WO2011002407A1 - Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia - Google Patents

Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia Download PDF

Info

Publication number
WO2011002407A1
WO2011002407A1 PCT/SE2010/050759 SE2010050759W WO2011002407A1 WO 2011002407 A1 WO2011002407 A1 WO 2011002407A1 SE 2010050759 W SE2010050759 W SE 2010050759W WO 2011002407 A1 WO2011002407 A1 WO 2011002407A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
imidazol
alkylc
amine
Prior art date
Application number
PCT/SE2010/050759
Other languages
French (fr)
Inventor
Jan Blid
Tobias Ginman
Ylva Gravenfors
Sofia KARLSTRÖM
Karin Kolmodin
Johan LINDSTRÖM
Niklas Plobeck
Fredrik Rahm
Britt-Marie Swahn
Jenny Viklund
Stefan Von Berg
Fredrik Von Kieseritzky
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2011002407A1 publication Critical patent/WO2011002407A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Novel compounds for treatment of neurodegeneration associated with diseases such as Alzheimer ' s disease or dementia
  • the present invention relates to novel compounds and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as medicaments for treatment and/or prevention of various diseases.
  • the invention relates to compounds, which are inhibitors of -secretase and hence inhibit the formation of amyloid ⁇ (A ⁇ ) peptides and will be used for treatment and/or prevention of A ⁇ -related pathologies such as Alzheimer's disease, 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's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's 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.
  • AD Alzheimer's disease
  • a ⁇ amyloid ⁇ -peptide
  • a ⁇ peptide is an integral fragment of the Type I protein APP (A ⁇ amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble A ⁇ can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis.
  • CSF cerebrospinal fluid
  • ⁇ -cleavages of APP there are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called ⁇ -, ⁇ -, and ⁇ -cleavages.
  • the ⁇ -cleavage which occurs roughly in the middle of the A ⁇ domain in APP is executed by the metalloproteases ADAMlO or ADAM 17 (the latter also known as TACE).
  • the ⁇ -cleavage occuring at the N terminus of A ⁇ , is generated by the transmembrane aspartyl protease Beta site APP Cleaving Enzyme 1 (BACEl).
  • the ⁇ -cleavage is effected by a multi-subunit aspartyl protease named ⁇ -secretase.
  • ADAM 10/ 17 cleavage followed by ⁇ -secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated A ⁇ fragment that fails to form amyloid deposits in humans.
  • This proteolytic route is commonly referred to as the non-amyloidogenic pathway.
  • Consecutive cleavages by BACEl and ⁇ -secretase generates the intact A ⁇ peptide, hence this processing scheme has been termed the amyloidogenic pathway.
  • amyloidogenic processing This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.
  • Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). ⁇ -amyloid deposits are predominately an aggregate of AB peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • AB peptide results from the cleavage of APP at the C-terminus by one or more ⁇ - secretases, and at the N-terminus by B-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the B- amyloidogenic pathway.
  • BACE B-secretase enzyme
  • BACE Beta site APP Cleaving Enzyme
  • BACE activity is correlated directly to the generation of AB peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of ABpeptide (Roberds, S. L., et al, Human Molecular Genetics, 2001, 10, 1317-1324).
  • 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 -secretase activity, and is considered to be the rate- limiting step in the production of amyloid- -peptide (A ).
  • 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.
  • 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, ⁇ -amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or 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, ⁇ -amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or 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 relates to a compound according to formula (I):
  • A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
  • C is selected from hydrogen, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Co_ 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylC 3 - 6 cycloalkenyl, Co- ⁇ alkylC ⁇ Cycloalkynyl, C 0-6 alkylaryl, Co- 6 alkylheteroaryl, Co- ealkylheterocyclyl, C 0 - 6 alkylOR 4 , Co- 6 alkylC0 2 R 4 , Co- 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, Co- 6 alkylCOR 4 , CHO, NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 ,
  • R 1 is selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl,
  • R 1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 2 is selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Co_ 6 alkylC 3 _ 6 cycloalkyl,
  • Co- 6 alkylCOR 4 CHO, NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , Co_ 6 alkylNR 4 (CO)R 4 , NR 4 (CO)N(R 4 ) 2 , NR 4 (CO)(CO)R 4 , NR 4 (C0)- (CO)N(R 4 ) 2 , Co- 6 alkylSR 4 , C 0 - 6 alkylOSO 2 R 4 , C 0 - 6 alkylSO 3 R 4 , C 0 - 6 alkylSO 2 R 4 , C 0 - 6 alkyl- SOR 4 , Co-6alkyl(S0 2 )N(R 4 ) 2 , Co- 6 alkyl(SO)N(R 4 ) 2 , Co-6alkylNR 4 (S)
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , CHO, C 0 - 6 alkylCN, C 0 - 6 alkylOR 4 , Ci_ 6 haloalkyl, Co- 6 alkylN(R 4 ) 2 , NR 4 C(O)R 4 , Co- 6 alkylC0 2 R 4 , Co- 6 alkylCON(R 4 ) 2 , C 0 - 6 alkylNR 4 (CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , NR 4 (CO)N(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , C 0 - 6 alkylCOR 4 , NR 4 (CO)(CO)R 4 , NR 4 (CO)(CO)N(R 4 ) 2 , C 0 - 6 alkylCOR 4 , NR 4 (CO)(CO)R 4 , NR 4 (
  • 6 alkylSR 4 Co-6alkyl(S0 2 )N(R 4 ) 2 , OC 2 . 6 alkyl- NR 4 (SO 2 )R 4 , Co- 6 alkyl(SO)N(R 4 ) 2 , OSO 2 R 4 , SO 3 R 4 , C 0 -6alkylNR 4 (SO 2 )N(R 4 )2, C 0 - 6 alkyl- NR 4 (SO)R 4 , Co- 6 alkylS0 2 R 4 , C 0 - 6 alkylSOR 4 , Ci ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkyl- C 3 _ 6 cycloalkyl, Co- 6 alkylC 3 _ 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, Co- 6 alkylheteroaryl
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, Ci_ 3 haloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkyl- C 3 - 6 cycloalkyl, Co- 6 alkylC 3 - 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, C 0 - 6 alkylaryl,
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylC 3 _ 6 cycloalkenyl, Co- ⁇ alkylC ⁇ Cycloalkynyl, C 0 - 6 alkylaryl, Co- ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl, wherein said Ci- ⁇ alkyl, C 2 - 6 alkenyl,
  • C 2 - 6 alkynyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, C 0 - 6 alkylaryl, Co-6alkylheteroaryl or Co-6alkyl- heterocyclyl is optionally substituted with one or more R 6 ;
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co- 6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylC 3-6 cycloalkyl, Co- ⁇ alkylheterocyclyl, Ci_6halo- alkyl, OC 2 -6alkylN(R 7 ) 2 , N(R 7 ) 2 , CON(R 7 ) 2 , NR 7 (CO)R 7 , O(CO)Ci_ 6 alkyl, (CO)OCi_ 6 alkyl, COR 7 , SON(R 7 ) 2 , (SO 2 )N(R 7 ) 2 , NR 7 SO 2 R 7 , NR 7 SOR 7 , SO 2 R 7 , SOR 7 , (CO)C 1 .
  • C 3 _ 6 cycloalkenyl, C ⁇ Cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC 1-3 alkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi_3alkyl, cyano or halogen;
  • the molecular weight of the compound of formula (I) is more than 300 g/mol. In one embodiment of the present invention, the molecular weight of the compound of formula (I) is less than 600 g/mol. In another embodiment of the invention, A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
  • C is selected from hydrogen, C h alky!, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Co_ 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylC 3 - 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, Co- 6 alkylheteroaryl, Co- ealkylheterocyclyl, C 0 - 6 alkylOR 4 , Co- 6 alkylC0 2 R 4 , Co- 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, Co-ealkylCOR 4 , CHO, NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , C
  • R 1 is selected from C 1-6 alkyl, C 2 -6alkenyl, C 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl,
  • Co- 6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, Co-ealkylheterocyclyl, Co- 6 alkylC0 2 R 4 , Co- 6 alkylN(R 4 ) 2 , C 0 - 6 alkylOR 4 , halogen, Co- 6 alkylCN, C 0 - 6 alkylCOR 4 , CHO, NO 2 , C 0 - 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , C 0 .
  • R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl,
  • Co- 6 alkylCOR 4 CHO, NO 2 , C 0 - 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , Co- 6 alkylNR 4 (CO)R 4 , Co- 6 alkylS0 3 R 4 , C 0 - 6 alkylSO 2 R 4 , C 0 - 6 alkylSOR 4 , Co-6alkyl(S0 2 )N(R 4 )2, Co- 6 alkyl(SO)N(R 4 ) 2 , C 0 -6alkylNR 4 (SO 2 )N(R 4 )2, C 0 - 6 alkylNR 4" (SO)R 4 and C 0 .
  • Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 0 . 6 alkyl- C 3-6 cycloalkyl, C 0-6 alkylaryl, Co-6alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 3 ;
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , CHO, C 0 - 6 alkylCN, C 0 - 6 alkylOR 4 , Ci-ehaloalkyl,
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, Ci_ 3 haloalkyl, C 2 - 6 alkenyl, C 2 -ealkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, Co-6alkylheteroaryl and Co- ⁇ alkylheterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, Co- ⁇ alkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R 6 ; R 4 is selected from hydrogen, Ci- ⁇ alkyl, Ci_ 3 haloalkyl, C 2 - 6 alkenyl
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Cr ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0 - 6 alkylaryl, Co- ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl, wherein said Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co-6alkylC3- ⁇ cycloalkyl, C 0 - 6 alkylaryl, Co- 6 alkylheteroaryl or Co-
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , 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- ⁇ alkylheterocyclyl, C 1 .
  • Ci_ 6 alkyl COR 7 , SON(R 7 ) 2 , (SO 2 )N(R 7 ) 2 , wherein said Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 0 .
  • 6 alkylaryl, C 0-6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl or Co-6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR 7 , C 1-6 alkyl, C 1-3 haloalkyl, or OCi_3haloalkyl.
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-3 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - ⁇ cycloalkyl, C 3-6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC 1-3 alkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more of hydroxy, OC 1-3 alkyl, cyano or halogen.
  • A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is selected from hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylC 3 _ 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, Co- ealkylheterocyclyl, Co-ealkylOR 4 , C 0 - 6 alkylCO 2 R 4 , C 0 - 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, Co- 6 alkylCOR 4 , CHO, NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , Co- 6 alkylNR 4 (CO
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl,
  • R 1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, Co-6alkyl- C 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, Co-6alkyl- heterocyclyl, C 0 - 6 alkylCO 2 R 4 , C 0 -6alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, C 0 - 6 alkylCOR 4 , CHO, NO 2 , Co.
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , CHO, C 0 - 6 alkylCN, C 0 - 6 alkylOR 4 , Ci_ 6 haloalkyl, Co- 6 alkylN(R 4 ) 2 , NR 4 C(O)R 4 , Co- 6 alkylC0 2 R 4 , Co- 6 alkylCON(R 4 ) 2 , C 0 - 6 alkylNR 4 (CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , NR 4 (CO)N(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , C 0 .
  • C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, Co-6alkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, C 1-3 haloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- ealkyKV ⁇ Cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, Co -6 alkylC 6 cycloalkynyl, C 0 - 6 alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl, Ci_6alkylOR 5 and Ci-6alkylN(R 5 ) 2 , wherein said Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, C 0 - 6 alkylaryl, Co- 6 alkyl- heteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylC 3-6 cycloalkenyl, Co -6 alkylC 6 cycloalkynyl, C 0 - 6 alkylaryl, Co- ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl, wherein said C h alky!, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - ⁇ cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, Co- ⁇ alkylaryl, Co- 6 alkylheteroaryl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylheterocyclyl, Ci_ 6 halo- alkyl, OC 2 - 6 alkylN(R 7 ) 2 , N(R 7 ) 2 , CON(R 7 ) 2 , NR 7 (CO)R 7 , O(CO)Ci_ 6 alkyl, (CO)OCi_ 6 alkyl, COR 7 , SON(R 7 ) 2 , (SO 2 )N(R 7 ) 2 , wherein said C ⁇ alkyl, C 2 .
  • A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
  • B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
  • C is selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylC 5 - 6 cycloalkenyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl, Co- 6 alkylheterocyclyl, Co- 6 alkyl0R 4 , C 0 - 6 alkylCO 2 R 4 , C 0 - 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, C 0 - 6 alkylCOR 4 , NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)R 4 , C 0 - 6 alkylNR 4 (CO)R 4 , C 0 - 6 alkylSR 4 , Co- 6 alkylS0 2 R 4 , Co- 6 alky
  • C 0 - 6 alkylCO 2 R 4 C 0 - 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, C 0 - 6 alkylCOR 4 , NO 2 , 0(CO)R 4 , Co-6alkylSR 4 , and Co-6alkylOR 4 , wherein said C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 3 ;
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , C 0 . 6 alkylCN, C 0 - 6 alkylOR 4 , C ⁇ haloalkyl,
  • Co -6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, Co-6alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, C ⁇ aUcyl, C 1-3 haloalkyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, Co-
  • Ci_6alkylOR 5 and Ci-6alkylN(R 5 ) 2 wherein said Ci- ⁇ alkyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Ci- ⁇ alkyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkyl- heterocyclyl and Co- 6 alkylheteroaryl, wherein said Ci- ⁇ alkyl,
  • Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , C 1-6 alkyl, Co-6alkylaryl, Co- ⁇ alkylheteroaryl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylheterocyclyl, Ci_ 6 haloalkyl, OC 2 .
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC 1-3 alkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC 1-3 alkyl, cyano or halogen.
  • A is aryl, such as phenyl or 2,3-dihydro-l,4- benzodioxine.
  • A is heteroaryl, such as pyridine or thiophene.
  • A is phenyl, pyridine, pyrazole, imidazole or thiophene.
  • R 1 is C ⁇ aUcyl, Co-6alkylOR 4 , Co-6alkylC3_6cyclo- alkyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co- ⁇ alkylheterocyclyl, Co-6alkylN(R 4 )2, halogen, C 0 - 6 alkylCN, C 0 - 6 alkylCON(R 4 ) 2 , C 0 . 6 alkylNR 4 (CO)R 4 , C 0 - 6 alkylSO 2 R 4 , or C 0 - 6 alkylSOR 4 .
  • R 1 is C 1-6 alkyl, Co- 6 alkylC 3 _ 6 cycloalkyl,
  • Co- ⁇ alkylheterocyclyl Co- ⁇ alkylOR 4 , halogen or Co-6alkylCN;
  • R 1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 .
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, C 1 .
  • R 4 is hydrogen, C 1-6 alkyl, Ci_6alkylOR 5 , Co- 6 alkylheterocyclyl or C ⁇ haloalkyl.
  • R 4 is methyl
  • B is aryl, such as phenyl.
  • R 2 is halogen, cyano or Co- 6 alkylOR 4 .
  • R 2 is C 1-6 alkyl, halogen, Co- ⁇ alkylCN or Co- ⁇ alkylOR 4 2
  • R is fluoro
  • R 4 is hydrogen.
  • C is selected from hydrogen, C ⁇ aUcyl, Co- 6 alkyl- aryl, Co- 6 alkylheteroaryl, Co- 6 alkylCN, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co-ealkylheterocyclyl, C 0 - 6 alkylOR 4 , Co. 6 alkylN(R 4 ) 2 , halogen, Co. 6 alkylCON(R 4 ) 2 or Co- 6 alkylNR 4 (CO)R 4 .
  • C is hydrogen, C 1-6 alkyl, C 2-6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- 6 alkylaryl, C 0 . 6 alkylheteroaryl, Co-ealkylheterocyclyl, C 0 - 6 alkylOR 4 , Co. 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN or C 0 - 6 alkylNR 4 (CO)R 4 .
  • C is aryl, such as phenyl, or heteroaryl, such as pyridyl, pyrazole, isoxazole, pyrrolopyridine or pyrimidyl.
  • R 3 is halogen, Co- ⁇ alkylCN, Co- ⁇ alkylOR 4 , C 1 .
  • Ci_ 6 alkyl C 2 -6alkenyl, C 2 -ealkynyl, Co- 6 alkylC 3 -6cycloalkyl , C 0 -6alkylSO 2 R 4 , C 0 .6alkyl(SO 2 )N(R 4 )2, C 0 .6alkylCO 2 R 4 , C 0 - 6 alkylCOR 4 , or Co-ealkylheterocyclyl.
  • R 3 is halogen, Co- 6 alkylCN, Co- 6 alkylOR 4 , C 1 . ehaloalkyl or C ⁇ alkyl, Co- 6 alkylS0 2 R 4 , C 0 -6alkyl(SO 2 )N(R 4 ) 2 , C 0 - 6 alkylCO 2 R 4 ,
  • R 3 is halogen or C 2 - 6 alkynyl.
  • A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is aryl;
  • C is hydrogen, C ⁇ aUcyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl, Co- ⁇ alkylOR 4 , Co_ 6 alkylN(R 4 ) 2 , halogen, C 0- ealkylCN or C 0 - 6 alkylNR 4 (CO)R 4 ;
  • R 2 is Ci-ealkyl, halogen, C 0 - 6 alkylCN or C 0 - 6 alkylOR 4 ;
  • R 3 is halogen, C 0 - 6 alkylCN, C 0 - 6 alkylOR 4 , Ci ⁇ haloalkyl, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, Ci_ 3 haloalkyl, Co- 6 alkylC 3 - 6 cycloalkyl, C 1 .
  • R 5 is Ci- 6 alkyl
  • R 6 is oxo, OR 7 , Ci-ealkyl
  • R 7 is Ci-ealkyl.
  • A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 1 ;
  • B is aryl
  • C is hydrogen, C 1-6 alkyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylaryl, Co-
  • R 2 is Ci-ealkyl, halogen, C 0 - 6 alkylCN or C 0 - 6 alkylOR 4 ;
  • R 3 is halogen, C 0 - 6 alkylCN, C 0 - 6 alkylOR 4 , Ci ⁇ haloalkyl, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, C ⁇ haloalkyl, Co- 6 alkylC 3 - 6 cycloalkyl and Co- ⁇ alkylheteroaryl.
  • 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 compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • prodrugs examples include in vivo hydro lysab Ie esters of a compound of the formula (I).
  • An in vivo hydro lysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Various forms of prodrugs are known in the art.
  • 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 tautomers, cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. 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 separated isomeric forms.
  • 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.
  • “Co-6 alkyl” denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group 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 having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C2-6alkenyl 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.
  • alkynyl used alone or as a suffix or prefix is intended to include to include both branched and straight-chain alkynyl or olefin 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.
  • ethynyl e.g. 1-propynyl, 2-propynyl
  • 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 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 one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • polycyclic rings include, but are not limited to, 2,3-dihydro-l,4-benzodioxine, 2,2-dioxo-l,3-dihydro-2- benzothiophene, 2-methyl-isoindolin- 1 -one, 2-methyl- 1 , 1 -dioxo-3H- 1 ,2-benzothiazole l-methyl-indolin-2-one and 2,3-dihydro-l-benzofuran.
  • cycloalkyl or "carbocyclyl” are intended to include saturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems.
  • 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.
  • C3-6 cycloalkyl denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenyl is intended to include unsaturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Preferred cycloalkenyls 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.
  • C3-6 cycloalkenyl denotes such groups as cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively or positively charged species such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, ammonium, lithium ion and sodium ion 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 with acetyl, formyl, methyl or mesyl; and a ring is optionally substituted with 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-hetero aromatic. 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, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydro-thiopyranyl, tetrahydro-thiopyran 1 -oxide, tetrahydro-thiopyran 1,1 -dioxide, lH-pyridin-2-one, and 2,5-dioxoimidazolidinyl.
  • heteroaryl refers to a heteroaromatic 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, benzo furyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, pyrrolopyridinyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, aza- benzoxazolyl, imidazothiazolyl, benzo[l,4]dioxinyl, benzo[l,3]dioxolyl and the like.
  • the heteroaryl group has from 1 to 20 carbon atoms, and in further embodiments from 3 to 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
  • haloalkyl used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups, having at least one halogen substituent and having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • Co- ⁇ haloalkyl denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. 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 non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • 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.
  • 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.
  • the present invention further includes all tautomeric forms of compounds of the invention.
  • tautomer means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.
  • keto-enol tautomerism where the resulting compound has the properties of both a ketone and an unsaturated alcohol.
  • Other examples of tautomerism include 2H-imidazol-4-amine and its tautomer l,2-dihydroimidazol-5-imine, and 2H-imidazol-4-thiol and its tautomer 1,2- dihydroimidazol-5-thione. It is understood that in compound representations throughout this description, only one of the possible tautomers is drawn or named.
  • stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Compounds of the invention further include hydrates and solvates.
  • the present invention further includes isotopically-labelled compounds of the invention.
  • An "isotopically" or “radio-labelled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 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 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labelled compounds will depend on the specific application of that radio-labelled compound. For example, for in vitro receptor labelling 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 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a "radio-labelled 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.
  • 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.
  • 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.
  • 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.
  • the compounds of the invention can be used as medicaments, e.g. to treat or prevent A ⁇ -related pathologies.
  • the compounds of the invention can be used for the manufacture of a medicament to treat or prevent A ⁇ -related pathologies.
  • a method for the treatment of A ⁇ - related pathologies comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, such as a mammal or a human being, in need thereof.
  • the compounds of the invention and their pharmaceutically acceptable salts thereby provides methods of treatment of A ⁇ -related pathologies, such as, but not limited to, Alzheimer's disease, Downs syndrome, ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, traumatic brain injury and cortical basal degeneration.
  • a ⁇ -related pathologies such as, but not limited to, Alzheimer's disease, Downs syndrome, ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“mild cognitive impairment"), memory loss, attention deficit symptoms associated with
  • composition comprising as active ingredient a therapeutically effective amount of a compound according formula (I) in association with pharmaceutically acceptable excipients, carriers or diluents.
  • a method of treating or preventing an A ⁇ -related pathology in a mammal comprising administering to said patient a therapeutically effective amount of a compound according to formula (I), and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor, wherein said A ⁇ -related pathology is Alzheimer Disease.
  • a ⁇ -related pathology defined herein may be applied as a mono therapy or may involve, in addition to the compound of the invention, conjoint treatment with therapy of value in treating one or more disease conditions referred to herein.
  • therapy 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.
  • Cognitive enhancing agents, memory enhancing agents and acetyl choline esterase inhibitors includes, but not limited to, donepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine
  • 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 the invention.
  • Additional conventional therapy may include one or more of the following categories of agents:
  • antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomi
  • atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • antipsychotics including for example amisulpride, aripiprazole, asenapine,
  • anxiolytics including for example alnespirone, azapirones, benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically
  • anticonvulsants including for example carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam,
  • oxcarbazepine phenobarbital, phenytoin, pregabaline, rufmamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Alzheimer's therapies including for example donepezil, rivastigmine, galantamine, memantine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and
  • migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pizotiphen, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • neuropathic pain therapies including for example lidocain, capsaicin, and anticonvulsants such as gabapentin, pregabalin, and antidepressants such as duloxetine, venlafaxine, amitriptyline, klomipramine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • nociceptive pain therapies such as paracetamol, NSAIDS and coxibs, such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfm, tramadol, and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • coxibs such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfm, trama
  • insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos, secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
  • 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 alternatively be used for the heating of reaction mixtures.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein, unless specified otherwise, A, B and C are defined as in formula (I) above; R 10 and R 11 are defined as optionally substituted aryl or heteroaryl groups; R is defined as for C in formula (I) above; R 12 may be defined as R 4 above; and LG represents a leaving group such as halogen (such as chlorine, bromine or iodine) or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate).
  • a compound of formula (IV) wherein R 10 and R 11 are defined as optionally substituted aryl or heteroaryl groups can be prepared from a compound of formula (II) as outlined in Scheme 1.
  • a benzophenone of formula (II), may be reacted with ammonia to form intermediate of formula (III) ⁇ Scheme I).
  • the compound of formula (III) is further reacted with ethyl 2- oxopropanoate to form a compound of formula (IV).
  • Said reaction may be performed at a temperature range between +100 0 C and +160 0 C, in a suitable solvent, such as methanol, ethanol or isopropyl alcohol.
  • H Formation of a corresponding compound of formula (VI):
  • the amino imidazole of formula (VI) may be obtained by an initial formation of a compound of formula (V), by reacting the alcohol of formula (IV) with a sulphurating reagent, such as phosphorus pentasulf ⁇ de, in the presence of a base, such as pyridine (Scheme 2).
  • a sulphurating reagent such as phosphorus pentasulf ⁇ de
  • a base such as pyridine
  • the transformation to a compound of formula (VI) may be performed by reacting the compound of formula (V) with ammonia, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide..
  • an oxidation agent such as tert-butyl hydroperoxide.
  • a compound of formula (III), may be obtained, as shown in (Scheme 3), by reacting a compound of formula (VII), wherein LG is defined as above, with an organometallic reagent such as an alkyl lithium, as for example butyl lithium, to form an intermediate compound of formula (VIII), wherein M is a metal, such as for example lithium.
  • the compound of formula (VIII) is further reacted with an aryl or heteroaryl nitrile of formula (IX), .
  • Said reaction may be performed at a temperature range between -78 0 C and 0 0 C, in a suitable solvent such as THF or 2-methyl-tetrahydrofuran.
  • An imine of formula (III) is reacted with ethanebis(thioamide) to form a compound of formula (X) (Scheme 4).
  • Said reaction may be performed at a temperature range between +100 0 C and +180 0 C, in a suitable solvent such as methanol, ethanol or isopropyl alcohol, preferably in a closed system.
  • An alkylating agent such as methyl iodide and an thioimidazole of formula (X) are reacted to form a compound of formula (XI) (Scheme 5).
  • the compound of formula (XI) may then be transformed into a compound of formula (VI) by reacting it with an organometallic reagent, such as methylmagnesium bromide, in the presence of a suitable catalyst, such as [l,3-bis(diphenylphosphino)propane]nickel(II) chloride.
  • the compound of formula (VI) may also be obtained by reacting compound of formula (XI) with a mixture of zinc iodide and methylmagnesium bromide in the presence of a suitable catalyst, such as bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent such as THF, 2-methyl-tetrahydrofuran or toluene.
  • a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride
  • a compound of formula (VI) may be obtained from a compound of formula (III), wherein R 13 is hydrogen, S(O)alkyl, C(O)alkyl, S(O) 2 alkyl, OH or Oalkyl (Scheme 6).
  • Compound (III) may optionally be coordinated to a Lewis acid, as for example BF 3 , AlCl 3 , or TiCl 4 , to facilitate the reaction.
  • An imine of formula (III) is reacted with 2-oxopropane thioamide (described in Asinger et al. Justus Liebigs Annalen der Chemie 1971, vol 744, p.
  • a compound of formula (V) is subsequently treated with ammonia, in a suitable solvent such as methanol, THF, or 2- methyl-tetrahydrofuran, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide, at a temperature between room temeprature and 150 0 C, optionally in a closed system, to yield the compound of formula (VI).
  • a suitable solvent such as methanol, THF, or 2- methyl-tetrahydrofuran
  • an oxidation agent such as tert-butyl hydroperoxide
  • a compound of formula (I), wherein C is an optionally substituted aryl or heteroaryl, may be obtained ⁇ Scheme T) by starting from, for example, a compound of formula (XII), wherein LG is as defined above, and reacting said compound of formula (XII) with a boronic acid or a boronic ester or a stannane of formula T-R , wherein T is for example B(OH) 2 , B(Oalkyl) 2 , or SnR 3 , and R is defined as above, in the presence of a transition metal catalyst such as a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(O), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone)
  • triphenylphosphine tri-tert-butylphosphine or 2-(dicyclohexylphosphino)biphenyl, or zinc and sodium 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.
  • Said reaction may be performed in a suitable solvent, such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, JV, ⁇ /-dimethylacetamide, acetonitrile or N,N- dimethylformamide, or mixtures thereof.
  • a suitable solvent such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, JV, ⁇ /-dimethylacetamide, acetonitrile or N,N- dimethylformamide, or mixtures thereof.
  • a compound of formula (I), wherein C is cyano may be obtained ⁇ Scheme T) by starting from, for example, a compound of formula (XII), wherein LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine), and reacting said compound of formula (XII) with a a metal cyano reagent such as copper(I) cyanide.
  • a compound of formula (XII) wherein C is cyano
  • LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine)
  • a compound of formula (I), wherein C is an alkyl group such as methyl may be generated from compound of formula (XII) ⁇ Scheme T), wherein LG represents a leaving group, such as a halogen, (such as iodide, bromide or chlorine), by reaction with an organometallic reagent generated from zinc iodide and methylmagnesium bromide under the influence of a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
  • a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
  • a compound of formula (I) wherein C is NHC(O)R 12 may be prepared according to
  • Scheme 7 by reacting a compound of formula (XII) with a compound R 12 C(O)NH 2 in the presence of a suitable palladium catalyst such as palladium(II) acetate, optionally in the presence of a suitable ligand such as Xantphos. Said reaction is preformed in the presence of a suitable base such as cesium carbonate in a suitable solvent such as THF or 2- methyltetrafuran at a temperature between 100 0 C to 160 0 C.
  • a suitable palladium catalyst such as palladium(II) acetate
  • a suitable ligand such as Xantphos
  • Solvent mixture compositions are given as volume percentages or volume ratios.
  • Microwave heating was performed in a Biotage Creator, Initiator or Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz. It is understood that microwaves can be used for the heating of reaction mixtures.
  • TLC Thin layer chromatography
  • Merck TLC-plates Silica gel 60 F254
  • Flash chromatography was performed on a Combi Flash® CompanionTM using RediSepTM normal-phase flash columns.
  • Straight phase flash column chromatography was manually performed on Merck Silica gel 60 (0.040- 0.063mm), or automatically using an ISCO Combiflash® CompanionTM system using the solvent system indicated. Phase separation was optionally performed on an Isolute® phase separator.
  • 1 H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz unless otherwise indicated. Spectra were obtained using a Bruker av400 NMR spectrometer operating at 400 MHz for 1 H and 100 MHz for 13 C equipped with a 3 mm flow injection SEI H/D- C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1 H, 376 MHz for 19 F, and 100 MHz for 13 C, equipped with a 4-nucleus probehead with Z-gradients.
  • 500 MHz spectra were recorded using a Bruker 500MHz Avance III NMR spectrometer, operating at 500 MHz for 1 H, 125 MHz for 13 C, and 50 MHz for 15 N equipped with a 5mm TXI probehead with Z-gradients.
  • 600 MHz spectra were recorded using a Bruker DRX600 NMR spectrometer, operating at 600 MHz for 1 H, 150 MHz for 13 C, and 60 MHz for 15 N equipped with a 5mm TXI (or BBO) probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS (0.00 ppm).
  • TMS 0.00 or the residual solvent signal of DMSO-de 2.49, CD 3 OD 3.30, acetone-d ⁇ 2.04 or CDCl 3 7.25 (unless otherwise indicated).
  • Resonance multiplicities are denoted s, d, t, q, m, br and app for singlet, doublet, triplet, quartet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G131 IA Quaternary Pump, a G1367 Well-Plate Autosampler, a Gl 316A Thermostatted Column Compartment and a Gl 315A Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Column Compartment and a G1315B Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C 18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min.
  • GC analyses were performed on a HP 6890 GC equipped with a Gl 512AX flame ionization detector supplied by Agilent Technologies.
  • the column used was DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific). A linear temperature gradient was typically applied.
  • Chiral GC analyses were performed on an HP 6890 GC equipped with a flame ionization detector supplied by Agilent Technologies.
  • the column used was a Cyclodex B ID 0.25 mm x 30 m, 0.25 m (Agilent Technologies). The temperature of the GC oven was typically held isocratically at for example 100 C for 30 minutes.
  • Mass spectra were run using an automated system with atmospheric pressure chemical (APCI or CI) or electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present).
  • UPLC-MS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Autosampler, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity UPLC PDA detector and a Waters 3100 Mass Spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 ⁇ M run at a flow rate of 0.5 ml/min.
  • UPLCMS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Solvent Manager, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity PDA detector and a Waters SQ Detector.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 ⁇ M run at a flow rate of 0.5 ml/min.
  • 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 ZQ 2000 single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on a Xbridge C18, 30x50mm, 3.5 ⁇ m column or on a Gemini C18 3.0 x 50, 3 m (Phenomenex) column run at a flow rate of 1 ml/min.
  • ES electrospray ion source
  • LC-MS analyses were performed on an LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode.
  • ES electrospray ion source
  • the column used was a Xbridge C18, 30x50mm, 3.5 ⁇ m or a Gemini C 18, 3.0 mm x 50 mm, 3 m, (Phenomenex) which was run at a flow rate of 1 ml/min.
  • 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 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 system consisted of a GC 6890N, G1530N, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer.
  • the mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH.
  • 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 50-550 and the scan speed was set to 2.91 scan/s.
  • the sample solution was either injected on the GC or introduced by direct inlet to the probe tip.
  • the GC column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 15m, 0.25 m (Varian Inc.). A linear temperature gradient was typically applied.
  • GCMS analysis was performed on a GC-MS system supplied by Agilent Technologies, consisting of a 6890N G1530N GC, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer.
  • the column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 30m, 0.25 m (Varian Inc.). Typically a linear temperature gradient was applied.
  • the mass spectrometer was equipped with a chemical ionisation (CI) ion source and the reactant gas was methane or 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 3.21 scan/s.
  • Preparative HPLC was performed on a Waters Auto purification HPLC-UV system with a diode array detector using for example a Waters Xterra® MS Cs column (30x150 mm, 10 m), a Phenomex Gemini-NX column (21x250 mm, 10 m), a Waters XBridge C8 column ( 19x250 mm, 10 m), or a Waters XBridgeTM C 18 column ( 19x250 mm, 10 m) .
  • Mobile phase A 0.1 M ammonium acetate in water/mobile phase B (95:5).
  • Mobile phase B Mobile phase B:
  • 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et 2 O (60 mL) and cooled to - 78 0 C.
  • n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution stirred for 30 min.
  • 4-Cyanopyridine (2.62 g, 25.20 mmol) was added in Et 2 O (40 mL) at -78 0 C and the reaction was allowed to warm to room temperature over 30 min.
  • MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water.
  • 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et 2 O (60 mL) and cooled to 78 0 C.
  • n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution stirred for 30 min.
  • 4-Methoxybenzonitrile (3.36 g, 25.20 mmol) was added in Et 2 O (40 mL) at -78 0 C and the reaction was allowed to warm to room temperature over 30 min.
  • MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water.
  • 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et 2 O (60 mL) and cooled to - 78 0 C.
  • n-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min.
  • 4-Methoxy-3,5-dimethylbenzonitrile (4.06 g, 25.20 mmol) was added in Et 2 O (40 mL) at -78 0 C and the reaction was allowed to warm to room temperature over 30 min.
  • MeOH (20 niL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water.
  • Methyl iodide (0.531 mL, 8.51 mmol) was added to a solution of 5-amino-2-(3- bromophenyl)-2-(4-(difluoromethoxy)phenyl)-2H-imidazole-4-thiol (1.17 g, 2.84 mmol) in THF (10 mL) and the resulting mixture was stirred at 50 0 C over night. The mixture was concentrated and the resulting residue was purified on a silica gel column eluted with 0-5% 0.1M NH 3 in MeOH in DCM to give 0.714 g (59% yield) of the title compound: MS (ES+) m/z 426, 428 [M+H] + .
  • 1,3-Dibromobenzene (4.23 mL, 34.99 mmol) was dissolved in Et 2 O (60 niL) and cooled to -78 0 C.
  • n-Butyllithium (15.40 mL, 38.49 mmol) was added and the solution stirred for 30 min.
  • a solution of 4-methoxy-3-methylbenzonitrile (5.15 g, 34.99 mmol) in Et 2 O (40 mL) was added at -78 0 C and the reaction was allowed to warm to room temperature over 2 h.
  • n-Butyllithium (2.000 niL, 5.00 mmol) was added dropwise to a solution of 4-bromo-2,6- dimethylpyridine (0.930 g, 5 mmol) in Et 2 O (12 mL) at -78 0 C under a nitrogen
  • n-Butyllithium (7.17 niL, 17.93 mmol) was added dropwise over 10 min to a solution of 3- bromo-5-(prop-l-ynyl)pyridine (2.93 g, 14.95 mmol) and triisopropyl borate (4.14 mL, 17.93 mmol) in THF (6 mL) and toluene (24 mL) at -78 0 C under a nitrogen atmosphere. The resulting mixture was stirred at -78 0 C for 45 min. The cooling bath was removed and the mixture was stirred at rt for 30 min before being cooled to -10 0 C.
  • Aqueous 2M HCl (15 mL) was added, the cooling bath removed and the mixture was stirred at rt for 1 h. The organics were removed under reduced pressure and the pH of the resulting aqueous residue was adjusted to 7-8 using an aqueous 20% NaOH solution. The aqueous mixture was diluted with brine (20 mL) and then saturated with solid NaCl and extracted with THF (3 x 25 mL). The combined organics were dried over MgSO 4 , filtered and concentrated.
  • n-Butyllithium (2.480 mL, 6.20 mmol) was added to a solution of (4-bromo-2- chlorophenoxy)(tert-butyl)dimethylsilane (1995 mg, 6.2 mmol) (Eur. J. Med. Chem., 2009, 44, 2765-2775) in Et 2 O (10 niL) at -78 0 C under a nitrogen atmosphere. After 45 min at - 78 0 C a solution of 3,5-dimethyl-4-methoxybenzonitrile (999 mg, 6.20 mmol) in THF (5 rnL) was added dropwise, the cooling bath was removed and the resulting mixture was stirred at rt for 1.5 h.
  • Methyl iodide (2.58 mL, 41.45 mmol) was added to a solution of 5-amino-2-(3- chlorophenyl)-2-(3,4-dimethoxyphenyl)-2H-imidazole-4-thiol (5 g, 13.82 mmol) in THF (70 mL) and the resulting mixture was stirred at 50 0 C over night. The volatiles were removed in vacuo and the resulting residue was taken up DCM (50 mL) and water (25 mL) and added to a phase separator.
  • Methylmagnesium bromide (11.35 mL, 34.05 mmol) was added to a solution of zinc iodide (10.87 g, 34.05 mmol) in THF (30 mL) at 0 0 C under a nitrogen atmosphere. Then a solution of 2-(3-chlorophenyl)-2-(3,4-dimethoxyphenyl)-5-(methylthio)-2H-imidazol-4- amine (1.6 g, 4.26 mmol) in THF (20 mL) was added followed by
  • Methylmagnesium bromide (9.60 mL, 28.80 mmol) was added to a solution of 2-(3- bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-(methylthio)-2H-imidazol-4- amine (1506 mg, 3.6 mmol) and [l,3-bis(diphenylphosphino)propane]nickel(II) chloride (976 mg, 1.80 mmol) in toluene (20 mL) at 0 0 C under a nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at rt for 4 h.
  • n-Butyllithium (2.5 M, 10.00 mL, 25.00 mmol) was added to a solution of 1,3- dibromobenzene (5.90 g, 25.00 mmol) in diethylether (50 mL) at -78 0 C under argon. After 30 min at -78 0 C, a solution of 4-(difluoromethoxy)-3,5-dimethylbenzonitrile (4.93 g, 25 mmol) in tetrahydrofurane (30 mL) was added, the cooling bath removed and the reaction mixture stirred at r.t. for 2 h.
  • n-Butyllithium, 2.5 M in hexanes (1.498 mL, 3.74 mmol) was added dropwise to a solution of 1,3-dibromobenzene (0.415 mL, 3.43 mmol) in dry Et 2 O (6 mL) at -78 0 C under an atmosphere of argon.
  • the reaction was stirred for 30 minutes before dropwise addition of a solution of 3-ethyl-4-methoxybenzonitrile (0.503 g, 3.12 mmol) in dry Et 2 O (4 mL).
  • the reaction was stirred in the slowly thawing cooling bath and it was quenched when the temperature had reached -60 0 C by addition of ammonium acetate (0.289 g, 3.74 mmol) in MeOH (2.5 mL).
  • the reaction was taken to rt, the solvents evaporated and the residue taken up in DCM and water.
  • the organic layer was separated and the aqueous phase extracted with DCM.
  • the organic phases were combined, washed with brine, dried over Na2SO ⁇ filtered and the solvents evaporated.
  • the crude imine intermediate was dissolved in MeOH (10 mL) and then 2-oxopropanethioamide (0.628 g, 6.08 mmol) was added.
  • 1,3-Dibromobenzene ( 9.54 g, 40.45 mmol ) was dissolved in Et 2 O (200 mL) and cooled to -78 0 C.
  • n-Butyllithium (16.18 mL, 40.45 mmol ) was added and the solution stirred for 30 min.
  • a solution of 1,5 -dimethyl- lH-pyrazole-4-carbonitrile (4.9 g, 40.45 mmol) in Et 2 O (20 mL) was added at -78 0 C and the reaction was allowed to warm to room temperature over 1 h.
  • a solution of ammonium acetate (4.05 g, 52.58 mmol) in methanol (30 mL) was added.
  • the resulting mixture was stirred at -78 0 C for 1 h, then allowed to attain r.t. over 1 h and stirred at r.t. for 30 min.
  • the mixture was cannulated into a 5 L reactor containing a solution of ammonium acetate (154 g, 2000.00 mmol) in methanol (300 mL) at 0 0 C, in such a fashion that the temperature obtained during the addition was kept below 10 0 C.
  • the volatiles were removed under reduced pressure and dichloromethane (700 mL) and water (500 mL) were added to the residue.
  • the mixture was stirred, the organic phase separated and concentrated under reduced pressure
  • the crude product was subjected to vacuum for 18 h in order to remove residual solvent and the product (616 g, quant, yield)
  • the organic phase was washed with 1 M citric acid in water (700 mL).
  • the water phase was back-extracted with toluene (500 mL).
  • the combined organic phases were concentrated to a solid, which was again treated with methanolic ammonia under pressure and worked up according to the conditions vide supra.
  • the reaction mixture was stirred, and the temperature increased to 90 0 C and held for 90 min, thereafter held at 80 0 C for 3 h.
  • the mixture was allowed to attain r.t. and the phases separated and activated charcoal added to the dioxane phase.
  • the mixture was filtered through celite, washed with ethylacetate and the filtrate concentrated in vacuum.
  • the obtained residue was dissolved in ethylacetate (600 mL) and aqueous sodium hydroxide (2M, 200 mL) was added with stirring.
  • the organic phase was separated and dried with magnesium sulfate.
  • Methylmagnesium bromide (4.442 mL, 13.33 mmol) was added to a solution of 2-(3- bromophenyl)-2-(4-(difluoromethoxy)phenyl)-5-(methylthio)-2H-imidazol-4-amine (710 mg, 1.67 mmol) and [l,3-bis(diphenylphosphino)propane]nickel(II) chloride (361 mg, 0.67 mmol) in toluene (15 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3.5 h then water (20 mL) and DCM (25 mL) were added.
  • aqueous 2M potassium carbonate (0.600 mL, 1.20 mmol) was added and the resulting mixture was heated in a microwave reactor at 150 0 C for 3 h.
  • the mixture was poured into a phase separator and extracted with DCM.
  • the combined organics were concentrated and the resulting residue was dissolved in MeOH and purified by preparative HPLC.
  • the fractions containing the title compound were pooled, the MeOH removed in vacuo and the resulting aqueous residue was diluted with saturated aqueous NaHCO 3 and extracted with DCM.
  • Example 37 The reaction described in Example 35 also gave a second product that was isolated after the preparative HPLC purification. The corresponding fractions were evaporated and freeze dried overnight to give the title compound (9.00 mg, 14% yield): 1 H-NMR (500 MHz, DMSO-de) ⁇ 7.34-7.32 (m, 2 H), 7.29-7.21 (m, 3 H), 7.11 (s, 2 H), 6.55 (t, 1 H), 2.35 (s, 3 H), 2.23 (s, 6 H); MS (ES+) m/z 344.1 [M+l] + .
  • Example 37 Example 37
  • the level of activity of the compounds was tested using the following methods:
  • the ⁇ -secretase enzyme used in the TR-FRET is prepared as follows:
  • the cDNA for the soluble part of the human ⁇ -Secretase (AA 1 - AA 460) was cloned using the ASP2-FclO-l-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 sBACE-Fc was stored in -80 0 C in Tris buffer, pH 9.2 and had a purity of 95%.
  • the enzyme (truncated form) was diluted to 6 ⁇ g/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 ⁇ M) in reaction buffer
  • the assay was performed in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676).
  • the final concentration of the enzyme was 2.7 ⁇ g/ml; the final concentration of substrate was 100 nM (Km of -250 nM).
  • the dimethylsulphoxide control instead of test compound, defined the 100% activity level and 0% activity was defined by wells lacking enzyme (replaced with reaction buffer).
  • a control inhibitor was also used in dose response assays and had an IC50 of -575 nM.
  • SH-S Y5 Y cells were cultured in DMEM /F- 12 with Glutamax, 10% FCS and 1 % nonessential aminoacids and cryopreserved and stored at -140 0 C at a concentration of 7.5x106 cells per vial. Thaw cells and seed at a cone, of 1.5xlO5/ml in DMEM /F- 12 with
  • MSD Meso Scale Discovery
  • MSD sAPP ⁇ plates were blocked in 3% BSA in Tris wash buffer (150 ⁇ l/well) for 1 hour in RT and washed 4 times in Tris wash buffer (150 ⁇ l/well). 50 ⁇ l of medium was transferred to the pre-blocked and washed MSD sAPP ⁇ microplates, and the cell plates were further used in an ATP assay to measure cytotoxicity. The MSD plates were incubated with shaking in RT for 1 hour followed by washing 4 times. 25 ⁇ l detection antibody was added (InM) per well followed by incubation with shaking in RT for Ih and washing 4 times. 150 ⁇ l Read Buffer was added per well and the plates were read in a SECTOR Imager.
  • ViaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP.
  • the assay was performed according to the manufacture's protocol. Briefly, 25 ⁇ L cell lysis reagent was added per well. The plates were incubated at room temperature for 10 min.
  • Typical IC50 values for the compounds of the present invention are in the range of about 1 to about 100,000 nM. Biological data is given below in Table II.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel compounds of formula (I) and 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, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or 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.

Description

Novel compounds for treatment of neurodegeneration associated with diseases, such as Alzheimer's disease or dementia
The present invention relates to novel compounds and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as medicaments for treatment and/or prevention of various diseases. In particular the invention relates to compounds, which are inhibitors of -secretase and hence inhibit the formation of amyloid β (Aβ) peptides and will be used for treatment and/or prevention of Aβ-related pathologies such as Alzheimer's disease, 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's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Background of the invention
The prime neuropatho logical event distinguishing Alzheimer's disease (AD) is deposition of the 40-42 residue amyloid β-peptide (Aβ) in brain parenchyma and cerebral vessels. A large body of genetic, biochemical and in vivo data support a pivotal role for Aβ in the pathological cascade that eventually leads to AD. Patients usually present early symptoms (commonly memory loss) in their sixth or seventh decades of life. The disease progresses with increasing dementia and elevated deposition of Aβ. In parallel, a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function. The prevailing working hypothesis regarding the temporal relationship between Aβ and tau pathologies states that Aβ deposition precedes tau aggregation in humans and animal models of the disease. Within this context, it is worth noting that the exact molecular nature of Aβ, mediating this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species ranging from lower order Aβ oligomers to supramolecular assemblies such as Aβ fibrils. The Aβ peptide is an integral fragment of the Type I protein APP (Aβ amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Aβ can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called α-, β-, and γ-cleavages. The α-cleavage, which occurs roughly in the middle of the Aβ domain in APP is executed by the metalloproteases ADAMlO or ADAM 17 (the latter also known as TACE). The β-cleavage, occuring at the N terminus of Aβ, is generated by the transmembrane aspartyl protease Beta site APP Cleaving Enzyme 1 (BACEl). The γ-cleavage, generating the Aβ C termini and subsequent release of the peptide, is effected by a multi-subunit aspartyl protease named γ-secretase. ADAM 10/ 17 cleavage followed by γ-secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated Aβ fragment that fails to form amyloid deposits in humans. This proteolytic route is commonly referred to as the non-amyloidogenic pathway. Consecutive cleavages by BACEl and γ-secretase generates the intact Aβ peptide, hence this processing scheme has been termed the amyloidogenic pathway. With this knowledge at hand, it is possible to envision two possible avenues of lowering Aβ production: stimulating non-amyloidogenic processing, or inhibit or modulate
amyloidogenic processing. This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). β-amyloid deposits are predominately an aggregate of AB peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, AB peptide results from the cleavage of APP at the C-terminus by one or more γ- secretases, and at the N-terminus by B-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the B- amyloidogenic pathway.
BACE activity is correlated directly to the generation of AB peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of ABpeptide (Roberds, S. L., et al, Human Molecular Genetics, 2001, 10, 1317-1324). 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 -secretase activity, and is considered to be the rate- limiting step in the production of amyloid- -peptide (A ).
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. 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, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or 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 A and portions thereof by inhibiting BACE through inhibitors such as the compounds provided herein.
The therapeutic potential of inhibiting the deposition of A has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors. Outline of the invention
The present invention relates to a compound according to formula (I):
Figure imgf000005_0001
(I)
wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1; B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
C is selected from hydrogen, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co- ealkylheterocyclyl, C0-6alkylOR4, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, Co-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(C0)- (CO)N(R4)2, Co_6alkylSR4, C0.6alkylOSO2R4, C0.6alkylSO3R4, C0.6alkylSO2R4, C0.6alkyl- SOR4, Co-6alkyl(S02)N(R4)2, Co-6alkyl(SO)N(R4)2, Co-6alkylNR4(S02)N(R4)2, C0-6alkyl- NR4(SO)R4, SF5 and OSF5, wherein said Ci_6alkyl, C2-6alkenyl, C2-ealkynyl, C0-6alkyl- C3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, C0-6alkylN(R4)2, C0.6alkylOR4, halogen,
Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co_6alkylSR4, C0.6alkylOSO2R4, C0.6alkylSO3R4, Co-6alkylS02R4, Co-6alkylSOR4, C0-6alkyl(SO2)N(R4)2, Co-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, Co-6alkylNR4(SO)R4, SF5, and OSF5, wherein said Chalky!, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R2 is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN,
Co-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co_6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(C0)- (CO)N(R4)2, Co-6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0-6alkylSO2R4, C0-6alkyl- SOR4, Co-6alkyl(S02)N(R4)2, Co-6alkyl(SO)N(R4)2, Co-6alkylNR4(S02)N(R4)2, C0-6alkyl- NR4(SO)R4and C0-6alkylOR4, wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3_6cycloalkyl, Co-βalkylaryl, Co_6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, Ci_6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0.6alkylSR4, Co-6alkyl(S02)N(R4)2, OC2.6alkyl- NR4(SO2)R4, Co-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkyl- NR4(SO)R4, Co-6alkylS02R4, C0-6alkylSOR4, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3_6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-6alkyl- heterocyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkyl- C3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl,
Co-6alkylheteroaryl, Co-δalkylheterocyclyl, C^alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl,
C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-6alkyl- heterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, C0-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, Ci_6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)Ci_6alkyl, (CO)OCi_6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C1.6alkyl- N(R7)2, (SO2)C1.6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C^alkyl, C2.6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or Co-6alkylC3-6cyclo- alkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C1-3haloalkyl, or OC1-3haloalkyl; R7 is selected from hydrogen, C^aUcyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.
δCycloalkyl, C3_6cycloalkenyl, CδCycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi_3alkyl, cyano or halogen;
as a free base or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the molecular weight of the compound of formula (I) is more than 300 g/mol. In one embodiment of the present invention, the molecular weight of the compound of formula (I) is less than 600 g/mol. In another embodiment of the invention, A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
C is selected from hydrogen, Chalky!, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co- ealkylheterocyclyl, C0-6alkylOR4, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, Co-ealkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)-
(CO)N(R4)2, Co-6alkylSR4, C0-6alkylNR4(SO)R4, SF5 and OSF5, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3; R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, C0-6alkylOR4, halogen, Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0.6alkylNR4(CO)R4, Co-6alkylS02R4, and C0-6alkylSOR4, wherein said C1-6alkyl, C2_6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl,
C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0.6alkylN(R4)2, halogen, C0-6alkylCN,
Co-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, Co-6alkylS03R4, C0-6alkylSO2R4, C0-6alkylSOR4, Co-6alkyl(S02)N(R4)2, Co-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4" (SO)R4 and C0.6alkylOR4, wherein said Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C0.6alkyl- C3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, Ci-ehaloalkyl,
Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0.6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, Co-6alkyl(S02)N(R4)2,
OC2-6alkylNR4(SO2)R4, Co-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, Co-6alkylNR4(S02)N(R4)2, C0-6alkylNR4(SO)R4, C0-6alkylSO2R4, C0-6alkylSOR4, Ci.6alkyl, C2-6alkenyl, C2-ealkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-βalkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylC3-6cycloalkyl, Co_6alkylC3_6cycloalkenyl, Co-δalkylCδCycloalkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R5 is selected from hydrogen, Crβalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3- δcycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, C1.
ehaloalkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)C1.6alkyl, (CO)OC1.
6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, wherein said Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C0.
6alkylaryl, C0-6alkylheteroaryl, Co-δalkylheterocyclyl or Co-6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C1-3haloalkyl, or OCi_3haloalkyl.
R7 is selected from hydrogen, C1-6alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- δcycloalkyl, C3-6cycloalkenyl, C6cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more of hydroxy, OC1-3alkyl, cyano or halogen.
In another embodiment of the invention, A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co- ealkylheterocyclyl, Co-ealkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, Co-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, Co-6alkylNR4(CO)R4, C0-6alkylSR4, C0-6alkylNR4(SO)R4, SF5 and OSF5, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkyl- heteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0-6alkylOR4, halogen,
Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, C0-6alkylNR4(CO)R4, C0-6alkylSO2R4, and C0-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylhetero- aryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkyl- C3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-6alkyl- heterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, CHO, NO2, Co.6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, C0-6alkylOR4, Co-6alkylS03R4, Co-6alkylS02R4, C0-6alkylSOR4 and Co_6alkyl(Sθ2)N(R4)2, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co-6alkylC3_6cyclo- alkyl, Co-6alkylaiyl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, Ci_6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0.6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkyl(SO2)N(R4)2, OC2-6alkyl- NR4(SO2)R4, Co-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkyl- NR4(SO)R4, Co-6alkylS02R4, C0-6alkylSOR4, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3_6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl,
Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Ci-βalkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- ealkyKVόCycloalkyl, C0-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-όalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Chalky!, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3- δcycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- βalkylaryl, Co-6alkylheteroaryl, Co-6alkylC3_6cycloalkyl, Co-6alkylheterocyclyl, Ci_6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)Ci_6alkyl, (CO)OCi_6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, wherein said C^alkyl, C2.6alkenyl, C2.6alkynyl, C0- βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or Co-6alkylC3-6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, Ci_3haloalkyl, or OCi_3haloalkyl; R7 is selected from hydrogen, C1-6alkyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3_ δcycloalkyl, C3_6cycloalkenyl, CδCycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more of hydroxy, OC1-3alkyl, cyano or halogen.
In one embodiment of the invention, A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
C is selected from hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylC5-6cycloalkenyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-6alkylheterocyclyl, Co- 6alkyl0R4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, Co-6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, C0-6alkylSR4, Co-6alkylS02R4, Co-6alkylSOR4, wherein said C^aUcyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co_6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3; R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC5_6cycloalkenyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0-6alkylOR4, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, Co-6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, C0-6alkylSR4, Co-6alkylS02R4, Co-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co_6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R2 is selected from C1-6alkyl, C0-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl,
C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, 0(CO)R4, Co-6alkylSR4, and Co-6alkylOR4, wherein said C1-6alkyl, C0-6alkylC3-6cycloalkyl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, C0.6alkylCN, C0-6alkylOR4, C^haloalkyl,
Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, 0(CO)R4, Co-6alkylCOR4, C0-6alkylSR4, Co-6alkylS02R4, C0-6alkylSOR4, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, C^aUcyl, C1-3haloalkyl, C0-6alkylC3-6cycloalkyl, Co-
6alkylaryl, C0-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-βalkyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkyl- heterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl,
Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, Co-6alkylaryl, Co- δalkylheteroaryl, Co-6alkylC3_6cycloalkyl, Co-6alkylheterocyclyl, Ci_6haloalkyl, OC2.
6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C i-6alkyl, (CO)OC1.6alkyl, COR7, SO2R7, SOR7, wherein said C1-6alkyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co- δalkylheterocyclyl or Co-6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C^haloalkyl, or OCijhaloalkyl;
R7 is selected from hydrogen, C1-6alkyl, C1-3haloalkyl, C3-6cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC1-3alkyl, cyano or halogen.
In another embodiment of the invention A is aryl, such as phenyl or 2,3-dihydro-l,4- benzodioxine.
In another embodiment of the invention, A is heteroaryl, such as pyridine or thiophene. In one embodiment of the invention, A is phenyl, pyridine, pyrazole, imidazole or thiophene.
In another embodiment of the invention, R1 is C^aUcyl, Co-6alkylOR4, Co-6alkylC3_6cyclo- alkyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Co-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCON(R4)2, C0.6alkylNR4(CO)R4, C0-6alkylSO2R4, or C0-6alkylSOR4.
In one embodiment of the invention, R1 is C1-6alkyl, Co-6alkylC3_6cycloalkyl,
Co-δalkylheterocyclyl, Co-βalkylOR4, halogen or Co-6alkylCN;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6.
In one embodiment of the invention, R4 is selected from hydrogen, Ci-βalkyl, C1.
3haloalkyl, Co-6alkylC3-6cycloalkyl, C^alkylOR5, Co-δalkylheterocyclyl or Co-6alkyl- heteroaryl.
In another embodiment of the invention, R4 is hydrogen, C1-6alkyl, Ci_6alkylOR5, Co- 6alkylheterocyclyl or C^haloalkyl.
In another embodiment of the invention, R4 is methyl.
In another embodiment of the invention B is aryl, such as phenyl. In another embodiment of the invention R2 is halogen, cyano or Co-6alkylOR4. In one embodiment of the invention, R2 is C1-6alkyl, halogen, Co-βalkylCN or Co-βalkylOR4 2
In another embodiment of the invention R is fluoro.
In another embodiment of the invention R4 is hydrogen. In another embodiment of the invention C is selected from hydrogen, C^aUcyl, Co-6alkyl- aryl, Co-6alkylheteroaryl, Co-6alkylCN, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-ealkylheterocyclyl, C0-6alkylOR4, Co.6alkylN(R4)2, halogen, Co.6alkylCON(R4)2 or Co-6alkylNR4(CO)R4. In one embodiment, C is hydrogen, C1-6alkyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co- 6alkylaryl, C0.6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylOR4, Co.6alkylN(R4)2, halogen, C0-6alkylCN or C0-6alkylNR4(CO)R4.
In another embodiment of the invention C is aryl, such as phenyl, or heteroaryl, such as pyridyl, pyrazole, isoxazole, pyrrolopyridine or pyrimidyl.
In one embodiment of the invention, R3 is halogen, Co-βalkylCN, Co-βalkylOR4, C1.
ehaloalkyl, Ci_6alkyl, C2-6alkenyl, C2-ealkynyl, Co-6alkylC3-6cycloalkyl , C0-6alkylSO2R4, C0.6alkyl(SO2)N(R4)2, C0.6alkylCO2R4, C0-6alkylCOR4, or Co-ealkylheterocyclyl.
In another embodiment of the invention R3 is halogen, Co-6alkylCN, Co-6alkylOR4, C1. ehaloalkyl or C^alkyl, Co-6alkylS02R4, C0-6alkyl(SO2)N(R4)2, C0-6alkylCO2R4,
C0-6alkylCOR4, or Co-ealkylheterocyclyl. In one embodiment, R3 is halogen or C2-6alkynyl.
In another embodiment of the invention A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is aryl; C is hydrogen, C^aUcyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co- 6alkylheteroaryl, Co-δalkylheterocyclyl, Co-βalkylOR4, Co_6alkylN(R4)2, halogen, C0- ealkylCN or C0-6alkylNR4(CO)R4;
R2 is Ci-ealkyl, halogen, C0-6alkylCN or C0-6alkylOR4;
R3 is halogen, C0-6alkylCN, C0-6alkylOR4, Ci^haloalkyl, Ci_6alkyl, C2-6alkenyl,
C2.6alkynyl, Co-ealkylCs-ecycloalkyl , C0.6alkylSO2R4, Co.6alkyl(S02)N(R4)2,
C0-6alkylCO2R4, C0-6alkylCOR4, or Co-ealkylheterocyclyl;
R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, Co-6alkylC3-6cycloalkyl, C1.
βalkylOR5, Co-δalkylheterocyclyl and Co-6alkylheteroaryl;
R5 is Ci-6alkyl;
R6 is oxo, OR7, Ci-ealkyl;
R7 is Ci-ealkyl.
In one embodiment, A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is aryl;
C is hydrogen, C1-6alkyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co-
6alkylheteroaryl, Co-δalkylheterocyclyl, Co-βalkylOR4, Co_6alkylN(R4)2, halogen, C0- ealkylCN or C0-6alkylNR4(CO)R4;
R2 is Ci-ealkyl, halogen, C0-6alkylCN or C0-6alkylOR4;
R3 is halogen, C0-6alkylCN, C0-6alkylOR4, Ci^haloalkyl, Ci_6alkyl, C2-6alkenyl,
C2-6alkynyl, Co-6alkylC3_6cycloalkyl or Co-δalkylheterocyclyl;
R4 is selected from hydrogen, Ci-βalkyl, C^haloalkyl, Co-6alkylC3-6cycloalkyl and Co- δalkylheteroaryl.
One embodiment of the present invention is a compound selected from
5-Methyl-2-phenyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-amine;
2-(4-Fluorophenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-m-tolyl-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine; (i?)-2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
(iS)-2-(4-Methoxyphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
(5)-2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
(i?)-2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4- amine;
5-Methyl-2-(5-methylthiophen-3-yl)-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
5 -Methyl-2-(5-methylthiophen-3-yl)-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4-amine;
2-(Biphenyl-3-yl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
5 -(3 -(4- Amino-2-(4-methoxyphenyl)-5 -methyl-2H-imidazol-2-yl)phenyl)nicotinonitrile;
3-(4-Amino-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-2-yl)benzonitrile;
2-(4-(Difluoromethoxy)phenyl)-5-methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4- amine;
N-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)pyrazine-2-carboxamide;
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-4-amine;
2-(4-Methoxy-3 -methylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
2-(3-(5-Fluoropyridin-3-yl)phenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-
4-amine;
4-(4-Amino-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-2-yl)-2,6- dimethylphenol;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4- amine; 2-(2,6-Dimethylpyridin-4-yl)-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4- amine;
2-(2,6-Dimethylpyridin-4-yl)-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H- imidazol-4-amine;
4-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2- chlorophenol;
5-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2'-fluoro-5'- methoxybiphenyl-2-ol;
2-(4-(Difluoromethoxy)-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
2-(4-(Difluoromethoxy)-3 ,5 -dimethylpheny l)-2-(3 -(5 -fluoropyridin-3 -yl)phenyl)-5 -methyl-
2H-imidazol-4-amine;
2-(3,4-dimethoxyphenyl)-5-methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H- imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-2H- imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-2-(3-(5-methoxypyridin-3-yl)phenyl)-5-methyl-
2H-imidazol-4-amine;
5-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)nicotinonitrile;
2-(4-(Difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2-phenyl-2H-imidazol-4-amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l-methyl-lH-pyrazol-4-yl)-2H-imidazol-4- amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l -methyl- lH-imidazol-5-yl)-2H-imidazol-4- amine;
4-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-N,N- dimethylpyridin-2-amine;
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
2-(3-Ethyl-4-methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine; 2-(3 -Ethyl-4-methoxyphenyl)-2-(3-(5 -fluoropyridin-3 -yl)phenyl)-5 -methyl-2H-imidazol-4- amine;
2-(2',3'-Difluorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-
4-amine;
2-( 1,5 -Dimethyl- lH-pyrazol-4-yl)-5-methyl-2-(3 '-(prop- l-ynyl)biphenyl-3-yl)-2H- imidazol-4-amine;
2-(3',5'-Dichlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-
4-amine;
2-(3'-Chlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4- amine;
2-( 1,5 -Dimethyl- lH-pyrazol-4-yl)-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4- amine;
2-[4'-(ethylsulfonyl)biphenyl-3-yl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(2'-fluoro-6'-methoxybiphenyl-3-yl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[3'-(methylsulfonyl)biphenyl-3-yl]-2H- imidazol-4-amine;
2-[3-(3,5-dimethyl-lH-pyrazol-4-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl- 2H-imidazol-4-amine;
l-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl-
4-yl}-N,N-dimethylmethanesulfonamide;
6-{3-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]phenyl}-l- methyl- 1 ,3-dihydro-2H-indol-2-one;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[3-(lH-pyrrolo[2,3-b]pyridin-3-yl)phenyl]-
2H-imidazol-4-amine;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[3-(2-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,2- benzisothiazol-5-yl)phenyl]-2H-imidazol-4-amine;
2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine; 2-(5 '-fluoro-2'-methoxybiphenyl-3 -yl)-2-(4-methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2H- imidazol-4-amine;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl-3-ol;
2-[3-(2,3-dihydro-l,4-benzodioxin-6-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5- methyl-2H-imidazol-4-amine;
3-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl-
4-yl}propanoic acid;
2-(4-methoxy-3 ,5 -dimethylpheny l)-2- [3 -(6-methoxypyridin-3 -yl)phenyl]-5 -methyl-2H- imidazol-4-amine;
2-(4-methoxy-3 ,5 -dimethylpheny l)-2- [3 -(2 -methoxypyrimidin-5 -yl)phenyl]-5 -methyl-2H- imidazol-4-amine;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-4- fluorobiphenyl-3-carboxylic acid;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[4'-(piperidin-l-ylcarbonyl)biphenyl-3-yl]- 2H-imidazol-4-amine;
2-(4-methoxy-3,5-dimethylphenyl)-2-[4'-(methoxymethoxy)biphenyl-3-yl]-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3, 5 -dimethylpheny l)-5-methyl-2- [3 -(I -methyl- lH-pyrazol-4-yl)phenyl] -2H- imidazol-4-amine;
2-[3-(6-ethoxypyridin-3-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3, 5 -dimethylpheny l)-5-methyl-2-(3-pyridin-4-ylphenyl)-2H-imidazol-4- amine;
l-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-6- fluorobiphenyl-3-yl}ethanone;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-3- methoxybiphenyl-4-carboxylic acid;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[2'-(morpholin-4-ylmethyl)biphenyl-3-yl]-
2H-imidazol-4-amine;
6-{3-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]phenyl}-2- methyl-2,3-dihydro- 1 H-isoindol- 1 -one; and 2-[3-(2,2-dioxido-l,3-dihydro-2-benzothiophen-5-yl)phenyl]-2-(4-methoxy-3,5- dimethylphenyl)-5-methyl-2H-imidazol-4-amine;
as a free base or a pharmaceutically acceptable salt thereof. 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 compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
Examples of prodrugs include in vivo hydro lysab Ie esters of a compound of the formula (I). An in vivo hydro lysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Various forms of prodrugs are known in the art.
The definitions set forth in this application are intended to clarify terms used throughout this application. The term "herein" means the entire application.
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 tautomers, cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. 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 separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in stable compounds.
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. 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 "Co-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, pentyl, 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 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 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.
As used herein, "alkynyl" used alone or as a suffix or prefix is intended to include to include both branched and straight-chain alkynyl or olefin 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 ethynyl, propynyl (e.g. 1-propynyl, 2-propynyl), 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 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 one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. Examples of polycyclic rings include, but are not limited to, 2,3-dihydro-l,4-benzodioxine, 2,2-dioxo-l,3-dihydro-2- benzothiophene, 2-methyl-isoindolin- 1 -one, 2-methyl- 1 , 1 -dioxo-3H- 1 ,2-benzothiazole l-methyl-indolin-2-one and 2,3-dihydro-l-benzofuran. As used herein, the terms "cycloalkyl" or "carbocyclyl" are 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.
As used herein, the term "cycloalkenyl" is intended to include unsaturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Preferred cycloalkenyls 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 cycloalkenyl" denotes such groups as cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
"Counterion" is used to represent a small, negatively or positively charged species such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, ammonium, lithium ion and sodium ion 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 with acetyl, formyl, methyl or mesyl; and a ring is optionally substituted with 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-hetero aromatic. 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, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydro-thiopyranyl, tetrahydro-thiopyran 1 -oxide, tetrahydro-thiopyran 1,1 -dioxide, lH-pyridin-2-one, and 2,5-dioxoimidazolidinyl. As used herein, "heteroaryl" refers to a heteroaromatic 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, benzo furyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, pyrrolopyridinyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, aza- benzoxazolyl, imidazothiazolyl, benzo[l,4]dioxinyl, benzo[l,3]dioxolyl and the like. In some embodiments, the heteroaryl group has from 1 to 20 carbon atoms, and in further embodiments from 3 to 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom. As used herein, "haloalkyl", used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups, having at least one halogen substituent and 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 "Co- δhaloalkyl" denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorofluoromethyl, 1-fluoroethyl, 3-fluoropropyl, 2-chloropropyl, 3,4-difluorobutyl. As used herein, the phrase "protecting group" means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999).
As used herein, "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. 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 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 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.
The present invention further includes all tautomeric forms of compounds of the invention. 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. Other examples of tautomerism include 2H-imidazol-4-amine and its tautomer l,2-dihydroimidazol-5-imine, and 2H-imidazol-4-thiol and its tautomer 1,2- dihydroimidazol-5-thione. It is understood that in compound representations throughout this description, only one of the possible tautomers is drawn or named.
As used herein "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Compounds of the invention further include hydrates and solvates. The present invention further includes isotopically-labelled compounds of the invention. An "isotopically" or "radio-labelled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 1231, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labelled compounds will depend on the specific application of that radio-labelled compound. For example, for in vitro receptor labelling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio- imaging applications 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labelled 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. 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.
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. 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.
In another aspect of the invention, there is provided that the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used as medicaments, e.g. to treat or prevent Aβ-related pathologies.
In another aspect of the invention, there is provided that the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used for the manufacture of a medicament to treat or prevent Aβ-related pathologies.
In another aspect of the invention, there is provided a method for the treatment of Aβ- related pathologies, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, such as a mammal or a human being, in need thereof. The compounds of the invention and their pharmaceutically acceptable salts thereby provides methods of treatment of Aβ-related pathologies, such as, but not limited to, Alzheimer's disease, Downs syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, traumatic brain injury and cortical basal degeneration.
In another aspect of the invention, there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according formula (I) in association with pharmaceutically acceptable excipients, carriers or diluents.
In another aspect of the invention, there is provided a method of treating or preventing an Aβ-related pathology in a mammal, such as human being, comprising administering to said patient a therapeutically effective amount of a compound according to formula (I), and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor, wherein said Aβ-related pathology is Alzheimer Disease.
The treatment of Aβ-related pathology defined herein may be applied as a mono therapy or may involve, in addition to the compound of the invention, conjoint treatment with therapy of value in treating one or more disease conditions referred to herein. Such therapy 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. Cognitive enhancing agents, memory enhancing agents and acetyl choline esterase inhibitors includes, but not limited to, donepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine
(Namenda, Axura or Ebixa). Atypical antipsychotic agents includes, but not limited to, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Abilify), risperidone
(marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon) and olanzapine/fluoxetine (marketed as Symbyax).
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 the invention.
Additional conventional therapy may include one or more of the following categories of agents:
(i) antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof. (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine,
benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(iv) anxiolytics including for example alnespirone, azapirones, benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(v) anticonvulsants including for example carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam,
oxcarbazepine, phenobarbital, phenytoin, pregabaline, rufmamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vi) Alzheimer's therapies including for example donepezil, rivastigmine, galantamine, memantine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof.
(viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pizotiphen, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(ix) stroke therapies including for thrombolytic therapy with eg activase and
desmoteplase, abciximab, citicoline, clopidogrel, eptifϊbatide, minocycline, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (xi) neuropathic pain therapies including for example lidocain, capsaicin, and anticonvulsants such as gabapentin, pregabalin, and antidepressants such as duloxetine, venlafaxine, amitriptyline, klomipramine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (xii) nociceptive pain therapies such as paracetamol, NSAIDS and coxibs, such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfm, tramadol, and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xiii) insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos, secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xiv) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference. 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 alternatively be used for the heating of reaction mixtures.
Another aspect of the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein, unless specified otherwise, A, B and C are defined as in formula (I) above; R10 and R11 are defined as optionally substituted aryl or heteroaryl groups; R is defined as for C in formula (I) above; R12 may be defined as R4 above; and LG represents a leaving group such as halogen (such as chlorine, bromine or iodine) or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate). A compound of formula (VI) may be equivalent to a compound of formula (I). Said process comprises of:
(i) Formation of a corresponding compound of formula (IV):
A compound of formula (IV) wherein R10 and R11 are defined as optionally substituted aryl or heteroaryl groups can be prepared from a compound of formula (II) as outlined in Scheme 1.
Figure imgf000036_0001
Scheme I
A benzophenone of formula (II), may be reacted with ammonia to form intermediate of formula (III) {Scheme I). The compound of formula (III) is further reacted with ethyl 2- oxopropanoate to form a compound of formula (IV). Said reaction may be performed at a temperature range between +100 0C and +160 0C, in a suitable solvent, such as methanol, ethanol or isopropyl alcohol. (H) Formation of a corresponding compound of formula (VI):
Figure imgf000036_0002
(IV) (V) (VI)
Scheme 2
The amino imidazole of formula (VI), may be obtained by an initial formation of a compound of formula (V), by reacting the alcohol of formula (IV) with a sulphurating reagent, such as phosphorus pentasulfϊde, in the presence of a base, such as pyridine (Scheme 2). The transformation to a compound of formula (VI) may be performed by reacting the compound of formula (V) with ammonia, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide.. (Hi) Formation of a corresponding compound of formula (III): R1 1— CN
(IX) NH
R10— LG R10-M Dio/\D11
K K
(VII) (VIII) (HI)
Scheme 3
A compound of formula (III), may be obtained, as shown in (Scheme 3), by reacting a compound of formula (VII), wherein LG is defined as above, with an organometallic reagent such as an alkyl lithium, as for example butyl lithium, to form an intermediate compound of formula (VIII), wherein M is a metal, such as for example lithium. The compound of formula (VIII) is further reacted with an aryl or heteroaryl nitrile of formula (IX), . Said reaction may be performed at a temperature range between -78 0C and 0 0C, in a suitable solvent such as THF or 2-methyl-tetrahydrofuran.
(iv) Formation of a corresponding compound of formula (X):
Figure imgf000037_0001
(HI) (X)
Scheme 4
An imine of formula (III) is reacted with ethanebis(thioamide) to form a compound of formula (X) (Scheme 4). Said reaction may be performed at a temperature range between +100 0C and +180 0C, in a suitable solvent such as methanol, ethanol or isopropyl alcohol, preferably in a closed system.
(v) Formation of a corresponding compound of formula (VI):
Figure imgf000038_0001
(X) (XI) (VI)
Scheme 5
An alkylating agent, such as methyl iodide and an thioimidazole of formula (X), are reacted to form a compound of formula (XI) (Scheme 5). The compound of formula (XI) may then be transformed into a compound of formula (VI) by reacting it with an organometallic reagent, such as methylmagnesium bromide, in the presence of a suitable catalyst, such as [l,3-bis(diphenylphosphino)propane]nickel(II) chloride. Alternatively, the compound of formula (VI) may also be obtained by reacting compound of formula (XI) with a mixture of zinc iodide and methylmagnesium bromide in the presence of a suitable catalyst, such as bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent such as THF, 2-methyl-tetrahydrofuran or toluene.
(vi) Formation of a corresponding compound of formula (VI):
Figure imgf000038_0002
(III) (V) (VI)
Scheme 6
A compound of formula (VI) may be obtained from a compound of formula (III), wherein R13 is hydrogen, S(O)alkyl, C(O)alkyl, S(O)2alkyl, OH or Oalkyl (Scheme 6). Compound (III) may optionally be coordinated to a Lewis acid, as for example BF3, AlCl3, or TiCl4, to facilitate the reaction. An imine of formula (III) is reacted with 2-oxopropane thioamide (described in Asinger et al. Justus Liebigs Annalen der Chemie 1971, vol 744, p. 51-64) in a solvent such as methanol at a temperature between room temperature and reflux temperature to yield a compound of formula (V). The compound of formula (V) is subsequently treated with ammonia, in a suitable solvent such as methanol, THF, or 2- methyl-tetrahydrofuran, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide, at a temperature between room temeprature and 150 0C, optionally in a closed system, to yield the compound of formula (VI).
(vii) Formation of a corresponding compound of formula (I):
Figure imgf000039_0001
(XII) (I)
Scheme 7
A compound of formula (I), wherein C is an optionally substituted aryl or heteroaryl, may be obtained {Scheme T) by starting from, for example, a compound of formula (XII), wherein LG is as defined above, and reacting said compound of formula (XII) with a boronic acid or a boronic ester or a stannane of formula T-R , wherein T is for example B(OH)2, B(Oalkyl)2, or SnR3, and R is defined as above, in the presence of a transition metal catalyst such as a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(O), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0). Optionally, a suitable ligand such as
triphenylphosphine, tri-tert-butylphosphine or 2-(dicyclohexylphosphino)biphenyl, or zinc and sodium triphenylphosphinetrimetasulfonate, is used. 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. Said reaction may be performed in a suitable solvent, such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, JV,Λ/-dimethylacetamide, acetonitrile or N,N- dimethylformamide, or mixtures thereof. (viii) Formation of a corresponding compound of formula (I):
A compound of formula (I), wherein C is cyano, may be obtained {Scheme T) by starting from, for example, a compound of formula (XII), wherein LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine), and reacting said compound of formula (XII) with a a metal cyano reagent such as copper(I) cyanide.
(ix) Formation of a corresponding compound of formula (I):
A compound of formula (I), wherein C is an alkyl group such as methyl may be generated from compound of formula (XII) {Scheme T), wherein LG represents a leaving group, such as a halogen, (such as iodide, bromide or chlorine), by reaction with an organometallic reagent generated from zinc iodide and methylmagnesium bromide under the influence of a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
(x) Formation of a corresponding compound of formula (I):
A compound of formula (I) wherein C is NHC(O)R12 may be prepared according to
Scheme 7 by reacting a compound of formula (XII) with a compound R12C(O)NH2 in the presence of a suitable palladium catalyst such as palladium(II) acetate, optionally in the presence of a suitable ligand such as Xantphos. Said reaction is preformed in the presence of a suitable base such as cesium carbonate in a suitable solvent such as THF or 2- methyltetrafuran at a temperature between 100 0C to 160 0C.
Compounds of formula (II), (III), (VII) or (IX), are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Terms and abbreviations: ACN acetonitrile;
aq aqueous;
Atm atmospheric pressure;
Boc t-butoxycarbonyl;
Cbz benzyloxycarbonyl;
dba dibenzylideneacetone;
DCM dichloromethane;
DIBAL-H diisobutylaluminium hydride;
DIPEA diisopropylethylamine;
DME 1 ,2-dimethoxyethane;
DMF N,N-dimethyl formamide;
DMSO dimethyl sulfoxide;
Et2O diethyl ether;
EtOAc ethyl acetate;
equiv. equivalent;
h hour(s);
HPLC high performance liquid chromatography;
MeOH methanol;
min minute(s);
MS mass spectrometry;
MW micro wave(s);
NMR nuclear magnetic resonance;
Psi pounds per square inch;
sat saturated;
SFC supercritical fluid chromatography;
TFA trifluoroacetic acid;
THF tetrahydrofuran;
TLC thin layer chromatography;
TMEDA tetramethy lethy lenediamine ;
UPLC ultra performance liquid chromatography
XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl General methods:
All solvents used were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials used were available from commercial sources, or prepared according to literature procedures. Room temperature refers to 20 - 25 C. Solvent mixture compositions are given as volume percentages or volume ratios.
Microwave heating was performed in a Biotage Creator, Initiator or Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz. It is understood that microwaves can be used for the heating of reaction mixtures.
Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F254) and and spots were UV visualized. Flash chromatography was performed on a Combi Flash® Companion™ using RediSep™ normal-phase flash columns. Straight phase flash column chromatography was manually performed on Merck Silica gel 60 (0.040- 0.063mm), or automatically using an ISCO Combiflash® Companion™ system using the solvent system indicated. Phase separation was optionally performed on an Isolute® phase separator.
1H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz unless otherwise indicated. Spectra were obtained using a Bruker av400 NMR spectrometer operating at 400 MHz for 1H and 100 MHz for 13C equipped with a 3 mm flow injection SEI H/D- C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1H, 376 MHz for 19F, and 100 MHz for 13C, equipped with a 4-nucleus probehead with Z-gradients. 500 MHz spectra were recorded using a Bruker 500MHz Avance III NMR spectrometer, operating at 500 MHz for 1H, 125 MHz for 13C, and 50 MHz for 15N equipped with a 5mm TXI probehead with Z-gradients. 600 MHz spectra were recorded using a Bruker DRX600 NMR spectrometer, operating at 600 MHz for 1H, 150 MHz for 13C, and 60 MHz for 15N equipped with a 5mm TXI (or BBO) probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS (0.00 ppm). The following reference signals were used: TMS 0.00, or the residual solvent signal of DMSO-de 2.49, CD3OD 3.30, acetone-dδ 2.04 or CDCl3 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m, br and app for singlet, doublet, triplet, quartet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.
HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G131 IA Quaternary Pump, a G1367 Well-Plate Autosampler, a Gl 316A Thermostatted Column Compartment and a Gl 315A Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min. Alternatively, HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Column Compartment and a G1315B Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C 18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min. Alternatively, HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C18, 3.0 x 50 mm, 3.0 m, 110 A run at a flow rate of 1.0 ml/min.
GC analyses were performed on a HP 6890 GC equipped with a Gl 512AX flame ionization detector supplied by Agilent Technologies. The column used was DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific). A linear temperature gradient was typically applied. Chiral GC analyses were performed on an HP 6890 GC equipped with a flame ionization detector supplied by Agilent Technologies. The column used was a Cyclodex B ID 0.25 mm x 30 m, 0.25 m (Agilent Technologies). The temperature of the GC oven was typically held isocratically at for example 100 C for 30 minutes. Mass spectra (MS) were run using an automated system with atmospheric pressure chemical (APCI or CI) or electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). UPLC-MS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Autosampler, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity UPLC PDA detector and a Waters 3100 Mass Spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 μM run at a flow rate of 0.5 ml/min. Alternatively, UPLCMS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Solvent Manager, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity PDA detector and a Waters SQ Detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 μM run at a flow rate of 0.5 ml/min.
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 ZQ 2000 single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on a Xbridge C18, 30x50mm, 3.5μm column or on a Gemini C18 3.0 x 50, 3 m (Phenomenex) column run at a flow rate of 1 ml/min. Alternatively, LC-MS analyses were performed on an LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. The column used was a Xbridge C18, 30x50mm, 3.5μm or a Gemini C 18, 3.0 mm x 50 mm, 3 m, (Phenomenex) which was run at a flow rate of 1 ml/min. Alternatively, 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 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 operated in positive and negative ion mode, switching between APCI and APPI mode. Separation was performed using a Gemini column C 18, 3.0 mm x 50 mm, 3 m, (Phenomenex) and run at a flow rate of 0.8 ml/min. Typical mobile phase systems for HPLC, UPLC-MS, and LCMS consisted of A: 1OmM NH4OAc (aq.) in 5% CH3OH) or 1OmM NH4OAc in 5% CH3CN and B: CH3OH or CH3CN and linear gradients from 100% A to 100% B was typically applied. GCMS analysis was performed on a GC/DIP-MS system supplied by Agilent
Technologies. The system consisted of a GC 6890N, G1530N, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer. The mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH. 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 50-550 and the scan speed was set to 2.91 scan/s. The sample solution was either injected on the GC or introduced by direct inlet to the probe tip. The GC column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 15m, 0.25 m (Varian Inc.). A linear temperature gradient was typically applied. Alternatively, GCMS analysis was performed on a GC-MS system supplied by Agilent Technologies, consisting of a 6890N G1530N GC, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer. The column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 m (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 30m, 0.25 m (Varian Inc.). Typically a linear temperature gradient was applied. The mass spectrometer was equipped with a chemical ionisation (CI) ion source and the reactant gas was methane or 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 3.21 scan/s. Preparative HPLC was performed on a Waters Auto purification HPLC-UV system with a diode array detector using for example a Waters Xterra® MS Cs column (30x150 mm, 10 m), a Phenomex Gemini-NX column (21x250 mm, 10 m), a Waters XBridge C8 column ( 19x250 mm, 10 m), or a Waters XBridge™ C 18 column ( 19x250 mm, 10 m) . Mobile phase A: 0.1 M ammonium acetate in water/mobile phase B (95:5). Mobile phase B:
MeCN or MeOH. Typically a linear gradient of mobile phase B was applied.
Preparative chiral chromatography for separation of enantiomers was run on a Berger Multigram II system (SFC) or a LaPrep® system (HPLC) using the specified column and mobile phase system.
Compounds have been named using CambridgeSoft MedChem ELN v2.1 or ACD/Name, version 10.0, or 10.06, software from Advanced Chemistry Development, Inc.
(ACD/Labs), Toronto ON, Canada, www.acdlabs.com, or Lexichem, version 1.7, software from OpenEye.
EXAMPLES
Below follows a number of non-limiting examples of compounds of the invention.
Example Ii
2-(3-Bromophenyl)-5-methyl-2-phenyl-2H-imidazol-4-ol
Figure imgf000046_0001
(3-Bromophenyl)(phenyl)methanone (280 mg, 1.07 mmol) was dissolved in ammonia (7M in MeOH) (4 niL, 28 mmol) and heated to 150 0C for Ih by microwave heating. Ethyl 2- oxopropanoate (1 mL, 9 mmol) was added 200 μL (1 equiv.) at a time and the reaction was stirred at 150 0C for 1 h by microwave heating between each addition giving at total of 5 h. The solvent was evaporated and preparative HPLC yielded 10.7 mg (3% yield) of the title compound: MS (ES-) m/z 327, 329 [M-H]". Example 2i
2-(3-Bromophenyl)-5-methyl-2-phenyl-2H-imidazol-4-amine
Figure imgf000047_0001
2-(3-Bromophenyl)-5-methyl-2-phenyl-2H-imidazol-4-ol (10.7 mg, 0.03 mmol) was dissolved in pyridine (1 rnL) and phosphorus pentasulfϊde (50 mg, 0.11 mmol) was added. The reaction was heated to 120 0C for 1 h. Ammonia (7M in MeOH) (1 mL, 7 mmol) and tert-butyl hydroperoxide (0.5 mL, 3.64 mmol) was added and the reaction was stirred at room temperature for 16 h. The solvents were evaporated and preparative HPLC yielded 7.5 mg (70% yield) of the title compound: MS (ES+) m/z 328, 330 [M+H]+.
Example 3i
(3-Bromophenyl)(pyridin-4-yl)methanimine
Figure imgf000047_0002
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to - 78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution stirred for 30 min. 4-Cyanopyridine (2.62 g, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was filtered and the solvent evaporated to yield 5 g (76% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 11.04 - 11.42 (m, 1 H) 8.70 (t, 2 H) 7.66 - 7.85 (m, 2 H) 7.54 (d, 2 H) 7.33 - 7.49 (m, 2 H); MS (ES+) m/z 261, 263 [M+H]+. Example 4i
2-(3-Bromophenyl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-ol
Figure imgf000048_0001
(3-Bromophenyl)(pyridin-4-yl)methanimine (470 mg, 1.80 mmol) was dissolved in ammonia (7M in MeOH) (3 mL, 21 mmol). Ethyl 2-oxopropanoate (1 mL, 9 mmol) was added 200 μL (1 equiv.) at a time and the reaction was stirred at 150 0C by microwave heating for 1 h between each addition giving at total of 5 h. Preparative HPLC yielded 22 mg (3.7% yield) of the title compound: MS (ES+) m/z 328, 330 [M+H]+. Example 5i
2-(3-Bromophenyl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-amine
Figure imgf000048_0002
2-(3-Bromophenyl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-ol (22 mg, 0.07 mmol) was dissolved in pyridine (1 mL) and phosphorus pentasulfϊde (50 mg, 0.11 mmol) was added. The reaction was heated to 120 0C for 1 h. Ammonia (33% in water) (0.156 mL, 2.67 mmol) and tert-butyl hydroperoxide (0.137 mL, 1.00 mmol) were added and the reaction was stirred at room temperature for 16 h. The solvents were evaporated and preparative HPLC yielded 4 mg (18% yield) of the title compound: MS (ES+) m/z 329, 331 [M+H]+. Example 6i
(3-Bromophenyl)(4-fluorophenyl)methanimine
Figure imgf000048_0003
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 niL) and cooled to - 78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution stirred for 30 min. 4-Fluorobenzonitrile (3.05 g, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20
mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4 The mixture was filtered and the solvent evaporated to yield 4.92 g (70% yield) of the title compound:
1H NMR (400 MHz, DMSO-J6) δ ppm 10.66 - 10.87 (m, 1 H) 7.13 - 7.83 (m, 8 H); MS (ES+) m/z 278, 280 [M+H]+.
Example 7i
5-Amino-2-(3-bromophenyl)-2-(4-fluorophenyl)-2H-imidazole-4-thiol
Figure imgf000049_0001
(3-Bromophenyl)(4-fluorophenyl)methanimine (1 g, 3.60 mmol) and ethanebis(thioamide) (0.432 g, 3.60 mmol) were taken up in MeOH (10 mL). The reaction was heated to 120 0C for 1 h by microwave heating. The solvent was evaporated. Column chromatography using EtOAc 0% to 50% in heptane yielded 497 mg (38% yield) of the title compound: MS (ES+) m/z 364, 366 [M+H]+.
Example 8i
2-(3-Bromophenyl)-2-(4-fluorophenyl)-5-(methylthio)-2H-imidazol-4-amine
Figure imgf000049_0002
5-Amino-2-(3-bromophenyl)-2-(4-fluorophenyl)-2H-imidazole-4-thiol (497 mg, 1.36 mmol) was dissolved in THF (7 niL). Iodomethane (0.255 niL, 4.09 mmol) was added and the reaction was heated to reflux for 16 h. The reaction mixture was filtered through a silica plug. Preparative HPLC yielded 25 mg (4.8% yield) of the title compound: MS (ES+) m/z 378, 380 [M+H]+.
Example 9i
2-(3-Bromophenyl)-2-(4-fluorophenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000050_0001
To a solution of zinc iodide (522 mg, 1.63 mmol) in tetrahydrofuran (2 mL) was added methylmagnesium bromide (0.545 mL, 1.63 mmol). To the formed slurry was then added 2-(3-bromophenyl)-2-(4-fluorophenyl)-5-(methylthio)-2H-imidazol-4-amine (103 mg, 0.27 mmol) in tetrahydrofuran (4 mL), followed by bis(triphenylphosphine)palladium(II) chloride (19.11 mg, 0.03 mmol). The reaction mixture was stirred at 40 0C for 2 h.
Preparative HPLC yielded 29 mg (31% yield) of the title compound: MS (ES+) m/z 346, 348 [M+H]+.
Example 1Oi
(3-Bromophenyl)(4-methoxyphenyl)methanimine
Figure imgf000050_0002
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to 78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution stirred for 30 min. 4-Methoxybenzonitrile (3.36 g, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was filtered and the solvent evaporated to yield 6.6 g (90% yield) of the title compound: MS (ES+) m/z 290, 292 [M+H]+.
Example Hi
5-Amino-2-(3-bromophenyl)-2-(4-methoxyphenyl)-2H-imidazole-4-thiol
Figure imgf000051_0001
(3-Bromophenyl)(4-methoxyphenyl)methanimine (6.6 g, 22.75 mmol) and
ethanebis(thioamide) (2.73 g, 22.75 mmol) were taken up in EtOH (60 mL). The reaction was divided into three 20 ml microwave vials and heated to 165 0C in a microwave for 2 h. The solvent was evaporated. Column chromatography using EtOAc 0% to 50% in DCM yielded 1.83 g (21% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 7.42 - 7.49 (m, 2 H) 7.12 - 7.22 (m, 4 H) 6.84 (d, 2 H) 5.53 (br. s., 2 H) 3.80 (s, 3 H); MS (ES+) m/z 376, 378 [M+H]+.
Example 12i
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-(methylthio)-2H-imidazol-4-amine
Figure imgf000051_0002
5-Amino-2-(3-bromophenyl)-2-(4-methoxyphenyl)-2H-imidazole-4-thiol (1.83 g, 4.86 mmol) was dissolved in THF (20 mL). Iodomethane (0.908 mL, 14.59 mmol) was added and the reaction was heated to 60 0C for 24 h. Column chromatography using EtOAc 0% to 100% in DCM yielded 1.6 g (84% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 7.59 (t, 1 H) 7.49 (d, 1 H) 7.36 - 7.43 (m, 3 H) 7.23 (t, 1 H) 6.83 (d, 2 H) 6.71 (br. s., 2 H) 3.69 (s, 3 H) 2.61 (s, 3 H); MS (ES+) m/z 387, 389 [M+H]+. Example 13i
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000052_0001
To a solution of zinc iodide (13.09 g, 40.99 mmol) in THF (20 niL) at 0 0C was added methylmagnesium bromide (3M in diethyl ether) (13.66 mL, 40.99 mmol). To the formed slurry was then added 2-(3-bromophenyl)-2-(4-methoxyphenyl)-5-(methylthio)-2H- imidazol-4-amine (1.6 g, 4.10 mmol) in THF (20 mL), followed by
bis(triphenylphosphine)palladium(II) chloride (0.288 g, 0.41 mmol). The reaction mixture was stirred at 50 0C for 3 h. MeOH was added to quench the reaction. The solvent was evaporated. Water was added resulting in a thick slurry which was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Column chromatography using EtOAc 0% to 100% in DCM yielded 884 mg (60% yield) of the title compound: MS (ES+) m/z 358, 360 (M+H)+.
Example 14i
(3-Bromophenyl)(4-methoxy-3,5-dimethylphenyl)methanimine
Figure imgf000052_0002
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to - 78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. 4-Methoxy-3,5-dimethylbenzonitrile (4.06 g, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20 niL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was filtered and the solvent evaporated to yield 7.7 g (96% yield) of the title compound: 1H-NMR (500 MHz, CDCl3) δ 2.23 (s, 6 H), 3.69 (s, 3 H), 7.06 - 7.24 (m, 3 H), 7.33 - 7.44 (m, 1 H), 7.52 (dd, 1 H), 7.67 (br. s., 1 H), MS (ES+) m/z 318, 320 [M+H]+.
Example 15i
5-Amino-2-(3-bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-imidazole-4-thiol
Figure imgf000053_0001
(3-Bromophenyl)(4-methoxy-3,5-dimethylphenyl)methanimine (7.7 g, 24.20 mmol) and ethanebis(thioamide) (2.91 g, 24.20 mmol) were taken up in EtOH (10 mL). The reaction was heated to 165 0C for 2 h by microwave heating. The solvent was evaporated. Column chromatography using 0% to 100% EtOAc in heptane yielded 2.11 g (22% yield) of the title compound: MS (ES+) m/z 404, 406 [M+H]+.
Example 16i
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-(methylthio)-2H-imidazol-4- amine
Figure imgf000053_0002
5-Amino-2-(3-bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-imidazole-4-thiol (2.11 g, 5.22 mmol) was taken up in THF (20 mL). Iodomethane (0.975 mL, 15.66 mmol) was added and the reaction was heated to 60 0C for 24 h. Column chromatography using EtOAc 0% to 100% in heptane yielded 1.82 g (83% yield) of the title compound: MS (ES+) m/z 418, 420 [M+H]+. Example 17i
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000054_0001
To a solution of zinc iodide (11.11 g, 34.80 mmol) in THF (40 mL) at 0 0C was added methylmagnesium bromide (3M in diethyl ether) (11.60 mL, 34.80 mmol). To the formed slurry was then added 2-(3-bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-
(methylthio)-2H-imidazol-4-amine (1.82 g, 4.35 mmol) in THF (20 mL), followed by bis(triphenylphosphine)palladium(II) chloride (0.305 g, 0.44 mmol). The reaction mixture was stirred at 50 0C for 3 h. The reaction mixture was filtered and the solid residue was washed with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Column chromatograpy using EtOAc with 10% HOAc, 0% to 100% in DCM yielded 0.4 g (24% yield) of the title compound: MS (ES+) m/z 386, 388 [M+H]+.
Example 18i
(3-Bromophenyl)(5-methylthiophen-3-yl)methanimine
Figure imgf000054_0002
4-Bromo-2-methylthiophene (2.82 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to -78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the solution was stirred for 30 min. 3-Bromobenzonitrile (4.59 g, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was stirred for 30 min. The reaction was then allowed to warm to room temperature over 30 min. MeOH (40 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4, filtered and the solvent evaporated to yield 6.5 g (92% yield) of the title compound: MS [ES+] m/z 280, 282 (M+H)+.
Example 19i
5-Amino-2-(3-bromophenyl)-2-(5-methylthiophen-3-yl)-2H-imidazole-4-thiol
Figure imgf000055_0001
(3-Bromophenyl)(5-methylthiophen-3-yl)methanimine (6.5 g, 23.20 mmol) and ethanebis(thioamide) (3 g, 24.96 mmol) were taken up in EtOH (10 mL). The reaction was heated to 165 0C for 2 h by microwave heating. The reaction mixture was diluted with DCM and filtered. Column chromatography using 0% to 100% EtOAc in heptane yielded 1.2 g (14% yield) of the title compound: MS (ES+) m/z 366, 368 [M+H]+.
Example 2Oi
2-(3-Bromophenyl)-5-(methylthio)-2-(5-methylthiophen-3-yl)-2H-imidazol-4-amine
Figure imgf000055_0002
5-Amino-2-(3-bromophenyl)-2-(5-methylthiophen-3-yl)-2H-imidazole-4-thiol (1.2 g, 3.28 mmol) was taken up in THF (40 mL). Iodomethane (0.612 mL, 9.83 mmol) was added and the reaction was heated to 60 0C for 24 h. Column chromatography using 0% to 100% EtOAc in heptane yielded 0.99 g (79% yield) of the title compound: MS (ES+) m/z 380, 382 [M+H]+. Example 21i
2-(3-Bromophenyl)-5-methyl-2-(5-methylthiophen-3-yl)-2H-imidazol-4-amine
Figure imgf000056_0001
2-(3 -Bromophenyl)-5 -(methylthio)-2-(5 -methylthiophen-3 -yl)-2H-imidazol-4-amine (0.99 g, 2.60 mmol) and l,3-bis(diphenylphosphino)propane nickel (II) chloride (0.564 g, 1.04 mmol) were dissolved in toluene (10 rnL). Methylmagnesium bromide (3M in diethyl ether) (6.94 rnL, 20.82 mmol) was added and the resultant suspension stirred at room temperature. After 1 h, water was added and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvents evaporated. Preparative HPLC yielded 320 mg (35% yield) of the title compound: MS (ES+) m/z 348, 350 [M+H]+.
Example 22i
(3-Bromophenyl)(4-(difluoromethoxy)phenyl)methanimine
Figure imgf000056_0002
The title compound was synthesized as described for Example 6i in 92% yield, starting from 4-(difluoromethoxy)benzonitrile (2.54 g, 15.00 mmol): 1H NMR (400 MHz, DMSO- d6) δ ppm 10.84 (br. s., 1 H) 7.67 - 7.75 (m, 2 H) 7.56 - 7.63 (m, 2 H) 7.40 - 7.49 (m, 2 H) 7.23 - 7.30 (m, 2 H) 7.35 (t, 1 H); MS (ES+) m/z 326, 328 [M+H]+.
Example 23i
5-Amino-2-(3-bromophenyl)-2-(4-(difluoromethoxy)phenyl)-2H-imidazole-4-thiol
Figure imgf000057_0001
The title compound was synthesized as described for Example 7i in 22% yield, starting from (3-bromophenyl)(4-(difluoromethoxy)phenyl)methanimine (4.24 g, 13 mmol):
1H NMR (400 MHz, DMSO-J6) δ ppm 13.23 (s, 1 H) 7.61 - 7.67 (m, 1 H) 7.57 (t, 1 H) 7.49 - 7.54 (m, 1 H) 7.38 - 7.46 (m, 2 H) 7.34 (t, 1 H) 7.15 - 7.20 (m, 1 H) 7.12 (t, 1 H) 6.87 - 6.95 (m, 1 H); MS (ES+) m/z 412, 414 [M+H]+.
Example 24i
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)phenyl)-5-(methylthio)-2H-imidazol-4-
Figure imgf000057_0002
Methyl iodide (0.531 mL, 8.51 mmol) was added to a solution of 5-amino-2-(3- bromophenyl)-2-(4-(difluoromethoxy)phenyl)-2H-imidazole-4-thiol (1.17 g, 2.84 mmol) in THF (10 mL) and the resulting mixture was stirred at 50 0C over night. The mixture was concentrated and the resulting residue was purified on a silica gel column eluted with 0-5% 0.1M NH3 in MeOH in DCM to give 0.714 g (59% yield) of the title compound: MS (ES+) m/z 426, 428 [M+H]+.
Example 25i
(3-Bromophenyl)(4-methoxy-3-methylphenyl)methanimine
Figure imgf000057_0003
1,3-Dibromobenzene (4.23 mL, 34.99 mmol) was dissolved in Et2O (60 niL) and cooled to -78 0C. n-Butyllithium (15.40 mL, 38.49 mmol) was added and the solution stirred for 30 min. A solution of 4-methoxy-3-methylbenzonitrile (5.15 g, 34.99 mmol) in Et2O (40 mL) was added at -78 0C and the reaction was allowed to warm to room temperature over 2 h. A solution of ammonium acetate (2.97 g, 38.49 mmol) in methanol (20 mL) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic layer were washed with brine, dried over MgSO4, filtered and the solvent evaporated to give the title product 10.5 g (99% yield): MS(CI+) m/z 304, 306 [M+H]+.
Example 26i
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000058_0001
(3-Bromophenyl)(4-methoxy-3-methylphenyl)methanimine (10.5 g, 34.52 mmol), 2- oxopropanethioamide (7.12 g, 69.04 mmol) and methanol (100 mL) were charged in a round-bottomed flask and the resulting mixture stirred at 60 0C (oil bath) for 4 h and then at 40 0C overnight. The solvent was evaporated and the crude product was purified by column chromatography on silica gel, gradient elution with 0-100% EtOAc in heptane to give the title compound, 4.09 g (30% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 13.08 (s, 1 H), 7.35 - 7.41 (m, 2 H), 7.23 - 7.28 (m, 1 H), 7.17 - 7.22 (m, 1 H), 6.96 - 7.04 (m, 2 H), 6.77 (d, 1 H), 3.59 (s, 3 H), 2.15 (s, 3 H), 1.94 (s, 3 H); MS(ES+) m/z 389, 391
[M+H]+. Example 27i
(3-Bromophenyl)(2,6-dimethylpyridin-4-yl)methanimine
Figure imgf000059_0001
n-Butyllithium (2.000 niL, 5.00 mmol) was added dropwise to a solution of 4-bromo-2,6- dimethylpyridine (0.930 g, 5 mmol) in Et2O (12 mL) at -78 0C under a nitrogen
atmosphere. After 45 min at -78 0C, a solution of 3-bromobenzonitrile (0.910 g, 5.00 mmol) in Et2O (4 mL) was added, the cooling bath was removed, and the resulting mixture was stirred at rt for 1 h. The mixture was quenched with dry MeOH (5 mL) and the solvents were removed in vacuo. The resulting residue was taken up in DCM (30 mL) and water (20 mL) and poured into a phase separator. The organic layer was collected and concentrated to give 1.44 g (quantitative yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 10.98 (s, 1 H) 7.82 (t, 1 H) 7.70 - 7.76 (m, 1 H) 7.50 - 7.54 (m, 1 H) 7.39 - 7.46 (m, 1 H) 7.17 (s, 1 H) 7.04 (s, 1 H) 2.46 (s, 6 H); MS (ES+) m/z 289, 291 [M+l]+. Example 28i
2-(3-Bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-4-methyl-lH-imidazole-5(2H)-thione
Figure imgf000059_0002
(3-Bromophenyl)(2,6-dimethylpyridin-4-yl)methanimine (1.446 g, 5 mmol) and 2- oxopropanethioamide (0.774 g, 7.50 mmol) were dissolved in MeOH (10 mL) and stirred at 50 0C over night. The mixture was concentrated and the resulting residue was purified on a silica gel column eluted with 0-75% EtOAc in heptane to give 1.39 g (74% yield) of the title compound: MS (ES+) m/z 374, 376 [M+l]+. Example 29i
2-(3-Bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4-amine
Figure imgf000060_0001
2-(3-Bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-4-methyl-lH-imidazole-5(2H)-thione (1.39 g, 3.71 mmol) was dissolved in 7M ammonia in MeOH (15.92 ml, 111.41 mmol) and heated in a microwave reactor at 110 0C for 2 h. The mixture was concentrated and purified on a silica gel column eluted with 0-15% 0.1 M NH3 in MeOH in DCM to give 445 mg (34% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.64 (t, 1 H) 7.53 (dt, 1 H) 7.37 (s, 1 H) 7.25 (t, 1 H) 7.11 (s, 2 H) 6.77 (br. s., 2 H) 2.35 (s, 6 H) 2.24 (s, 3 H); MS (ES+) m/z 357, 359 [M+l]+.
Example 3Oi
3-Bromo-5-(prop-l-ynyl)pyridine
Figure imgf000060_0002
To a solution of 3,5-dibromopyridine (5 g, 21.11 mmol), copper(I) iodide (0.238 mL, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.220 g, 1.06 mmol) in toluene (250 mL) was added l-(trimethylsilyl)-l-propyne (3.16 mL, 21.11 mmol), triethylamine (9.71 mL, 69.65 mmol) and IM tetrabutylammonium fluoride in THF (21.11 mL, 21.11 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt over night. The mixture was concentrated and the resulting residue was taken up in water (20 mL) and DCM (2OmL) and poured into a phase separator. The organic phase was collected and the aqueous phase was extracted once with DCM (20 mL). The combined organics were concentrated and purified on a silica gel column eluted with 0-30% EtOAc in heptane to give 2.93 g (71% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 8.66 (d, 1 H) 8.58 (d, 1 H) 8.12 (t, 1 H) 2.10 (s, 3 H); MS (CI) m/z 196, 198 [M+H]+.
Example 3 Ii
5-(Prop-l-ynyl)pyridin-3-yl boronic acid
Figure imgf000061_0001
n-Butyllithium (7.17 niL, 17.93 mmol) was added dropwise over 10 min to a solution of 3- bromo-5-(prop-l-ynyl)pyridine (2.93 g, 14.95 mmol) and triisopropyl borate (4.14 mL, 17.93 mmol) in THF (6 mL) and toluene (24 mL) at -78 0C under a nitrogen atmosphere. The resulting mixture was stirred at -78 0C for 45 min. The cooling bath was removed and the mixture was stirred at rt for 30 min before being cooled to -10 0C. Aqueous 2M HCl (15 mL) was added, the cooling bath removed and the mixture was stirred at rt for 1 h. The organics were removed under reduced pressure and the pH of the resulting aqueous residue was adjusted to 7-8 using an aqueous 20% NaOH solution. The aqueous mixture was diluted with brine (20 mL) and then saturated with solid NaCl and extracted with THF (3 x 25 mL). The combined organics were dried over MgSO4, filtered and concentrated.
Recrystallization from MeOH gave 1.5 g (62% yield) of the title compound: MS (ES-) m/z 160 [M-I]". Example 32i
2-Chloro-4-(imino(4-methoxy-3,5-dimethylphenyl)methyl)phenol
Figure imgf000061_0002
n-Butyllithium (2.480 mL, 6.20 mmol) was added to a solution of (4-bromo-2- chlorophenoxy)(tert-butyl)dimethylsilane (1995 mg, 6.2 mmol) (Eur. J. Med. Chem., 2009, 44, 2765-2775) in Et2O (10 niL) at -78 0C under a nitrogen atmosphere. After 45 min at - 78 0C a solution of 3,5-dimethyl-4-methoxybenzonitrile (999 mg, 6.20 mmol) in THF (5 rnL) was added dropwise, the cooling bath was removed and the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with a solution of ammonium acetate (0.445 mL, 6.20 mmol) in MeOH (5 mL) and the solvents were removed in vacuo. The resulting precipitate was taken up in DCM (50 mL), EtOAc (20 mL) and water (20 mL). The formed precipitate was collected by filtration and dried in vacuo to give 600 mg (33% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 10.05 (br. s., 1 H) 7.59 (br. s., 1 H) 7.24 (d, 1 H) 7.19 (s, 2 H) 6.50 - 6.66 (m, 1 H) 3.71 (s, 3 H) 2.27 (s, 6 H); MS (ES+) m/z 290, 292 [M+ 1]+.
Example 33i
2-(3-Chloro-4-hydroxyphenyl)-2-(4-methoxy-3,5-dimethylphenyl)-4-methyl-lH- imidazole-5(2H)-thione
Figure imgf000062_0001
2-Oxopropanethioamide (633 mg, 6.13 mmol) was added to a solution of 2-chloro-4- (imino(4-methoxy-3,5-dimethylphenyl)methyl)phenol (600 mg, 2.07 mmol) in MeOH (50 mL) and THF (15 mL) at 50 0C. The resulting mixture was stirred at 50 0C over weekend. The mixture was concentrated and purified on a silica gel column eluted with 0-40%
EtOAc in heptane to give 650 mg (84% yield) of the title compound: MS (ES+) m/z 375, 377 [M+l]+.
Example 34i
(3-Chlorophenyl)(3,4-dimethoxyphenyl)methanimine
Figure imgf000063_0001
The title compound was synthesized as described in Example 32i in 99% yield starting from l-bromo-3-chlorobenzene and 3,4-dimethoxybenzonitrile: MS (CI) m/z 276, 278 [M+H]+.
Example 35i
5-Amino-2-(3-chlorophenyl)-2-(3,4-dimethoxyphenyl)-2H-imidazole-4-thiol
Figure imgf000063_0002
(3-Chlorophenyl)(3,4-dimethoxyphenyl)methanimine (13.51 g, 49 mmol),
ethanebis(thioamide) (17.67 g, 147 mmol) and EtOH (56 mL) were divided into four vials and each vial was heated in a microwave reactor at 160 0C for 30 min. The mixtures were pooled and concentrated onto silica and purified on a silica gel column eluted with 20-60% EtOAc in heptane to give 5 g (28% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 13.17 (s, 1 H) 7.31 - 7.43 (m, 4 H) 6.88 - 7.02 (m, 3 H) 3.73 (s, 3 H) 3.69 (s, 3 H); MS (ES+) m/z 362, 364 [M+l]+.
Example 36i
2-(3-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-5-(methylthio)-2H-imidazol-4-amine
Figure imgf000063_0003
Methyl iodide (2.58 mL, 41.45 mmol) was added to a solution of 5-amino-2-(3- chlorophenyl)-2-(3,4-dimethoxyphenyl)-2H-imidazole-4-thiol (5 g, 13.82 mmol) in THF (70 mL) and the resulting mixture was stirred at 50 0C over night. The volatiles were removed in vacuo and the resulting residue was taken up DCM (50 mL) and water (25 mL) and added to a phase separator. The organic phase was collected, concentrated onto silica and purified on a silica gel column eluted with 0-80% EtOAc in heptane to give 1.6 g (31% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 7.43 - 7.48 (m, 2 H) 7.23 - 7.33 (m, 2 H) 7.05 - 7.10 (m, 2 H) 6.84 - 6.89 (m, 1 H) 6.73 (br. s., 2 H) 3.70 (s, 3 H) 3.68 (s, 3 H) 2.63 (s, 3 H); MS (ES+) m/z 376, 378 [M+l]+.
Example 37i
2-(3-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000064_0001
Methylmagnesium bromide (11.35 mL, 34.05 mmol) was added to a solution of zinc iodide (10.87 g, 34.05 mmol) in THF (30 mL) at 0 0C under a nitrogen atmosphere. Then a solution of 2-(3-chlorophenyl)-2-(3,4-dimethoxyphenyl)-5-(methylthio)-2H-imidazol-4- amine (1.6 g, 4.26 mmol) in THF (20 mL) was added followed by
bis(triphenylphosphine)palladium(II) chloride (0.299 g, 0.43 mmol). The resulting mixture was stirred at 50 0C for 4 h. The mixture was cooled to 0 0C and carefully quenched with MeOH (10 mL). The volatiles were removed in vacuo and the resulting residue was taken up in DCM (75 mL) and water (25 mL) and poured into a phase separator. The organic phase was collected and the water phase extracted with DCM (50 mL). The water phase was then made acidic with IM aqueous HCl (30 mL) and extracted with DCM (25 mL).
The combined organics were concentrated and purified on a silica gel column eluted with 10-90% EtOAc in heptane to give 1.18 g (81 % yield) of the title compound: 1H NMR (400
MHz, DMSO-J6) δ ppm 7.40 - 7.50 (m, 2 H) 7.20 - 7.35 (m, 2 H) 7.00 - 7.12 (m, 2 H) 6.80 - 6.92 (m, 1 H) 6.68 (br. s., 2 H) 3.61 - 3.74 (m, 6 H) 2.24 (s, 3 H); MS (ES+) m/z 344, 346 [M+ 1]+.
Example 38i
(3-Bromophenyl)(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)methanimine
Figure imgf000065_0001
The title compound was synthesized as described in Example 32i in quantitative yield starting from 1,3-dibromobenzene and 2,3-dihydrobenzo[b][l,4]dioxine-6-carbonitrile: MS (CI) m/z 318, 320 [M+H]+.
Example 39i
5-Amino-2-(3-br omophenyl)-2-(2,3-dihydrobenzo [b] [ 1 ,4] dioxin-6-yl)-2H-imidazole-4- thiol
Figure imgf000065_0002
The title compound was synthesized as described in Example 35i in 17% yield starting from (3-bromophenyl)(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)methanimine and
ethanebis(thioamide): 1H NMR (400 MHz, DMSO-J6) δ ppm 13.13 (s, 1 H) 7.55 (t, 1 H) 7.47 - 7.53 (m, 1 H) 7.38 - 7.43 (m, 1 H) 7.32 (t, 1 H) 6.80 - 6.87 (m, 3 H) 4.21 (s, 4 H); MS (ES+) m/z 404, 406 [M+ 1]+.
Example 4Oi
2-(3-Bromophenyl)-2-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)-5-(methylthio)-2H- imidazol-4-amine
Figure imgf000066_0001
The title compound was synthesized as described in Example 36i starting from 5-amino-2- (3-bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2H-imidazole-4-thiol and methyl iodide: MS (ES+) m/z 418, 420 [M+l]+.
Example 41i
l-CS-BromophenylJ-l-Cl^-dihydrobenzoIbl ll^ldioxin-ό-yO-S-methyl-lH-imidazoM- amine
Figure imgf000066_0002
Methylmagnesium bromide (9.60 mL, 28.80 mmol) was added to a solution of 2-(3- bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-(methylthio)-2H-imidazol-4- amine (1506 mg, 3.6 mmol) and [l,3-bis(diphenylphosphino)propane]nickel(II) chloride (976 mg, 1.80 mmol) in toluene (20 mL) at 0 0C under a nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at rt for 4 h. The mixture was quenched with ice and IM aqueous HCl (30 mL) and extracted with DCM (100 mL). The combined organics were concentrated onto silica and purified on a silica gel column eluted with 0- 15% 0.1M NH3 in MeOH in DCM. The crude product was dissolved in MeOH/DMSO and purified by preparative HPLC. The fractions containing the title compound were pooled and the MeOH removed in vacuo. The resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator and concentrated to give 130 mg (9% yield) of the title compound: MS (ES+) m/z 386, 388 [M+l]+. Example 42i
4-(Difluoromethoxy)-3,5-dimethylbenzonitrile
Figure imgf000067_0001
A three-necked round bottom flask (500 mL) equipped with dry ice condenser (-78 0C, acetone/dry ice) was charged with a solution of 4-hydroxy-3,5-dimethyl-benzonitrile (7.8 g, 53 mmol) in zPrOH (100 mL). Aqueous sodium hydroxide solution (2.65M, 100 mL) was added. The reaction mixture was stirred vigorously at 40 0C for 5 h while chlorodifluoromethane was bubbled continuously into the solution at a moderate rate. The reaction mixture was then cooled to room temperature and extracted with Et2O (3 x 80 mL). The combined extracts were washed with water (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient of 1% to 5% ethyl acetate in hexane to afford 4.5 g (43% yield) of 4- difluoromethoxy-3,5-dimethyl-benzonitrile: 1H NMR (400 MHz, CDCl3) ppm 7.39 (s, 2
H), 6.39 (t, J= 73.6 Hz, 1 H), 2.34 (s, 6 H); 19F NMR (376 MHz, CDCl3) ppm -79.42 (d, J = 73.4 Hz, 2 F); ESMS m/z: [M+l]+ 198.15; CHN: Calcd for C10H9F2NO: C 60.91, H
4.60, N 7.10; Found: C 61.34, H 4.05, N 7.20.
Example 43i
(3-Bromophenyl)(4-(difluoromethoxy)-3,5-dimethylphenyl)methanimine
Figure imgf000067_0002
n-Butyllithium (2.5 M, 10.00 mL, 25.00 mmol) was added to a solution of 1,3- dibromobenzene (5.90 g, 25.00 mmol) in diethylether (50 mL) at -78 0C under argon. After 30 min at -78 0C, a solution of 4-(difluoromethoxy)-3,5-dimethylbenzonitrile (4.93 g, 25 mmol) in tetrahydrofurane (30 mL) was added, the cooling bath removed and the reaction mixture stirred at r.t. for 2 h. A solution of ammonium acetate (1.927 g, 25.00 mmol) in methanol (20 mL) was added, the solvents evaporated and the residue taken up in dichloromethane (40 mL) and water (25 mL). The organic phase was separated, dried with MgSO4 and evaporated to give the title compound (8.71 g, 98% yield): MS (ES+) m/z 354.0, 356.0 [M+l]+.
Example 44i
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-4-methyl-lH- imidazole-5(2H)-thione
Figure imgf000068_0001
(3-Bromophenyl)(4-(difluoromethoxy)-3,5-dimethylphenyl)methanimine (1030 mg, 2.91 mmol), 2-oxopropanethioamide (600mg, 5.82 mmol) and methanol (5 mL) were charged in a round-bottomed flask and the resulting mixture stirred at 60 0C for 4 h and then at 40 0C overnight. The solvent was evaporated and the residue dissolved in dichloromethane (5 mL) and vacuum filtered through a silica pad, which was rinsed with dichloromethane (25 mL). The filtrate was evaporated to give the title compound (1319 mg, quantitative yield). An analytical sample was obtained by recrystalization from boiling pentane: 1H-NMR (500 MHz, DMSO-de) δ 2.22 (s, 6 H), 2.32 (s, 3 H), 6.94 (t, 1 H), 7.19 (s, 2 H), 7.37 (t, 1 H), 7.44 (d, 1 H), 7.58-7.55 (m, 2 H), 13.29 (s, 1 H); MS (ES-) m/z 439.0, 441.0 [M-I]".
Example 45i
2-Oxopropanethioamide
Figure imgf000068_0002
A solution of acetyl cyanide (140 niL, 1764.24 mmol) in 2-methyltetrahydrofuran (850 niL) was stirred at -10 0C as hydrogen sulfide (Sigma- Aldrich lecture bottle) was bubbled through the solution. The addition of hydrogen sulfide was stopped after 15 min and to the stirred mixture, triethylamine (1.230 mL, 8.82 mmol) in 2-methyltetrahydrofuran (13 mL) was added slowly over 30 mins (exothermic reaction). Hydrogen sulfide addition was continued for 3 h at 5 0C, 3 h at 10 0C and overnight at 15 0C. Nitrogen gas was bubbled though the solution for 30 min, followed by evaporation of the volatiles. To the residue was added a mixture of heptane (100 mL) and ethylacetate (100 mL). A solid was filtered off (79 g, 43% yield) and the filtrate was purified by a short-plug silica gel
chromatography, eluting with 50% ethylacetate in heptane to give (79 g, 43% yield) of the title compound. Both crops contained desired product of adequate purity according to GC- MS. (158 g, 87 % yield): GCMS (ES+) m/z 104 [M+l].
Example 46i
(3-Chlorophenyl)(l-methyl-lH-pyrazol-4-yl)methanimine
dissolved in Et2O (30 mL) and
Figure imgf000069_0001
was added, and the the solution stirred for 30 min. 1 -Methyl- lH-pyrazole-4-carbonitrile (1 g, 9.34 mmol) was added in Et2O (20 mL) at -78 0C and the reaction was allowed to warm to room temperature over 1 h, then MeOH (10 mL) containing ammonium acetate (0.720 g, 9.34 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with Brine and dried over MgSO4, filtered and the solvent evaporated to give the product (1.4 g, 68% yield): MS (ES) m/z 220 [M+l]+.
Example 47i
2-(3-Chlorophenyl)-4-methyl-2-(l-methyl-lH-pyrazol-4-yl)-lH-imidazole-5(2H)- thione
stirred
Figure imgf000070_0001
with 2-oxopropanethToamide (413 mg, 4.00 mmol) in dry MeOH (3 mL) at 60 0C for 48 h. 2-Oxopropanethioamide (206 mg, 2.00 mmol) was added and the heating continued. The reaction was stopped after another 48 h. The reaction mixture was evaporated onto silica gel and purified by chromatography on silica (0-5% MeOH in CH2Cl2) to give 2-(3- chlorophenyl)-4-methyl-2-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-imidazole-5 (2H)-thione (530 mg, 87% yield): MS (ES) m/z 305 [M+l]+. Example 48i
2-(3-Chlorophenyl)-5-methyl-2-(l-methyl-lH-pyrazol-4-yl)-2H-imidazol-4-amine
Figure imgf000070_0002
in dry MeOH (3 mL) at 60 0C for 12 h. The solvent was evaporated in vacuo and another portion of ammonia in MeOH was added and heating continued over night. The reaction mixture was concentrated in vacuo and purified by chromatography on silica (0 - 10% MeOH in CH2Cl2 with 1% NH4OH) to give 2-(3-chlorophenyl)-5-methyl-2-(l -methyl- IH- pyrazol-4-yl)-2H-imidazol-4-amine (0.123 g, 25% yield): 1H NMR (400 MHz, CD3OD) ppm 7.46 (m, 1 H), 7.39 (m, 1 H), 7.37 - 7.32 (m, 2 H), 7.30 - 7.24 (m, 2 H), 3.60 (s, 3 H), 2.33 (s, 3 H); MS (ES) m/z 288 [M+l]+. Example 49i
(3-Chlorophenyl)(l-methyl-lH-imidazol-5-yl)methanimine.
and
Figure imgf000071_0001
cooled to -78 0C. n-Butyllithium (0.932 mL, 2.33 mmol) was added and the the solution stirred for 30 min. 1 -Methyl- lH-imidazole-5-carbonitrile (250 mg, 2.33 mmol) was added in Et2O (10 mL) at -78 0C and the reaction was allowed to warm to room temperature over 1 h, then MeOH (2.5mL) containing ammonium acetate (180 mg, 2.33 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine, dried over MgSO4, and filtered and then the solvent was evaporated to give the product (0.33 g, 64% yield): MS (ES) m/z 220 [M+l]+.
Example 5Oi
2-(3-Chlorophenyl)-5-methyl-2-(l-methyl-lH-imidazol-5-yl)-2H-imidazol-4-amine
Figure imgf000071_0002
(3 -Chlorophenyl)(l -methyl- lH-imidazol-5-yl)methanimine (330 mg, 1.50 mmol) was stirred with 2-oxopropanethioamide (310 mg, 3.00 mmol) in dry MeOH (3 mL) at 60 0C for 48 h. One more equivalent of 2-oxopropanethioamide was added and heating continued 12 h. Ammonia in methanol (7M, 1.500 mL, 10.50 mmol) was added and heating was continued at 60 0C for 48 h. The reaction mixture was evaporated onto silica gel and purified by chromatography on silica (0-5% MeOH in CH2Cl2) to give 2-(3-chlorophenyl)- 5 -methyl-2-(l -methyl- lH-imidazol-5-yl)-2H-imidazol-4-amine (105 mg, 35% yield). 1H NMR (400 MHz, CD3OD) ppm 7.58 (m, 1 H), 7.33 - 7.26 (m, 3 H), 7.23 (m, 1 H), 6.86 (m, 1 H), 3.50 (s, 3 H), 2.36 (s, 3 H); MS (ES) m/z 288 [M+l]+.
Example 51i
4-((3-Chlorophenyl)(imino)methyl)-N,N-dimethylpyridin-2-amine
Figure imgf000072_0001
l-Bromo-3-chlorobenzene (0.798 niL, 6.79 mmol) was dissolved in Et2O (30 niL) and cooled to -78 0C. n-Butyllithium (2.72 mL, 6.79 mmol) was added and the the solution stirred for 30 min. 2-(Dimethylamino)isonicotinonitrile (1 g, 6.79 mmol) was added in Et2O (30 mL) at -78 0C and the reaction was allowed to warm to room temperature over Ih. MeOH (7 mL) containing ammonium acetate (0.523 g, 6.79 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4, filtered and the solvent evaporated to give the product (1.4 g, 79% yield): MS (ES) m/z 260 [M+l]+.
Example 52i
4-(4-Amino-2-(3-chlorophenyl)-5-methyl-2H-imidazol-2-yl)-N,N-dimethylpyridin-2- amine
Figure imgf000072_0002
4-((3-Chlorophenyl)(imino)methyl)-N,N-dimethylpyridin-2-amine (1.4 g, 5.39 mmol) was stirred with 2-oxopropanethioamide (1.112 g, 10.78 mmol) in dry MeOH (10 mL) at 60 0C for 20 h. One more equivalent of 2-oxopropanethioamide was added and heating continued 12 h. 7M ammonia in MeOH (10 mL, 70.00 mmol) was added and heating was continued at 60 0C for 2 days. The solvent was evaporated in vacuo and another portion of ammonia in MeOH was added and heating continued 2 days. The reaction mixture was evaporated in vacuo and purifed by chromatography on silica (0-10% MeOH in CH2Cl2 w 1% NH4OH) followed by prepartive HPLC to give 4-(4-amino-2-(3-chlorophenyl)-5-methyl-2H- imidazol-2-yl)-N,N-dimethylpyridin-2-amine (343 mg, 20% yield): 1H NMR (400 MHz, CD3OD) ppm 7.94 (d, J = 5.5 Hz, 1 H), 7.40 (m, 1 H), 7.35 (m, 1 H), 7.31 - 7.25 (m, 2 H), 6.68 (m, 1 H), 6.62 (dd, J = 5.5, 1.5 Hz, 1 H), 3.03 (s, 6 H), 2.37 (s, 3 H); MS (ES) m/z 328 [M+l]+. Example 53i
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-4-methyl-lH-imidazole-5(2H)-thione
Figure imgf000073_0001
n-Butyllithium, 2.5 M in hexanes (1.498 mL, 3.74 mmol) was added dropwise to a solution of 1,3-dibromobenzene (0.415 mL, 3.43 mmol) in dry Et2O (6 mL) at -78 0C under an atmosphere of argon. The reaction was stirred for 30 minutes before dropwise addition of a solution of 3-ethyl-4-methoxybenzonitrile (0.503 g, 3.12 mmol) in dry Et2O (4 mL). The reaction was stirred in the slowly thawing cooling bath and it was quenched when the temperature had reached -60 0C by addition of ammonium acetate (0.289 g, 3.74 mmol) in MeOH (2.5 mL). The reaction was taken to rt, the solvents evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The organic phases were combined, washed with brine, dried over Na2SOφ filtered and the solvents evaporated. The crude imine intermediate was dissolved in MeOH (10 mL) and then 2-oxopropanethioamide (0.628 g, 6.08 mmol) was added. The mixture was heated under an atmosphere of argon at 50 0C for 10 hours and was then allowed to stand at rt for ~70 hours. The solvent was evaporated and purification by flash chromatography on silica gel using a gradient from 0-80% EtOAc in heptane gave the title compound (0.369 g, 30% yield): MS (ES+) m/z 403 [M+H]+.
Example 54i
3-Bromophenyl)(l,5-dimethyl-lH-pyrazol-4-yl)methanimine
Figure imgf000074_0001
1,3-Dibromobenzene ( 9.54 g, 40.45 mmol ) was dissolved in Et2O (200 mL) and cooled to -78 0C. n-Butyllithium (16.18 mL, 40.45 mmol ) was added and the solution stirred for 30 min. A solution of 1,5 -dimethyl- lH-pyrazole-4-carbonitrile (4.9 g, 40.45 mmol) in Et2O (20 mL) was added at -78 0C and the reaction was allowed to warm to room temperature over 1 h. A solution of ammonium acetate (4.05 g, 52.58 mmol) in methanol (30 mL) was added. The solvents were evaporated and the residue was taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic layers were washed with brine, dried over MgSOφ filtered and the solvent evaporated to give the crude title product (11.65 g): MS(CI+) m/z 278, 280 [M+H]+.
Example 55i
2-(3-Bromophenyl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000074_0002
A mixture of (3-bromophenyl)(l,5-dimethyl-lH-pyrazol-4-yl)methanimine (11.48 g, 41.27 mmol) and 2-oxopropanethioamide (8.51 g, 82.55 mmol) in methanol (10OmL) was stirred at 60 0C (oil bath temperature) for 4 h and then at 40 0C overnight. The solvent was evaporated and the crude product was purified by column chromatography on silica gel, elution with 0-100% EtOAc in heptane to give to give 12g of crude 2-(3-bromophenyl)-2- (l,5-dimethyl-lH-pyrazol-4-yl)-4-methyl-lH-imidazole-5(2H)-thione that was used as such in the next step: MS(ES+) m/z 363, 365 [M+H]+.
Example 56i
2-(3-Bromophenyl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine
Figure imgf000075_0001
2-(3-Bromophenyl)-2-( 1,5 -dimethyl- lH-pyrazol-4-yl)-4-methyl-lH-imidazole-5 (2H)- thione (12 g, 33.03 mmol) and 7M ammonia in methanol (10.57 mL, 73.98 mmol) were mixed and heated in a microwave reactor at 100 0C for 1 h. The mixture was concentrated and the resulting residue was dissolved in 7M ammonia in methanol (10.57 mL, 73.98 mmol) and heated in a microwave reactor at 100 0C for 1 h. The solvent was evaporated and the crude product was subjected to column chromatography on silica gel, elution with 0-100% EtOAc in heptane to give 5.2 g of 2-(3-bromophenyl)-2-(l,5-dimethyl-lH- pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (45% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.50 (t, 1 H), 7.34 - 7.42 (m, 2 H), 7.19 - 7.24 (m, 1 H), 7.18 (s, 1 H), 6.60 (br. s., 2 H), 3.63 (s, 3 H), 2.21 (d, 6 H); MS(ES+) m/z 346, 348 [M+H]+.
Example 57i
4-Methoxy-3,5-dimethylbenzonitrile
Figure imgf000076_0001
5-Bromo-2-methoxy-l,3-dimethylbenzene (294 mL, 1841.12 mmol) and copper(I) cyanide (196 g, 2189.09 mmol) were added to N,N-dimethylformamide (1700 mL) and the resulting mixture heated at 136 0C overnight. The mixture was allowed to attain r.t. and then poured into a solution of ammonia (25% in water, 1 L) and water (1 L). Toluene (2 L) was added and the mixture was stirred for 20 min, then the organic phase was separated, filtered and concentrated. The residue was purified by gradient column chromatography over silica, eluting with 0-50% ethylacetate in heptanes. The desired fractions were evaporated to give the title compound (289 g, 97% yield): 1H-NMR (500 MHz, CDCl3) δ 2.43 (s, 7 H), 3.89 (s, 3 H), 7.46 (s, 2 H); MS (CI+) m/z 162 [M+ 1]+.
Example 58i
(3-Bromophenyl)(4-methoxy-3,5-dimethylphenyl)methanimine
Figure imgf000076_0002
To diethylether (3 L) in a 10 L cryogenic reactor was added 1,3-dibromobenzene (230 mL, 1904.76 mmol) under a nitrogen atmosphere. The temperature was adjusted to -78 0C and n-butyllithium (2.5M, 800 mL, 2000.00 mmol) was added over 40 min, while keeping the temperature below -65 0C. After stirring at -72 0C for 1 h, a solution of 4-methoxy-3,5- dimethylbenzonitrile (307 g, 1904.76 mmol) in diethylether (1 L) was added over 50 min, while keeping the temperature below -65 0C. The resulting mixture was stirred at -78 0C for 1 h, then allowed to attain r.t. over 1 h and stirred at r.t. for 30 min. The mixture was cannulated into a 5 L reactor containing a solution of ammonium acetate (154 g, 2000.00 mmol) in methanol (300 mL) at 0 0C, in such a fashion that the temperature obtained during the addition was kept below 10 0C. The volatiles were removed under reduced pressure and dichloromethane (700 mL) and water (500 mL) were added to the residue. The mixture was stirred, the organic phase separated and concentrated under reduced pressure The crude product was subjected to vacuum for 18 h in order to remove residual solvent and the product (616 g, quant, yield)
was used as such without further purification: 1H-NMR (500 MHz, CDCl3) δ 2.23 (s, 6 H), 3.69 (s, 3 H), 7.06 - 7.24 (m, 3 H), 7.33 - 7.44 (m, 1 H), 7.52 (dd, 1 H), 7.67 (br. s., 1 H); MS (CI+) m/z 318, 320 [M+l]+.
Example 59i
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000077_0001
To a solution of (3-bromophenyl)(4-methoxy-3,5-dimethylphenyl)methanimine (490 g, 1308.89 mmol) in 2 L methanol was added 2-oxopropanethioamide (243 g, 2356.00 mmol). The resulting mixture was stirred at 60 0C for 5 h. The temperature was adjusted to 40 0C and the mixture stirred overnight. The mixture was concentrated under vacuum to give a precipitate that was filtered off, washed with methanol and dried to give the title compound (272 g, 52 % yield): 1H-NMR (500 MHz, CDCl3) δ 2.34 (s, 6 H), 3.80 (s, 3 H), 7.36 (t, 1 H), 7.48 (s, 2 H), 7.70 (m, 2 H), 7.91 (t, 1 H); MS (ES-) m/z 401 403 [M-I]".
Example 6Oi
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000078_0001
In a 5 L pressure vessel a mixture of 2-(3-bromophenyl)-2-(4-methoxy-3,5- dimethylphenyl)-4-methyl-lH-imidazole-5(2H)-thione (550 g, 1363.63 mmol) in 7 M ammonia in methanol (2 L) was heated until an internal temperature of 67 0C was reached. The mixture was heated and stirred at this temperature overnight. The mixture was cooled to r.t. and concentrated to a solid, which was dissolved in ethylacetate (1.5 L). 1 M citric acid in water (1.5 L) and toluene (1 L) were added. The resulting mixture was stirred and the phases allowed to separate. The organic phase was washed with 1 M citric acid in water (700 mL). The water phase was back-extracted with toluene (500 mL). The combined organic phases were concentrated to a solid, which was again treated with methanolic ammonia under pressure and worked up according to the conditions vide supra. The obtained product was dried under reduced pressure for 24 h to give the title compound (436 g, 83 % yield): 1H-NMR (500 MHz, CDCl3) δ 2.20 (s, 6 H), 2.40 (s, 3 H), 3.65 (s, 3 H), 7.07 (s, 2 H), 7.11 (t, 1 H), 7.33 (d, 1 H), 7.39 (d, 1 H), 7.62 (s, 1 H); MS (ES+) m/z 386 388 [M+1]+.
Example 1
5-Methyl-2-phenyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000078_0002
2-(3-Bromophenyl)-5-methyl-2-phenyl-2H-imidazol-4-amine (7.5 mg, 0.02 mmol), pyridin-3-ylboronic acid (5.62 mg, 0.05 mmol) and bis(triphenylphosphine)palladium(II) chloride (3.21 mg, 4.57 μmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.057 rnL, 0.06 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 1.5 mg (20% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (br. s., 1 H) 8.57 (d, 1 H) 7.86 (dt, 1 H) 7.81 (s, 1 H) 7.57 - 7.65 (m, 3 H) 7.37 - 7.47 (m, 2 H) 7.21 - 7.36 (m, 4 H) 2.36 (s, 3 H); MS (ES+) m/z 327 [M+H]+.
Example 2
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-4-yl)-2H-imi(iazol-4-amine
2-(3-Bromophenyl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-amine (4 mg, 0.01 mmol), 3- methoxyphenylboronic acid (3.69 mg, 0.02 mmol) and bis(triphenylphosphine)palladium- (II) chloride (1.706 mg, 2.43 μmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.030 mL, 0.03 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 1.0 mg (23% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (br. s., 2 H) 7.80 (s, 1 H) 7.46 - 7.61 (m, 4 H) 7.31 - 7.43 (m, 2 H) 7.15 (d, 1 H) 7.07 - 7.13 (m, 1 H) 6.89 (dd, 2.02 Hz, 1 H) 3.86 (s, 3 H) 2.40 (s, 3 H); MS (ES+) m/z 357 [M+H]+.
Example 3
2-(4-Fluorophenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000079_0002
2-(3-Bromophenyl)-2-(4-fluorophenyl)-5-methyl-2H-imidazol-4-amine (29 mg, 0.08 mmol), pyridin-3-ylboronic acid (20.59 mg, 0.17 mmol) and bis(triphenylphosphine)- palladium(II) chloride (11.76 mg, 0.02 mmol) were taken up in DME (1 rnL) and water (0.5 rnL). Sodium carbonate (IM in water) (0.209 mL, 0.21 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 16.4 mg (57% yield) of the title compound: 1H NMR (400 MHz, methanol-*/*) δ ppm 8.74 (s, 1 H) 8.51 (d, 1 H) 8.04 (d, 1 H) 7.67 (s, 1 H) 7.57 (d, 1 H) 7.38 - 7.53 (m, 5 H) 7.02 (t, 2 H) 2.38 (s, 3 H); MS (ES+) m/z 345 [M+H]+.
Example 4
2-(4-Methoxyphenyl)-5-methyl-2-m-tolyl-2H-imidazol-4-amine
Figure imgf000080_0001
To a solution of zinc iodide (13.09 g, 40.99 mmol) in THF (20 mL) at 0 0C was added methylmagnesium bromide (3M in diethyl ether) (13.66 mL, 40.99 mmol). To the formed slurry was then added 2-(3-bromophenyl)-2-(4-methoxyphenyl)-5-(methylthio)-2H- imidazol-4-amine (1.6 g, 4.10 mmol) in THF (20 mL), followed by bis(triphenyl- phosphine)palladium(II) chloride (0.288 g, 0.41 mmol). The reaction mixture was stirred at 50 0C for 3 h. MeOH was added to quench the reaction. The solvent was evaporated.
Water was added resulting in a thick slurry which was washed with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 23.5 mg (201% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 7.46 (d, 2 H) 7.30 - 7.36 (m, 2 H) 7.17 (t, 1 H) 7.03 (d, 1 H) 6.82 (d, 2 H) 5.19 (br. s., 2 H) 3.77 (s, 3 H) 2.32 (s, 3 H) 2.31 (s, 3 H); MS (ES+) m/z 294 [M+H]+.
Example 5
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000081_0001
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (217 mg, 0.38 mmol), pyrimidin-5-ylboronic acid (95 mg, 0.76 mmol) and bis(triphenylphosphine)- palladium(II) chloride (53.6 mg, 0.08 mmol) were taken up in DME (3 mL) and water (1.5 mL). Sodium carbonate (IM in water) (0.954 mL, 0.95 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 35.9 mg (26% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1 H) 8.93 (s, 2 H) 7.77 (s, 1 H) 7.61 - 7.70 (m, 1 H) 7.50 (d, 2 H) 7.44 (d, 2 H) 6.84 (d, 2 H) 3.78 (s, 3 H) 2.36 (s, 3 H); MS (ES+) m/z 358 [M+H]+.
Example 6
(if)-and (S)-2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-
4-amine
Figure imgf000081_0002
Chromatographic separation of the enantiomers of 2-(4-methoxyphenyl)-5-methyl-2-(3- (pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine. 2-(4-Methoxyphenyl)-5-methyl-2-(3- (pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine (35 mg, 0.10 mmol) was dissolved in ethanol (2 mL) and the resulting solution was injected (2 stacked injections) on a Chiralpak AD column (21.2 x 250 mm), using ethanol/CO2 (25:75) + 0.1% DEA as eluent at a flow rate of 50 mL/min to yield:
Isomer 1, the first enantiomer to elute was concentrated in vacuo to yield 13.5 mg (39% yield): 1H NMR (400 MHz, methanol-^) δ ppm 9.11 (s, 1 H) 9.00 (s, 2 H) 7.70 (s, 1 H) 7.60 (d, 1 H) 7.50 - 7.55 (m, 1 H) 7.42 - 7.49 (m, 1 H) 7.29 (d, 2 H) 6.83 (d, 2 H) 3.74 (s, 3 H) 2.37 (s, 3 H); MS (ES+) m/z 358 [M+H]+.
Isomer 2, the second enantiomer to elute was concentrated in vacuo to yield 14.4 mg (41% yield) : 1H NMR (400 MHz, methanol-^) δ ppm 9.11 (s, 1 H) 9.00 (s, 2 H) 7.70 (s, 1 H) 7.60 (d, 1 H) 7.51 - 7.55 (m, 1 H) 7.43 - 7.49 (m, 1 H) 7.29 (d, 2 H) 6.83 (d, 2 H) 3.74 (s, 3 H) 2.37 (s, 3 H); MS (ES+) m/z 358 [M+H]+.
Example 7
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H- imidazol-4-amine
Figure imgf000082_0001
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine (183 g, 473.74 mmol), (l,r-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (11.69 g, 14.21 mmol) and pyrimidine-5-boronic acid (61.6 g, 497.43 mmol) were dissolved in dioxane (1.32 L) and an aqueous solution of potassium carbonate (2M, 0.592 L, 1184.36 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred, and the temperature increased to 90 0C and held for 90 min, thereafter held at 80 0C for 3 h. The mixture was allowed to attain r.t. and the phases separated and activated charcoal added to the dioxane phase. The mixture was filtered through celite, washed with ethylacetate and the filtrate concentrated in vacuum. The obtained residue was dissolved in ethylacetate (600 mL) and aqueous sodium hydroxide (2M, 200 mL) was added with stirring. The organic phase was separated and dried with magnesium sulfate. The solvent was evaporated in vacuum and the residue recrystallized from acetonitrile (600 mL) to give, after drying in vacuum oven at 45 0C for 2 days, the title compound (134 g, 73% yield): 1H-NMR (400 MHz, CDCl3) δ 2.24 (s, 6 H), 2.38 (s, 3 H), 3.68 (s, 3 H), 7.22 (s, 2 H), 7.42 - 7.48 (m, 2 H), 7.81 (s, 1 H), 8.94 (s, 2 H), 9.18 (s, 1 H); MS (ES+) m/z 386.2 [M+ 1]+. Example 8
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000083_0001
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (200 mg, 0.35 mmol), pyridin-3-ylboronic acid (86 mg, 0.70 mmol) and bis(triphenylphosphine)- palladium(II) chloride (49.4 mg, 0.07 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium carbonate (IM in water) (0.879 mL, 0.88 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 39.2 mg (31% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (d, 1 H) 8.57 (dd, 1 H) 7.86 (ddd, 1 H) 7.77 (s, 1 H) 7.60 (d, 1 H) 7.50 (d, 2 H) 7.37 - 7.47 (m, 2 H) 7.34 (dd, 1 H) 6.83 (d, 2 H) 5.18 (br. s., 2 H) 3.77 (s, 3 H) 2.35 (s, 3 H); MS (ES+) m/z 357 [M+H]+.
Example 9
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H- imidazol-4-amine
Figure imgf000083_0002
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine (270 mg, 0.70 mmol), pyrimidin-5-ylboronic acid (173 mg, 1.40 mmol) and
bis(triphenylphosphine)palladium(II) chloride (98 mg, 0.14 mmol) were taken up in DME (8 mL) and water (4 mL). Sodium carbonate (IM in water) (1.747 mL, 1.75 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 87.6 mg (32.5% yield) of the title compound: 1H NMR (400 MHz, methanol-^) δ ppm 9.12 (s, 1 H) 9.02 (s, 2 H) 7.70 (s, 1 H) 7.62 (d, 1 H) 7.51 - 7.56 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.04 (s, 2 H) 3.66 (s, 3 H) 2.37 (s, 3 H) 2.21 (s, 6 H); MS (ES+) m/z 386 [M+H]+.
Example 10
(R)- and (S)-2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyrimidin-5- yl)phenyl)-2H-imidazol-4-amine
Figure imgf000084_0001
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine (150 mg, 0.40 mmol) was dissolved in methanol (7.5 mL) and the solution was injected (15 stacked injections) on a Chiralpak AD-H column (21.2 x 250 mm), using methanol/CO2 (10:90) + 0.1% DEA as eluent at a flow rate of 50 mL/min to yield:
Isomer 1, example 10a, with unknown absolute configuration. The first enantiomer to elute was concentrated in vacuo to yield 29.6 mg (11% yield): 1H NMR (400 MHz, methanol-^) δ ppm 9.12 (s, 1 H) 9.02 (s, 2 H) 7.70 (s, 1 H) 7.62 (d, 1 H) 7.51 - 7.56 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.04 (s, 2 H) 3.66 (s, 3 H) 2.37 (s, 3 H) 2.21 (s, 6 H); MS (ES+) m/z 386 [M+H]+ Isomer 2, example 10b, with unknown absolute configuration. The second enantiomer to elute was concentrated in vacuo to yield 29.2 mg (11% yield): 1H NMR (400 MHz, methanol-^) δ ppm 9.12 (s, 1 H) 9.02 (s, 2 H) 7.70 (s, 1 H) 7.62 (d, 1 H) 7.51 - 7.56 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.04 (s, 2 H) 3.66 (s, 3 H) 2.37 (s, 3 H) 2.21 (s, 6 H); MS (ES+) m/z 386 [M+H]+. Example 11
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine
2-(3 -Bromophenyl)-2-(4-(difluoromethoxy)-3 ,5 -dimethylphenyl)-4-methyl- 1 H-imidazole- 5(2H)-thione (1.30Og, 2.96 mmol) and 7M ammonia in methanol (10 mL) were charged in a flask and the resulting mixture heated at 40 0C. After 24 h the solvents were evaporated, the residue redissolved in 7M ammonia in methanol (10 mL) and the resulting mixture stirred at 45 0C for an additional 24 h. The solvents were evaporated and the crude material purified by gradient column chromatography (40 g silica column eluted with 0-100% ethylacetate in heptane). The desired fractions were evaporated to give the title compound (496 mg, 40% yield): 1H-NMR (500 MHz, DMSO-d6) δ 2.18 (s, 6 H), 2.23 (s, 3 H), 6.89 (br. s, 2 H), 6.88 (t, 1 H), 7.23 (t, 1 H), 7.29 (s, 2 H), 7.38 (d, 1 H), 7.54 (d, 1 H), 7.65 (t, 1 H); MS (ES+) m/z 422.0, 424.0 [M+l].
Example 12
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-
4-amine
Figure imgf000085_0002
2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine (0.2 g, 0.52 mmol), pyridin-3-ylboronic acid (0.127 g, 1.04 mmol) and bis(triphenyl- phosphine)palladium(II) chloride (0.073 g, 0.10 mmol) were taken up in DME (5 mL) and water (1.5 rnL). Sodium carbonate (IM in water) (1.294 mL, 1.29 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 9.7 mg (3.1% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (br. s., 1 H) 8.79 (d, 1 H) 8.73 (d, 1 H) 7.94 (dd, 1 H) 7.87 (s, 1 H) 7.74 (d, 1 H) 7.61 - 7.68 (m, 1 H) 7.58 (t, 1 H) 7.08 (s, 2 H) 6.74 (br. s., 2 H) 3.68 (s, 3 H) 2.52 (s, 3 H) 2.25 (s, 6 H); MS (ES+) m/z 385 [M+H]+.
Example 13
5-Methyl-2-(5-methylthiophen-3-yl)-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000086_0001
2-(3-Bromophenyl)-5-methyl-2-(5-methylthiophen-3-yl)-2H-imidazol-4-amine (160 mg, 0.46 mmol), pyridin-3-ylboronic acid (113 mg, 0.92 mmol) and bis(triphenylphosphine)- palladium(II) chloride (64.5 mg, 0.09 mmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (1.149 mL, 1.15 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 9.5 mg (6% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (br. s., 1 H) 8.58 (d, 1 H) 7.87 (d, 1 H) 7.81 (s, 1 H) 7.64 (d, 1 H) 7.39 - 7.49 (m, 2 H) 7.31 - 7.37 (m, 1 H) 7.05 (s, 1 H) 6.80 (s, 1 H) 2.40 (s, 3 H) 2.34 (s, 3 H); MS (ES+) m/z 347 [M+H]+.
Example 14
5-Methyl-2-(5-methylthiophen-3-yl)-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine
Figure imgf000087_0001
2-(3-Bromophenyl)-5-methyl-2-(5-methylthiophen-3-yl)-2H-imidazol-4-amine (160 mg, 0.46 mmol), pyrimidin-5-ylboronic acid (114 mg, 0.92 mmol) and bis(triphenyl- phosphine)palladium(II) chloride (64.5 mg, 0.09 mmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (1.149 mL, 1.15 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 13.5 mg (8.5% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1 H) 8.95 (s, 2 H) 7.80 (s, 1 H) 7.64 - 7.72 (m, 1 H) 7.44 - 7.49 (m, 2 H) 7.06 (d, 1 H) 6.79 (s, 1 H) 5.08 (br. s., 2 H) 2.41 (s, 3 H) 2.37 (s, 3 H); MS (ES+) m/z 348 [M+H]+.
Example 15
2-(Biphenyl-3-yl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000087_0002
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (100 mg, 0.28 mmol), phenylboronic acid (40.8 mg, 0.33 mmol) and bis(triphenylphosphine)palladium- (II) chloride (19.59 mg, 0.03 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium carbonate (IM in water) (0.698 mL, 0.70 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was filtered. Preparative HPLC yielded 20 mg (20% yield) of the title compound: 1H NMR (400 MHz, methanol-^) δ ppm 7.61 (s, 1 H) 7.48 - 7.56 (m, 3 H) 7.25 - 7.43 (m, 7 H) 6.85 (d, 2 H) 3.76 (s, 3 H) 2.38 (s, 3 H); MS (ES+) m/z 356 [M+H]4
Example 16
5-(3-(4-Amino-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-2-yl)phenyl)nicotinonitrile
Figure imgf000088_0001
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (96 mg, 0.27 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinonitrile (61.7 mg, 0.27 mmol) and bis(triphenylphosphine)palladium(II) chloride (37.6 mg, 0.05 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium carbonate (IM in water) (0.670 mL, 0.67 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was filtered and preparative HPLC yielded 19.7 mg (19% yield) of the title compound: 1H NMR (400 MHz, methanol-*/*) δ ppm 9.00 (d, 1 H) 8.85 (d, 1 H) 8.39 (t, 1 H) 7.70 (s, 1 H) 7.60 (d, 1 H) 7.50 - 7.56 (m, 1 H) 7.40 - 7.49 (m, 1 H) 7.28 (d, 2 H) 6.83 (d, 2 H) 3.74 (s, 3 H) 2.37 (s, 3 H); MS (ES+) m/z 382 [M+H]+.
Example 17
3-(4-Amino-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-2-yl)benzonitrile
Figure imgf000088_0002
2-(3-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (240 mg, 0.67 mmol) was dissolved in propionitrile (2.5 mL, 35.45 mmol) and copper(I) cyanide (72.0 mg, 0.80 mmol) was added. The reaction was heated to 180 0C for 2.5 h by microwave heating. Water was added and the reaction mixture was extacted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 5.3 mg (2.6% yield) of the title compound: 1H NMR (400 MHz, methanol- d4) δ ppm 7.65 - 7.73 (m, 2 H) 7.61 (d, 1 H) 7.46 (t, 1 H) 7.27 (d, 2 H) 6.84 (d, 2 H) 3.76 (s, 3 H) 2.40 (br. s., 3 H); MS (ES+) m/z 305 [M+H]+.
Example 18
2-(4-(Difluoromethoxy)phenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-
Figure imgf000089_0001
Methylmagnesium bromide (4.442 mL, 13.33 mmol) was added to a solution of 2-(3- bromophenyl)-2-(4-(difluoromethoxy)phenyl)-5-(methylthio)-2H-imidazol-4-amine (710 mg, 1.67 mmol) and [l,3-bis(diphenylphosphino)propane]nickel(II) chloride (361 mg, 0.67 mmol) in toluene (15 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3.5 h then water (20 mL) and DCM (25 mL) were added. The pH was adjusted to 6 and the organic phase was separated, concentrated and purified on a silica gel column eluted with 0-10% 0. IM NH3 in MeOH in DCM. The resulting crude product; 2-(3-bromophenyl)-2-(4-(difluoromethoxy)phenyl)-5-methyl-2H- imidazol-4-amine (60 mg, 0.15 mmol), pyrimidine-5-boronic acid (22.63 mg, 0.18 mmol), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride (12.52 mg, 0.02 mmol), 2M aqueous potassium carbonate (0.228 mL, 0.46 mmol) and DMF (1 mL) were mixed in a vial and heated in a microwave reactor at 150 0C for 15 min. The mixture was filtered and purified by preparative HPLC. The fractions containing product were pooled, and the MeOH removed in vacuo. The resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were poured into a phase separator, the organic phase was collected and concentrated to give 16 mg (2% yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) δ ppm 9.19 (s, 1 H) 9.02 (s, 2 H) 7.86 (t, 1 H) 7.58 - 7.68 (m, 4 H) 7.44 (t, 1 H) 7.06 (d, 2 H) 7.15 (t, 1 H) 6.70 (br. s., 2 H) 2.25 (s, 3 H); MS (ES+) m/z 394 [M+H]+. Example 19
N-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)pyrazine-2-carboxamide
Figure imgf000090_0001
To a mixture of Xantphos (30.8 mg, 0.05 mmol), cesium carbonate (154 mg, 0.47 mmol), palladium(II) acetate (7.98 mg, 0.04 mmol) and pyrazinamide (72.9 mg, 0.59 mmol) in a microwave vial under argon was added a solution of 2-(3-bromophenyl)-2-(4- (difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine (100 mg, 0.24 mmol) in dry tetrahydrofuran (1.0 mL). The reaction mixture was heated with microwaves at 150 0C for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and evaporated.
The mixture was diluted with MeOH (5 mL), filtered and purified by preparative HPLC. The product was partitioned between Saturated aqueous NaHCO3 and DCM . The organic layer was separated, dried with Na2SO4 and concentrated to give the title compound, 7 mg (6% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 10.66 (s, 1 H), 9.28 (d, 1 H), 8.92 (d, 1 H), 8.79 (dd, 1 H), 8.05 - 8.18 (m, 1 H), 7.60 - 7.74 (m, 1 H), 7.28 - 7.36 (m, 3 H), 7.20 - 7.27 (m, 1 H), 6.87 (t, 1 H), 6.62 (br. s., 2 H), 2.23 (s, 3 H), 2.18 (s, 6 H);
MS(ES+) m/z 465 [M+H]+. Example 20
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000091_0001
2-(3 -Bromophenyl)-2-(4-methoxy-3 -methylphenyl)-4-methyl- 1 H-imidazole-5 (2H)-thione (4.09 g, 10.51 mmol) and 7M ammonia in methanol (18 mL, 126mmol) were mixed and heated in a microwave reactor at 100 0C for 1 h. The mixture was concentrated and the resulting residue was dissolved in 7M ammonia in methanol (18 mL, 126 mmol) and heated in a microwave reactor at 100 0C for 1 h. The solvent was evaporated and the crude product was subjected to column chromatography on silica gel, gradient elution with 0- 100% EtOAc in heptane to give 2-(3-bromophenyl)-2-(4-methoxy-3-methylphenyl)-5- methyl-2H-imidazol-4-amine, 2.240 g, (57% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.60 (t, 1 H), 7.46 - 7.51 (m, 1 H), 7.33 - 7.38 (m, 1 H), 7.29 (dd, 1 H), 7.26 (d, 1 H), 7.20 (t, 1 H), 6.79 (d, 1 H), 6.63 (br. s., 2 H), 3.71 (s, 3 H), 2.22 (s, 3 H), 2.07 (s, 3 H);
MS(ES+) m/z 372, 374 [M+H]+.
Example 21
2-(4-Methoxy-3-methylphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine
Figure imgf000091_0002
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-4-amine (300 mg, 0,81 mmol), pyrimidin-5-yl boronic acid (120 mg, 0,97 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride (33,1 mg, 0,04 mmol), 2M aqueous potassium carbonate (1,209 mL, 2,42 mmol) and dioxane (4 mL) were mixed in a vial under Ar. The obtained mixture was heated in a microwave reactor at 130 0C for 15 min. The mixture was diluted with MeOH (5 mL), filtered and purified by preparative HPLC. The product was partitioned between saturated aqueous NaHCO3 and DCM (3 x 3 mL). The organic layer was concentrated to give 2-(4-methoxy-3-methylphenyl)-5-methyl- 2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine 38 mg (46% yield). 1H NMR (500 MHz, DMSO-J6) δ ppm 9.18 (s, 1 H), 9.01 (s, 2 H), 7.81 (t, 1 H), 7.51 - 7.69 (m, 2 H), 7.27 - 7.50 (m, 3 H), 6.79 (d, 1 H), 6.60 (br. s, 2 H), 3.71 (s, 3 H), 2.24 (s, 3 H), 2.08 (s, 3 H); MS (ES) m/z 372 [M+l]+.
Example 22
2-(3-(5-Fluoropyridin-3-yl)phenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H- imidazol-4-amine
Figure imgf000092_0001
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-4-amine (300 mg, 0,81 mmol), 5-fluoropyridin-3-ylboronic acid (300 mg, 2,13 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) chloride (33,1 mg, 0,04 mmol), 2M aqueous potassium carbonate (1,209 mL, 2,42 mmol) and dioxane (4 mL) were mixed in a vial and heated in a microwave reactor at 130 0C for 15 min. The mixture was diluted with MeOH (5 mL), filtered and purified by preparative HPLC. The product was partitioned between saturated aqueous NaHCO3 and DCM. The organic layer was concentrated to give 199 mg of the title compound (64% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.65 (s, 1 H), 8.57 (d, 1 H), 7.92 (dt, 1 H), 7.81 (s, 1 H), 7.49 - 7.67 (m, 2 H), 7.24 - 7.46 (m, 3 H), 6.79 (d, 1 H), 6.60 (br. s., 2 H), 3.70 (s, 3 H), 2.23 (s, 3 H), 2.07 (s, 3 H); MS (ES) m/z 389 [M+ 1]+. Example 23 4-(4-Amino-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-2-yl)-2,6- dimethylphenol
Figure imgf000093_0001
Boron tribromide (0,074 mL, 0,78 mmol) was added, slowly at 0 0C, to a solution of 2-(4- methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine (100 mg, 0,26 mmol) in DCM (5 mL). The mixture was stirred at the above temperature for 5 min and allowed to reach room temperature and then stirred for 18 h. The reaction was quenched with water and the pH adjusted to >7 with aq. sat. NaHCO3 solution. The mixture was extracted with CHCl3 and the organic layer was dried with MgSO4, filtered, and then the solvent was evaporated in vacuo. The crude product was purified by preparative HPLC to give 44 mg (46% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 9.19 (s, 1 H), 9.01 (s, 2 H), 7.74 - 7.90 (m, 1 H), 7.62 (dd, 1 H), 7.55 - 7.59 (m, 1 H), 7.41 (t, 1 H), 7.13 (s, 2 H), 6.55 (br. s., 2 H), 2.22 (s, 3 H), 2.08 (s, 6 H); MS (ES) m/z 372 [M+l]+.
Example 24
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H- imidazol-4-amine
Figure imgf000093_0002
A mixture of 2-(3-bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4- amine (89 mg, 0.25 mmol), S-chloropyridine-S-boronic acid (47.2 mg, 0.30 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride (10.28 mg, 0.01 mmol), potassium carbonate (2M aqueous solution, 0.250 mL, 0.50 mmol) and dioxane (2.5 mL) was heated in a microwave reactor at 130 0C for 15 min. The mixture was concentrated and the resulting residue was taken up in DCM (5 mL) and water (3 mL) and poured into a phase separator. The organic layer was collected, concentrated and purified by preparative HPLC to yield 2-(3-(5-chloropyridin-3-yl)phenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H- imidazol-4-amine (45 mg, 46% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.75 (d, 1 H) 8.63 (d, 1 H) 8.14 (t, 1 H) 7.84 (t, 1 H) 7.62 - 7.67 (m, 1 H) 7.61 (dd, 1 H) 7.42 (t, 1 H) 7.20 (s, 2 H) 6.73 (br. s., 2 H) 2.34 - 2.38 (m, 6 H) 2.23 - 2.26 (m, 3 H); MS (ES+) m/z 390, 392 [M+l]+.
Example 25
2-(2,6-Dimethylpyridin-4-yl)-2-(3 '-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4- amine
Figure imgf000094_0001
The title compound was synthesized as described in Example 24 in 23% yield starting from 2-(3-bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4-amine and 3- methoxybenzeneboronic acid: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.76 (t, 1 H) 7.54 (dt, 1 H) 7.49 (ddd, 1 H) 7.37 (dt, 2 H) 7.18 (s, 2 H) 7.08 - 7.13 (m, 1 H) 7.03 - 7.08 (m, 1 H) 6.92 - 6.97 (m, 1 H) 6.72 (br. s., 2 H) 3.81 (s, 3 H) 2.33 - 2.39 (m, 6 H) 2.25 (s, 3 H); MS (ES+) m/z 385 [M+ 1]+. Example 26 2-(2,6-Dimethylpyridin-4-yl)-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H- imidazol-4-amine
Figure imgf000095_0001
The title compound was synthesized as described in Example 24 in 28% yield starting from 2-(3-bromophenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4-amine and 5- (prop-l-ynyl)pyridin-3-ylboronic acid: 1H NMR (500 MHz, DMSO-J6) δ ppm 8.72 (d, 1 H) 8.58 (d, 1 H) 7.97 (t, 1 H) 7.82 (t, 1 H) 7.62 (dt, 1 H) 7.55 - 7.60 (m, 1 H) 7.41 (t, 1 H) 7.20 (s, 2 H) 6.73 (br. s., 2 H) 2.33 - 2.38 (m, 6 H) 2.25 (s, 3 H) 2.12 (s, 3 H); MS (ES+) m/z 394 [M+l]+.
Example 27
4-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2- chlorophenol
Figure imgf000095_0002
2-(3-Chloro-4-hydroxyphenyl)-2-(4-methoxy-3,5-dimethylphenyl)-4-methyl-lH- imidazole-5(2H)-thione (650 mg, 1.73 mmol) was dissolved in 7M ammonia in methanol (4 mL, 28.00 mmol) and stirred at 45 0C for 24 h. The mixture was concentrated and the resulting residue was dissolved in 7M ammonia in methanol (4 mL, 28.00 mmol) and stirred at 45 0C for 24 h. This was repeated twice more. The mixture was concentrated and the resulting residue was slurried in DCM (5 mL). The first precipitate was filtered off and discarded. The filtrate was left at rt and after 15 min more precipitation occurred. The second precipitate was collected by filtration to give 217 mg (35% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 10.02 (br. s., 1 H) 7.35 (d, 1 H) 7.24 (dd, 1 H) 7.12 (s, 2 H) 6.83 (d, 1 H) 6.55 (br. s., 2 H) 3.57 (s, 3 H) 2.20 (s, 3 H) 2.14 (s, 6 H); MS (ES+) m/z 358, 360 [M+l]+.
Example 28
5-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2'-fluoro- 5 '-methoxybiphenyl-2-ol
Figure imgf000096_0001
A mixture of 4-(4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)- 2-chlorophenol (35.8 mg, 0.1 mmol), 2-fluoro-5-methoxyphenylboronic acid (34.0 mg, 0.20 mmol), palladium(II) acetate (2.245 mg, 10.00 μmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (8.21 mg, 0.02 mmol), cesium fluoride (7.75 μL, 0.21 mmol), water (0.053 mL) and 1,4-dioxane (1 mL) was heated in a microwave reactor at 130 0C for 1 h. The mixture was concentrated and the resulting residue was dissolved in MeOH and purified by preparative HPLC. The fractions containing the title compound were pooled and the MeOH was removed in vacuo. The resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM (5 mL). The organic layer was collected and discarded. The aqueous phase was extracted with EtOAc (3 x 3 mL), the combined organics were dried over MgSO4, filtered and concentrated to give 18 mg (40% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 9.46 (br. s., 1 H) 7.33 (dd, 1 H) 7.28 (d, IH) 7.17 (s, 2 H) 7.13 (t, 1 H) 6.90 (ddd, 1 H) 6.76 - 6.82 (m, 2 H) 6.49 (br. s., 2 H) 3.74 (s, 3 H) 3.57 (s, 3 H) 2.19 (s, 3 H) 2.14 (s, 6 H); MS (ES+) m/z 448, 449 [M+ 1]+. Example 29
2-(4-(Difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-
2H-imidazol-4-amine
Figure imgf000097_0001
The title compound was synthesized as described in Example 24 in 58% yield starting from 2-(3-bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4- amine and 5-pyrimidinylboronic acid: 1H NMR (500 MHz, DMSO-J6) δ ppm 9.19 (s, 1 H) 9.03 (s, 2 H) 7.87 (s, 1 H) 7.67 (d, 1 H) 7.60 (d, 1 H) 7.43 (t, 1 H) 7.38 (s, 2 H) 6.88 (t, 1 H) 6.66 (br. s., 2 H) 2.24 (s, 3 H) 2.18 (s, 6 H); MS (ES+) m/z 422 [M+l]+.
Example 30
2-(4-(Difluoromethoxy)-3,5-dimethylphenyl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5- methyl-2H-imidazol-4-amine
Figure imgf000097_0002
The title compound was synthesized as described in Example 24 in 58% yield starting from 2-(3-bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4- amine and 5-fluoropyridine-3-boronic acid: 1H NMR (500 MHz, DMSO-J6) δ ppm 8.67 (s, 1 H) 8.58 (d, 1 H) 7.95 (dt, 1 H) 7.86 (s, 1 H) 7.65 (d, 1 H) 7.57 (d, 1 H) 7.41 (t, 1 H) 7.37 (s, 2 H) 6.88 (t, 1 H) 6.65 (br. s., 2 H) 2.24 (s, 3 H) 2.18 (s, 6 H); MS (ES+) m/z 439
[M+ 1]+. Example 31
2-(3,4-dimethoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000098_0001
2-(3-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-5-methyl-2H-imidazol-4-amine (138 mg, 0.4 mmol), 5-pyrimidinylboronic acid (59.5 mg, 0.48 mmol), palladium(II) acetate (8.98 mg, 0.04 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (32.8 mg, 0.08 mmol) and MeCN (1.5 mL) were added into a vial and stirred at rt for 2 min. Then aqueous 2M potassium carbonate (0.600 mL, 1.20 mmol) was added and the resulting mixture was heated in a microwave reactor at 150 0C for 3 h. The mixture was poured into a phase separator and extracted with DCM. The combined organics were concentrated and the resulting residue was dissolved in MeOH and purified by preparative HPLC. The fractions containing the title compound were pooled, the MeOH removed in vacuo and the resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator, the organic phase was collected and concentrated to give 3 mg (2% yield) of the title compound: 1H NMR (400 MHz, methanol-^) δ ppm 9.10 (s, 1 H) 8.98 (s, 2 H) 7.67 (t, 1 H) 7.59 (dt, 1 H) 7.48 - 7.54 (m, 1 H) 7.41 - 7.48 (m, 1 H) 6.95 - 7.02 (m, 2 H) 6.86 (d, 1 H) 3.77 (s, 3 H) 3.73 (s, 3 H) 2.36 (s, 3 H); MS (ES+) m/z 388 [M+l]+.
Example 32 l-Cl^-DihydrobenzoIbl ll^ldioxin-ό-yO-S-methyl-l-CS-Cpyrimidin-S-yOphenyO-lH- imidazol-4-amine
Figure imgf000099_0001
The title compound was synthesized as described in Example 24 in 5% yield starting from 2-(3-bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2H-imidazol-4- amine and 5-pyrimidinylboronic acid: 1H NMR (400 MHz, methanol-^) δ ppm 9.09 (s, 1 H) 8.99 (s, 2 H) 7.65 - 7.71 (m, 1 H) 7.56 - 7.62 (m, 1 H) 7.49 - 7.54 (m, 1 H) 7.41 - 7.49 (m, 1 H) 6.77 - 6.85 (m, 2 H) 6.68 - 6.74 (m, 1 H) 4.16 (s, 4 H) 2.34 (s, 3 H); two protons not observed; MS (ES+) m/z 386 [M+ 1]+.
Example 33
2-(2,3-Dihydrobenzo [b] [ 1 ,4] dioxin-6-yl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-
2H-imidazol-4-amine
Figure imgf000099_0002
The title compound was synthesized as described in Example 24 in 5% yield starting from 2-(3-bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2H-imidazol-4- amine and 5-fluoropyridine-3-boronic acid: 1H NMR (400 MHz, methanol-^) δ ppm 8.56 - 8.66 (m, 1 H) 8.37 - 8.45 (m, 1 H) 7.79 - 7.89 (m, 1 H) 7.63 - 7.70 (m, 1 H) 7.53 - 7.60 (m, 1 H) 7.37 - 7.51 (m, 2 H) 6.76 - 6.87 (m, 2 H) 6.67 - 6.74 (m, 1 H) 4.16 (s, 4 H) 2.34 (s, 3 H); two protons not observed; MS (ES+) m/z 403 [M+ 1]+.
Example 34
2-(2,3-Dihydrobenzo [b] [ 1 ,4] dioxin-6-yl)-2-(3-(5-methoxypyridin-3-yl)phenyl)-5- methyl-2H-imidazol-4-amine
Figure imgf000100_0001
The title compound was synthesized as described in Example 24 in 2% yield starting from 2-(3-bromophenyl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2H-imidazol-4- amine and 3-methoxypyridin-5-boronic acid: H NMR (400 MHz, methanol-^) δ ppm 8.27 - 8.35 (m, 1 H) 8.14 - 8.22 (m, 1 H) 7.60 - 7.67 (m, 1 H) 7.50 - 7.59 (m, 2 H) 7.34 - 7.49 (m, 2 H) 6.75 - 6.85 (m, 2 H) 6.67 - 6.74 (m, 1 H) 4.16 (s, 4 H) 3.91 (s, 3 H) 2.34 (s, 3 H); two protons not observed; MS (ES+) m/z 415 [M+ 1]+.
Example 35
5-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)nicotinonitrile
Figure imgf000100_0002
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4- amine (82mg, 0.19 mmol), 5-cyanopyridin-3-ylboronic acid (34.5 mg, 0.23 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (7.10 mg, 9.71 μmol), 2M aq. potassium carbonate (0.146 mL, 0.29 mmol) and dioxane (2 mL) were charged in a vial. The resulting mixture was heated at 130 0C for 15 min by microwaves. The mixture was filtered, evaporated, redissolved in acetonitrile (1 mL) and purified by preparative HPLC. The desired fractions were evaporated and freeze dried overnight to give the title compound (42.0 mg, 49% yield): 1H-NMR (500 MHz, DMSO- d6) δ 2.19 (s, 6 H), 2.24 (s, 3 H), 6.65 (br s, 2 H), 6.87 (t, 1 H), 7.38 (s, 2 H), 7.43 (t, 1 H), 7.61 (d, 1 H), 7.68 (d, 1 H), 7.90 (s, 1 H), 8.56 (s, 1 H), 9.01 (s, 1 H), 9.07 (s, 1 H); MS (ES+) m/z 446.1 [M+l]+.
Example 36
2-(4-(Difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2-phenyl-2H-imidazol-4-amine
Figure imgf000101_0001
The reaction described in Example 35 also gave a second product that was isolated after the preparative HPLC purification. The corresponding fractions were evaporated and freeze dried overnight to give the title compound (9.00 mg, 14% yield): 1H-NMR (500 MHz, DMSO-de) δ 7.34-7.32 (m, 2 H), 7.29-7.21 (m, 3 H), 7.11 (s, 2 H), 6.55 (t, 1 H), 2.35 (s, 3 H), 2.23 (s, 6 H); MS (ES+) m/z 344.1 [M+l]+. Example 37
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l-methyl-lH-pyrazol-4-yl)-2H-imidazol-4- amine
Figure imgf000102_0001
2-(3-Chlorophenyl)-5-methyl-2-(l -methyl- lH-pyrazol-4-yl)-2H-imidazol-4-amine (66 mg, 0.23 mmol), 3-methoxyphenylboronic acid (69.7 mg, 0.46 mmol) and cesium fluoride (0.018 mL, 0.48 mmol) was dissolved in dioxane (1 mL) and water (0.053 mL). The solution was purged of air by bubbling nitrogen for 5 min, then 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (18.83 mg, 0.05 mmol) and palladium(II) acetate (5.15 mg, 0.02 mmol) was added, the vial capped and heated in a microwave reactor at 130 0C for 2 x 1 h. 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (18.83 mg, 0.05 mmol) and
palladium(II) acetate (5.15 mg, 0.02 mmol) were added and the heating was continued for 1 h. The solvent was evaporated in vacuo and the crude product purified by HPLC to give 2-(3'-methoxybiphenyl-3-yl)-5-methyl-2-(l -methyl- lH-pyrazol-4-yl)-2H-imidazol-4- amine (33.0 mg, 40% yield): 1H NMR (400 MHz, CD3OD) ppm 7.67 (m, 1 H), 7.52 - 7.46 (m, 2 H), 7.44 - 7.27 (m, 4 H), 7.14 - 7.06 (m, 2 H), 6.88 (m, 1 H), 3.82 (2 s, 6 H), 2.36 (s, 3 H); MS (ES) m/z 360 [M+l]+.
Example 38
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l-methyl-lH-imidazol-5-yl)-2H-imidazol-4- amine
Figure imgf000103_0001
mg, 0.27 mmol), 3-metAtyphenylboronic acid (81 mg, 0.54 mmol) and cesium fluoride (0.021 rnL, 0.56 mmol) was dissolved in dioxane (1 mL) and water (0.053 mL). The solution was purged of air by bubbling nitrogen for 5 min, then 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (21.97 mg, 0.05 mmol) and palladium(II) acetate (6.01 mg, 0.03 mmol) was added, the vial capped and heated in a microwave reactor at 130 0C for 3 h. 2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (21.97 mg, 0.05 mmol) and palladium(II) acetate (6.01 mg, 0.03 mmol) were added and the reaction was continued for 1 h. The solvent was evaporated in vacuo and the crude product purified by HPLC to give 2-(3'- methoxybiphenyl-3-yl)-5-methyl-2-(l -methyl- lH-imidazol-5-yl)-2H-imidazol-4-amine (43.0 mg, 45% yield): 1H NMR (400 MHz, CD3OD) ppm 7.60 (m, 1 H), 7.53 (m, 2 H), 7.39 (m, 1 H), 7.30 (m, 2 H), 7.08 (m, 2 H), 6.89 (m, 2 H), 3.81 (s, 3 H), 3.52 (s, 3 H), 2.38 (s, 3 H); MS (ES) m/z 360 [M+l]+.
Example 39
4-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-N,N- dimethylpyridin-2-amine
Figure imgf000104_0001
4-(4-Amino-2-(3-chlorophenyl)-5-methyl-2H-imidazol-2-yl)-N,N-dimethylpyridin-2- amine (100 mg, 0,31 mmol), 3-methoxyphenylboronic acid (93 mg, 0,61 mmol) and cesium fluoride (97 mg, 0,64 mmol) was dissolved in dioxane (4 mL) and water (100 μl) and degassed by bubbling nitrogen for 5 min. 2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl (25,05 mg, 0,06 mmol) and palladium(II) acetate (6,85 mg, 0,03 mmol) was added before capping the vial and heating in microwave oven for 3 h at 130 0C. The solvent was evaporated and the crude product dissolved in MeOH and filtered before purification by HPLC to give 4-(4-amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H- imidazol-2-yl)-N,N-dimethylpyridin-2-amine (55,0 mg, 45% yield): 1H NMR (400 MHz, CD3OD) ppm 7.94 (d, J= 5.5 Hz, 1 H), 7.65 (m, 1 H), 7.51 (m, 1 H), 7.43 - 7.27 (m, 3 H), 7.10 (m, 2 H), 6.88 (m, 1 H), 6.72 (m, 1 H), 6.67 (m, 1 H), 3.82 (s, 3 H), 3.02 (s, 6 H), 2.36 (s, 3 H); MS (ES) m/z 400 [M+ 1]+.
Example 40
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000104_0002
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-4-methyl-lH-imidazole-5(2H)-thione (0.369 g, 0.91 mmol) was dissolved in 7M ammonia in MeOH (9.80 ml, 68.62 mmol) in a microwave vial under argon. The vial was sealed and heated by micro waves at 100 0C for 60 minutes. To get full conversion the volatiles were evaporated and another portion of 7M ammonia in MeOH (9.80 ml, 68.62 mmol) was added before heating for another hour at 100 0C. The procedure above was repeated one more time.. The volatiles were evaporated and the residue was dissolved in EtOAc, filtered, and the EtOAc evaporated. Purification by flash chromatography on silica gel using a gradient from 0-100% EtOAc in heptane gave the title compound (141 mg, 40% yield): 1H NMR (500 MHz, DMSO-J6 (ref 2.49 ppm)) ppm 7.59 (t, 1 H) 7.48 (dt, 1 H) 7.35 (ddd, 1 H) 7.29 (dd, 1 H) 7.25 (d, 1 H) 7.20 (t, 1 H) 6.63 (br. s., 2 H) 3.71 (s, 3 H) 2.21 (s, 3 H) 1.04 (t, 3 H); MS (ES+) m/z 386, 388 [M+H]+.
Example 41
2-(3-Ethyl-4-methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine
Figure imgf000105_0001
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (0.055 g, 0.14 mmol), pyrimidin-5-ylboronic acid (0.021 g, 0.17 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II)chloride (5.86 mg, 7.12 μmol), potassium carbonate (2M in water, 0.214 mL, 0.43 mmol) and dioxane (1 mL) were mixed in a vial under argon. The vial was sealed and heated with microwaves at 130 0C for 15 minutes. The reaction mixture was diluted with MeOH (3 mL), filtered and purified by preparative HPLC to give the title compound (20 mg, 36% yield): 1H NMR (500 MHz, DMSO-J6 (ref 2.49 ppm)) ppm 9.17 (s, 1 H) 8.99 (s, 2 H) 7.80 (t, 1 H) 7.61 (dt, 1 H) 7.57 (ddd, 1 H) 7.31 - 7.45 (m, 3 H) 6.80 (d, 1 H) 6.60 (br. s., 2 H) 3.70 (s, 3 H) 2.23 (s, 3 H) 1.04 (t, 3 H); MS (ES+) m/z 386 [M+H]+. Example 42
2-(3-Ethyl-4-methoxyphenyl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-2H- imidazol-4-amine
Figure imgf000106_0001
The title compound was synthesized as described for Example 41 starting from 2-(3- bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine (0.055 g, 0.14 mmol) and 5-fluoropyridin-3-ylboronic acid (0.024 g, 0.17 mmol) to yield 36 mg (63% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6 (ref 2.49 ppm)) ppm 8.63 (t, 1 H) 8.56 (d, 1 H) 7.91 (ddd, 1 H) 7.79 (t, 1 H) 7.58 (dt, 1 H) 7.55 (ddd, 1 H) 7.31 - 7.41 (m, 3 H) 6.80 (d, 1 H) 6.59 (br. s., 2 H) 3.70 (s, 3 H) 2.23 (s, 3 H) 1.04 (t, 3 H); MS (ES+) m/z 403 [M+H]+.
Example 43
2-(2',3'-Difluorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H- imidazol-4-amine
Figure imgf000106_0002
2-(3-Bromophenyl)-2-( 1,5 -dimethyl- lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (300 mg, 0.87 mmol), 2,3-difluorophenylboronic acid (274 mg, 1.73 mmol) , [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride (35.6 mg, 0.04 mmol), cesium carbonate (847 mg, 2.60 mmol) and DME: EtOH: Water 6:3:1 (5 mL) were mixed. The mixture was heated in a microwave reactor at 150 0C for 30 min. To the mixture was added EtOAc, water and brine and the organic phase was collected, dried (MgSO4), filtered and purified by preparative HPLC to give 2-(2',3'-difluorobiphenyl-3-yl)-2-(l,5-dimethyl-lH- pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (195 mg, 59% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.59 (s, 1 H), 7.45 - 7.51 (m, 1 H), 7.40 - 7.45 (m, 1 H), 7.34 - 7.40 (m, 2 H), 7.26 - 7.34 (m, 1 H), 7.21 - 7.26 (m, 1 H), 7.20 (s, 1 H), 6.56 (br. s., 2 H), 3.62 (s, 3 H), 2.24 (s, 3 H), 2.21 (s, 3 H); MS (ES) m/z 380 [M+l]+.
Example 44
2-(l,5-Dimethyl-lH-pyrazol-4-yl)-5-methyl-2-(3'-(prop-l-ynyl)biphenyl-3-yl)-2H- imidazol-4-amine
Figure imgf000107_0001
The title compound was synthesized as described for Example 43 starting from 2-(3- bromophenyl)-2-(l ,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (300 mg, 0.87 mmol), and 3-(prop-l-ynyl)phenylboronic acid (554 mg, 3.47 mmol) to 64 mg, (19% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.64 (t, 1 H), 7.48 - 7.53 (m, 2 H), 7.40 - 7.48 (m, 3 H), 7.30 - 7.39 (m, 2 H), 7.22 (s, 1 H), 6.56 (br. s, 2 H), 3.62 (s, 3 H), 2.23 (s, 3 H), 2.22 (s, 3 H), 2.07 (s, 3 H);MS (ES) m/z 382 [M+l]+. Example 45
2-(3',5'-Dichlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H- imidazol-4-amine
Figure imgf000108_0001
The title compound was synthesized as described for Example 43 starting from 2-(3- bromophenyl)-2-(l ,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (300 mg, 0.87 mmol), and 3,5-dichlorophenylboronic acid (248 mg, 1.30 mmol) to yield 104 mg (29% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.65 (t, 1 H), 7.61 (t, 1 H), 7.55 (d, 2 H), 7.47 - 7.54 (m, 2 H), 7.36 (t, 1 H), 7.22 (s, 1 H), 6.58 (br. s, 2 H), 3.61 (s, 3 H), 2.22 (d, 6 H); MS (ES) m/z 412 [M+l]+.
Example 46
2-(3'-Chlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4- amine
Figure imgf000108_0002
The title compound was synthesized as described for Example 43 starting from 2-(3- bromophenyl)-2-(l ,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (300 mg, 0.87 mmol), and 3-chlorophenylboronic acid (203 mg, 1.30 mmol) to yield 117 mg (35% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.59 (t, 1 H), 7.47 - 7.52 (m, 1 H), 7.38 - 7.45 (m, 4 H), 7.34 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.15 (s, 1 H), 6.50 (br. s., 2 H), 3.55 (s, 3 H), 2.16 (d, 6 H); MS (ES) m/z 378 [M+l]+.
Example 47
2-(l,5-Dimethyl-lH-pyrazol-4-yl)-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-
4-amine
Figure imgf000109_0001
The title compound was synthesized as described for Example 43 starting from 2-(3- bromophenyl)-2-(l ,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4-amine (300 mg, 0.87 mmol), and 3-methoxyphenylboronic acid (263 mg, 1.73 mmol) to yield 108 mg (33% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 7.59 (t, 1 H), 7.47 - 7.52 (m, 1 H), 7.38 - 7.45 (m, 4 H), 7.34 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.15 (s, 1 H), 6.50 (br. s., 2 H), 3.55 (s, 3 H), 2.16 (d, 6 H); MS (ES) m/z 374 [M+ 1]+.
General method for Example 48-73 (Table I)
Figure imgf000109_0002
To a mixture of 2-(3-Bromophenyl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine (0.20 mmol, 1.0 eq) and the corresponding boronic acid (0.40 mmol, 2.0 eq) in a mixture of dioxane, ethanol and water (2 mL, v:v:v = 4:1 :1) was added Pd2(dba)3 (0.02 mmol, 0.1 eq) and XPhos (0.02 mmol, 0.1 eq) followed by Na2CO3 (0.40 mmol, 2.0 eq) under nitrogen. The reaction mixture was stirred at 90 0C overnight. The crude product was purified by preparative TLC to afford the respective compound in Table I.
Table I.
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
The level of activity of the compounds was tested using the following methods:
TR-FRET Assay
The β-secretase enzyme used in the TR-FRET is prepared as follows:
The cDNA for the soluble part of the human β-Secretase (AA 1 - AA 460) was cloned using the ASP2-FclO-l-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 sBACE-Fc was stored in -80 0C in Tris buffer, pH 9.2 and had a purity of 95%. The enzyme (truncated form) was diluted to 6 μg/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 μM) in reaction buffer
(NaAcetate, chaps, triton x-100, EDTA pH4.5). The robotic systems Biomek FX and Velocity 11 were used for all liquid handling and the enzyme and substrate solutions were kept on ice until they were placed in the robotic system. Enzyme (9 μl) was added to the plate then 1 μl of compound in dimethylsulphoxide was added, mixed and pre-incubated for 10 minutes. Substrate (10 μl) was then added, mixed and the reaction proceeded for 15 minutes at room temperature. The reaction was stopped with the addition of Stop solution (7 μl, NaAcetate, pH 9). The fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 340nm and an emission wavelength of 615nm. The assay was performed in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676). The final concentration of the enzyme was 2.7 μg/ml; the final concentration of substrate was 100 nM (Km of -250 nM). The dimethylsulphoxide control, instead of test compound, defined the 100% activity level and 0% activity was defined by wells lacking enzyme (replaced with reaction buffer). A control inhibitor was also used in dose response assays and had an IC50 of -575 nM. sAPPβ release assay SH-S Y5 Y cells were cultured in DMEM /F- 12 with Glutamax, 10% FCS and 1 % nonessential aminoacids and cryopreserved and stored at -1400C at a concentration of 7.5x106 cells per vial. Thaw cells and seed at a cone, of 1.5xlO5/ml in DMEM /F- 12 with
Glutamax, 10% FCS and 1% non-essential aminoacids to a 96-well tissue culture treated plate, lOOμl cell susp/well. The cell plates were then incubated for 7 hours at 37 0C, 5% CO2. The cell medium was removed, followed by addition of 90 μl compound diluted in DMEM /F- 12 with Glutamax, 10% FCS, 1% non-essential aminoacids and 1% PeSt to a final cone, of 1% DMSO. The compounds were incubated with the cells for 16h (over night) at 37 0C, 5% CO2.
Meso Scale Discovery (MSD) plates were used for the detection of sAPPβ release.
MSD sAPPβ plates were blocked in 3% BSA in Tris wash buffer (150μl/well) for 1 hour in RT and washed 4 times in Tris wash buffer (150μl/well). 50 μl of medium was transferred to the pre-blocked and washed MSD sAPPβ microplates, and the cell plates were further used in an ATP assay to measure cytotoxicity. The MSD plates were incubated with shaking in RT for 1 hour followed by washing 4 times. 25 μl detection antibody was added (InM) per well followed by incubation with shaking in RT for Ih and washing 4 times. 150 μl Read Buffer was added per well and the plates were read in a SECTOR Imager.
ATP assay
As indicated in the sAPPβ release assay, after transferring 50 μL medium from the cell plates for sAPPβ detection, the plates were used to analyse cytotoxicity using the
ViaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP.
The assay was performed according to the manufacture's protocol. Briefly, 25μL cell lysis reagent was added per well. The plates were incubated at room temperature for 10 min.
Two min after addition of 50 μL reconstituted ViaLightTM Plus ATP reagent, the luminescence was measured in a Wallac Victor2 1420 multilabel counter.
Results
Typical IC50 values for the compounds of the present invention are in the range of about 1 to about 100,000 nM. Biological data is given below in Table II.
Table II.
Figure imgf000117_0001
Table II. continued:
Figure imgf000118_0001

Claims

1. A compound according to formula (I):
Figure imgf000119_0001
(I)
wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
C is selected from hydrogen, C^aUcyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co_6alkylC3_6cycloalkenyl, Co-δalkylCδCycloalkynyl, Co-βalkylaryl, Co_6alkylheteroaryl, C0- ealkylheterocyclyl, C0-6alkylOR4, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, Co-ealkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)- (CO)N(R4)2, Co_6alkylSR4, C0.6alkylOSO2R4, C0.6alkylSO3R4, C0.6alkylSO2R4, C0.6alkyl- SOR4, Co-6alkyl(S02)N(R4)2, Co-6alkyl(SO)N(R4)2, Co-6alkylNR4(S02)N(R4)2, C0-6alkyl- NR4(SO)R4, SF5 and OSF5, wherein said Chalky!, C2.6alkenyl, C2-6alkynyl, C0.6alkyl- C3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl,
Co_6alkylC3_6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-βalkylaryl, Co_6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, C0-6alkylOR4, halogen,
Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co_6alkylSR4, C0.6alkylOSO2R4, C0.6alkylSO3R4, Co-6alkylS02R4, Co-6alkylSOR4, C0-6alkyl(SO2)N(R4)2, C0-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, Co.6alkylNR4(SO)R4, SF5, and OSF5, wherein said C^alkyl, C2_6alkenyl, C2_6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from C^alkyl, C2_6alkenyl, C2_6alkynyl, Co-6alkylC3_6cycloalkyl,
Co-6alkylC3_6cycloalkenyl, Co-δalkylCδCycloalkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0.6alkylN(R4)2, halogen, C0-6alkylCN,
Co-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(C0)- (CO)N(R4)2, Co-6alkylSR4, Co-6alkylOS02R4, Co-6alkylS03R4, Co-6alkylS02R4, C0-6alkyl- SOR4, Co.6alkyl(S02)N(R4)2, C0.6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkyl- NR4(SO)R4and C0-6alkylOR4, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C0-6alkyl- C3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, C^haloalkyl, C0-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0-6alkylCON(R4)2, C0.6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkyl(SO2)N(R4)2, OC2.6alkyl- NR4(SO2)R4, Co-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkyl- NR4(SO)R4, C0-6alkylSO2R4, C0.6alkylSOR4, C^alkyl, C2.6alkenyl, C2.6alkynyl, C0.6alkyl- C3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C^alkyl, C2_6alkenyl, C2_6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-βalkylheteroaryl or Co-6alkyl- heterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Ci-βalkyl, C^haloalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkyl- C3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl,
Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl,
C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-6alkyl- heterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, Ci_6halo- alkyl, OC2.6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C i_6alkyl, (CO)OC i_6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C1.6alkyl- N(R7)2, (SO2)C1_6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or Co-6alkylC3_6cyclo- alkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C1-3haloalkyl, or OC1-3haloalkyl;
R7 is selected from hydrogen, C1-6alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C3-6cycloalkenyl, C6cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi_3alkyl, cyano or halogen;
as a free base or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R2; C is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co- 6alkylheterocyclyl, C0-6alkylOR4, Co-6alkylC02R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN, Co-ealkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(C0)- (CO)N(R4)2, Co-6alkylSR4, C0-6alkylNR4(SO)R4, SF5 and OSF5, wherein said Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0-6alkylOR4, halogen,
Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, Co-6alkylS02R4, and C0-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R2 is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl,
Co-ealkylCs-δCycloalkenyl, Co-βalkylCecycloalkynyl, Co-6alkylaiyl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN,
Co-ealkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co_6alkylNR4(CO)R4, C0.6alkylSO3R4, Co-6alkylS02R4, C0.6alkylSOR4, Co.6alkyl(S02)N(R4)2, C0.6alkyl(SO)N(R4)2, C0.6alkylNR4(SO2)N(R4)2, Co-ealkylNR4" (SO)R4 and C0-6alkylOR4, wherein said Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0.6alkylCN, C0.6alkylOR4, Ci_6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, Co-6alkyl(S02)N(R4)2,
OC2.6alkylNR4(SO2)R4, C0.6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0.6alkylNR4(SO2)N(R4)2, Co-6alkylNR4(SO)R4, Co-6alkylS02R4, C0-6alkylSOR4, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Ci-βalkyl, C^haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylC3-6cycloalkyl, Co_6alkylC3_6cycloalkenyl, Co_6alkylC6cycloalkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6; or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R5 is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-δalkylCδCycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3- δcycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, C1.
ehaloalkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)C1.6alkyl, (CO)OC1. ealkyl, COR7, SON(R7)2, (SO2)N(R7)2, wherein said Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C0- βalkylaryl, Co_6alkylheteroaryl, Co-δalkylheterocyclyl or Co_6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C^haloalkyl, or OC^haloalkyl.
R7 is selected from hydrogen, C^aUcyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.
δCycloalkyl, C3_6cycloalkenyl, CδCycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more of hydroxy, OCi_3alkyl, cyano or halogen.
3. A compound according to claim 1 or claim 2, wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ;
C is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co- 6alkylheterocyclyl, C0-6alkylOR4, Co-6alkylC02R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN, Co-ealkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, Co-6alkylNR4(CO)R4, C0-6alkylSR4, C0-6alkylNR4(SO)R4, SF5 and OSF5, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkyl- heteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, C0-6alkylOR4, halogen,
Co_6alkylCN, C0.6alkylCOR4, CHO, NO2, C0.6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, C0-6alkylNR4(CO)R4, C0-6alkylSO2R4, and C0-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylhetero- aryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R2 is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl, Co_6alkyl- C3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaiyl, Co-6alkylheteroaryl, Co-6alkyl- heterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co_6alkylNR4(CO)R4, C0-6alkylOR4, C0.6alkylSO3R4, Co-6alkylS02R4, C0.6alkylSOR4 and Co-6alkyl(S02)N(R4)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cyclo- alkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, Ci^haloalkyl, C0-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0-6alkylCON(R4)2, C0.6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, Co-6alkyl(S02)N(R4)2, OC2-6alkyl- NR4(SO2)R4, Co-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, Co-6alkylNR4(S02)N(R4)2, C0-6alkyl- NR4(SO)R4, Co.6alkylS02R4, C0.6alkylSOR4, C^alkyl, C2.6alkenyl, C2.6alkynyl, C0.6alkyl- C3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl,
Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-βalkylheteroaryl or Co-6alkylhetero- cyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Ci-βalkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- ealkyKVόCycloalkyl, C0-6alkylC3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-δalkylheterocyclyl, C^alkylOR5 and Ci-6alkylN(R5)2, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S said heterocyclic ring optionally being substituted with one or more R6; R5 is selected from hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-ealkylCs-δCycloalkenyl, Co-βalkylCecycloalkynyl, C0-6alkylaryl, Co-δalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3- δcycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, Ci_6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C i_6alkyl, (CO)OC i_6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, wherein said Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C0- βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or Co-6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, Ci_3haloalkyl, or OC^haloalkyl;
R7 is selected from hydrogen, C1-6alkyl, Ci_3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C3-6cycloalkenyl, C6cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more of hydroxy, OC1-3alkyl, cyano or halogen.
4. A compound according to claim 1, wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R ; C is selected from hydrogen, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, Co_6alkylC3_6cycloalkyl, Co-ealkylCs-δCycloalkenyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Co- 6alkyl0R4, Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, Co-6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, C0-6alkylSR4, Co-6alkylS02R4,
Co-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R ; R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl,
C0-6alkylC5-6cycloalkenyl, C0-6alkylaryl, C0-6alkylheteroaryl, Co-δalkylheterocyclyl, Co-6alkylC02R4, Co-6alkylN(R4)2, C0-6alkylOR4, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, Co-6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, C0-6alkylSR4, Co-6alkylS02R4, Co-6alkylSOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6; R2 is selected from C1-6alkyl, Co-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl,
Co-6alkylC02R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, C0-6alkylCOR4, NO2, 0(CO)R4, Co-6alkylSR4, and Co_6alkylOR4, wherein said C1-6alkyl, C0-6alkylC3-6cycloalkyl, or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, C0-6alkylCN, C0-6alkylOR4, C^haloalkyl,
Co-6alkylN(R4)2, NR4C(O)R4, Co-6alkylC02R4, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, 0(CO)R4, Co-6alkylCOR4, C0-6alkylSR4, Co-6alkylS02R4, C0-6alkylSOR4, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, Co-6alkylC3-6cycloalkyl, Co- βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci_6alkylOR5 and Ci-6alkylN(R5)2, wherein said C^aUcyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkyl- heterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl,
Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6alkyl, C0-6alkylaryl, Co-
6alkylheteroaryl, C0-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, C1-6haloalkyl, OC2- 6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C i.6alkyl, (CO)OCi.6alkyl, COR7, SO2R7, SOR7, wherein said C1-6alkyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co- δalkylheterocyclyl or Co-6alkylC3_6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, C1-3haloalkyl, or OCi_3haloalkyl;
R7 is selected from hydrogen, C1-6alkyl, C1-3haloalkyl, C3-6cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen or OC1-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC1-3alkyl, cyano or halogen;
as a free base or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 3, wherein A is phenyl, pyridine, pyrazole, imidazole or thiophene.
6. A compound according to any one of claims 1 to 5, wherein R1 is C1-6alkyl, Co- δalkylOR4, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-βalkylheteroaryl,
Co-ealkylheterocyclyl, Co-6alkylN(R4)2, halogen, C0-6alkylCN, Co-6alkylCON(R4)2, Co-6alkylNR4(CO)R4, C0-6alkylSO2R4, and C0-6alkylSOR4.
7. A compound according to claim 4, wherein R1 is C1-6alkyl, Co-6alkylC3_6cycloalkyl, Co-δalkylheterocyclyl, Co-6alkylOR4, halogen or Co-βalkylCN;
or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6.
8. A compound according to any one of claims 1 to 7, wherein R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, Co-6alkylC3-6cycloalkyl, Ci_6alkylOR5, Co-ealkylheterocyclyl or Co-6alkylheteroaryl.
9. A compound according to claim 8, wherein R4 is hydrogen, C1-6alkyl, C^alkylOR5, Co- δalkylheterocyclyl or C1-3haloalkyl.
10. A compound according to any one of claims 1 to 9, wherein B is aryl.
11. A compound according to claim 10, wherein said aryl is phenyl.
12. A compound according to any one of claims 1 to 11, wherein B is not substituted.
13. A compound according to any one of claims 1 to 11, wherein B is substituted.
14. A compound according to claim 13, wherein R2 is C^aUcyl, halogen, Co-6alkylCN or Co-ealkylOR4.
15. A compound according to claim 14, wherein said halogen is fluoro.
16. A compound accoding to claim 14, wherein said Co-6alkylOR4 is OH.
17. A compound according to any one of claims 1 to 16, wherein C is selected from hydrogen, C1-6alkyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-6alkylCN, C2-6alkenyl, C2- ealkynyl, C0-6alkylC3-6cycloalkyl, Co-ealkylheterocyclyl, C0-6alkylOR4, C0-6alkylN(R4)2, halogen, Co-6alkylCON(R4)2 or C0-6alkylNR4(CO)R4.
18. A compound according to claim 17, wherein C is hydrogen, Ci_6alkyl, C2-6alkynyl, Co- 6alkylC3_6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Co- ealkylOR4, C0-6alkylN(R4)2, halogen, C0-6alkylCN or C0-6alkylNR4(CO)R4,.
19. A compound according to claim 18, wherein C is aryl, heteroaryl, C2-6alkynyl, OR4 or NR4(CO)R4.
20. A compound according to claim 19, wherein said heteroaryl is pyridyl, pyrazole, isoxazole, pyrrolopyridine or pyrimidyl.
21. A compound according to any one of claims 1 to 20, wherein C is not substituted.
22. A compound according to any one of claims 1 to 20, wherein C is substituted.
23. A compound according to claim 22, wherein R3 is halogen, Co-6alkylCN, Co-6alkylOR4, Ci-δhaloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylS02R4,
Co-6alkyl(S02)N(R4)2, C0-6alkylCO2R4, Co-ealkylCOR4, or Co-ealkylheterocyclyl.
24. A compound according to claim 23, wherein R is halogen or C2_6alkynyl.
25. A compound according to claim 1, wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is aryl;
C is hydrogen, C^aUcyl, C2-6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co- δalkylheteroaryl, Co-δalkylheterocyclyl, Co-6alkylOR4, Co-6alkylN(R4)2, halogen, Co- 6alkylCN or C0-6alkylNR4(CO)R4;
R2 is Ci-ealkyl, halogen, C0-6alkylCN or C0-6alkylOR4;
R3 is halogen, C0-6alkylCN, C0-6alkylOR4, Ci^haloalkyl, Ci_6alkyl, C2-6alkenyl,
C2-6alkynyl, Co-ealkylCs-ecycloalkyl , Co-6alkylS02R4, C0-6alkyl(SO2)N(R4)2,
C0-6alkylCO2R4, C0-6alkylCOR4, or Co-ealkylheterocyclyl ;
R4 is selected from hydrogen, Ci-βalkyl, Ci_3haloalkyl, Co-6alkylC3-6cycloalkyl, C1.
βalkylOR5, Co-δalkylheterocyclyl and Co-6alkylheteroaryl;
R5 is Ci-ealkyl;
R6 is oxo, OR7, Ci_6alkyl;
R7 is Ci.6alkyl;
as a free base or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 1, wherein
A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1;
B is aryl;
C is selected from hydrogen, C^alky^ Co-βalkylaryl, Co_6alkylheteroaryl and Co-βalkylCN, wherein said Ci_6alkyl, Co-6alkylaryl or Co-6alkylheteroaryl is optionally substituted with one or more R3;
R1 is selected from Ci_6alkyl, Co-6alkylOR4 and halogen, wherein said Ci_6alkyl is optionally substituted with one or more R3;
R3 is selected from cyano, Co-6alkylCN and Co-6alkylOR4; R4 is selected from Ci-βalkyl or Ci-shaloalkyl.
27. A compound selected from
5-Methyl-2-phenyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-4-yl)-2H-imidazol-4-amine;
2-(4-Fluorophenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-m-tolyl-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
(i?)-2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine; (5)-2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
(5)-2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
(7?)-2-(4-Methoxy-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
2-(4-Methoxy-3,5-dimethylphenyl)-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4- amine;
5-Methyl-2-(5-methylthiophen-3-yl)-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
5 -Methyl-2-(5-methylthiophen-3-yl)-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4-amine;
2-(Biphenyl-3-yl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
5 -(3 -(4- Amino-2-(4-methoxyphenyl)-5 -methyl-2H-imidazol-2-yl)phenyl)nicotinonitrile;
3-(4-Amino-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-2-yl)benzonitrile;
2-(4-(Difluoromethoxy)phenyl)-5-methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
2-(3-Bromophenyl)-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4- amine;
N-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)pyrazine-2-carboxamide;
2-(3-Bromophenyl)-2-(4-methoxy-3-methylphenyl)-5-methyl-2H-imidazol-4-amine; 2-(4-Methoxy-3 -methylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4- amine;
2-(3 -(5 -Fluoropyridin-3 -yl)phenyl)-2-(4-methoxy-3 -methylphenyl)-5 -methyl-2H-imidazol-
4-amine;
4-(4-Amino-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-2-yl)-2,6- dimethylphenol;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-(2,6-dimethylpyridin-4-yl)-5-methyl-2H-imidazol-4- amine;
2-(2,6-Dimethylpyridin-4-yl)-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4- amine;
2-(2,6-Dimethylpyridin-4-yl)-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H- imidazol-4-amine;
4-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2- chlorophenol;
5-(4-Amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl)-2'-fluoro-5'- methoxybiphenyl-2-ol;
2-(4-(Difluoromethoxy)-3 ,5 -dimethylphenyl)-5 -methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H- imidazol-4-amine;
2-(4-(Difluoromethoxy)-3 ,5 -dimethylphenyl)-2-(3 -(5 -fluoropyridin-3 -yl)phenyl)-5 -methyl- 2H-imidazol-4-amine;
2-(3,4-dimethoxyphenyl)-5-methyl-2-(3 -(pyrimidin-5 -yl)phenyl)-2H-imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H- imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-2H- imidazol-4-amine;
2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-2-(3-(5-methoxypyridin-3-yl)phenyl)-5-methyl-
2H-imidazol-4-amine;
5-(3-(4-Amino-2-(4-(difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2- yl)phenyl)nicotinonitrile;
2-(4-(Difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2-phenyl-2H-imidazol-4-amine; 2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l-methyl-lH-pyrazol-4-yl)-2H-imidazol-4- amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(l -methyl- lH-imidazol-5-yl)-2H-imidazol-4- amine;
4-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-N,N- dimethylpyridin-2-amine;
2-(3-Bromophenyl)-2-(3-ethyl-4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
2-(3-Ethyl-4-methoxyphenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4- amine;
2-(3-Ethyl-4-methoxyphenyl)-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-2H-imidazol-4- amine;
2-(2',3'-Difluorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-
4-amine;
2-( 1,5 -Dimethyl- lH-pyrazol-4-yl)-5-methyl-2-(3 '-(prop- l-ynyl)biphenyl-3-yl)-2H- imidazol-4-amine;
2-(3',5'-Dichlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-
4-amine;
2-(3'-Chlorobiphenyl-3-yl)-2-(l,5-dimethyl-lH-pyrazol-4-yl)-5-methyl-2H-imidazol-4- amine;
2-( 1,5 -Dimethyl- lH-pyrazol-4-yl)-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4- amine;
2-[4'-(ethylsulfonyl)biphenyl-3-yl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(2'-fluoro-6'-methoxybiphenyl-3-yl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[3'-(methylsulfonyl)biphenyl-3-yl]-2H- imidazol-4-amine;
2-[3-(3,5-dimethyl-lH-pyrazol-4-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-
2H-imidazol-4-amine;
l-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl-
4-yl}-N,N-dimethylmethanesulfonamide; 6-{3-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]phenyl}-l- methyl- 1 ,3-dihydro-2H-indol-2-one;
2-(4-methoxy-3 ,5 -dimethylpheny l)-5 -methyl-2- [3 -( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)phenyl]-
2H-imidazol-4-amine;
2-(4-methoxy-3, 5 -dimethylpheny l)-5 -methyl-2- [3 -(2-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,2- benzisothiazol-5-yl)phenyl]-2H-imidazol-4-amine;
2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(5'-fluoro-2'-methoxybiphenyl-3-yl)-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl-3-ol;
2-[3-(2,3-dihydro-l,4-benzodioxin-6-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5- methyl-2H-imidazol-4-amine;
3-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]biphenyl- 4-yl}propanoic acid;
2-(4-methoxy-3 ,5 -dimethylpheny l)-2- [3 -(6-methoxypyridin-3 -yl)phenyl]-5 -methyl-2H- imidazol-4-amine;
2-(4-methoxy-3 ,5 -dimethylpheny l)-2- [3 -(2 -methoxypyrimidin-5 -yl)phenyl]-5 -methyl-2H- imidazol-4-amine;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-4- fluorobiphenyl-3-carboxylic acid;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[4'-(piperidin-l-ylcarbonyl)biphenyl-3-yl]-
2H-imidazol-4-amine;
2-(4-methoxy-3,5-dimethylphenyl)-2-[4'-(methoxymethoxy)biphenyl-3-yl]-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3, 5 -dimethylpheny l)-5 -methyl-2- [3 -(I -methyl- lH-pyrazol-4-yl)phenyl] -2H- imidazol-4-amine;
2-[3-(6-ethoxypyridin-3-yl)phenyl]-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H- imidazol-4-amine;
2-(4-methoxy-3, 5 -dimethylpheny l)-5-methyl-2-(3-pyridin-4-ylphenyl)-2H-imidazol-4- amine; l-{3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-6- fluorobipheny 1-3 -y 1 } ethanone ;
3'-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]-3- methoxybiphenyl-4-carboxylic acid;
2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2-[2'-(morpholin-4-ylmethyl)biphenyl-3-yl]- 2H-imidazol-4-amine;
6-{3-[4-amino-2-(4-methoxy-3,5-dimethylphenyl)-5-methyl-2H-imidazol-2-yl]phenyl}-2- methyl-2,3-dihydro- 1 H-isoindol- 1 -one; and
2-[3-(2,2-dioxido-l,3-dihydro-2-benzothiophen-5-yl)phenyl]-2-(4-methoxy-3,5- dimethylphenyl)-5-methyl-2H-imidazol-4-amine;
as a free base or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a
pharmaceutically acceptable salt thereof, in association with pharmaceutically acceptable excipients, carriers or diluents.
29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use as a medicament.
30. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for treating or preventing an Aβ-related pathology.
31. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, 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.
32. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for treating or preventing Alzheimer Disease.
33. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology.
34. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
35. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Alzheimer's Disease.
36. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
37. A method of treating or preventing an Aβ-related pathology in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
38. The method of claim 37, 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.
39. A method of treating or preventing Alzheimer's Disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
40. A method of treating or preventing an Aβ-related pathology in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27 and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
41. A process for preparing a compound of formula (VI)
Figure imgf000139_0001
wherein R10 and R11 are optionally substituted aryl or heteroaryl groups,
comprising the steps of
a) reacting a compound of formula (III)
Figure imgf000139_0002
with 2-oxopropane thioamide to yield a compound of formula (V)
Figure imgf000140_0001
and
b) treating a compound of formula (V) with ammonia, optionally in the presence of an oxidation agent.
PCT/SE2010/050759 2009-07-02 2010-07-02 Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia WO2011002407A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22253009P 2009-07-02 2009-07-02
US61/222,530 2009-07-02

Publications (1)

Publication Number Publication Date
WO2011002407A1 true WO2011002407A1 (en) 2011-01-06

Family

ID=43411289

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2010/050759 WO2011002407A1 (en) 2009-07-02 2010-07-02 Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia

Country Status (4)

Country Link
AR (1) AR077447A1 (en)
TW (1) TW201105650A (en)
UY (1) UY32751A (en)
WO (1) WO2011002407A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013025883A1 (en) 2011-08-17 2013-02-21 Amgen Inc. Heteroaryl sodium channel inhibitors
WO2013054108A1 (en) 2011-10-10 2013-04-18 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8865911B2 (en) 2010-12-22 2014-10-21 Astrazeneca Ab Compounds and their use as BACE inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US9000183B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
CN108658784A (en) * 2018-04-26 2018-10-16 联化科技股份有限公司 (R) synthetic method of -1- (4- aminomethyl phenyls) ethamine
US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058602A2 (en) * 2005-11-21 2007-05-24 Astrazeneca Ab Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer’s disease, neurodegeneration and dementia.
WO2007058601A1 (en) * 2005-11-21 2007-05-24 Astrazeneca Ab Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer’s disease, neurodegeneration and dementia
WO2008076043A1 (en) * 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino-5,5-diaryl-imidazol-4-ones
WO2008076045A1 (en) * 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino- 5-aryl-imidazol-4 -ones
US20080287460A1 (en) * 2007-05-15 2008-11-20 Astex Therapeutics Limited New compounds 835

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058602A2 (en) * 2005-11-21 2007-05-24 Astrazeneca Ab Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer’s disease, neurodegeneration and dementia.
WO2007058601A1 (en) * 2005-11-21 2007-05-24 Astrazeneca Ab Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer’s disease, neurodegeneration and dementia
WO2008076043A1 (en) * 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino-5,5-diaryl-imidazol-4-ones
WO2008076045A1 (en) * 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino- 5-aryl-imidazol-4 -ones
US20080287460A1 (en) * 2007-05-15 2008-11-20 Astex Therapeutics Limited New compounds 835

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9428475B2 (en) 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9918985B2 (en) 2010-12-22 2018-03-20 Astrazeneca Ab Compounds and their use as BACE inhibitors
US8865911B2 (en) 2010-12-22 2014-10-21 Astrazeneca Ab Compounds and their use as BACE inhibitors
US10231967B2 (en) 2010-12-22 2019-03-19 Astrazeneca Ab Compounds and their use as BACE inhibitors
US9248129B2 (en) 2010-12-22 2016-02-02 Astrazeneca Ab Compounds and their use as BACE inhibitors
WO2013025883A1 (en) 2011-08-17 2013-02-21 Amgen Inc. Heteroaryl sodium channel inhibitors
US9650336B2 (en) 2011-10-10 2017-05-16 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
WO2013054108A1 (en) 2011-10-10 2013-04-18 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000183B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt
CN108658784A (en) * 2018-04-26 2018-10-16 联化科技股份有限公司 (R) synthetic method of -1- (4- aminomethyl phenyls) ethamine
CN108658784B (en) * 2018-04-26 2020-12-18 联化科技股份有限公司 Synthesis method of (R) -1- (4-methylphenyl) ethylamine

Also Published As

Publication number Publication date
AR077447A1 (en) 2011-08-31
TW201105650A (en) 2011-02-16
UY32751A (en) 2011-01-31

Similar Documents

Publication Publication Date Title
WO2011002407A1 (en) Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia
US8030500B2 (en) Substituted isoindoles for the treatment and/or prevention of Aβ- related pathologies
US10231967B2 (en) Compounds and their use as BACE inhibitors
US20100125081A1 (en) New compounds 574
US20100125087A1 (en) New compounds 575
WO2011002409A1 (en) 5h-pyrrolo[3,4-£>]pyrazin-7-amine derivatives inhibitors of beta-secretase
WO2011002408A1 (en) Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia
EA009743B1 (en) Pyrimidin-4-one derivatives and their use as p38kinase modulators
WO2008121064A1 (en) New imidazo[4,5-b]pyridine-6-halo-7-aryl/heteroaryl compounds 705
WO2014195323A1 (en) Pyrimidine compounds and their use as gamma secretase modulators
WO2012064269A1 (en) COMPOUNDS AND THEIR USE FOR TREATMENT OF Αβ-RELATED DISEASES
WO2014195322A1 (en) Triazole compounds and their use as gamma secretase modulators
US20120165346A1 (en) Compounds and their use as BACE inhibitors
EP3044210A2 (en) Novel cytochrome p450 inhibitors and their method of use
EP3224241A1 (en) Bis(sulfonamide) derivatives and their use as mpges inhibitors
EP3049084A1 (en) Novel functionalized 5-(phenoxymethyl)-1,3-dioxane analogs exhibitng cytochrome p450 inhibition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10794460

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10794460

Country of ref document: EP

Kind code of ref document: A1