.0. The product was 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 (all antibodies and the streptavidin coated beads were diluted in PBS containing 0.5% BSA and 0.5% Tween20). Then, 100 μL of 0.2 mg/mL streptavidin coated beads (Dynabeads M-280) and a 1:5000 dilution of ruthenylated goat anti-rabbit (Ru-GaR) antibody was added. The mixture was measured for electro- chemiluminescence in a BioVeris M8 Analyzer after 2 hours of incubation with shaking at RT. The dimethyl sulfoxide control defined 100% activity level and 0% activity was defined by exclusion of the enzyme (using 40 mM MES pH 5.0 buffer instead).
Fluorescent Assay
The enzyme was diluted to 52 μg/ml in 40 mM MES pH 5.0. The substrate (Dabcyl-Edans) was diluted to 30 μM in 40 mM MES pH 5.0. Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is 5%). The assay is done in a Corning 384 well round bottom, low volume, non-binding surface plate (Corning #3676). Enzyme (9 μL) together with 1 μL of compound in dimethyl sulfoxide were added to the plate and pre-incubated for 10 min. Substrate (10 μL) was added and the reaction proceeded in the dark at RT for 25 min. The final dilution of enzyme was 23 μg/ml, and the final concentration of substrate was 15 μM (Km of 25 μM). The fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 360 nm and an emission wavelength of 485 nm using a protocol for labelled Edans peptide. The dimethyl sulfoxide control defined 100% activity level and 0% activity was defined by exclusion of the enzyme (using 40 mM MES pH 5.0 buffer instead).
TR-FRET Assay
Enzyme was diluted to 6 μg/mL and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM in reaction buffer (NaAcetate, chaps, triton x-100, EDTA pH 4.5). Compounds were diluted to the desired concentration in dimethyl sulfoxide (final dimethyl sulfoxide concentration in assay is 5%). The assay was done in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676). Enzyme (9 μL) and 1 μL of compound in dimethyl sulfoxide was added to the plate, mixed and pre-incubated for 10 min. Substrate (10 μL) was added and the reaction proceeded in the dark for 15 min at RT. The reaction was stopped with the addition of 7 μL NaAcetate, pH 9. The fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 340 nm and an emission wavelength of 615 nm. The final concentration of the en∑yme was 2.7 μg/ml and the final concentration of the substrate was 100 nM (Km of 290 nM). The dimethyl sulfoxide control defined the 100% activity level and 0% activity was defined by exclusion of the enzyme (using reaction buffer instead).
BACE Biacore 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-VAEF was coupled to channel 2 of the same chip. The two peptides were dissolved at 0.2 mg/mL in 20 mM sodium 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 0.5 M N-ethyl-N' (3-dimethylaminopropyl)-carbodiimide and 0.5 M N- hydroxysuccinimide at 5 μL/min for 7 min. Then the stock solution of the control peptide was injected in channel 1 for 7 min at 5 μL/min., and then the remaining activated carboxyl groups were blocked by injecting 1 M ethanolamine for 7 min at 5 μL/min.
BACE Biacore Assay Protocol
The BACE Biacore assay was done by diluting BACE to 0.5 μM in sodium acetate buffer at pH 4.5 (running buffer minus dimethyl sulfoxide). The diluted BACE was mixed with dimethyl sulfoxide or compound diluted in dimethyl sulfoxide at a final concentration of 5% dimethyl sulfoxide. The BACE/inhibitor mixture was incubated for 30 minutes at RT before being injected over channel 1 and 2 of the CM5 Biacore chip at a rate of 20 μL/min. 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 dimethyl sulfoxide control was defined as 100% and the effect of the compound was reported as percent inhibition of the dimethyl sulfoxide control.
Beta-Secretase Whole Cell Assays Generation ofHEK293-APP695
The pcDNA3.1 plasmid encoding the cDNA of human full-length APP695 was stably transfected into HEK-293 cells using the Lipofectamine transfection reagent according to manufacture's protocol (Invitrogen). Colonies were selected with 0.1-0.5 mg/mL of zeocin. 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.
Cell culture for HEK293-APP695
HEK293 cells stably expressing human wild-type APP (HEK293-APP695) were grown at 37 0C, 5% CO2 in DMEM containing 4500 g/L glucose, GlutaMAX and sodium pyruvate supplemented with 10% FBS, 1% non-essential amino acids and 0.1 mg/mL of the selection antibiotic zeocin.
Aβ40 release assay HEK293-APP695 cells were harvested at 80-90% confluence and seeded at a concentration of 0.2x106 cells/mL, 100 mL cell suspension/well, onto a black clear bottom 96-well poly-D-lysine coated plate. After over night incubation at 37 0C, 5% CO2, the cell medium was replaced with cell culture medium with penicillin and streptomycin (100 U/mL, 100 μg/mL, respectively) containing test compounds in a final dimethyl sulfoxide concentration of 1%. Cells were exposed to the test compounds for 24 h at 37 0C, 5% CO2. To quantify the amount of released Aβ, 100 μL cell medium was transferred to a round bottom polypropylene 96-well plate (assay plate). The cell plate was saved for the ATP assay, as described below. To the assay plate, 50 μL of primary detection solution containing 0.5 μg/mL of the rabbit anti-Aβ40 antibody and 0.5 μg/mL of the biotinylated monoclonal mouse 6E10 antibody in DPBS with 0.5 %BSA and 0.5% Tween-20 was added per well and incubated over night at 40C. Then, 50 μL of secondary detection solution containing 0.5 μg/mL of a ruthenylated goat anti-rabbit antibody and 0.2 mg/mL of streptavidin coated beads (Dynabeads M-280) was added per well. The plate was vigorously shaken at RT for 1-2 hours. The plate was then measured for electro- chemiluminescence in a BioVeris M8 Analyzer.
Cell culture for- sh-sy5y
SH-SY5Y cells were grown 37 0C with 5% CO2 in DMEM/F-12 1:1 containing GlutaMAX supplemented with 1 mM HEPES, 10% FBS and 1% non-essential amino acids.
sAPPβ release assay SH-SY5Y cells were harvested at 80-90% confluence and seeded at a concentration of 1.5x106 cells/mL, 100 mL cell suspension/well, onto a black clear flat bottom 96-well tissue culture plate. After 7 hours of incubation at 37 0C, 5% CO2, the cell medium was replaced with 90 μl cell culture medium with penicillin and streptomycin (100 U/mL, 100 μg/mL, respectively) containing test compounds in a final dimethyl sulfoxide concentration of 1%. Cells were exposed to the test compounds for 18 h at 37 0C, 5% CO2. To measure sAPPβ released into the cell medium, sAPPβ microplates from Meso Scale Discovery (MSD) were used and the assay was performed according to the manufacture's protocol. Briefly, 25 μL cell medium was transferred to a previously blocked MSD sAPPβ microplate. The cell plate was saved for the ATP assay, as described below. The sAPPβ was captured during shaking at RT for 1 hour, by antibodies spotted in the wells of the microplate. After multiple washes, SULFO-TAG labeled detection antibody was added (25μL/well, final concentration InM) to the assay plate and the plate was incubated with shaking at RT for 1 hour. Following multiple washes, 150 μl/well of Read Buffer T was added to the plate. After 10 minutes at RT the plate was read in the SECTOR™ Imager for electro-chemiluminescence.
ATP assay
As indicated above, after transferring medium for analysis of Aβ40 or sAPPβ from the cell plate, the plate was used to analyze cytotoxicity using the ViaLight™ Plus cell 30 proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP. The assay was performed according to the manufacture's protocol. Briefly, 50 μL cell lysis reagent was added per well. The plates were incubated at RT for 10 min. Two min after addition of 100 μL reconstituted ViaLight™ Plus ATP reagent, the luminescence was measured in a Wallac Victor2 1420 multilabel counter.
hERG Assay Cell culture
The hERG-expressing Chinese hamster ovary Kl (CHO) cells described by (Persson, Carlsson, Duker, & Jacobson, 2005) were grown to semi-confluence at 37 °C in a humidified environment (5% CO2) in F- 12 Ham medium containing L-glutamine, 10% foetal calf serum (FCS) and 0.6 mg/ml hygromycin (all Sigma- Aldrich). Prior to use, the monolayer was washed using a pre-warmed (37°C) 3 ml aliquot of Versene 1:5,000 (Invitrogen). After aspiration of this solution the flask was incubated at 37 °C in an incubator with a further 2 ml of Versene 1:5,000 for a period of 6 minutes. Cells were then detached from the bottom of the flask by gentle tapping and 10 ml of Dulbecco's Phosphate-Buffered Saline containing calcium (0.9 mM) and magnesium (0.5 mM) (PBS; Invitrogen) was then added to the flask and aspirated into a 15 ml centrifuge tube prior to centrifugation (50 g, for 4 mins). The resulting supernatant was discarded and the pellet gently re-suspended in 3 ml of PBS. A 0.5 ml aliquot of cell suspension was removed and the number of viable cells (based on trypan blue exclusion) was determined in an automated reader (Cedex; Innovatis) so that the cell re-suspension volume could be adjusted with PBS to give the desired final cell concentration. It is the cell concentration at this point in the assay that is quoted when referring to this parameter. CHO-KvI.5 cells, which were used to adjust the voltage offset on IonWorks™ HT, were maintained and prepared for use in the same way.
Electrophysiology
The principles and operation of this device have been described by (Schroeder, Neagle, Trezise, & Worley, 2003). Briefly, the technology is based on a 384-well plate (PatchPlate™) in which a recording is attempted in each well by using suction to position and hold a cell on a small hole separating two isolated fluid chambers. Once sealing has taken place, the solution on me underside of the PatchPlate is changed to one containing amphotericin B. This permeablises the patch of cell membrane covering the hole in each well and, in effect, allows a perforated, whole-cell patch clamp recording to be made.
A β-test IonWorks™ HT from Essen Instrument was used. There is no capability to warm solutions in this device hence it was operated at room temperature (~21°C), as follows. The reservoir in the "Buffer" position was loaded with 4 ml of PBS and that in the "Cells" position with the CHO-hERG cell suspension described above. A 96-well plate (V-bottom, Greiner Bio-one) containing the compounds to be tested (at 3-fold above their final test concentration) was placed in the "Plate 1" position and a PatchPlate™ was clamped into o the PatchPlate™ station. Each compound plate was laid-out in 12 columns to enable ten, 8- point concentration-effect curves to be constructed; the remaining two columns on the plate were taken up with vehicle (final concentration 0.33% DMSO), to define the assay baseline, and a supra-maximal blocking concentration of cisapride (final concentration 10 μM) to define the 100% inhibition level. The fluidics-head (F-Head) of IonWorks™ HT s then added 3.5 μl of PBS to each well of the PatchPlate™ and its underside was perfused with "internal" solution that had the following composition (in mM): K-Gluconate 100, KCl 40, MgCl2 3.2, EGTA 3 and HEPES 5 (all Sigma-Aldrich; pH 7.25-7.30 using 10 M KOH). After priming and de-bubbling, the electronics-head (E-head) then moved round the PatchPlate™ performing a hole test (i.e. applying a voltage pulse to determine whether the 0 hole in each well was open). The F-head then dispensed 3.5 μl of the cell suspension described above into each well of the PatchPlate™ and the cells were given 200 seconds to reach and seal to the hole in each well. Following this, the E-head moved round the PatchPlate™ to determine the seal resistance obtained in each well. Next, the solution on the underside of the PatchPlate™ was changed to "access" solution that had the following 5 composition (in mM): KCl 140, EGTA 1, MgCl2 1 and HEPES 20 (pH 7.25-7.30 using 10 M KOH) plus 100 Dg/ml of amphotericin B (Sigma-Aldrich). After allowing 9 minutes for patch perforation to take place, the E-head moved round the PatchPlate™ 48 wells at a time to obtain pre-compound hERG current measurements. The F-head then added 3.5 μl of solution from each well of the compound plate to 4 wells on the PatchPlate™ (the final 0 DMSO concentration was 0.33% in every well). This was achieved by moving from the most dilute to the most concentrated well of the compound plate to minimise the impact of any compound carry-over. After approximately 3.5 mins incubation, the E-head then moved around all 384-wells of the PatchPlate™ to obtain post-compound hERG current measurements. In this way, non-cumulative concentration-effect curves could be produced where, providing the acceptance criteria were achieved in a sufficient percentage of wells (see below), the effect of each concentration of test compound was based on recording from between 1 and 4 cells.
The pre- and post-compound hERG current was evoked by a single voltage pulse consisting of a 20 s period holding at -70 mV, a 160 ms step to -60 mV (to obtain an estimate of leak), a 100 ms step back to -70 mV, a 1 s step to + 40 mV, a 2 s step to -30 mV and finally a 500 ms step to -7OmV. In between the pre- and post-compound voltage pulses there was no clamping of the membrane potential. Currents were leak-subtracted based on the estimate of current evoked during the +1OmV step at the start of the voltage pulse protocol. Any voltage offsets in IonWorks™ HT were adjusted in one of two ways. When determining compound potency, a depolarising voltage ramp was applied to CHO- KvI.5 cells and the voltage noted at which there was an inflection point in the current trace (i.e. the point at which channel activation was seen with a ramp protocol). The voltage at which this occurred had previously been determined using the same voltage command in conventional electrophysiology and found to be -15 mV (data not shown); thus an offset potential could be entered into the IonWorks™ HT software using this value as a reference point. When determining the basic electrophysiological properties of hERG, any offset was adjusted by determining the hERG tail current reversal potential in IonWorks™ HT, comparing it with that found in conventional electrophysiology (-82 mV) and then making the necessary offset adjustment in the IonWorks™ HT software. The current signal was sampled at 2.5 kHz.
Pre- and post-scan hERG current magnitude was measured automatically from the leak subtracted traces by the IonWorks™ HT software by taking a 40 ms average of the current during the initial holding period at —70 mV (baseline current) and subtracting this from the peak of the tail current response. The acceptance criteria for the currents evoked in each well were: pre-scan seal resistance >60 MΩ, pre-scan hERG tail current amplitude >150 p A; post-scan seal resistance >60 MΩ. The degree of inhibition of the hERG current was assessed by dividing the post-scan hERG current by the respective pre-scan hERG current for each well.
Results
Typical IC50 values for the compounds of the present invention are in the range of about 1 to about 10,000 nM. Biological data on exemplified final compounds is given below in Table 1.
Figure imgf000136_0001
Figure imgf000138_0001

Claims

Claims
1. A compound of formula I:
(R1),
Figure imgf000139_0001
A is independently selected from a 5, 6 or 7 membered heterocyclic ring optionally substituted with one or more R1;
B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one or more R2;
R1 is independently selected from halogen, cyano, nitro, OR6, C1-6alkyl, C2-6alkenyl, C2-δalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylC3-6cycloalkyl, C0-6alkylC3. όcycloalkenyl, C0-6alkylC3-6cycloalkynyl, C0-6alkylC3-6heterocyclyl, NR6R7, CONR6R7, NR6(CO)R7, 0(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6(SO2)R7, SO2R6, SOR6, OSO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-βalkylaryl, Co- όalkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC3- δcycloalkynyl, and C0-6alkylC3-6heterocyclyl may be optionally substituted with one or more C; or two R1 substituents may together with the atom to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more C;
R2, R3 and R4 are independently selected from halogen, cyano, nitro, OR6, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylQ-όcycloalkyl, Co- 6alkylC3-6cycloalkenyl, Co-6alkylC3.6cycloalkynyl, C0-6alkylC3-6heterocyclyl, NR6R7, CONR6R7, NR6(CO)R7, 0(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6(SO2)R7, SO2R6, SOR6, OSO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co.6alkylheteroaryl, C0.6alkylC3-6cycloalkyl, C0.6alkylC3-6cycloalkenyl, C0-6alkylC3- 6cycloalkynyl and Co-ealkylCs-eheterocyclyl may be optionally substituted with one or more C; or two R2, R3 or R4 substituents may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more C;
R5 is independently selected from hydrogen, cyano, OR6, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, C0-6alkylC3- gcycloalkenyl, Co.6alkylC3-6cycloalkynyl, C0-6alkylC3-6heterocyclyl, CONR6R7, CO2R6, COR6, SO2R6 and SO3R6 wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-ealkylaryl, C0. 6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC3- 6cycloalkynyl, C0-6alkylC3-6heterocyclyl may be optionally substituted with one or more C;
C is independently selected from halogen, nitro, CN, OR6, Q-ealkyl, C2-6alkenyl, C2-6alkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, C0-6alkylC3- 6cycloalkenyl, Co-6alkylC3-6cycloalkynyl, Co-βalkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, NR6R7, CONR6R7, NR6(CO)R7, O(CO)R6, CO2R6, COR6, (SO2)NR6R7, NR6SO2R7, SO2R6, SOR6, OSO2R6 and SO3R6, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- ealkylaryl, Co-eheteroaryl, Co-6alkylC3.6cycloalkyl, C0-6alkylC3-6cycloalkenyl, Co-6alkylC3. βcycloalkynyl or Co-ealkylheterocyclyl may be optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR6, C1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;
R6 and R7 are independently selected from hydrogen, C1-6alkyl, C0-6alkylaryl, heteroaryl, Co-6alkylC3-6cycloalkyl, Co.6alkylC3-6cycloalkenyl, Co-6alkylC3-6cycloalkynyl, C0- 6alkylheterocyclyl, fluoromethyl, difluoromethyl and trifluoromethyl; or R6 and R7 may together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S;
m = 0, 1, 2 or 3; n = O5 I5 2 or 3; p = 0, l, 2 or 3; q = 0, 1, 2 or 3; as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
2. A compound according to claim 1, wherein R5 is hydrogen.
3. A compound according to claim 1 or 2, wherein A is selected from a 5 or 6 membered heterocyclic ring.
4. A compound according to any one of claims 1 to 3, wherein m is 0.
5. A compound according to any one of claims 1 to 3, wherein m is 1 or 2, wherein R is independently selected from halogen, cyano, OR6, NR6(CO)R7, CO2R6, NR6(SO2)R7 and SO2R6.
6. A compound according to claim 5, wherein R6 and R7 are independently selected from hydrogen, C^alkyl and trifluoromethyl.
7. A compound according to any one of claims 1 to 6, wherein q is 0.
8. A compound according to any one of claims 1 to 7, wherein B is selected from phenyl or pyridyl optionally substituted with one or more R2.
9. A compound according to claim 8, wherein B is phenyl substituted with one R2.
10. A compound according to claim 9, wherein one R2 is selected from OR6 and OSO2R6.
11. A compound according to claim 10, wherein R6 is C1-6alkyl.
12. A compound according to any one of claims 1 to 7, wherein B is a 5 membered heteroaromatic ring optionally substituted with one R2.
13. A compound according to claim 12, wherein R2 is C1-6alkyl.
14. A compound according to any one of claims 1 to 13, wherein p is 1 or 2.
15. A compound according to claim 14, wherein R3 is selected from halogen, cyano, nitro, OR6, C1-6alkyl, SO2R6 and OSO2R6 and wherein said C1-6alkyl, is optionally substituted with one or more C.
16. A compound according to claim 15, wherein C is halogen.
17. A compound according to claim 15, wherein R6 is Ci^alkyl or trifluoromethyl.
18. A compound according to claim 1, wherein A is independently selected from a 5 or 6 membered heterocyclic ring;
B is independently selected from phenyl or a 6 membered heteroaromatic ring optionally substituted with one R2;
R2 and R3 are independently selected from halogen, cyano, nitro, OR6, C^aUcyl, SO2R6 and OSO2R6, wherein said C1-6alkyl, may be optionally substituted with one or more C; R5 is hydrogen;
C is halogen;
R6 is selected from, Q-galkyl and trifluoromethyl; m = 0; n = 0 or l; p = 1 or 2; q = 0.
19. A compound according to claim 1, wherein
A is independently selected from a 5 or 6 membered heterocyclic ring optionally substituted with one or more R1;
B is independently selected from phenyl or from a 5 or 6 membered heteroaromatic ring optionally substituted with one R2; R1 is independently selected from halogen, cyano, OR6, NR6(CO)R7, CO2R6, NR6(SO2)R7 and SO2R6;
R2 and R3 are independently selected from halogen, OR6, C1-6alkyl and OSO2R6; R5 is hydrogen; R6 and R7 are independently selected from hydrogen, C^alkyl, and trifluoromethyl; m = 0, 1 or 2; n = O or 1; p = 1 or 2; q = 0.
20. A compound according to claim 1, wherein
A is a 6 membered heterocyclic ring substituted with two R1;
B is a 6 membered heteroaromatic ring;
R1 is halogen; R3 is independently selected from halogen and OR6;
R4 is halogen;
R5 is hydrogen;
R6 is C1-6alkyl; m = 2; n = 0; p = 2; and q = l.
21. A compound, selected from: 8-(3l-Methoxybiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6-amine hydrochloride;
8-(3'-Chlorobiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-(3]pyrimidin-6-amine hydrochloride;
4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimida2θ[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate;
4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate 0.75 acetate; 4-[6-Amino-8-(3^5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl propane- 1 -sulfonate 0.5 acetate;
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl propane- 1 -sulfonate 0.75 acetate; 4-{6-Amino-8-[3'-(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl}phenyl propane- 1 -sulfonate 0.5 acetate;
4-[6-Amino-8-(4'-fluoro-3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chloro-2l-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin~8-yljphenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(2',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl propane- 1 -sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3J4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropane sulfonate 0.75 acetate; 4-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropanesulfonate 0.75 acetate;
4-[6-Ammo-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropane sulfonate 0.75 acetate;
4-{6-Amino-8-[3'-(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- 0 α]pyrimidin-8-yl}phenyl cyclopropane sulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chloro-2'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl cyclopropane sulfonate 0.75 acetate;
4-[6-Amino-8-(2',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl cyclopropane sulfonate 0.5 acetate; 5 4-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate acetate;
4-[6-Amino-8-(3'-cyanobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate acetate;
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-αjpyrimidin-8- 0 yljphenyl methanesulfonate 0.25 acetate;
4-{6-Amino-8-[3'-(trifluoromethoxy)biphenyl-3-ylj-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl}phenyl methanesulfonate 0.5 acetate; 4-[6-Amino-8-(2'-fluoro-3'-metlioxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(2'-fluoro-5'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- tf]pyrimidin-8-yl]phenyl methanesulfonate 0.25 acetate; 4-[6-Amino-8-(3'-ethoxybiphenyl-3-yl)-2,3,4,8-tetraliydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(3'-nitrobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(2',5'-dimethoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin- 8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(3'-cyano-4'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.5 acetate;
4-[6-Amino-8-(5'-cyano-2'-fluorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-8-yl]phenyl methanesulfonate 0.75 acetate; 4-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate acetate;
3'-[6-Amino-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]-5- methoxybiphenyl-3-yl methanesulfonate acetate;
3'-[6-Amino-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]-5- chlorobiphenyl-3-yl methanesulfonate acetate;
4-[5-Amino-7-(3'-methoxybiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.25 acetate;
4-[5-Amino-7-(3';,5'-dichlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.25 acetate; 4-[5-Amino-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl methanesulfonate 0.5 acetate;
4-[5-Amino-7-(3'-methoxybiρhenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]ρhenyl propane-2-sulfonate 0.5 acetate;
4-[5-Amino-7-(3',5'-dichlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yljphenyl propane-2-sulfonate 0.5 acetate;
4-[5-Amino-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl propane-2-sulfonate 0.5 acetate; 3'-[5-Amino-7-(4-methoxyphenyl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7-yl]-5- methoxybiphenyl-3-yl methanesulfonate acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydro-imidazo[l,5-a]pyrimidin-8-yl)-biphenyl-3- carbonitrile hydrochloride; 5 8-(3'-Methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine 0.25 acetate;
8-(3'-Chlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine 0.25 acetate;
8-(2'-Fluoro-3t-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- 0 α]pyrimidin-6-amine 0.25 acetate;
8-(2'-Fluoro-5'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
3l-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-6- fluorobipheny 1-3 -carbonitrile 0.25 acetate; s 3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-β]pyrimidin-8-yl)-5- chlorobiphenyl-3-yl methanesulfonate 0.5 acetate;
3'-(6-Amino-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-4- fluorobiphenyl-3-carbonitrile 0.25 acetate; δ-CS'-Chloro^'-fluorobiphenyl-S-y^-S-pyridin^-yl^^^^-tetrahydroimidazotUS- 0 α]pyrimidin-6-amine 0.25 acetate;
8-Pyridin-4-yl-8-[3'-(trifluoromethyl)biphenyl-3-yl]-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
8-[3'-(Methylsulfonyl)biρhenyl-3-yl]-8-ρyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6~amine 0.25 acetate; 5 8-(3',5'-Dichlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-
6-amine 0.25 acetate;
8-(3t-Chloro-5'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate;
8-(2',3'-Dichlorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin- o 6-amine 0.25 acetate;
8-(3'-Ethoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine 0.5 acetate; S-CS'-Chloro-Z'-fluorobiphenyl-S-yO-S-pyridin^-yl-Zβ^^-tetxahydroimidazotl^- α]pyrimidin-6-amine 0.25 acetate;
8-(4'-Fluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 0.25 acetate; 5 3'-(6-Aniino-8-pyridin-4-yl-2,3,458-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-5- methoxybiphenyl-3-yl methanesulfonate 0.25 acetate;
8-(2',5'-Dichlorobiplienyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-
6-amine 0.25 acetate;
8-(3'-Chloro-4'-fluorobiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[l,5- o α]pyrimidin-6-arnine 0.25 acetate; and
3,3-Difluoro-8-(2',6-difluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l ,5 -α]pyrimidin-6-amine acetate.
22. A compound, selected from: s 4-[5-Amino-7-(3'-chlorobiphenyl-3-yl)-2,7-dihydro-3H-imidazo[l,5-α]imidazol-7- yl]phenyl trifluoromethanesulfonate 0.75 acetate;
4-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl trifluoromethanesulfonate acetate;
8-(2'-Fluoro-5'-methoxybiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazq[l,5- 0 α]pyrimidin-6-amine hydrochloride;
8-(5'-Chloro-2'-fluorobiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-
6-amine hydrochloride;
8-(3',5'-Dichlorobiphenyl-3-yl)-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine hydrochloride; 5 3'-(6-Amino-8-phenyl-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl)-5- methoxybiphenyl-3-yl methanesulfonate hydrochloride;
8-(3',5'-Dichlorobiphenyl-3-yl)-8-(4-methoxyρhenyl)-3-(methylsulfonyl)-2,3,4,8- tetrahydroimidazo[l,5-α]ρyrimidin-6-amine 2.0 acetate;
6-Amino-8-(3',5'-dichlorobiρhenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- o tetrahydroimidazo[l ,5-α]pyrimidin-3-ol;
8-(3',5t-Dichlorobiphenyl-3-yl)-3-methoxy-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine; 6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo [ 1 , 5-α]pyrimidine-3 -carbonitrile;
6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l ,5-α]pyrimidine-3-carboxylic acid; iV-[6-amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-metlioxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-3-yl]acetamide;
N-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahy droimidazo [1,5 -α]pyrimidin-3 -y l]methanesulfonamide ;
(45)-6-amino-8-(3',5'-dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidine-4-carboxylic acid;
8-(3'55'-Dichlorobiphenyl-3-yl)-3,3-difluoro-8-(4-methoxyρhenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-aniine 0.75 acetate;
3,3-Difluoro-8-(2'-fluoro-5'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 0.25 acetate; 3,3-Difluoro-8-(2'-fluoro-3'-methoxybiphenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 0.75 acetate;
3,3-Difluoro-8-(3'-methoxybiplienyl-3-yl)-8-ρyridm-4-yl-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine 1.25 acetate;
8-(3',5'-Dichlorobiphenyl-3-yl)-3-fluoro-8-(4-methoxyphenyl)-2,3,4,8- tetrahydroimidazo[l,5-α]pyrimidin-6-amine 1.5 acetate; δ-CS'^'-Dichlorobiphenyl-S-y^-S-CS-fury^^^^^-tetrahydroimidazotl^-αlpyrimidin-β- amine acetate;
8-(3t,5'-Dichlorobiphenyl-3-yl)-8-(2-furyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine acetate; 8-(2-Furyl)-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-6- amine acetate;
8-(3',5'-Dichlorobiphenyl-3-yl)-8-(2-methyl-l,3-thiazol-4-yl)-2,3,4,8- tetrahydroimidazo[l ,5-α]pyrimidin-6-amine acetate;
S-CS'^'-Dichlorobiphenyl-S-y^-δ-CS-tliieny^^^^^-tetrahydroimidazotljS-αlpyrimidm-β- amine acetate;
S-lβ-Amino-S-tS'^'-bisCtrifluoromethy^biphenyl-S-yll^^^^-tetrahydroimidazotljS- α]pyrimidin-8-yl}phenyl methanesulfonate; 3-[6-Amino-8-(3l-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl trifluoromethanesulfonate;
S-CS'^'-Dichlorobiphenyl-S-yO-S-CS-methoxypheny^^^^^-tetrahydroimidazotl^- σ]pyrimidin-6-amine; 8-(3'-Chlorobiphenyl-3-yl)-8-(3-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine;
8-(3'-Methoxybiρhenyl-3-yl)-8-(3-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine;
3-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate;
3-[6-Amino-8-(3'-chlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate;
3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl methanesulfonate; 3-[6-Amino-8-(3t,5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate;
3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl propane- 1 -sulfonate;
3-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-(3]pyrimidin-8- yl]phenyl cyclopropanesulfonate;
3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yl]phenyl cyclopropanesulfonate;
3-[6-Amino-8-(3',5'-dichlorobiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl trifluoromethanesulfonate; 3-[6-Amino-8-(3'-methoxybiphenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl trifluoromethanesulfonate;
3'-[6-Amino-8-(3-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8-yl]-5- methoxybiphenyl-3 -yl methanesulfonate;
3-[6-Amino-8-(3',5'-dimethylbiρhenyl-3-yl)-2,3,4,8-tetrahydroimidazo[l,5-α]pyrimidin-8- yljphenyl methanesulfonate; and
8-(3'55'-Dichlorobiphenyl-3-yl)-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[l,5- α]pyrimidin-6-amine.
23. A compound, said compound being: 3,3-Difluoro-8-(2',6-difluoro-3'-methoxybiρhenyl-3-yl)-8-pyridin-4-yl-2,3,4,8- tefrahydroimidazo[l,5-α]pyrimidin-6-amine acetate.
24. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 23 in association with pharmaceutically acceptable excipients, carriers or diluents.
25. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for use as a medicament.
26. Use of a compound of any one of claims 1 to 23 as a medicament for treating or preventing an Aβ-related pathology.
27. Use of a compound of any one of claims 1 to 23 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.
28. Use of a compound of any one of claims 1 to 23 in the manufacture of a medicament for treating or preventing an Aβ-related pathology.
29. Use of a compound of any one of claims 1 to 23 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.
30. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 23.
31. 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 any one of claims 1 to 23.
32. The method of claim 31, 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.
33. The method of claim 31 , wherein said mammal is a human.
34. 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 any one of claims 1 to 23 and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
35. The method of claim 34, 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.
o 36. The method of claim 34, wherein said mammal is a human.
A
PC: see extra sheet cording to International Patent Classification (IPC) or to both national classification and IPC FIELDS SEARCHED nimum documentation searched (classification system followed by classification symbols) PC: C07D ocumentation searched other than minimum documentation to the extent that such documents are included in the fields searched E, DK, FI , NO classes as above ectronic data base consulted during the international search (name of data base and, where practicable, search terms used)
PO-INTERNAU WPI DATA, PAJ, CHEM.ABS.DATA, MARPAT DOCUMENTS CONSIDERED TO BE RELEVANT ategory" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
US 20050282826 Al (M.S. MALAMAS ET AL), 1-36 22 December 2005 (22.12.2005), claims
,X WO 2006076284 A2 (WYETH), 20 July 2006 1-36 (20.07.2006)
D Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: "T" later document published after the international filing date or priority " document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention " earlier application or patent but published oa or after the international filing date "X" document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive " document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) "Y" document of particular relevance: the claimed invention cannot be " document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with one or more other such documents, such combination being obvious to a person skilled in the art document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search report
17 October 2007
Name and mailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Carolina Gomes Lager1of / MRo Facsimile No. +46 8 666 02 86 Telephone No. + 46 8 782 25 00
Form PCT/ISA/210 (second sheet) (April 2007) International patent classification (IPC)
C07D 487/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01)
Download your patent documents at www.prv.se
The cited patent documents can be downloaded at www.prv.se by following the links:
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Paper copies can be ordered at a cost of 50 SEK per copy from PRV InterPat (telephone number 08-782 28 85) .
Cited literature, if any, will be enclosed in paper form.
Form PCT/ISA/210 (extra sheet) (April 2007)
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