WO2013106678A1 - Tetrasubstituted benzenes - Google Patents

Tetrasubstituted benzenes Download PDF

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Publication number
WO2013106678A1
WO2013106678A1 PCT/US2013/021187 US2013021187W WO2013106678A1 WO 2013106678 A1 WO2013106678 A1 WO 2013106678A1 US 2013021187 W US2013021187 W US 2013021187W WO 2013106678 A1 WO2013106678 A1 WO 2013106678A1
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Prior art keywords
alkyl
compound
group
pharmaceutically acceptable
acceptable salt
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PCT/US2013/021187
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French (fr)
Inventor
Amy Ripka
Gideon Shapiro
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Envivo Pharmaceuticals, Inc.
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Publication of WO2013106678A1 publication Critical patent/WO2013106678A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • AD Alzheimer's disease
  • the disorder is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death.
  • the disorder is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. These plaques are considered to play an important role in the pathogenesis of the disease.
  • plaques mainly comprise of fibrillar aggregates of ⁇ -amyloid peptide ( ⁇ ), which are products of the amyloid precursor protein (APP), a 695 amino-acid protein.
  • APP amyloid precursor protein
  • APP amyloid precursor protein
  • C99 fragment is subsequently processed by the proteolytic activity of ⁇ - secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides ( ⁇ 37-42 amino acids).
  • N-terminal truncations can also be found e.g., ⁇ (4-42, 11-42) for convenience ⁇ 40 and ⁇ 42 as used herein incorporates these N- terminal truncated peptides.
  • the ⁇ peptides Upon secretion, the ⁇ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques.
  • ⁇ 42 is believed to be the most neurotoxic, the shorter peptides have less propensity to aggregate and form plaques.
  • the ⁇ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca, inclusion body myositis and Down's Syndrome.
  • ⁇ -secretase is an association of four proteins: Aphl, Nicastrin, Presenillin and Pen-2 (review De Strooper 2003, Neuron 38, 9).
  • ⁇ 42 is selectively increased in patients carrying particular mutations in one of these components, presenilin. These mutations are correlated with early onset a familial AD. Inhibition of ⁇ -secretase resulting in the lowering of ⁇ 42 is a desirable activity for the pharmaceutical community and numerous inhibitors have been found, e.g., Thompson et al. (Bio. Org. and Med. Chem. Letters 2006, 16, 2357-63), Shaw et al. (Bio. Org. and Med. Chem. Letters 2006, 17, 511-16) and
  • NSAIDs nonsteroidal, anti-inflammatory drugs
  • Flurbiprofen for example Flurbiprofen
  • Other publications that disclose agents said to reduce ⁇ 42 through the modulation of ⁇ -secretase include: WO 04/074232, WO 05/054193, Perreto et al Journal of Medicinal Chemistry 2005, 48, 5705-20,
  • the present invention provides an unexpectedly superior class of compounds, Formulas I and II, with improved metabolic stability, as well as methods for preparing the compounds, and methods of using the compounds to treat one or more symptoms of Alzheimer's disease.
  • the compounds of the invention which show increased metabolic stability (i.e., reduced glucuronide isomerization) are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of ⁇ peptides produced by ⁇ -secretase.
  • GSMs gamma secretase modulators
  • the compounds alter the relative levels of ⁇ peptides produced by ⁇ -secretase without significantly changing the total level of ⁇ peptides produced.
  • A is C0 2 H
  • Ri is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Cy)cycloalkyl, -(CH 2 ) 0 _iOR 6 and -(CH 2 )o_iSR 6 ,
  • each alkyl or cycloalkyl of Ri and R 2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF , or C 1 -C4 alkyl,
  • Re is selected from the group consisting of H, Ci-C 6 alkyl and (C 3 -C 7 )cycloalkyl;
  • R 3 is selected from the group consisting of:
  • Ci-C 7 alkyl optionally and independently interrupted by one or more -0-, -S-,
  • R4 is selected from the group consisting of:
  • Ci-C 7 alkyl group optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0) 2 - groups,
  • Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF 3, CN, N0 2 , OH, Ci-C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R6, OC(0)OR 6 , OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SRs, S(0)R 6 , S(0) 2 R 6 , S(0) 2 NHR 7 , S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R 7 )C(0)R 6 , NHC(0)OR 6
  • R 5 is selected from the group consisting of: N0 2 , NH 2 , aryl, heteroaryl, F, CI, Br, CN, OH, C 1 -C4 alkoxy, SR 6 , S(0) 2 R 6 , S(0) 2 N(R 7 ) 2 , (C C 4 ) alkyl, (C 0 -C 3 )alkyl-(C 3 -C 7 ) cycloalkyl, -O(C 0 - C 3 alkyl)(C 3 - C 7 )cycloalkyl and (C 2 -C 4 ) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF 3 , or Ci-C 4 alkyl,
  • R 3 and R4 is Z.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention, and a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the invention provides a method for treating a neurodegenerative disorder comprising administering to a patient and effective amount of the pharmaceutical composition of the invention.
  • the present invention provides an unexpectedly superior class of compounds, Formulas I and II, with improved metabolic stability, as well as methods for preparing the compounds, and methods of using the compounds to treat one or more symptoms of Alzheimer's disease.
  • Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic Ci-Cs hydrocarbon, unless some other number of carbon atoms is specified. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and, in the case of a double bond, both cis and trans isomers are included.
  • An optionally substituted alkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, OH, (Ci- C 4 )alkoxy, (C 3 -Ce)cycloalkyloxy, (Ci-C 4 )alkylthio, (C 3 -C6)cycloalkylthio-, -C(0)NH 2 , - C(0)NH(Ci-C 4 )alkyl, -C(0)N[(Ci-C 4 )alkyl(Ci-C 4 )alkyl], (C 1 -C4 alkyl)-C(O)-, (Ci- C 4 )alkylsulfonyl-, -S(0) 2 NH 2 , -S(0) 2 NH(Ci-C 4 )alkyl and-S(0) 2 N[(Ci-C 4 )alkyl(Ci-C 4 )alkyl].
  • alkyl groups include, but are not limited to, methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans- 2-butenyl, isobutenyl and propargyl.
  • Ci-C 4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.
  • an optionally substituted alkyl can be independently substituted with one or more substituents selected from the group consisting of F, OH, oxo and (Ci-C )alkoxy.
  • an optionally substituted alkyl can be independently substituted with up to three fluorines.
  • C x -C y includes all subsets, e.g., Ci-C 4 includes Ci-C 2 , C 2 -C 4 , and C 1 -C 3 as well as Ci, C 2 , C 3 and C 4 .
  • Acyl is an alkyl-C(O)- group wherein alkyl is as defined above.
  • Examples of acyl groups include acetyl and proprionyl.
  • Alkoxy is an alkyl-O- group wherein alkyl is as defined above.
  • Ci-C 4 alkoxy is the subset of alkyl-O- where the subset of alkyl is limited to a total of up to 4 carbon atoms.
  • alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy.
  • Alkoxyalkyl is an alkyl-0-(Ci-C 4 alkyl)- group wherein alkyl is as defined above.
  • alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
  • Alkoxyalkyloxy is an alkoxy-alkyl-O- group wherein alkoxy and alkyl are as defined above.
  • alkoxyalkyloxy groups include methoxymethyloxy (CH30CH 2 0-) and methoxyethyloxy (CH 3 OCH 2 CH 2 0-) groups.
  • Alkylthio is alkyl-S- group wherein alkyl is as defined above.
  • Ci-C 4 alkylthio is the subset of alkyl-S- where the subset of alkyl is limited to a total of up to 4 carbon atoms.
  • Alkylsulfonyl is alkyl-S0 2 - wherein alkyl is as defined above.
  • alkylsulfonyl groups include methanesulfonyl and isopropylsufonyl.
  • Alkylamino is alkyl -NH- wherein alkyl is as defined above.
  • Dialkylamino is (alkyl) 2 -N- wherein alkyl is as defined above.
  • Amido is H 2 NC(0)-.
  • Alkylamido is alkyl -NHC(O)- wherein alkyl is as defined above.
  • Dialkylamido is (alkyl) 2 -NC(0)- wherein alkyl is as defined above.
  • Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.
  • Aryl is a phenyl or napthyl group.
  • An optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF 3, CN, OH, (Ci-C4)alkoxy, (Ci-C4)alkylthio, (C 3 -Cv)cycloalkylthio, (C 3 -Cy)cycloalkyloxy, aryloxy, (Ci- C 4 )alkoxy(Ci-C 4 )alkyloxy, hetero(C 3 -C 7 )cycloalkyloxy, heteroaryloxy, -OC(0)Ra, -OC(0)NHR a , - OC(0)N(R a )(R b ), -S(0)R a , -NHRa, -N(R a )(R b ), -NHC(0)R a , -N(R a )C(0)R b ,
  • R a , R b and R are independently selected from the group consisting of (Ci-C 6 )alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, -CH 2 CH 2 OH, - CH 2 CH 2 OMe, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(Ci-C 4 )alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero(C 3 - C 7 )cycloalkyl and hetero(C 3 -C 7 )cycloalkyl(Ci-C4)alkyl, each of which is optionally and independently substituted with up to three groups selected from the group consisting of halogen, (Ci-C 6 )alkyl
  • an optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF , CN, (Ci- C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C4)alkoxy, (C 3 -C 7 )cycloalkylthio, (C 3 -C 7 )cycloalkyloxy, hetero(C 3 - C 7 )cycloalkyl, C(0)NH 2 , -C(0)NHR a and -C(0)N(R a )(R b ) wherein R a and R b are defined as above.
  • an optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF , CN, (Ci-C 6 )alkyl, (C 3 - C 7 )cycloalkyl, (C 3 - C 7 )cycloalkyloxy and hetero(C 3 -C 7 )cycloalkyl.
  • Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.
  • Aryloxy is an aryl-O- group wherein aryl is as defined above.
  • Arylalkoxy is an aryl-(Ci-C4 alkyl)-0- group wherein aryl is as defined above.
  • Carboxy is a C0 2 H or C0 2 Rj group wherein Rd is independently selected from (Ci-C 6 )alkyl, (C 3 - C 7 )cycloalkyl, aryl(Ci-C 3 )alkyl, (C 3 -C 7 )cycloalkyl(Ci-C 3 )alkyl, and alkoxyalkyl, wherein alkyl is as defined above.
  • Cycloalkyl is a C 3 -C 7 cyclic non-aromatic hydrocarbon which may contain a single double bond.
  • An optionally substituted cycloalkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, OH, (Ci-C 6 )alkyl, (Ci-C4)alkoxy, - (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkylalkyl, (C 3 -C 7 )cycloalkyloxy, (Ci-C 4 )alkylthio, (C 3 - C 6 )cycloalkylthio-, -C(0)NH 2 , -C(0)NH(Ci-C 4 )alkyl, -C(0)N[(Ci-C 4 )alkyl(Ci-C 4 )alkyl], (C 1 -C4 alkyl)-C(O)-, (
  • an optionally substituted cycloalkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, (Ci- C 4 )alkoxy, (C 3 -C 7 )cycloalkyl, -C(0)NH(Ci-C 4 )alkyl, -C(0)N[(Ci-C 4 )alkyl(Ci-C 4 )alkyl], (C 1 -C4 alkyl)-C(O)-, (Ci-C 4 )alkylsulfonyl-, -S(0) 2 NH(C C 4 )alkyl and -S(0) 2 N[(Ci-C 4 )alkyl(Cr
  • an optionally substituted cycloalkyl can be independently substituted with one substituent selected from the group consisting of oxo, OH, (Ci- C 6 )alkyl, (Ci-C 4 )alkoxy, (C 3 -C 7 )cycloalkylalkyl, (C 3 -C 7 )cycloalkyloxy, (Ci-C 4 )alkylthio, (C 3 - C6)cycloalkylthio-,
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
  • Cycloalkyloxy is a cycloalkyl-O- group wherein cycloalkyl is as defined above.
  • C 3 -C 6 cycloalkyloxy is the subset of cycloalkyl-O- where cycloalkyl contains 3-6 carbon atoms.
  • Cycloalkylthio is a cycloalkyl-S- group wherein cycloalkyl is as defined above.
  • Examples include cyclopropylthio, cyclobutylthio and cyclopentylthio.
  • Cycloalkylalkyl is a cycloalkyl-(Ci-C 4 alkyl)- group. Examples include
  • Cycloalkylalkoxy is a cycloalkyl-(Ci-C 4 alkyl)-0- group wherein cycloalkyl and alkyl are as defined above.
  • Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
  • Cycloalkylalkylthio is a cycloalkyl-(Ci-C 4 )alkyl-S- group wherein cycloalkyl and alkyl are as defined above.
  • Examples of cycloalkylalkylthio groups include cyclopropylmethanethio, cyclobutylmethanethio and cyclopentylmethanethio.
  • Halogen is F, CI, Br or I.
  • Preferred halogens are F, CI and Br.
  • a heteroaryl group can be: (a) a tetrazole, (b) 1,2,3,4-oxatriazole, (c) 1,2,3,5- oxatriazole, or (d) a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C.
  • heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and
  • An optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CN, OH, (Ci-C 4 )alkoxy, (Ci- C 4 )alkylthio, (C 3 -Cv)cycloalkylthio, (C 3 -Cy)cycloalkyloxy, aryloxy, (Ci-C 4 )alkoxy(Ci- C 4 )alkyloxy, hetero(C 3 -C 7 )cycloalkyloxy, heteroaryloxy, -OC(0)R a , - OC(0)NHR a ,
  • R a , R b and R are independently selected from the group consisting of (Ci-C 6 )alkyl, (Ci-C 4 )alkoxy(Ci-C 4 )alkyl, -CH 2 CH 2 OH,
  • an optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF 3 , CN, (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 4 )alkoxy, (C 3 - C 7 )cycloalkylthio, (C 3 -C 7 )cycloalkyloxy, hetero(C 3 -C 7 )cycloalkyl, C(0)NH 2 , -C(0)NHR a and -C(0)N(R a )(R b ), wherein R a and R b are defined as above.
  • an optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF 3 , CN, (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyloxy and hetero(C 3 - C 7 )cycloalkyl.
  • Heteroarylalkyl is a heteroaryl-(Ci-C 4 alkyl)- group wherein heteroaryl and alkyl are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethyl and 4- pyridinylethyl.
  • Heteroaryloxy is a heteroaryl-0 group wherein heteroaryl is as defined above.
  • Heteroarylalkoxy is a heteroaryl-(Ci-C4 alkyl)-0- group wherein heteroaryl and alkoxy are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethoxy and 4- pyridinylethoxy.
  • Heterobicyclic ring system is a bicyclic ring system having 8-10 atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic.
  • An optionally substituted heterobicyclic ring system can be independently substituted with one or more substituents selected from the group consisting of (Ci-C 6 )alkyl, (Ci-C4)alkoxy, (C 3 - Cy)cycloalkyl, (C 3 -Cy)cycloalkyloxy, (C 3 -Cy)cycloalkyl(Ci-C 3 )alkyl, halogen, alkylsulfonyl and cyano.
  • an optionally substituted heterobicyclic ring system can be independently substituted with one or more substituents selected from the group consisting of (Ci-C 6 )alkyl, (C 3 - Cy)cycloalkyl, (C 3 -Cy)cycloalkyloxy, halogen and cyano.
  • Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, l,2,3,4-tetrahydro-l,5- naphthyridyl, 1,6-naphthyridyl, l,2,3,4-tetrahydro-l,6- naphthyridyl 1 ,7-naphthyridyl, 1,2,3,4- tetrahydro-l,7-naphthyridinyl, 1,8-naphthyridyl, 1,2,3,4- tetrahydro-l,8-naphthyridyl, 2,6- naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazol
  • Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from the group consisting of C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C.
  • An optionally substituted heterocycloalkyl can be independently substituted on a carbon atom with one or more substituents selected from the group consisting of OH, (Ci-C 6 )alkyl and (Ci-C4)alkoxy groups and up to two oxo groups.
  • an optionally substituted heterocycloalkyl can be independently substituted on said nitrogen with one or more substituents selected from the group consisting of (Ci-C6)alkyl, acyl, -C(0)0-(Ci-C4)alkyl, -C(0)NH-(Ci-C 4 )alkyl and a -C(0)N((C 1 -C 4 )alkyl) 2 group.
  • Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms.
  • heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N- methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5- diazabicyclo[2.2.2]octanyl, 2,5- diazabicyclo[2.2.1]heptanyl, octahydro-lH-pyrido[l,2-a]pyrazine, 3- thia-6- azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl.
  • Heterocycloalkylalkyl is a heterocycloalkyl-(Ci-C 4 alkyl)- group wherein
  • heterocycloalkyl and alkyl are as defined above.
  • Heterocycloalkyloxy is a heterocycloalkyl-O- group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkylalkoxy is a heterocycloalkyl-(Ci-C4 alkyl)-0- group wherein heterocycloalkyl and alkyl are as defined above.
  • Oxo is a -C(O)- group.
  • Phenyl is a benzene ring.
  • An optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CN, OH, (Ci-C4)alkoxy, (Ci-C4)alkylthio, (C 3 -Cv)cycloalkylthio, (C 3 -Cy)cycloalkyloxy, aryloxy, (Ci- C 4 )alkoxy(Ci- C 4 )alkyloxy, hetero(C 3 -C 7 )cycloalkyloxy, heteroaryloxy, -OC(0)R a , -OC(0)NHR a , -OC(0)N(R a )(R b ), -S(0)R a , -NHR a , -N(R a )(R b ), -NHC(0)R a , -N(R a )C(0)R
  • R a , R b and R c are independently selected from the group consisting of (Ci-C 6 )alkyl, (Ci-C 4 )alkoxy(Ci-C 4 )alkyl, -CH 2 CH 2 OH,
  • an optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen CF 3j CN, (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 4 )alkoxy, (C 3 -C 7 )cycloalkylthio, (C 3 - C 7 )cycloalkyloxy, hetero(C 3 - C 7 )cycloalkyl, C(0)NH 2 , -C(0)NHR a and -C(0)N(R a )(R b ), wherein R a and R b are defined as above.
  • an optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CN, (Ci- C 6 )alkyl, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyloxy and hetero(C 3 -C 7 )cycloalkyl.
  • Restricted phenyl is an optionally substituted benzene ring which can be independently substituted with up to three groups selected from the group consisting of halogen, CF 3j CN, (Ci- C 4 )alkoxy, (Ci- C 4 )alkylthio, (C 3 -C 7 )cycloalkylthio, (C 3 -C 7 )cycloalkyloxy, (Ci-C 4 )alkoxy(Ci- C 4 )alkyloxy, hetero(C 3 -C 7 )cycloalkyloxy, -OC(0)NHR a , -OC(0)N(R a )(R b ), -C(0)NH 2 , -C(0)NHR a , - C(0)N(R a )(R b ), -COR a and R, wherein R a , R b and R c are independently selected from the group consisting of (Ci- C 6 )alkoxy,
  • Cy)cycloalkylalkoxy CN, CHF 2, CF 3 , CH 2 CF 3 , piperidnyl, morpholinyl, N-Me-piperazinyl, piperazinyl, OCF 3 , OCHF 2 , OCH 2 CF 3 and SMe, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds, and none of which are substituted; or R a and R b taken together with the atom(s) to which they are attached form a 5-6 membered ring.
  • PhNTf 2 1, 1,1-trifluoro-N-phenyl-N-
  • the invention provides compounds of Formula I or II
  • A is C0 2 H
  • Ri is selected from the group consisting of (Ci-C 6 )alkyl (e.g., (Ci-C3)alkyl), (C 3 - C 7 )cycloalkyl, -(CH 2 ) 0 _iOR6 and -(CH 2 ) 0 -iSR 6 ;
  • each alkyl or cycloalkyl of Ri and R 2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF 3 , or C 1 -C4 alkyl;
  • Re is selected from the group consisting of H, Ci-C 6 alkyl and (C 3 -C 7 )cycloalkyl;
  • X is a bond or a divalent linking group selected from the group consisting of -0-,
  • R 3 is selected from the group consisting of:
  • Ci-C 7 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0) 2 - groups,
  • Z is a mono-or bi-cyclic ring system having 3 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF 3 , CN, N0 2 , OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 , OC(0)OR 6 , OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SRe, S(0)R 6 , S(0) 2 R6, S(0) 2 NHR 7 , S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R 7 )C(0)R 6 , NHC(0)OR 6 , N(R 7 )C(0)OR 6 , N(R
  • R4 is selected from the group consisting of:
  • Ci-C 7 alkyl group optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0) 2 - groups,
  • Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R ⁇ , CF 3, CN, N0 2 , OH, Ci-C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3, OC(0)R 6 , OC(0)OR 6 , OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SRs, S(0)R 6 , S(0) 2 Rs, S(0) 2 NHR 7 , S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R 7 )C(0)R 6 , NHC(0)OR 6 , N(R 7 )C(0)OR 6 N(R 7 )C
  • R 5 is selected from the group consisting of N0 2 , NH 2 , aryl, heteroaryl, F, CI, Br, CN, OH, C1-C4 alkoxy, SR 6 , S(0) 2 R 6 or S(0) 2 N(R 7 ) 2 , (C 1 -C4) alkyl, (C 0 -C 3 )alkyl-(C 3 -C 7 ) cycloalkyl, -0(Co-C 3 alkyl)(C 3 -C 7 )cycloalkyl and (C 2 -C 4 ) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF 3 , C 1 -C4 alkyl,
  • R 3 and R4 is Z.
  • Ri is (Ci-C 6 )alkyl or (C 3 -C 7 )cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C 6 )alkyl or (C 3 -C 7 )cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C6)alkyl. In certain embodiments of the invention, Ri is (Ci-C 3 )alkyl. In certain embodiments of the invention, Ri is methyl or ethyl. In certain
  • Ri is -SR 5 or -OR 5 (e.g., wherein 5 is (Ci- C 3 )alkyl)).
  • R 2 is -(Co-C 3 )alkyl-(C 3 -C 7 )cycloalkyl.
  • R 2 is -(C 3 -C 7 )cycloalkyl or -CH 2 -(C 3 - C 7 )cycloalkyl.
  • R 2 is cyclopentyl, cyclopropylmethyl, or cyclobutylmethyl .
  • X is a bond.
  • X is -0-, -OCH 2 -, -OCH(R 7 )-, -CH 2 0-, -S-, -S(0) 2 -, - S(0) 2 N(H)-, -S(0) 2 N(R 7 )-, -C(0)NH- or -C(0)N(R 7 )-.
  • X is -0-, - S(0) 2 -, -S(0) 2 N(H)- or -S(0) 2 N(R 7 )-.
  • X is -O- or -S(0) 2 -.
  • Y is a bond.
  • Y is -0-, -OCH 2 -, -OCH(R 7 ), -CH 2 0-, -S-, -S(0) 2 -, -S(0) 2 N(H)-, -S(0) 2 N(R 7 )-, -C(0)NH- or -C(0)N(R 7 )-.
  • Y is -0-, -S(0) 2 -, -S(0) 2 N(H)- or -S(0) 2 N(R 7 )-.
  • Y is -O- or -S(0) 2 -.
  • R 3 is a Ci-C 7 alkyl group optionally interrupted by -0-, -S-, -S(O)-, or -S(0) 2 - groups.
  • R 3 is a Ci-C 7 alkyl group.
  • R 3 is a C 1 -C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl.
  • R 3 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • R 3 is heterocycloalkylalkyl.
  • R 3 is a group Z as defined above wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF 3 , CN, N0 2 , OH, C 1 -C4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3, OC(0)R 6, OC(0)OR 6, OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SR 6 , S(0)R 6 , S(0) 2 R 6 , S(0) 2 NHR 7, S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R
  • Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic.
  • monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl.
  • monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl.
  • Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl.
  • Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl.
  • bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
  • bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl.
  • the mono-or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.
  • R 4 is a C 1 -C 7 alkyl group optionally interrupted by -0-, -S-, -S(O)-, or -S(0) 2 - groups.
  • R 4 is a C 1 -C 7 alkyl group.
  • R 4 is a Ci-C 4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl.
  • R 4 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • R 4 is heterocycloalkylalkyl.
  • R 4 is a group Z as defined above wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3, CN, N0 2 , OH, C r C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3, OC(0)R 6 , OC(0)OR6, OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SR 6 , S(0)R 6 , S(0) 2 R6, S(0) 2 NHR 7 ,
  • Z comprises mono-or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic.
  • monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl.
  • Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl.
  • Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl.
  • bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl.
  • bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
  • bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl.
  • the mono-or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.
  • Other embodiments include compounds of Formulas III, IV, V, and VI wherein R 2 , R 3 , R4, R 5 , X, Y and Z are as defined above and Ri is methyl or ethyl.
  • Other embodiments include compounds of Formulas III, IV, V, and VI wherein R 3 , R 4 , R 5 and Z are as defined above; Ri is methyl or ethyl and R 2 is -(C 0 -C 3 )alkyl-(C 3 -C7)cycloalkyl.
  • R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, - 0-, -OCH 2 -, -C(O)-, -S-, -S(0) 2 -, -S(0) 2 N(R 7 )- and -N(R 7 )S(0) 2 -.
  • R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -0-, -S(0) 2 - and -S(0) 2 N(R 7 ).
  • Another embodiment comprises compounds of Formulas III, IV, V, and VI wherein R ls R 2 , R 3 , R 4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -O- and S(0) 2 N(R 7 ).
  • a further embodiment comprises compounds of Formulas III, IV, V, and VI wherein R ls R 2 , R 3 , R4, R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond and -0-.
  • R ls R 2 , R5, X, Y and Z are as defined above and R 3 and R 4 and are independently selected from the group consisting of a Ci-C 7 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0) 2 - groups, cycloalkylalkyl and heterocycloalkylalkyl.
  • R ls R 2 , R 5 , X, Y and Z are as defined above and R 3 and R 4 and are independently selected from the group consisting of C 1 -C4 alkyl and cyclopropylmethyl.
  • Other embodiments include compounds of Formulas III, IV, V, and VI wherein R ls R 2 , R 5 , Z are as defined above and X, Y and are independently selected from the group consisting of a bond, -S-, -S0 2 - and -O- and R 3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl.
  • R ls R 2 , R5, X, Y and Z are as defined above and R3 and R 4 and are independently chosen from a group Z wherein Z is as defined above.
  • R ls R 2 , R3, R 4 and R 5 , X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3, CN, N0 2 , OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 , OC(0)OR 6 , OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SR 6 , S(0)R 6 , S(0) 2 Rs, S(0) 2 NHR 7 , S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R 7 )C(0)R 6 , NHC(0)OR 6 , N(R 7 )C(0)OR 6, N(R 7 )C(0)NH(
  • Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms
  • R ls R 2 , R 3 , R4 X, Y and Z are as defined above and R 5 is N0 2 , NH 2 , F, CI, Br, CN, OH, C1-C4 alkoxy, SR 6 , S(0) 2 R 6 or S(0) 2 N(R 7 ) 2 .
  • Other embodiments include compounds of Formulas III, IV, V, and VI wherein R ls R 2 , R 3 , R4 X, Y and Z are as defined above and R 5 is aryl or heteroaryl.
  • R ls R 2 , R 3 , R4 X, Y and Z are as defined above and R 5 is chlorine or fluorine.
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R 2 , R 3 , R 4 , R 5 , X, Y and Z are as defined above and Ri is hydrogen.
  • Other embodiments include compounds of Formulas VII, VIII, ⁇ , and X wherein R 3 , R4, R 5 and Z are as defined above; Ri is methyl or ethyl and R 2 is -(Co-C 3 )alkyl-(C 3 -C 7 )cycloalkyl.
  • R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, - 0-, -OCH 2 -, -C(O)-, -S-, -S(0) 2 -, -S(0) 2 N(R 7 )- and -N(R 7 )S(0) 2 -.
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -0-, -S(0) 2 - and -S(0) 2 N(R 7 ).
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -O- and S(0) 2 N(R 7 ).
  • R ls R 2 , R 3 , R4 and R 5 , and Z are as defined above and X and Y are independently selected from the group consisting of a bond and -0-.
  • R ls R 2 , R 5 , X, Y and Z are as defined above and R 3 and R4 and are independently selected from the group consisting of a Ci-C 7 alkyl, optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0) 2 - groups, cycloalkylalkyl and heterocycloalkylalkyl.
  • R ls R 2 , R 5 , X, Y and Z are as defined above and R 3 and R 4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl.
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 5 , Z are as defined above and X, Y and are independently selected from the group consisting of a bond, -S-, -S0 2 - and -O- and R 3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl.
  • R ls R 2 , R 5 , X, Y and Z are as defined above and R 3 and R4 and are independently chosen from a group Z wherein Z is as defined above.
  • R ls R 2 , R 3 , R4 and R 5 , X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF 3, CN, N0 2 , OH, Ci-C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R6, OC(0)OR 6 , OC(0)NHR 7 , OC(0)N(R 7 ) 2 , SR 6 , S(0)Rs, S(0) 2 Rs, S(0) 2 NHR 7 , S(0) 2 N(R 7 ) 2 , NHR 7 , N(R 7 ) 2 , NHC(0)R 6 , N(R 7 )C(0)R 6 , NHC(0)OR6, N(R 7 )C(0)OR 6 , N(R 7 )C(0)NH(R 7 )
  • N(R 7 )C(0)NH(R 7 ) 2 C(0)NH 2 , C(0)NHR 7 , C(0)N(R 7 ) 2 , C0 2 H, C0 2 R6 and CORg.
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 3 , R4 and R5, X and Y are as defined above, and Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing ring bearing up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3 , CN, N0 2 , OH, Ci-C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 ,
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 4 X, Y and Z are as defined above and R 5 is N0 2 , NH 2 , F, CI, Br, CN, OH, C 1-C4 alkoxy, SR 6 , S(0) 2 R6 or S(0) 2 N(R 7 ) 2 .
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 4 X, Y and Z are as defined above and R5 is aryl or heteroaryl.
  • Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R ls R 2 , R 4 X, Y and Z are as defined above and R 5 is chlorine or fluorine.
  • the compounds of formulas I - IX are expected to alter the activity of ⁇ -secretase and are expected to be useful for the treatment of Alzheimer's disease and other neurodegenerative disorders.
  • A is C0 2 H.
  • a compound of formula (I) is selected.
  • a compound of formula (II) is selected.
  • a compound of formula (III) is selected.
  • a compound of formula (IV) is selected.
  • a compound of formula (V) is selected.
  • a compound of formula (VI) is selected.
  • a compound of formula (VII) is selected.
  • a compound of formula (VIII) is selected.
  • a compound of formula (IX) is selected.
  • Ri is methyl or ethyl.
  • R 2 is cyclopentyl.
  • R 2 is cyclopentyl, cyclopropylmethyl, or cyclobutylmethyl.
  • Ri is -SCH 3 and R 2 is -CH 2 -(C 3 - Cv)cycloalkyl.
  • Ri is selected from the group consisting of (Ci-C 6 )alkyls, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF 3 , C1-C4 alkyl.
  • Ri is selected from: the group consisting of n-propyl, iso- propyl, iso-butyl, n-butyl, iso- pentyl, and n-pentyl wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF 3 , C1-C4 or alkyl.
  • Ri is n-propyl. In another embodiment Ri is iso-butyl. In another embodiment Ri is n-butyl. In another embodiment Ri is iso-pentyl. In another embodiment Ri is n-pentyl.
  • R 2 is chosen from (Co-C 3 )alkyl-(C 3 -Cy)cycloalkyls wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF 3 , or C1-C4 alkyl.
  • R 2 is selected from the group consisting of cyclopentyl, cyclopropylmethyl and cyclobutylmethyl. In another embodiment R 2 is cyclopentyl. In another embodiment R 2 is cyclopropylmethyl. In another embodiment R 2 is cyclobutylmethyl.
  • R 6 is Ci-C 6 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0) 2 - groups, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 ) cycloalkylalkyl, or heterocycloalkylalkyl.
  • R ⁇ is Ci-C 6 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0) 2 - groups.
  • R ⁇ (C 3 -C 7 )cycloalkyl In another embodiment R ⁇ is a (Co- C 3 )alkyl-(C 3 -C 7 )cycloalkyl. In another embodiment R 6 heterocycloalkylalkyl. In another embodiment R 6 is (CH 2 ) n Q. In another embodiment R ⁇ is -CH 2 -Q. In another embodiment Q is aryl. In another embodiment Q is heteroaryl. In another embodiment Q is monocyclic heteroaryl. In another embodiment Q is bicyclic heteroaryl.
  • X is a bond or a divalent linking group selected from the group consisting of -0-, -OCH 2 -, -OCH(R 7 )-, -OCH 2 CH 2 -,-CH 2 0-, -CH 2 OCH 2 - and
  • X is a bond or a divalent linking group selected from the group consisting of -S-, -SCH 2 -, -CH 2 S- and -CH 2 SCH 2 -.
  • X is a bond or a divalent linking group selected from the group consisting of -O- and -S-.
  • X is a bond
  • X is the divalent linking group -0-.
  • X is the divalent linking group -S-.
  • Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH 2 -, -OCH(R 7 )-, -OCH 2 CH 2 -, -CH 2 0-, -CH 2 OCH 2 - and -CH 2 CH 2 0.
  • Y is a bond or a divalent linking group selected from the group consisting of -S-, -SCH 2 -, -CH 2 S- and -CH 2 SCH 2 -.
  • Y is a bond or a divalent linking group selected from the group consisting of -O- and -S-.
  • Y is a bond
  • Y is the divalent linking group -0-.
  • Y is the divalent linking group -S-.
  • R 3 is a C 1 -C4 alkyl group.
  • R 3 is a Ci-C 3 alkyl group.
  • R 3 is a C 2 -C 3 alkyl group.
  • R 3 is selected from the group consisting of ethyl, n-propyl, iso-propyl, trifluoroethyl and trifluoropropyl.
  • R 3 is ethyl
  • R 3 is n-propyl
  • R 3 is iso-propyl
  • R 3 is trifluoroethyl.
  • R 3 is trifluoropropyl. [0108] In another embodiment R 3 is a (C 4 -C 10 ) cycloalkylalkyl group.
  • R 3 is a (Co-C 3 )alkyl-(C 3 -Cy)cycloalkyl group.
  • R 3 is a (C 3 -C 7 ) cycloalkyl group.
  • R 3 is a (Ci-C 3 )alkyl-(C 3 -C 7 ) cycloalkyl group.
  • R 3 is a (Ci)alkyl-(C 3 -C 7 ) cycloalkyl group.
  • R 3 is a (Ci)alkyl-(C 3 -C 4 ) cycloalkyl group.
  • R 3 is a cyclopropylmethyl group.
  • R 3 is a cyclobutylmethyl group.
  • R 3 is heterocycloalkylalkyl group.
  • R 3 is represented by the group Z as defined herein.
  • R 3 is not cyclopropylmethyl.
  • Z is monocyclic.
  • Z is bicyclic.
  • Z is heteroaryl
  • Z is unsubstituted heteroaryl.
  • Z is benzo[b]thiophenyl, benzo[c] [ 1 ,2,5]oxadiazoyl, benzo[c][l,2,5]thiadiazolyl or benzo[d]thiazolyl.
  • Z is benzo[b]thiophenyl or benzo[d]thiazolyl.
  • Z is benzo[c][l,2,5]oxadiazoyl or benzo[c][l,2,5]thiadiazolyl.
  • Z is benzo[b]thiophenyl.
  • Z is benzo[c] [ 1 ,2,5]oxadiazoyl.
  • Z is benzo[c] [ 1 ,2,5]thiadiazolyl.
  • Z is benzo[d]thiazolyl.
  • Z is aryl
  • Z is substituted phenyl.
  • Z is 4-substituted phenyl.
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3 , CN, N0 2 , OH, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 , OC(0)OR 6 , OC(0)NHR 7 ,
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R ⁇ , CF 3 , CN, N0 2 , C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 , OC(0)OR 6 , SRg, NHR 7 , N(R 7 ) 2 C0 2 H, C0 2 R 6 and COR 6 .
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3 , CN, N0 2 , C 1 -C 4 alkoxy, aryloxy, OCH 2 CH 2 OCH 3 , OC(0)R 6 , OC(0)OR 6 and SR 6 .
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R 6 , CF 3 , CN, N0 2 , C 1 -C 4 alkoxy, OCH 2 CH 2 OCH 3 , OC(0)R6, OC(0)OR 6 and SR 6 .
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, Ci-C 6 alkyl, (Co-C 3 )alkyl-(C 3 - C 7 )cycloalkyl, CF 3 , C1-C4 alkoxy and SR 6 .
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C 3 alkyl, (C 3 -C 6 )cycloalkyl, CF 3 , C 1 -C4 alkoxy, S-(Ci- C 4 )alkyl and S-(C 0 -C 3 )alkyl-(C 3 -C 7 )cycloalkyl.
  • Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C 3 alkyl, (C 3 -C 6 )cycloalkyl, CF 3 , C1-C4 alkoxy and S-(Ci- C 3 )alkyl.
  • Z is susbsituted once with CF 3 , OCF 3 , OCH 2 CF 3 , F, CI, SMe, Me, Et, or i-Pr.
  • Z is susbsituted with F. In another embodiment Z is susbsituted with CI.
  • Z is susbsituted with Ci-C 3 alkyl.
  • Z is susbsituted with (C 3 -C 6 )cycloalkyl.
  • Z is susbsituted with CF 3 .
  • Z is susbsituted with C 1 -C 4 alkoxy. In another embodiment Z is susbsituted with S-(Ci-C 3 )alkyl.
  • R4 is a Ci-C 7 alkyl group. In another embodiment R 4 is a C 1 -C 4 alkyl group. In another embodiment R 4 is a Ci-C 3 alkyl group. In another embodiment R 4 is a C 2 -C 3 alkyl group.
  • R 4 is selected from the group consisting of ethyl, n- propyl, iso-propyl, trifluoroethyl and trifluoropropyl.
  • R 4 is ethyl. In another embodiment R 4 is n-propyl. In another embodiment R 4 is iso-propyl. In another embodiment R 4 is trifluoroethyl. In another embodiment R 4 is trifluoropropyl. In another embodiment R 4 is a (C 4 -C 10 ) cycloalkylalkyl group.
  • R 4 is a (Co-C 3 )alkyl-(C 3 -Cy) cycloalkyl group. In another embodiment R 4 is a (C 3 -C 7 ) cycloalkyl group.
  • R 4 is a (Ci-C 3 )alkyl-(C 3 -Cy) cycloalkyl group. In another embodiment R 4 is a (Ci)alkyl-(C 3 -Cy) cycloalkyl group.
  • R 4 is a (Ci)alkyl-(C 3 -C 4 ) cycloalkyl group. In another embodiment R 4 is a cyclopropylmethyl group.
  • R 4 is a cyclobutylmethyl group.
  • R 4 is heterocycloalkylalkyl group. In another embodiment R 4 is represented by the group Z as defined herein. In another embodiment R 4 is not cyclopropylmethyl.
  • R 5 is, F, CI, Br, CN, C1-C4 alkoxy, SRe, (C1-C4) alkyl, (C 0 - C 3 )alkyl-(C 3 - C 7 ) cycloalkyl, -(C 3 -C 7 ) cycloalkyl or (C 2 -C 4 ) alkynyl, where each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF 3 , C1-C4 alkyl.
  • R 5 is F, CI, Br, CN, C 1 -C4 alkoxy, SRe, (C 1 -C4) alkyl, (C 0 - C 3 )alkyl-(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) cycloalkyl or (C 2 -C 4 ) alkynyl, where each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF 3 , C1-C4 alkyl.
  • R 5 is F, CI, Br, CN, C 1 -C4 alkoxy, -S-(Ci-C 4 )alkyl or (Ci- C 4 ) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF 3 , Ci-C 4 alkyl.
  • R 5 is F, CI, Br, O H , CN, C C 4 alkyl, C C 3 alkoxy, -S- (Ci-C 3 )alkyl, or (C 1 -C 3 ) alkyl, or -0-(Co-C 3 )alkyl-(C 3 -C 7 ) cycloalkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF 3 , or Ci- C 4 alkyl.
  • R 5 is F, CI, Br or CN.
  • R 5 is F or CI. In another embodiment R 5 is F. [0158] In another embodiment R5 is CI. In another embodiment R5 is Br. In another embodiment R5 is CN.
  • R5 is C 1 -C 3 alkoxy, -S-(Ci-C 3 )alkyl or (C 1 -C 3 ) alkyl.
  • R5 is C 1 -C 3 alkoxy.
  • R5 is tri-fluoroethoxy or tri-fluoropropoxy.
  • R5 is (C 1 -C 3 ) alkyl.
  • R 5 is CF 3 .
  • R5 is -S-(Ci-C 3 )alkyl.
  • R 5 is -S-Me, -S-Et or -S-CH 2 CF 3 .
  • R5 is SR 6 .
  • R 5 is (Co-C 3 )alkyl-(C 3 -Cy) cycloalkyl, (C 2 -C 4 ) alkynyl, or -(C 3 - C 7 ) cycloalkyl.
  • R5 is (Co-C 3 )alkyl-(C 3 -Cy) cycloalkyl.
  • R 5 is (C 2 -C 4 ) alkynyl.
  • R5 is trifluroethynyl.
  • R5 is (C 3 -C7) cycloalkyl.
  • R5 is cyclopropyl
  • R 5 is N0 2 or NH 2 .
  • R5 is aryl or heteroaryl.
  • the compound is a compound selected from the group consisting of examples from the Exemplification section.
  • a racemic compound described in the disclosure is selected.
  • a pharmaceutical composition comprising of the compound of any of the previous embodiments and a pharmaceutically acceptable carrier.
  • a method for treating a neurodegenerative disorder comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.
  • a method for treating Alzheimer's Disease comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments is provided.
  • compounds of Formula (I -IX) may contain asymmetric centers and exist as different enantiomers or diastereomers. All enantiomers or diastereomeric forms are embodied herein.
  • compositions in the disclosure may be in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids.
  • Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc.
  • Salts derived from organic bases include ammonia, primary (e.g., tromethamine), secondary and tertiary amines, and amino acids (e.g., lysine).
  • Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric,
  • Salts derived from organic acids include Ci_ 6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as /?ara-tolouene sulfonic acid and benzene sulfonic acid.
  • Ci_ 6 alkyl carboxylic acids such as acetic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid
  • alkylsulfonic acids such as methanesulphonic
  • aryl sulfonic acids such as /?ara-tolouene sulfonic acid and benzene sulfonic acid.
  • Compounds and pharmaceutically acceptable salts thereof may be in the form of a solvates. This occurs when a compound of formula (I-IX)) crystallizes in a manner that it incorporates solvent molecules into the crystal lattice. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
  • solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
  • Formulas I-IX include solvate and/or salts of the depicted compound.
  • Compounds in the disclosure may exist in different crystal forms known as polymorphs. Practitioners of the art will recognize that certain chemical groups may exist in multiple tautomeric forms. The scope of this disclosure is meant to include all such tautomeric forms.
  • a tetrazole may exist in two tautomeric forms, 1- H tetrazole and a 2-H tetrazole. This is depicted in figure below. This example is not meant to be limiting in the scope of tautomeric forms.
  • the tetrasubstituted benzene compounds may be prepared and/or substituted in the manner described in PCT Application No. PCT/US2008/087968, the content of which is herein incorporated by reference in its entirety.
  • the 1 -position acetic acid moiety common to compounds of Formulas I and II, as the free acid itself or as an ester derivative thereof, is already present in the case of a 4- hydroxyphenyl acetic acid or 4-hydroxyphenyl acetic acid ester starting material.
  • the acetic acid moiety can be introduced by standard nucleophilic aromatic substitution of the 4-fluoro group with an
  • X-R 3 and Y-R 4 groups or intermediate groups that are further elaborated to X-R 3 and Y-R 4 can be carried out by substitution or manipulation of suitable 3 or 4-position functional groups in appropriate starting materials or intermediates en route to Formulas I and II respectively.
  • X or Y is a bond
  • a 3 or 4- position halogen or triflate group is replaced with an aryl or heteroaryl group by carbon-carbon bond forming reaction typically a Suzuki coupling reaction.
  • a 3 or 4-position halogen e.g., the corresponding 2-fluoro group of a 2,4-difluoronitrobenzene starting material
  • substitution reaction is performed using HO-R 3 or HS-R 3 or H 2 N-R 3 and a base (e.g., NaH, K 2 CO 3 ) in a suitable solvent (e.g., DMF).
  • a suitable solvent e.g., DMF
  • N(H)S(0) 2 - or -N(R 5 )S(0) 2 - can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding sulfonylchloride.
  • Compounds where X or Y is NHC(O)- or -N(R 5 )C(0)- can be prepared by reduction of a 3 or 4- position nitro group to the corresponding aniline followed by reaction with the corresponding carboxylic acid chloride.
  • X or Y is a -C(O)-
  • an organometallic reagent e.g., a Grignard reagent or organolithium
  • a 3 or 4-position cyano group directly or in a 2-step sequence by addition of an organometallic reagent to a 3 or 4- position
  • C(0)N(Rs)- can be prepared by addition of a corresponding amine to a 3 or 4-position carboxylic acid which in turn may be prepared by hydrolysis of a 3 or 4-position cyano group.
  • Either aromatic nucleophilic substitution of a 2-fluoro-l -nitrobenzene intermediate or alkylation of a 3 or 4-hydroxybenzene intermediate with the corresponding alkyl bromide or triflate may be used to prepare compounds of Formulas I and II where the R4 group is OCH 2 CF 3 , C 2 -C 4 alkoxy, or cyclopropyloxymethyl.
  • R 4 group is an alkyl, aryl or heteroaryl group attached by a carbon-carbon bond
  • R 4 group is an alkyl, aryl or heteroaryl group attached by a carbon-carbon bond
  • a Suzuki coupling reaction an aryl or heteroaryl boronic acid or borate ester is reacted with an intermediate compound having a 3 or 4-position halogen or triflate group.
  • This method results in replacement of the halogen or triflate group with an aryl or heteroaryl group which is then bonded to the intermediate at the carbon atom previously bearing the boronic acid or ester group.
  • R 4 group is a heteroaryl group attached by a carbon-nitrogen bond
  • Compounds wherein the R 4 group is a heteroaryl group attached by a carbon-nitrogen bond may be prepared by reacting a 3 or 4-iodo intermediate with a heteroaromatic heterocycle having an acidic N-H group under Ulman reaction or copper catalyzed reaction conditions.
  • the nitrile may be treated with an azide, such as sodium azide or tributylstanyl azide (Bu 3 SnN 3 ) at a temperature of 20-100 °C, optionally with a solvent such as DMF, THF or DMSO.
  • alkoxyalkyl, heteroarylalkyl or arylalkyl Rg group is introduced in the first step by treating ethyl 4- benzyloxyphenylacetate one equivalent of a suitable deprotonating base such as sodium hydride in an appropriate organic solvent followed by the addition of the corresponding reactive alkyl bromide RgBr such as isobutylbromide to yield XX where R9 is hydrogen.
  • a second alkyl or aralkyl group is present this alkylation step is repeated using R 9 Br as an alkylating agent.
  • a spirocyclic ring is formed by Rg and R 9 (e.g., cyclopropyl) then the appropriate dibromide is used (e.g., dibromoethane in the case of cyclopropyl).
  • the benzyl group is then removed under standard catalytic hydrogenation conditions and the resulting phenol is treated with bromine in acetic acid to give the bromophenol intermediate XXI.
  • Nitration of XXI then yields nitrophenol intermediate XXII which then us subjected to a standard base mediated aliphatic or aromatic nucleophilic substitution reaction with an alkyl or aryl halide R 4 -X to give intermediate XXIII where R 4 is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl. This is then followed by introduction of the Z group by standard reactions.
  • Such reactions are exemplified by the well- established Suzuki coupling of a substituted aryl or heteroaryl boronic acid derivative Z-B(OH)2 using a suitable palladium(O) catalyst typically bearing with phosphine ligands (e.g., Pd(PPh3)4 or tetrakistriphenylphosphine) in the case where Z is linked by a carbon-carbon bond and by copper
  • phosphine ligands e.g., Pd(PPh3)4 or tetrakistriphenylphosphine
  • the nitro group is converted to the corresponding aniline by any number of standard reduction conditions (e.g., SnCl 2 reduction).
  • This is followed by conversion of the resulting aniline to the diazonium salt which is then converted "in situ" either directly to R 5 either directly in the case where R 5 is F, CI, Br, CN, OH, C 1 -C4 alkoxy or SR 6 , by using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol or in a subsequent step e.g., oxidation (e.g., with MCPBA) of the product of thiol coupling when R 5 is S(0) 2 R 6 ; e.g., Suzuki coupling of the bromide product when R 5 is heteroaryl e.g., treatment of an intermediate sulfonylchloride obtained via CuCl/S0 2 conditions with an amine
  • R 2 is R 9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl;
  • R5 is F or CI;
  • R 3 and Z are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 4.
  • the 4-halo group of 2,4,5- trifluoronitrobenzene or 2,4,5-trichloronitrobenzene is selectively displaced by reaction with a 2- substituted diethylmalonate R 8 YCH(C0 2 Et) 2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXI.
  • a 2- substituted diethylmalonate R 8 YCH(C0 2 Et) 2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXI.
  • the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R 3 -J-H compound (wherein J is O, S) under basic conditions (e.g., NaH/DMF) followed by reduction and Sandmeyer reaction to give iodide XXXII.
  • R 2 is R9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl;
  • X is O;
  • R 5 is CI;
  • R 3 and Z are as described previously and thus having general Formula XXXVIII may be prepared generally as depicted in Scheme 5.
  • the 4-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R 8 CH 2 (C0 2 Et) 2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXV.
  • a 2-substituted diethylmalonate R 8 CH 2 (C0 2 Et) 2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXV.
  • the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R 3 -O- H compound under basic conditions (e.g., NaH/DMF) followed by reduction and chlorination reaction (e.g., with N-chlorosuccinimide) to give chloroaniline intermediates of general formula XXXVI.
  • R 2 is R 9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl;
  • R 5 is NO 2 , NH 2 , CN, SR 6 , SO 2 R 6 , SO 2 N(R 7 ) 2 F, CI, Br;
  • R 3 and Z are as described previously and thus having general Formula XLII may be prepared generally as depicted in Scheme 6.
  • the 2- fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a an alcohol or thiol of formula R 3 -J-H under basic conditions (e.g., NaH/DMF).
  • the 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XXXIX.
  • Reduction of the nitro group of XXXIX followed by nitration of the resulting aniline give nitroaniline intermediates of Formula XL.
  • Sandmeyer iodination reaction, followed by Suzuki coupling and finally alkylation reaction to introduce Rs then gives intermediates of general Formula XLI.
  • the nitro group of XLI may be optionally reduced via any number of standard reduction conditions
  • R 5 is F, CI, Br, CN, OH, Ci-
  • diazotization of the aniline is followed by direct "in situ" conversion to R 5 using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol.
  • copper salt i.e., CuCl, CuBr, CuCN
  • nucleophile i.e., water, alcohol or thiol.
  • R 5 is S(0) 2
  • R 6 may be prepared by subsequent step oxidation (e.g., with
  • R 2 is R 9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl;
  • R 5 is N0 2 , NH 2 , CN, SR5, SO2R5, S0 2 N(Rv) 2 F, CI, Br;
  • R 3 and Z are as described previously and thus having general Formula XLV may be prepared generally as depicted in Scheme 7.
  • R5 is F, CI, Br, CN, OH, C1-C4 alkoxy or SR ⁇
  • diazotization of the aniline is followed by direct "in situ" conversion to R 5 using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol.
  • Intermediates where R 5 is S(0) 2 R6 may be prepared by subsequent step oxidation (e.g., with MCPBA) of the above products of thiol coupling wherein R 5 is SR 6 .
  • R 5 is e.g., heteroaryl, C 2 -C 4 alkynyl or cyclopropyl
  • R 5 is Br or I
  • R 5 is CF 3
  • R5 is I.
  • R 5 is S(0) 2 N(Rv) 2
  • R 9 may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/S0 2 conditions) with an amine HN(R 7 ) 2
  • Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R 9 followed by standard ester hydrolysis.
  • R 2 is R 9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl;
  • X-R 3 and R 5 are identical (J- R 3 in Scheme 8) and are either C 1 -C 4 alkoxy or SR 6 groups; and Z is as described previously and thus having general Formula L may be prepared generally as depicted in Scheme 8.
  • the 2 and 6- fluoro groups of 2,4,6-trifluoronitrobenzene are selectively displaced by reaction with a an alcohol or thiol of formula R 3 -J-H under basic conditions (e.g., NaH/DMF).
  • the 4- fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XLVIIL
  • Reduction of the nitro group of followed by Sandmeyer iodination reaction of the resulting aniline gives intermediates of Formula XLVIII.
  • Suzuki coupling and followed by alkylation reaction to introduce R 8 then gives intermediates of general Formula XLIX.
  • Final products having general Formula L are then prepared by optional alkylation reaction to introduce R 9 followed by standard ester hydrolysis.
  • the present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas I - IX, a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
  • the pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof.
  • the dosage can be an oral dosage form that is a controlled release dosage form.
  • the oral dosage form can be a tablet or a caplet.
  • the compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.
  • the compound can be administered parenterally, such as intravenous (i.v.) administration.
  • the formulations for administration will commonly comprise a solution of the compound of the Formulas I - IX dissolved in a pharmaceutically acceptable carrier.
  • Suitable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.
  • formulations may be sterilized by conventional, well known sterilization techniques.
  • the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of compound of Formulas I - IX in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally- acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • a compound of Formulas I - IX can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject.
  • the formulations for administration will commonly comprise a solution of the compound of
  • Formulas I - IX dissolved in a pharmaceutically acceptable carrier.
  • the compound of Formulas I - IX is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna.
  • the compound of Formulas I -IX is introduced intraocullarly, to thereby contact retinal ganglion cells.
  • the pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.
  • the pharmaceutical composition comprising a compound of
  • Formulas I -IX is administered into a subject intrathecally.
  • intrathecal administration is intended to include delivering a pharmaceutical composition comprising a compound of Formulas I - IX directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebro ventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al., Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al, Cancer Drug Delivery, 1 : 169-179, the contents of which are incorporated herein by reference).
  • lumbar region is intended to include the area between the third and fourth lumbar (lower back) vertebrae.
  • cisterna magna is intended to include the area where the skull ends and the spinal cord begins at the back of the head.
  • Cerebral ventricle is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord.
  • the pharmaceutical compositions comprising the compound of Formulas I - IX or by the use of infusion pumps.
  • the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the pharmaceutical compositions may be formulated in solid form and re- dissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formulas I - IX is administered by lateral cerebro ventricular injection into the brain of a subject.
  • the injection can be made, for example, through a burr hole made in the subject's skull.
  • the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject.
  • the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
  • the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
  • the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient.
  • Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • compositions for oral use can be obtained through combination of a compound of Formulas I - IX with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores.
  • carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • aqueous solutions or suspensions for intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl -pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
  • the suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient are cocoa butter and polyethylene glycols.
  • the compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
  • Aqueous suspensions can contain a compound of Formulas I - IX in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g.,
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as aqueous suspension
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolality.
  • Oil suspensions can be formulated by suspending a compound of Formulas I -IX in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997.
  • the pharmaceutical formulations can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day.
  • the desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • the compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders.
  • the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.
  • Rat primary neocortical cultures are established through the dissection of the neocortices from 10-12 El 7 embryos harvested from time-pregnant SD (Sprague Dawley) rats (Charles River Laboratories). Following dissection, the combined neocortical tissue specimen volume is brought up to 5mL with dissection medium (DM; lxHBSS (Invitrogen Corp., cat#14185-052) /lOmM HEPES (Invitrogen Corp., cat# 15630-080)/ ImM Sodium Pyruvate (Invitrogen Corp., cat# 11360-070)) supplemented with lOOuL Trypsin (0.25%; Invitrogen Corp., cat# 15090-046) and lOOuL DNase I (0.1% stock solution in DM, Roche Diagnostics Corp., cat# 0104159), undergoing digestion via incubation at 37°C for 10 minutes.
  • DM dissection medium
  • lxHBSS Invitrogen Corp.
  • Digested tissue is washed once in plating medium (PM; NeuroBasal (Invitrogen Corp., cat# 21103-049) / 10%) Horse Serum (Sigma-Aldrich Co., cat# HI 138) / 0.5mM L-Glutamine (Invitrogen Corp., cat# 25030-081)), then resuspended in a fresh lOmL PM volume for trituration.
  • Trituration consists of 18 cycles with a 5mL-serological pipet, followed by 18 cycles with a flame-polished glass Pasteur pipet.
  • the volume is elevated to 50mL with PM, the contents then passed over a 70um cell-strainer (BD Biosciences, cat# 352350) and transferred directly to a wet-ice bath.
  • the cell- density is quantified using a hemacytometer, and diluted to allow for the plating of 50000 cells/well/ lOOuL in pre-coated 96-well PDL-coated plates (Corning, Inc., cat# 3665).
  • C-terminal recognition-site Abeta x ⁇ 42 and Rat N-terminal recognition-site Abetai ⁇ x capture-antibodies are used to coat (lOOuL/well) flat-bottomed F96 MicroWellTM (MaxiSorpTM surface) plates (Nalge Nunc International, cat# 439454), and incubated overnight at 4°C for eventual use in the ELISA assay.
  • DMSO dimethyl sulphoxide
  • DMSO dimethyl sulphoxide
  • DMSO and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor (GSI), are incorporated as solvent and positive controls, respectively.
  • DAPT N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester
  • GSI gamma-secretase inhibitor
  • Each coated capture-antibody ELISA plate undergoes 4x 250uL/well Phosphate- buffered saline with 0.05% Tween ® -20 SigmaUltra (PBS-T; Fluka, cat# 79383/Sigma- Aldrich Co., cat# P7949) washes. The ELISA plates are then overlaid with 120uL/well PBS-T
  • Bovine Serum Albumin Diluent/Blocking solution BSA; Kirkegaard & Perry Laboratories (KPL), Inc., cat# 50-61-01
  • BSA Bovine Serum Albumin Diluent/Blocking solution
  • Rat Abetai ⁇ 42 and rat Abetai ⁇ 40 peptide (American Peptide Co., cat# 62-0-84/62-0- 86A) DMSO stock solutions are serially-diluted 1 :2 in FM yielding a final concentration range of 0- 500pg/mL, to be plated on the respective ELISA plates for determination of the corresponding standard curve, from which concentrations of specific or total Abeta peptides in the presence of a particular drug concentration can be calculated.
  • the conditioned medium from the duplicate culture plates are collected and combined into one round-bottom 96-well transfer plate which is incubated on wet-ice.
  • the culture plates are rinsed once with 120ul/well FM, and replenished immediately with ⁇ FM, being returned to the incubator for 10 minutes.
  • Cell-viability is evaluated by adding 20uL/well of warmed CellTiter 96 ® Aqueous One Solution (MTS/PES; Promega Corp., cat# G3581), and returning the plates to the incubator for 30-90 minutes.
  • Plate absorbance at 492nm is read on a spectrophotometer, and from which, the ratio of absorbance of compound-treated cells to absorbance of solvent (DMSO)-treated control cells is calculated. The calculation of the corresponding EC50 values is performed following non-linear curve-fitting using GraphPad Prism ® software.
  • a corresponding transfer-plate is created containing 120 ⁇ 11 of either the rat Abetai ⁇ 42 or rat Abetai ⁇ 40 peptide standard solutions, in duplicate, and 110- 115 ⁇ 11 of the collected conditioned-medium plate, half designated for the Abeta x ⁇ 42 ELISA, and the other half for the Abetai ⁇ x ELISA.
  • the ELISA plates undergo a second set of 4x 250uL/well PBS-T washes, immediately followed by being overlaid with their designated transfer-plate.
  • the ELISA plates incubate on an orbital-shaker for 16-18 hours at 4°C.
  • Detection antibody solution is prepared by diluting beta- Amyloid 17-24 (4G8) biotinylated monoclonal antibody (Covance, Inc., cat# SIG-39240-200) 1 : 1500 in PBS-T supplemented with 0.67% BSA.
  • the ELISA plates undergo 4x 250uL/well PBS-T washes, and are overlaid with lOOuL/well of 4G8 diluted detection-antibody solution.
  • the Abeta x ⁇ 42 ELISA plates are incubated on an orbital-shaker at room-temperature for 90 minutes, the Abetai ⁇ x ELISA plates for 60 minutes.
  • the ⁇ peptide is proteolytically derived from a larger integral membrane amyloid precursor protein (APP).
  • APP integral membrane amyloid precursor protein
  • the production of ⁇ is derived from proteolytic cleavages at its N- and C- termini within ⁇ - ⁇ by the ⁇ and ⁇ -secretase activities, respectively.
  • Transfected cells overexpressing ⁇ - ⁇ or its equivalent producing the ⁇ peptide can be used to monitor the effects of synthetic compounds on the production of ⁇ .
  • kits containing the necessary antibodies and reagents for such an analysis are available, for example, but not limited to the Genetics Company, Wako, Covance, and Innogenetics. The kits are essentially used according to the manufacturers recommendations similar to the assay that is described by Citron et al, (1997) Nature Medicine 3:67-72 and the original assay described by Seubert et al, (1992) Nature 359:325-327.
  • Conditioned Medium samples are removed for analysis/quantitation of the various ⁇ peptide levels by differential ELISA's, e.g., as described in accompanying instructions to the kits. Those compounds examined which do not demonstrate any overt toxicity (determined by
  • a compound with the value "A” had an IC 50 value less than or equal to 100 nM.
  • a compound with the value "B” had an IC 50 value greater than 100 nM and less than 500 nM:
  • Microsomal glucuronidation reactions were conducted using the UGT Reaction Mix solutions (A and B) from BD Biosciences and following the vendor's protocol. 10 ⁇ of test article or control compound was incubated with 0.5 mg/mL of human or rat liver microsomes. Samples were taken at 0 and 60 minutes and acetonitrile was added to terminate the reactions. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide. Control reactions were run for each compound substituting water for the glucuronic acid solution to monitor for any loss of parent compound due to degradation or unanticipated microsomal reactions.
  • Hepatocyte experiments were run using cryopreserved human hepatocytes (single donor) obtained from Celsis/In Vitro Technologies. Cells were thawed and counted according to the vendor's protocols using the trypan blue exclusion method to obtain the count of live cells. Test article and control compounds were incubated at a concentration of 5 uM in KHB buffer (Celsis/In Vitro Technologies) containing 1 million cells per mL. Samples were taken at 0, 60 and 120 minutes. The reactions were terminated with addition of acetonitrile. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide.
  • Mobile phase A water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide;
  • Mobile phase B 95:5 acetonitrile/ water with 0.05%> (v/v) formic acid and 0.05%> (v/v) 5 N ammonium hydroxide.
  • the API 3200 QTRAP mass spectrometer was used in MRM mode with negative electrospray ionization. MRM transitions and mass spec settings were optimized for each compound.
  • Standard curves were created by quadratic or linear regression with l/x*x weighting. Calibration standards were prepared 1-10,000 ng/mL, but the highest (and sometimes lowest) standards were often not acceptable for quantitation and only those standards with reasonable back- calculated accuracies were included in the calibration curve. Ideally, only standards with
  • GSMs gamma secretase modulators
  • compounds of the disclosure are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of ⁇ peptides produced by ⁇ -secretase.
  • GSMs gamma secretase modulators
  • the compounds alter the relative levels of ⁇ peptides produced by ⁇ -secretase without
  • Certain compounds of the disclosure modulate ⁇ -secretase activity with respect to APP proteolytic processing and in so doing lower the production of ⁇ 42 both in vitro in cells and in vivo in animals. In some cases this effect occurs at concentrations that do not significantly impair the viability of cells in vitro and at doses that are well tolerated in vivo. Certain compounds of the disclosure lower ⁇ 42 secretion in native neuronal and cellular construct assay systems with EC50 values that are below 1 micromolar (Class A compounds, Table 14) while others have EC50 values from 1-5 micromolar (Class B
  • Certain compounds of the disclosure do not appear to significantly interfere with ⁇ - secretase related Notch processing activity. Compounds that significantly interfere with ⁇ -secretase related Notch processing activity have been associated with toxic side-effects. Certain compounds of the disclosure have favorable pharmacokinetic (PK) properties in animals. Thus, certain of the compounds are orally bioavailable, penetrate into the brain and have favorable PK parameters including half-life and clearance supporting pharmaceutical application in humans. In turn, certain compounds of the disclosure significantly lower ⁇ 42 production in the brains of non-transgenic and transgenic animals after single dose and multi-dose oral administration with no overt side effects.
  • PK pharmacokinetic
  • single oral doses of ⁇ 30 milligrams/kilogram are efficacious at lowering ⁇ 42 production in the brains of rats (e.g., Sprague-Dawley) and wild type mice (e.g., C57BL/6).
  • Certain compounds of the disclosure which lower ⁇ 42 at doses of ⁇ 30 milligrams/kilogram appear to be well tolerated and show no overt or clinical chemical toxicity after subchronic 14- day administration at doses >30 milligrams/kilogram/day.
  • Certain compounds of the disclosure have favorable absorption-distribution-metabolism and excretion (ADME) properties.
  • ADME absorption-distribution-metabolism and excretion
  • carboxylic acid compounds which are less prone to acylgluconoride formation are expected to be less toxic.
  • certain desirable compounds of the disclosure are less prone to acylglucoronidation than NSAID compounds that remain on the market are regarded as safe (e.g., flurbiprofen).
  • Enantiomer 1 1H-NMR (DMSO-D 6 , 500MHz): 12.56 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.46 (d, 1H); 7.26 (d, 1H); 4.30 (q, 2H); 2.23-2.20 (m, 1H); 2.10-1.98 (m, 2H); 1.90- 1.85 (m, 1H); 1.82- 1.70 (m, 2H); 1.68- 1.60 (m, 2H); 1.58- 1.50 (m, 1H); 1.45 (s, 3H); Chiral HPLC: >98% ee at 9.66 min.
  • Enantiomer 1 1H-NMR (CDC1 3 , 500MHz): 7.72 (d, 2H); 7.63 (d, 2H), 7.42 (d, 1H); 7.22 (d, 1H); 3.98 (q, 2H); 2.98-2.86 (m, 2H); 1.68 (s, 3H); 0.61-0.59 (m, 1H); 0.50-0.48 (m, 2H); 0.10.05( m, 2H); Chiral HPLC: >98% ee at 10.50 min. Column; Chiral Pak IA, 250x4.6 mm, 5 ⁇ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes).
  • Enantiomer 2 1H-NMR (CDC1 3 , 500MHz): 7.72 (d, 2H); 7.63 (d, 2H), 7.42 (d, 1H); 7.22 (d, 1H); 3.98 (q, 2H); 2.98-2.86 (m, 2H); 1.68 (s, 3H); 0.61-0.59 (m, 1H); 0.50-0.48 (m, 2H); 0.10.05( m, 2H); Chiral HPLC: >98% ee at 10.50 min. Column; Chiral Pak IA, 250x4.6 mm, 5 ⁇ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes).
  • Enantiomer 1 1H-NMR (DMSO-D 6 , 500MHz): 12.60 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.57 (d, 1H); 7.37 (d, 1H); 4.30 (q, 2H); 2.78-2.70 (m, 1H); 1.72-1.63 (m, 1H); 1.58- 1.48 (m, 4H); 1.46 (s, 3H); 1.41- 1.30 (m, 2H); 1.18- 0.90 (m, 1H); Chiral HPLC: >98% ee at 5.7 min.

Abstract

Provided herein are tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease.

Description

TETRASUBSTITUTED BENZENES
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application 61/586,064 filed on Janurary 12, 2012, and is related to PCT Application No. PCT/US2008/087968, filed on December 22, 2008, both of which are hereby expressly incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disorder that is associated (though not exclusively) with aging. The disorder is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disorder is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. These plaques are considered to play an important role in the pathogenesis of the disease.
[0003] These plaques mainly comprise of fibrillar aggregates of β-amyloid peptide (Αβ), which are products of the amyloid precursor protein (APP), a 695 amino-acid protein. APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ- secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Αβ 37-42 amino acids). N-terminal truncations can also be found e.g., Αβ (4-42, 11-42) for convenience Αβ40 and Αβ42 as used herein incorporates these N- terminal truncated peptides. Upon secretion, the Αβ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques. Αβ42 is believed to be the most neurotoxic, the shorter peptides have less propensity to aggregate and form plaques. The Αβ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca, inclusion body myositis and Down's Syndrome.
[0004] γ-secretase is an association of four proteins: Aphl, Nicastrin, Presenillin and Pen-2 (review De Strooper 2003, Neuron 38, 9). Αβ42 is selectively increased in patients carrying particular mutations in one of these components, presenilin. These mutations are correlated with early onset a familial AD. Inhibition of γ-secretase resulting in the lowering of Αβ42 is a desirable activity for the pharmaceutical community and numerous inhibitors have been found, e.g., Thompson et al. (Bio. Org. and Med. Chem. Letters 2006, 16, 2357-63), Shaw et al. (Bio. Org. and Med. Chem. Letters 2006, 17, 511-16) and
Asberom et al. (Bio. Org. and Med. Chem. Letters 2007, 15, 2219-2223). Inhibition of γ- secretase though is not without side-effects, some of which are due to the γ-secretase complex processing substrates other than C99, e.g., Notch. A more desirable approach is to modulate the proteolytic activity of the γ-secretase complex in a manner that lowers Αβ42 in favor of shorter peptides without significantly affecting the activity of γ-secretase on substrates such as Notch.
[0005] Compounds that have shown modulation of γ-secretase include certain nonsteroidal, anti-inflammatory drugs (NSAIDs), for example Flurbiprofen, (Stock et al, Bio. Org. and Med. Chem. Letters 2006, 16, 2219-2223). Other publications that disclose agents said to reduce Αβ42 through the modulation of γ-secretase include: WO 04/074232, WO 05/054193, Perreto et al Journal of Medicinal Chemistry 2005, 48, 5705-20,
WO05/108362, WO 06/008558, WO 06/021441, WO 06/041874, WO 06/045554, WO04110350, WO 06/043964, WO 05/115990, EP1847524, WO 07/116228, WO
07/110667, WO 07/124394, EP184752, EP 01849762, WO 07/125364.
[0006] As such there is a need for improved gamma secretase modulators for use in treatment of AD.
SUMMARY OF THE INVENTION
[0007] The present invention provides an unexpectedly superior class of compounds, Formulas I and II, with improved metabolic stability, as well as methods for preparing the compounds, and methods of using the compounds to treat one or more symptoms of Alzheimer's disease. The compounds of the invention, which show increased metabolic stability (i.e., reduced glucuronide isomerization) are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Αβ peptides produced by γ-secretase. In certain embodiments, the compounds alter the relative levels of Αβ peptides produced by γ-secretase without significantly changing the total level of Αβ peptides produced.
[0008] Accordingly, one aspect of the invention provides compounds of Formula I or II
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof,
wherein:
A is C02H;
Ri is selected from the group consisting of (Ci-C6)alkyl, (C3-Cy)cycloalkyl, -(CH2)0_iOR6 and -(CH2)o_iSR6,
R2 is independently selected from the group consisting of: (a) (Ci-C6)alkyl, (b) (Co- C3)alkyl-(C3-C7)cycloalkyl, (c) a Ci-C6 alkyl that is independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, (d) (C3-C7)cycloalkyl, (e) (Co-C3)alkyl-(C3-C7)cycloalkyl, (f) heterocycloalkylalky, and (g) (CH2)nQ wherein n= 0-2 and wherein Q is a monocyclic or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from the group consisting of alkyl, halogen, CF , OH, OCF , alkoxy, OCH2CH2OCH , NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio and alkylsulfonyl,
wherein each alkyl or cycloalkyl of Ri and R2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF , or C1-C4 alkyl,
Re is selected from the group consisting of H, Ci-C6 alkyl and (C3-C7)cycloalkyl;
each R7 is independently selected from the group consisting of Ci-C6 alkyl, alkoxyethyl, (C3-C7)cycloalkyl, (Co- C3)alkyl-(C3-C7)cycloalkyl, heterocycloalkylalkyl and (CH2)nQ, wherein n= 0-2 and wherein Q is a mono or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C and wherein Q is optionally substituted with up to 3 groups independently selected from the group consisting of alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio and alkylsulfonyl; or in the case when two R7 are attached to the same N and are both alkyl, they can be taken together to form a 5- membered or 6-membered ring optionally containing O, S, N(H) or N-alkyl;
X is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(Ry)-, - CH(R7)0-, - OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, -CH20-,
-CH2OCH2-, - CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-,
-NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and
-N(R7)S(0)2-, wherein the point of attachment of divalent linking groups, X, to R3 in the
Formulas I and II is to the right;
Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -CH(R7)0-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, -CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-, -NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and -N(R7)S(0)2- wherein the point of attachment of divalent linking groups, Y, to R4 in the Formulas I and II is to the right;
R3 is selected from the group consisting of:
(a) Ci-C7 alkyl optionally and independently interrupted by one or more -0-, -S-,
-S(O)-, or -S(0)2- groups,
(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl, and
(d) Z, wherein Z is a mono-or bi-cyclic ring system having 3 to 10 ring atoms
independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6;
R4 is selected from the group consisting of:
(a) Ci-C7 alkyl group optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups,
(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl and (d) Z, wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, Ci-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6; and
R5 is selected from the group consisting of: N02, NH2, aryl, heteroaryl, F, CI, Br, CN, OH, C1-C4 alkoxy, SR6, S(0)2R6, S(0)2N(R7)2, (C C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, -O(C0- C3alkyl)(C3- C7)cycloalkyl and (C2-C4) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, or Ci-C4 alkyl,
provided that one or both of R3 and R4 is Z.
[0009] Another aspect of the invention provides a pharmaceutical composition comprising the compound of the invention, and a pharmaceutically acceptable carrier or excipient.
[0010] Another aspect of the invention provides a method for treating a neurodegenerative disorder comprising administering to a patient and effective amount of the pharmaceutical composition of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention provides an unexpectedly superior class of compounds, Formulas I and II, with improved metabolic stability, as well as methods for preparing the compounds, and methods of using the compounds to treat one or more symptoms of Alzheimer's disease.
[0012] The present invention, including compounds, methods, and pharmaceutical
compositions will be described with reference to the following definitions that, for convenience, are set forth below. Unless otherwise specified, the below terms used herein are defined as follows:
I. Definitions
[0013] Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic Ci-Cs hydrocarbon, unless some other number of carbon atoms is specified. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and, in the case of a double bond, both cis and trans isomers are included. An optionally substituted alkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, OH, (Ci- C4)alkoxy, (C3-Ce)cycloalkyloxy, (Ci-C4)alkylthio, (C3-C6)cycloalkylthio-, -C(0)NH2, - C(0)NH(Ci-C4)alkyl, -C(0)N[(Ci-C4)alkyl(Ci-C4)alkyl], (C1-C4 alkyl)-C(O)-, (Ci- C4)alkylsulfonyl-, -S(0)2NH2, -S(0)2NH(Ci-C4)alkyl and-S(0)2N[(Ci-C4)alkyl(Ci-C4)alkyl]. Examples of alkyl groups include, but are not limited to, methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans- 2-butenyl, isobutenyl and propargyl. Ci-C4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms. In other cases, an optionally substituted alkyl can be independently substituted with one or more substituents selected from the group consisting of F, OH, oxo and (Ci-C )alkoxy. In other cases, an optionally substituted alkyl can be independently substituted with up to three fluorines.
[0014] In each case in which a size range for the number of atoms in a ring or chain is disclosed, all subsets are disclosed. Thus, Cx-Cy includes all subsets, e.g., Ci-C4 includes Ci-C2, C2-C4, and C1-C3 as well as Ci, C2, C3 and C4.
[0015] Acyl is an alkyl-C(O)- group wherein alkyl is as defined above. Examples of acyl groups include acetyl and proprionyl.
[0016] Alkoxy is an alkyl-O- group wherein alkyl is as defined above. Ci-C4 alkoxy is the subset of alkyl-O- where the subset of alkyl is limited to a total of up to 4 carbon atoms. Examples of alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy.
[0017] Alkoxyalkyl is an alkyl-0-(Ci-C4 alkyl)- group wherein alkyl is as defined above. Examples of alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
[0018] Alkoxyalkyloxy is an alkoxy-alkyl-O- group wherein alkoxy and alkyl are as defined above. Examples of alkoxyalkyloxy groups include methoxymethyloxy (CH30CH20-) and methoxyethyloxy (CH3OCH2CH20-) groups.
[0019] Alkylthio is alkyl-S- group wherein alkyl is as defined above. Ci-C4 alkylthio is the subset of alkyl-S- where the subset of alkyl is limited to a total of up to 4 carbon atoms.
[0020] Alkylsulfonyl is alkyl-S02- wherein alkyl is as defined above. Examples of alkylsulfonyl groups include methanesulfonyl and isopropylsufonyl.
[0021] Alkylamino is alkyl -NH- wherein alkyl is as defined above.
[0022] Dialkylamino is (alkyl)2-N- wherein alkyl is as defined above.
[0023] Amido is H2NC(0)-.
[0024] Alkylamido is alkyl -NHC(O)- wherein alkyl is as defined above.
[0025] Dialkylamido is (alkyl)2-NC(0)- wherein alkyl is as defined above. [0026] Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.
[0027] Aryl is a phenyl or napthyl group. An optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF3, CN, OH, (Ci-C4)alkoxy, (Ci-C4)alkylthio, (C3-Cv)cycloalkylthio, (C3-Cy)cycloalkyloxy, aryloxy, (Ci- C4)alkoxy(Ci-C4)alkyloxy, hetero(C3-C7)cycloalkyloxy, heteroaryloxy, -OC(0)Ra, -OC(0)NHRa, - OC(0)N(Ra)(Rb), -S(0)Ra, -NHRa, -N(Ra)(Rb), -NHC(0)Ra, -N(Ra)C(0)Rb, -NHC(0)ORa, -N(Ra)C(0)ORb, -N(Ra)-C(0)-NH(Rb), -N(Ra)-C(0)-N(Rb)2, -C(0)NH2, -C(0)NHRa,
-C(0)N(Ra)(Rb), -C02H, -C02Ra, -CORa and Rc, wherein Ra, Rb and R, are independently selected from the group consisting of (Ci-C6)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, -CH2CH2OH, - CH2CH2OMe, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C4)alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero(C3- C7)cycloalkyl and hetero(C3-C7)cycloalkyl(Ci-C4)alkyl, each of which is optionally and independently substituted with up to three groups selected from the group consisting of halogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3- C7)cycloalkylalkoxy, CN, CHF2, CF3, CH2CF3, NHMe, NMe2, piperidnyl, morpholinyl, N-Me- piperazinyl, piperazinyl, OCF , OCHF2, OCH2CF , and SMe, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds, and none of which are substituted; or Ra and R, taken together with the atom(s) to which they are attached form a 5-6 membered ring. In other cases, an optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF , CN, (Ci- C6)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (C3-C7)cycloalkylthio, (C3-C7)cycloalkyloxy, hetero(C3- C7)cycloalkyl, C(0)NH2, -C(0)NHRa and -C(0)N(Ra)(Rb) wherein Ra and Rb are defined as above. In further cases, an optionally substituted aryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF , CN, (Ci-C6)alkyl, (C3- C7)cycloalkyl, (C3- C7)cycloalkyloxy and hetero(C3-C7)cycloalkyl.
[0028] Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.
[0029] Aryloxy is an aryl-O- group wherein aryl is as defined above.
[0030] Arylalkoxy is an aryl-(Ci-C4 alkyl)-0- group wherein aryl is as defined above. Carboxy is a C02H or C02Rj group wherein Rd is independently selected from (Ci-C6)alkyl, (C3- C7)cycloalkyl, aryl(Ci-C3)alkyl, (C3-C7)cycloalkyl(Ci-C3)alkyl, and alkoxyalkyl, wherein alkyl is as defined above.
[0031] Cycloalkyl is a C3-C7 cyclic non-aromatic hydrocarbon which may contain a single double bond. An optionally substituted cycloalkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, OH, (Ci-C6)alkyl, (Ci-C4)alkoxy, - (C3-C7)cycloalkyl, (C3-C7)cycloalkylalkyl, (C3-C7)cycloalkyloxy, (Ci-C4)alkylthio, (C3- C6)cycloalkylthio-, -C(0)NH2, -C(0)NH(Ci-C4)alkyl, -C(0)N[(Ci-C4)alkyl(Ci-C4)alkyl], (C1-C4 alkyl)-C(O)-, (Ci-C4)alkylsulfonyl-, -S(0)2NH2, -S(0)2NH(Ci-C4)alkyl and-S(0)2N[(Ci- C4)alkyl(Ci-C4)alkyl]. In other cases, an optionally substituted cycloalkyl can be independently substituted with one or more substituents selected from the group consisting of F, oxo, (Ci- C4)alkoxy, (C3-C7)cycloalkyl, -C(0)NH(Ci-C4)alkyl, -C(0)N[(Ci-C4)alkyl(Ci-C4)alkyl], (C1-C4 alkyl)-C(O)-, (Ci-C4)alkylsulfonyl-, -S(0)2NH(C C4)alkyl and -S(0)2N[(Ci-C4)alkyl(Cr
C4)alkyl]. In further cases, an optionally substituted cycloalkyl can be independently substituted with one substituent selected from the group consisting of oxo, OH, (Ci- C6)alkyl, (Ci-C4)alkoxy, (C3-C7)cycloalkylalkyl, (C3-C7)cycloalkyloxy, (Ci-C4)alkylthio, (C3- C6)cycloalkylthio-,
-C(0)NH2, -C(0)NH(Ci-C4)alkyl, -C(0)N[(Ci-C4)alkyl(Ci-C4)alkyl], (C1-C4 alkyl)-C(O)-, (Ci- C4)alkylsulfonyl-, -S(0)2NH2, -S(0)2NH(Ci-C4)alkyl and-S(0)2N[(Ci- C4)alkyl(Ci-C4)alkyl].
[0032] Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
[0033] Cycloalkyloxy is a cycloalkyl-O- group wherein cycloalkyl is as defined above.
Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C3-C6 cycloalkyloxy is the subset of cycloalkyl-O- where cycloalkyl contains 3-6 carbon atoms.
[0034] Cycloalkylthio is a cycloalkyl-S- group wherein cycloalkyl is as defined above.
Examples include cyclopropylthio, cyclobutylthio and cyclopentylthio.
[0035] Cycloalkylalkyl is a cycloalkyl-(Ci-C4alkyl)- group. Examples include
cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
[0036] Cycloalkylalkoxy is a cycloalkyl-(Ci-C4 alkyl)-0- group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
[0037] Cycloalkylalkylthio is a cycloalkyl-(Ci-C4)alkyl-S- group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkylthio groups include cyclopropylmethanethio, cyclobutylmethanethio and cyclopentylmethanethio.
[0038] Halogen is F, CI, Br or I. Preferred halogens are F, CI and Br.
[0039] A heteroaryl group can be: (a) a tetrazole, (b) 1,2,3,4-oxatriazole, (c) 1,2,3,5- oxatriazole, or (d) a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C.
Examples of heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and
benzimidazolyl. An optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF3, CN, OH, (Ci-C4)alkoxy, (Ci- C4)alkylthio, (C3-Cv)cycloalkylthio, (C3-Cy)cycloalkyloxy, aryloxy, (Ci-C4)alkoxy(Ci- C4)alkyloxy, hetero(C3-C7)cycloalkyloxy, heteroaryloxy, -OC(0)Ra, - OC(0)NHRa,
-OC(0)N(Ra)(Rb), -S(0)Ra, -NH2, -NHRa, -N(Ra)(Rb), -NHC(0)Ra, -N(Ra)C(0)Rb, -NHC(0)ORa, -N(Ra)C(0)ORb, -N(Ra)-C(0)-NH(Rb), -N(Ra)-C(0)-N(Rb)2, - C(0)NH2, -C(0)NHRa,
-C(0)N(Ra)(Rb), -C02H, -C02Ra, -CORa and R, wherein Ra, Rb and R, are independently selected from the group consisting of (Ci-C6)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, -CH2CH2OH,
-CH2CH2OMe, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C4)alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero(C3-C7)cycloalkyl and hetero(C3-C7)cycloalkyl(Ci-C4)alkyl, each of which is optionally and independently substituted with up to three groups selected from the group consisting of halogen, (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3- C7)cycloalkylalkoxy, CN, N02, NH2, CHF2, CF3, CH2CF3, NHMe, NMe2, piperidnyl, morpholmyl, N-Me-piperazinyl, piperazinyl, OCF3, OCHF2, OCH2CF3 and SMe, each of which are attached via carbon-carbon or carbon- nitrogen or carbon-oxygen single bonds, and none of which are substituted; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring. In other cases, an optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF3, CN, (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (C3- C7)cycloalkylthio, (C3-C7)cycloalkyloxy, hetero(C3-C7)cycloalkyl, C(0)NH2, -C(0)NHRa and -C(0)N(Ra)(Rb), wherein Ra and Rb are defined as above. In further cases, an optionally substituted heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen CF3, CN, (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyloxy and hetero(C3- C7)cycloalkyl.
[0040] Heteroarylalkyl is a heteroaryl-(Ci-C4 alkyl)- group wherein heteroaryl and alkyl are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethyl and 4- pyridinylethyl.
[0041] Heteroaryloxy is a heteroaryl-0 group wherein heteroaryl is as defined above.
[0042] Heteroarylalkoxy is a heteroaryl-(Ci-C4 alkyl)-0- group wherein heteroaryl and alkoxy are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethoxy and 4- pyridinylethoxy.
[0043] Heterobicyclic ring system is a bicyclic ring system having 8-10 atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic. An optionally substituted heterobicyclic ring system can be independently substituted with one or more substituents selected from the group consisting of (Ci-C6)alkyl, (Ci-C4)alkoxy, (C3- Cy)cycloalkyl, (C3-Cy)cycloalkyloxy, (C3-Cy)cycloalkyl(Ci-C3)alkyl, halogen, alkylsulfonyl and cyano. In other cases, an optionally substituted heterobicyclic ring system can be independently substituted with one or more substituents selected from the group consisting of (Ci-C6)alkyl, (C3- Cy)cycloalkyl, (C3-Cy)cycloalkyloxy, halogen and cyano. Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, l,2,3,4-tetrahydro-l,5- naphthyridyl, 1,6-naphthyridyl, l,2,3,4-tetrahydro-l,6- naphthyridyl 1 ,7-naphthyridyl, 1,2,3,4- tetrahydro-l,7-naphthyridinyl, 1,8-naphthyridyl, 1,2,3,4- tetrahydro-l,8-naphthyridyl, 2,6- naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl, benzo[<i][l,2,3]triazyl, benzo[e][l,2,4]triazyl, pyrido[2,3-£]pyrazyl, pyrido[2,3-c]pyridazyl, pyrido[2,3-d]pyrimidyl, pyrido[3,2-£]pyrazyl, pyrido[3,2-c]pyridazyl, pyrido[3,2-d]pyrimidyl, pyrido[3,4-£]pyrazyl, pyrido[3,4-c]pyridazyl, pyrido[3,4-d]pyrimidyl, pyrido[4,3-£]pyrazyl, pyrido[4,3-c]pyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl, 1H- benzo[<i][l,2,3]triazoyl, lH-benzo[d]imidazoyl, 1H- indazoyl, lH-indoyl, 2H- benzo[<i][l,2,3]triazoyl, 2H-pyrazolo[3,4-£]pyridinyl, 2H- pyrazolo[4,3-£]pyridinyl,
[1 ,2,3]triazolo[l ,5-a]pyridinyl, [1 ,2,4]triazolo[l ,5-a]pyridinyl, [1 ,2,4]triazolo[4,3-a]pyridinyl, benzo[¾]thienyl, benzo[c][l,2,5]oxadiazyl, benzo[c][l,2,5]thiadiazolyl, benzo[<i]isothiazoyl, benzo[<i]isoxazoyl, benzo[<i]oxazoyl, benzo[<i]thiazoyl, benzofuryl, imidazo[l,2-a]pyrazyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-a]pyrimidyl, imidazo[l,2-£]pyridazyl, imidazo[l,2- c]pyrimidyl, imidazo[l,5-a]pyrazyl, imidazo[l,5-a]pyridinyl, imidazo[l,5-a]pyrimidyl, imidazo[l,5-¾]pyridazyl, imidazo[l,5- c]pyrimidyl, indolizyl, pyrazolo[l,5-a]pyrazyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrimidyl, pyrazolo[l,5-£]pyridazine, pyrazolo[l,5- c]pyrimidine, pyrrolo[l,2-a]pyrazine, pyrrolo[l,2-a]pyrimidyl, pyrrolo[l,2-£]pyridazyl, pyrrolo[l,2-c]pyrimidyl, lH-imidazo[4,5- £]pyridinyl, lH-imidazo[4,5-c]pyridinyl, 1H- pyrazolo[3,4-£]pyridinyl, lH-pyrazolo[3,4-c]pyridinyl, lH-pyrazolo[4,3-£]pyridinyl, 1H- pyrazolo[4,3-c]pyridinyl, lH-pyrrolo[2,3-£]pyridinyl, lH-pyrrolo[2,3-c]pyridinyl, 1H- pyrrolo[3,2-£]pyridinyl, lH-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl, 3H-imidazo[4,5-£]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, benzo[c]isothiazyl, benzo[c]isoxazyl, furo[2,3-£]pyridinyl, furo[2,3- c]pyridinyl, furo[3,2-¾]pyridinyl, furo[3,2-c]pyridiyl, isothiazolo[4,5-£]pyridinyl, isothiazolo[4,5- c]pyridinyl, isothiazolo[5,4-£]pyridinyl, isothiazolo[5,4-c]pyridinyl, isoxazolo[4,5-£]pyridinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[5,4-£]pyridinyl, isoxazolo[5,4-c]pyridinyl, oxazolo[4,5- £]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-£]pyridinyl, oxazolo[5,4-c]pyridinyl, thiazolo[4,5-£]pyridiyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-£]pyridinyl, thiazolo[5,4- c]pyridinyl, thieno[2,3-¾]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-¾]pyridinyl and thieno[3,2- c]pyridinyl.
[0044] Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from the group consisting of C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C. An optionally substituted heterocycloalkyl can be independently substituted on a carbon atom with one or more substituents selected from the group consisting of OH, (Ci-C6)alkyl and (Ci-C4)alkoxy groups and up to two oxo groups. In the case where the heterocycloalkyl group contains a nitrogen, an optionally substituted heterocycloalkyl can be independently substituted on said nitrogen with one or more substituents selected from the group consisting of (Ci-C6)alkyl, acyl, -C(0)0-(Ci-C4)alkyl, -C(0)NH-(Ci-C4)alkyl and a -C(0)N((C1-C4)alkyl)2 group. Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms. Examples of heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N- methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5- diazabicyclo[2.2.2]octanyl, 2,5- diazabicyclo[2.2.1]heptanyl, octahydro-lH-pyrido[l,2-a]pyrazine, 3- thia-6- azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl.
[0045] Heterocycloalkylalkyl is a heterocycloalkyl-(Ci-C4 alkyl)- group wherein
heterocycloalkyl and alkyl are as defined above.
[0046] Heterocycloalkyloxy is a heterocycloalkyl-O- group wherein heterocycloalkyl is as defined above.
[0047] Heterocycloalkylalkoxy is a heterocycloalkyl-(Ci-C4 alkyl)-0- group wherein heterocycloalkyl and alkyl are as defined above.
[0048] Oxo is a -C(O)- group.
[0049] Phenyl is a benzene ring. An optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF3, CN, OH, (Ci-C4)alkoxy, (Ci-C4)alkylthio, (C3-Cv)cycloalkylthio, (C3-Cy)cycloalkyloxy, aryloxy, (Ci- C4)alkoxy(Ci- C4)alkyloxy, hetero(C3-C7)cycloalkyloxy, heteroaryloxy, -OC(0)Ra, -OC(0)NHRa, -OC(0)N(Ra)(Rb), -S(0)Ra, -NHRa, -N(Ra)(Rb), -NHC(0)Ra, -N(Ra)C(0)Rb, -NHC(0)ORa, -N(Ra)C(0)ORb, -N(Ra)-C(0)-NH(Rb), -N(Ra)-C(0)-N(Rb)2, -C(0)NH2, -C(0)NHRa,
-C(0)N(Ra)(Rb), -C02H, -C02Ra, -CORa and Rc wherein Ra, Rb and Rc are independently selected from the group consisting of (Ci-C6)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, -CH2CH2OH,
-CH2CH2OMe, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C4)alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero(C3-C7)cycloalkyl and hetero(C3-C7)cycloalkyl(Ci-C4)alkyl, each of which is optionally and independently substituted with up to three groups selected from the group consisting of halogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3- C7)cycloalkylalkoxy, CN, N02, NH2, CHF2, CF3, CH2CF3, NHMe, NMe2, piperidnyl, morpholinyl, N-Me-piperazinyl, piperazinyl, OCF3, OCHF2, OCH2CF3 and SMe, each of which are attached via carbon-carbon or carbon-nitrogen or carbon- oxygen single bonds, and none of which are substituted; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring. In other cases, an optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen CF3j CN, (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, (C3-C7)cycloalkylthio, (C3- C7)cycloalkyloxy, hetero(C3- C7)cycloalkyl, C(0)NH2, -C(0)NHRa and -C(0)N(Ra)(Rb), wherein Ra and Rb are defined as above. In further cases, an optionally substituted phenyl can be independently substituted with one or more substituents selected from the group consisting of halogen, CF3, CN, (Ci- C6)alkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyloxy and hetero(C3-C7)cycloalkyl.
[0050] Restricted phenyl is an optionally substituted benzene ring which can be independently substituted with up to three groups selected from the group consisting of halogen, CF3j CN, (Ci- C4)alkoxy, (Ci- C4)alkylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkyloxy, (Ci-C4)alkoxy(Ci- C4)alkyloxy, hetero(C3-C7)cycloalkyloxy, -OC(0)NHRa, -OC(0)N(Ra)(Rb), -C(0)NH2, -C(0)NHRa, - C(0)N(Ra)(Rb), -CORa and R, wherein Ra, Rb and Rc are independently selected from the group consisting of (Ci- C6)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl, -CH2CH2OH,
-CH2CH2OMe, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl(C1-C4)alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero(C3-Cy)cycloalkyl and hetero(C3-Cy)cycloalkyl(Ci-C4)alkyl, each of which is optionally and independently substituted with up to three groups selected from the group consisting of halogen, (Ci-C6)alkyl, (C3-Cy)cycloalkyl, (C3- Cy)cycloalkyloxy, (C3-
Cy)cycloalkylalkoxy, CN, CHF2, CF3, CH2CF3, piperidnyl, morpholinyl, N-Me-piperazinyl, piperazinyl, OCF3, OCHF2, OCH2CF3 and SMe, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds, and none of which are substituted; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
[0051] Abbreviations used in the following examples and preparations include:
Αβ Amyloid-beta
ABL Αβ lowering
Ac acyl (Me-C(O)-)
AD Alzheimer's Disease
APP Amyloid Precursor Protein
Bn Benzyl
b/p brain/plasma
BSA Bovine serum Albumin
c Cyclo
calcd. Calculated
cBu Cylcobutyl
c-Bu Cylcobutyl
Cmax Maximal concentration
cPr Cyclopropyl
c-Pr Cyclopropyl
CHAPS 3-[3-cholamidopropyl)-dimethyl-ammonio]-l -propane sulfonate
CTF Carboxy Terminal Fragment
CSF Cerebrospinal fluid
DAPT N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-l,l- dimethylethyl ester
DCC N.N', Dicyclohexylcarbodiimide
DEA Di-ethylamine DIEA Di-isopropylethyl amine
DMAP 4-Dimethylamino Pyridine
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
Dppf 1 ,4-Bis(diphenylphosphino) ferrocene
EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
EDTA Ethylene Diamine Tetra- Acetic Acid
ELISA Enzyme-Linked Immuno Sorbent Assay
Et?N Triethylamine
Eq. Equivalent
g gram(s)
HOBt 1-Hydroxybenzotriazole
HPLC High Pressure Liquid Chromatography
h Hour(s)
hr Hour(s)
i.v. or IV. Intravenous
KHMDS Potassium Hexamethydisilazide
LC-MS Liquid Chromatography-Mass Spectrometry
LDA Lithium Di-isopropylamide
m Multiplet
MeOH Methyl Alcohol or Methanol
m meta
mcpba meto-chloro perbenzoic acid
min Minute(s)
mmol millimoles
mmole millimoles
ul Microliter
μΐ Microliter
Ms Mesylate
MS Mass Spectrometry
MW Molecular Weight (all values are ±0.05)
n normal NBS N-Bromosuccinimide
NCS N-Chlorosuccinimide
NIS N-Iodosuccinimide
NMR Nuclear Magnetic Resonance
NMM N-Methyl Morpholine
NSAIDS Non-Steroidal Anti-Inflammatory Drugs
o ortho
o/n overnight
p para
PBS Phosphate Buffered Saline
PEPPSI l ,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl) palladium(II) dichloride
PhNTf2 1, 1,1-trifluoro-N-phenyl-N-
(trifluoromethylsulfonyl)methanesulfonamide
POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp) palladate (2-) p.s.i. Pounds per square inch
PPAA 1 -Propanephosphonic Acid Cyclic Anhydride
PyBOP® Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate
P Pharmacokinetics
RT (or rt) room temperature (about 20-25°C)
s Singlet
sat. Saturated
sec secondary
t Triplet
tert tertiary
TBAF Tetra-butyl ammonium fluoride
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
TMB 3,3' 5, 5' Tetramethylbenzidine
TMS Trimethylsilyl
Tf Triflate Ts Tosylate
v/v volume/volume
wt/v weight/volume
II. Compounds
[0052] In one embodiment, the invention provides compounds of Formula I or II
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is C02H;
Ri is selected from the group consisting of (Ci-C6)alkyl (e.g., (Ci-C3)alkyl), (C3- C7)cycloalkyl, -(CH2)0_iOR6 and -(CH2)0-iSR6;
R2 is independently selected from the group consisting of: (a) (Ci-C6)alkyl, (b) (Co- C3)alkyl-(C3-C7)cycloalkyl, (c) a Ci-C6 alkyl that is independently interrupted by one or more - 0-, -S-, -S(O)-, or -S(0)2- groups, (d) (C3-C7)cycloalkyl, (e) (C0-C3)alkyl-(C3-C7)cycloalkyl, (f) heterocycloalkylalky, and (g) (CH2)nQ wherein n= 0-2 and wherein Q is a monocyclic or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from the group consisting of alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio and alkylsulfonyl,
wherein each alkyl or cycloalkyl of Ri and R2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, or C1-C4 alkyl;
Re is selected from the group consisting of H, Ci-C6 alkyl and (C3-C7)cycloalkyl;
each R7 is independently selected from the group consisting of Ci-C6 alkyl, alkoxyethyl, (C3-C7)cycloalkyl, (C0- C3)alkyl-(C3-C7)cycloalkyl, heterocycloalkylalkyl and (CH2)nQ, wherein n= 0-2 and wherein Q is a mono or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C and wherein Q is optionally substituted with up to 3 groups independently selected from the group consisting of alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio and alkylsulfonyl; or in the case when two R7 are attached to the same N and are both alkyl, they can be taken together to form a 5- membered or 6-membered ring optionally containing O, S, N(H) or N-alkyl;
X is a bond or a divalent linking group selected from the group consisting of -0-,
-OCH2-, -OCH(R7)-, - CH(R7)0-, - OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-,
-CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-,
-C(0)N(R7)-, -NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-,
-N(H)S(0)2- and -N(R7)S(0)2- wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right;
Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7), -CH(R7)0-,-OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, -CH20-, -CH2OCH2-, -CH2CH20-, -S-, - SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-, -NHC(O)-, -N(R7)C(0)- , -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and -N(R7)S(0)2- wherein the point of attachment of divalent linking groups, Y, to R4 in the Formulas I and II is to the right;
R3 is selected from the group consisting of:
(a) Ci-C7 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0)2- groups,
(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl, and
(d) Z, wherein Z is a mono-or bi-cyclic ring system having 3 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRe, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6;
R4 is selected from the group consisting of:
(a) Ci-C7 alkyl group optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, (b) (Co-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl, and
(d) Z, wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R^, CF3, CN, N02, OH, Ci-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6; and
R5 is selected from the group consisting of N02, NH2, aryl, heteroaryl, F, CI, Br, CN, OH, C1-C4 alkoxy, SR6, S(0)2R6 or S(0)2N(R7)2, (C1-C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, -0(Co-C3alkyl)(C3-C7)cycloalkyl and (C2-C4) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl,
provided that one or both of R3 and R4 is Z.
[0053] In certain embodiments of the invention, Ri is (Ci-C6)alkyl or (C3-C7)cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C6)alkyl or (C3-C7)cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C6)alkyl. In certain embodiments of the invention, Ri is (Ci-C3)alkyl. In certain embodiments of the invention, Ri is methyl or ethyl. In certain
embodiments of the invention, Ri is -SR5 or -OR5 (e.g., wherein 5 is (Ci- C3)alkyl)).
[0054] In certain embodiments of the invention, R2 is -(Co-C3)alkyl-(C3-C7)cycloalkyl.
[0055] In certain embodiments of the invention, R2 is -(C3-C7)cycloalkyl or -CH2-(C3- C7)cycloalkyl.
[0056] In certain embodiments of the invention, R2 is cyclopentyl, cyclopropylmethyl, or cyclobutylmethyl .
[0057] In one embodiment X is a bond. In another embodiment X is a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, - CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-, - NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and -N(R7)S(0)2-, wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right. In another embodiment X is -0-, -OCH2-, -OCH(R7)-, -CH20-, -S-, -S(0)2-, - S(0)2N(H)-, -S(0)2N(R7)-, -C(0)NH- or -C(0)N(R7)-. In a further embodiment X is -0-, - S(0)2-, -S(0)2N(H)- or -S(0)2N(R7)-. In another embodiment X is -O- or -S(0)2-.
[0058] In one embodiment Y is a bond. In another embodiment Y is a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, - CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-, - NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and -N(R7)S(0)2-, wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right. In another embodiment Y is -0-, -OCH2-, -OCH(R7), -CH20-, -S-, -S(0)2-, -S(0)2N(H)-, -S(0)2N(R7)-, -C(0)NH- or -C(0)N(R7)-. In a further embodiment Y is -0-, -S(0)2-, -S(0)2N(H)- or -S(0)2N(R7)-. In another embodiment Y is -O- or -S(0)2-.
[0059] In one embodiment R3 is a Ci-C7 alkyl group optionally interrupted by -0-, -S-, -S(O)-, or -S(0)2- groups. In another embodiment R3 is a Ci-C7 alkyl group. In a further embodiment R3 is a C1-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R3 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0060] In another embodiment R3 is heterocycloalkylalkyl. In another embodiment R3 is a group Z as defined above wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SR6, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6, N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02Re and COR6. In the latter embodiment Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono-or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.
[0061] In one embodiment R4 is a C1-C7 alkyl group optionally interrupted by -0-, -S-, -S(O)-, or -S(0)2- groups. In another embodiment R4 is a C1-C7 alkyl group. In a further embodiment R4 is a Ci-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R4 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In another embodiment R4 is heterocycloalkylalkyl. In another embodiment R4 is a group Z as defined above wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, CrC4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SR6, S(0)R6, S(0)2R6, S(0)2NHR7,
S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6,
N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6. In the latter embodiment Z comprises mono-or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono-or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.
[0062] Other embodiments include compounds of Formulas III, IV, V, and VI and pharmaceutically acceptable salts thereof wherein Rls R2, R3, R4, R5, X, Y and Z are as defined above.
Figure imgf000022_0001
[0063] Other embodiments include compounds of Formulas VII, VIII, IX, and X and pharmaceutically acceptable salts thereof wherein Rls R2, R3, R4 R5, X, Y and Z are as defined above.
Figure imgf000023_0001
[0064] Other embodiments include compounds of Formulas III, IV, V, and VI wherein R2, R3, R4, R5, X, Y and Z are as defined above and Ri is methyl or ethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R3, R4, R5 and Z are as defined above; Ri is methyl or ethyl and R2 is -(C0-C3)alkyl-(C3-C7)cycloalkyl.
[0065] Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, - 0-, -OCH2-, -C(O)-, -S-, -S(0)2-, -S(0)2N(R7)- and -N(R7)S(0)2-. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -0-, -S(0)2- and -S(0)2N(R7). Another embodiment comprises compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -O- and S(0)2N(R7). A further embodiment comprises compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4, R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond and -0-.
[0066] Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently selected from the group consisting of a Ci-C7 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0)2- groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R5, Z are as defined above and X, Y and are independently selected from the group consisting of a bond, -S-, -S02- and -O- and R3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a group Z wherein Z is as defined above.
[0067] Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 and R5, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SR6, S(0)R6, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6, N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6, and CORg. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 and R5, X and Y are as
defined above, and Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms
independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SR6, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6, N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6, and CORg.
[0068] Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 X, Y and Z are as defined above and R5 is N02, NH2 , F, CI, Br, CN, OH, C1-C4 alkoxy, SR6, S(0)2R6 or S(0)2N(R7)2. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 X, Y and Z are as defined above and R5 is aryl or heteroaryl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R3, R4 X, Y and Z are as defined above and R5 is chlorine or fluorine.
[0069] Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R2, R3, R4, R5, X, Y and Z are as defined above and Ri is hydrogen. Other embodiments include compounds of Formulas VII, VIII, ΓΧ, and X wherein R3, R4, R5 and Z are as defined above; Ri is methyl or ethyl and R2 is -(Co-C3)alkyl-(C3-C7)cycloalkyl.
[0070] Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, - 0-, -OCH2-, -C(O)-, -S-, -S(0)2-, -S(0)2N(R7)- and -N(R7)S(0)2-. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -0-, -S(0)2- and -S(0)2N(R7). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond, -O- and S(0)2N(R7). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, and Z are as defined above and X and Y are independently selected from the group consisting of a bond and -0-.
[0071] Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently selected from the group consisting of a Ci-C7 alkyl, optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0)2- groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R5, Z are as defined above and X, Y and are independently selected from the group consisting of a bond, -S-, -S02- and -O- and R3 and R4 and are independently selected from the group consisting of C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a group Z wherein Z is as defined above.
[0072] Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, Ci-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SR6, S(0)Rs, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6, N(R7)C(0)NH(R7),
N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and CORg. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R3, R4 and R5, X and Y are as defined above, and Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing ring bearing up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, Ci-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6,
OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2R6, S(0)2NHR7,
S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)Rs, NHC(0)ORs, N(R7)C(0)ORs,
N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6.
[0073] Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R4 X, Y and Z are as defined above and R5 is N02, NH2 , F, CI, Br, CN, OH, C 1-C4 alkoxy, SR6, S(0)2R6 or S(0)2N(R7)2. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R4 X, Y and Z are as defined above and R5 is aryl or heteroaryl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein Rls R2, R4 X, Y and Z are as defined above and R5 is chlorine or fluorine.
[0074] The compounds of formulas I - IX are expected to alter the activity of γ-secretase and are expected to be useful for the treatment of Alzheimer's disease and other neurodegenerative disorders.
[0075] In another embodiment A is C02H. In another embodiment a compound of formula (I) is selected. In another embodiment a compound of formula (II) is selected.
[0076] In another embodiment a compound of formula (III) is selected. In another embodiment a compound of formula (IV) is selected. In another embodiment a compound of formula (V) is selected. In another embodiment a compound of formula (VI) is selected. In another embodiment a compound of formula (VII) is selected. In another embodiment a compound of formula (VIII) is selected. In another embodiment a compound of formula (IX) is selected.
[0077] In certain embodiments of the invention, Ri is (Ci-C6)alkyl and R2 is (Co-C3)alkyl-(C3- C7)cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C6)alkyl and R2 is -(C3- C7)cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C6)alkyl and R2 is -CH2-(C3- C7)cycloalkyl. In certain embodiments of the invention, Ri is (Ci-C3)alkyl. In certain
embodiments of the invention, Ri is methyl or ethyl. In certain embodiments of the invention, R2 is cyclopentyl. In certain embodiments of the invention, R2 is cyclopentyl, cyclopropylmethyl, or cyclobutylmethyl. In certain embodiments of the invention, Ri is -SCH3 and R2 is -CH2-(C3- Cv)cycloalkyl. In another embodiment Ri is selected from the group consisting of (Ci-C6)alkyls, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.
[0078] In another embodiment Ri is selected from: the group consisting of n-propyl, iso- propyl, iso-butyl, n-butyl, iso- pentyl, and n-pentyl wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 or alkyl.
[0079] In another embodiment Ri is n-propyl. In another embodiment Ri is iso-butyl. In another embodiment Ri is n-butyl. In another embodiment Ri is iso-pentyl. In another embodiment Ri is n-pentyl.
[0080] In another embodiment R2 is chosen from (Co-C3)alkyl-(C3-Cy)cycloalkyls wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, or C1-C4 alkyl.
[0081] In another embodiment R2 is selected from the group consisting of cyclopentyl, cyclopropylmethyl and cyclobutylmethyl. In another embodiment R2 is cyclopentyl. In another embodiment R2 is cyclopropylmethyl. In another embodiment R2 is cyclobutylmethyl.
[0082] In another embodiment R6 is Ci-C6 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, (C3-C7)cycloalkyl, (C4-C8) cycloalkylalkyl, or heterocycloalkylalkyl. In another embodiment R^ is Ci-C6 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups.
[0083] In another embodiment R^ (C3-C7)cycloalkyl. In another embodiment R^ is a (Co- C3)alkyl-(C3-C7)cycloalkyl. In another embodiment R6 heterocycloalkylalkyl. In another embodiment R6 is (CH2)nQ. In another embodiment R^ is -CH2-Q. In another embodiment Q is aryl. In another embodiment Q is heteroaryl. In another embodiment Q is monocyclic heteroaryl. In another embodiment Q is bicyclic heteroaryl. In another embodiment X is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-,-OCH(R7)-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, -CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S- and -CH2SCH2-.
[0084] In another embodiment X is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -OCH2CH2-,-CH20-, -CH2OCH2- and
-CH2CH20.
[0085] In another embodiment X is a bond or a divalent linking group selected from the group consisting of -CH2-, -C(O)-, -CH=CH- and -CH2CH2-.
[0086] In another embodiment X is a bond or a divalent linking group selected from the group consisting of -S-, -SCH2-, -CH2S- and -CH2SCH2-.
[0087] In another embodiment X is a bond or a divalent linking group selected from the group consisting of -O- and -S-.
[0088] In another embodiment X is a bond.
[0089] In another embodiment X is the divalent linking group -0-.
[0090] In another embodiment X is the divalent linking group -S-.
[0091] In another embodiment Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, - CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S- and -CH2SCH2-.
[0092] In another embodiment Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7)-, -OCH2CH2-, -CH20-, -CH2OCH2- and -CH2CH20.
[0093] In another embodiment Y is a bond or a divalent linking group selected from the group consisting of -CH2-, -C(O)-, - CH=CH- and -CH2CH2-.
[0094] In another embodiment Y is a bond or a divalent linking group selected from the group consisting of -S-, -SCH2-, -CH2S- and -CH2SCH2-.
[0095] In another embodiment Y is a bond or a divalent linking group selected from the group consisting of -O- and -S-.
[0096] In another embodiment Y is a bond.
[0097] In another embodiment Y is the divalent linking group -0-.
[0098] In another embodiment Y is the divalent linking group -S-.
[0099] In another embodiment R3 is a C1-C4 alkyl group.
[0100] In another embodiment R3 is a Ci-C3 alkyl group.
[0101] In another embodiment R3 is a C2-C3 alkyl group.
[0102] In another embodiment R3 is selected from the group consisting of ethyl, n-propyl, iso-propyl, trifluoroethyl and trifluoropropyl.
[0103] In another embodiment R3 is ethyl.
[0104] In another embodiment R3 is n-propyl.
[0105] In another embodiment R3 is iso-propyl.
[0106] In another embodiment R3 is trifluoroethyl.
[0107] In another embodiment R3 is trifluoropropyl. [0108] In another embodiment R3 is a (C4-C10) cycloalkylalkyl group.
[0109] In another embodiment R3 is a (Co-C3)alkyl-(C3-Cy)cycloalkyl group.
[0110] In another embodiment R3 is a (C3-C7) cycloalkyl group.
[0111] In another embodiment R3 is a (Ci-C3)alkyl-(C3-C7) cycloalkyl group.
[0112] In another embodiment R3 is a (Ci)alkyl-(C3-C7) cycloalkyl group.
[0113] In another embodiment R3 is a (Ci)alkyl-(C3-C4) cycloalkyl group.
[0114] In another embodiment R3 is a cyclopropylmethyl group.
[0115] In another embodiment R3 is a cyclobutylmethyl group.
[0116] In another embodiment R3 is heterocycloalkylalkyl group.
[0117] In another embodiment R3 is represented by the group Z as defined herein.
[0118] In another embodiment R3 is not cyclopropylmethyl.
[0119] In another embodiment Z is monocyclic.
[0120] In another embodiment Z is bicyclic.
[0121] In another embodiment Z is heteroaryl.
[0122] In another embodiment Z is unsubstituted heteroaryl.
[0123] In another embodiment Z is benzo[b]thiophenyl, benzo[c] [ 1 ,2,5]oxadiazoyl, benzo[c][l,2,5]thiadiazolyl or benzo[d]thiazolyl.
[0124] In another embodiment Z is benzo[b]thiophenyl or benzo[d]thiazolyl.
[0125] In another embodiment Z is benzo[c][l,2,5]oxadiazoyl or benzo[c][l,2,5]thiadiazolyl.
[0126] In another embodiment Z is benzo[b]thiophenyl.
[0127] In another embodiment Z is benzo[c] [ 1 ,2,5]oxadiazoyl.
[0128] In another embodiment Z is benzo[c] [ 1 ,2,5]thiadiazolyl.
[0129] In another embodiment Z is benzo[d]thiazolyl.
[0130] In another embodiment Z is aryl.
[0131] In another embodiment Z is substituted phenyl.
[0132] In another embodiment Z is 4-substituted phenyl.
[0133] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7,
OC(0)N(R7)2, SR6, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6, N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and CORg. [0134] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R^, CF3, CN, N02, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, SRg, NHR7, N(R7)2C02H, C02R6 and COR6.
[0135] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, C1-C4 alkoxy, aryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6 and SR6.
[0136] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, C1-C4 alkoxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6 and SR6.
[0137] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of halogen, Ci-C6 alkyl, (Co-C3)alkyl-(C3- C7)cycloalkyl, CF3, C1-C4 alkoxy and SR6.
[0138] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C3 alkyl, (C3-C6)cycloalkyl, CF3, C1-C4 alkoxy, S-(Ci- C4)alkyl and S-(C0-C3)alkyl-(C3-C7)cycloalkyl.
[0139] In another embodiment Z is optionally susbsituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C3 alkyl, (C3-C6)cycloalkyl, CF3, C1-C4 alkoxy and S-(Ci- C3)alkyl.
[0140] In another embodiment Z is susbsituted once with CF3, OCF3, OCH2CF3, F, CI, SMe, Me, Et, or i-Pr.
[0141] In another embodiment Z is susbsituted with F. In another embodiment Z is susbsituted with CI.
[0142] In another embodiment Z is susbsituted with Ci-C3 alkyl.
[0143] In another embodiment Z is susbsituted with (C3-C6)cycloalkyl.
[0144] In another embodiment Z is susbsituted with CF3.
[0145] In another embodiment Z is susbsituted with C1-C4 alkoxy. In another embodiment Z is susbsituted with S-(Ci-C3)alkyl. In another embodiment R4 is a Ci-C7 alkyl group. In another embodiment R4 is a C1-C4 alkyl group. In another embodiment R4 is a Ci-C3 alkyl group. In another embodiment R4 is a C2-C3 alkyl group.
[0146] In another embodiment R4 is selected from the group consisting of ethyl, n- propyl, iso-propyl, trifluoroethyl and trifluoropropyl.
[0147] In another embodiment R4 is ethyl. In another embodiment R4 is n-propyl. In another embodiment R4 is iso-propyl. In another embodiment R4 is trifluoroethyl. In another embodiment R4 is trifluoropropyl. In another embodiment R4 is a (C4-C10) cycloalkylalkyl group.
[0148] In another embodiment R4 is a (Co-C3)alkyl-(C3-Cy) cycloalkyl group. In another embodiment R4 is a (C3-C7) cycloalkyl group.
[0149] In another embodiment R4 is a (Ci-C3)alkyl-(C3-Cy) cycloalkyl group. In another embodiment R4 is a (Ci)alkyl-(C3-Cy) cycloalkyl group.
[0150] In another embodiment R4 is a (Ci)alkyl-(C3-C4) cycloalkyl group. In another embodiment R4 is a cyclopropylmethyl group.
[0151] In another embodiment R4 is a cyclobutylmethyl group.
[0152] In another embodiment R4 is heterocycloalkylalkyl group. In another embodiment R4 is represented by the group Z as defined herein. In another embodiment R4 is not cyclopropylmethyl.
[0153] In another embodiment R5 is, F, CI, Br, CN, C1-C4 alkoxy, SRe, (C1-C4) alkyl, (C0- C3)alkyl-(C3- C7) cycloalkyl, -(C3-C7) cycloalkyl or (C2-C4) alkynyl, where each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.
[0154] In another embodiment R5 is F, CI, Br, CN, C1-C4 alkoxy, SRe, (C1-C4) alkyl, (C0- C3)alkyl-(C3-C7) cycloalkyl, -(C3-C7) cycloalkyl or (C2-C4) alkynyl, where each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.
[0155] In another embodiment R5 is F, CI, Br, CN, C1-C4 alkoxy, -S-(Ci-C4)alkyl or (Ci- C4) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, Ci-C4 alkyl.
[0156] In another embodiment R5 is F, CI, Br, O H , CN, C C4 alkyl, C C3 alkoxy, -S- (Ci-C3)alkyl, or (C1-C3) alkyl, or -0-(Co-C3)alkyl-(C3-C7) cycloalkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, or Ci- C4 alkyl. In another embodiment R5 is F, CI, Br or CN.
[0157] In another embodiment R5 is F or CI. In another embodiment R5 is F. [0158] In another embodiment R5 is CI. In another embodiment R5 is Br. In another embodiment R5 is CN.
[0159] In another embodiment R5 is C1-C3 alkoxy, -S-(Ci-C3)alkyl or (C1-C3) alkyl.
[0160] In another embodiment R5 is C1-C3 alkoxy.
[0161] In another embodiment R5 is tri-fluoroethoxy or tri-fluoropropoxy.
[0162] In another embodiment R5 is (C1-C3) alkyl.
[0163] In another embodiment R5 is CF3.
[0164] In another embodiment R5 is -S-(Ci-C3)alkyl.
[0165] In another embodiment R5 is -S-Me, -S-Et or -S-CH2CF3.
[0166] In another embodiment R5 is SR6.
[0167] In another embodiment R5 is (Co-C3)alkyl-(C3-Cy) cycloalkyl, (C2-C4) alkynyl, or -(C3- C7) cycloalkyl.
[0168] In another embodiment R5 is (Co-C3)alkyl-(C3-Cy) cycloalkyl.
[0169] In another embodiment R5 is (C2-C4) alkynyl.
[0170] In another embodiment R5 is trifluroethynyl.
[0171] In another embodiment R5 is (C3-C7) cycloalkyl.
[0172] In another embodiment R5 is cyclopropyl.
[0173] In another embodiment R5 is N02 or NH2.
[0174] In another embodiment R5 is aryl or heteroaryl.
[0175] In another embodiment the compound is a compound selected from the group consisting of examples from the Exemplification section. In another embodiment a racemic compound described in the disclosure is selected.
[0176] In another embodiment a single enantiomer of the previous embodiments is selected.
[0177] In another embodiment a single enantiomer of configuration (R) of the previous embodiments is selected.
[0178] In another embodiment a single enantiomer of configuration (S) of the previous embodiments is selected.
[0179] In another embodiment a solvate of a compound of formula (I-IX) is selected.
[0180] In another embodiment a polymorph of compound of formula (I-IX) is selected.
[0181] In a separate embodiment, a pharmaceutical composition comprising of the compound of any of the previous embodiments and a pharmaceutically acceptable carrier. [0182] In a separate embodiment, a method for treating a neurodegenerative disorder comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.
[0183] In another embodiment, a method for treating Alzheimer's Disease comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments is provided.
[0184] In some embodiments, compounds of Formula (I -IX) may contain asymmetric centers and exist as different enantiomers or diastereomers. All enantiomers or diastereomeric forms are embodied herein.
[0185] Compounds in the disclosure, e.g., compounds of Formulas I-IX, may be in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable" refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary (e.g., tromethamine), secondary and tertiary amines, and amino acids (e.g., lysine). Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric,
methanesulphonic, hydrobromic. Salts derived from organic acids include Ci_6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as /?ara-tolouene sulfonic acid and benzene sulfonic acid. For detailed list of salts see P.H.Stahl and C.G. Wermuth (eds.) "Handbook of Pharmaceutical Salts, Properties, Selection and Use" Wiley- VCH (ISBN 3-906390-26-8), the content of which is herein incorporated by reference in its entirety.
[0186] Compounds and pharmaceutically acceptable salts thereof may be in the form of a solvates. This occurs when a compound of formula (I-IX)) crystallizes in a manner that it incorporates solvent molecules into the crystal lattice. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone. In some embodiments, Formulas I-IX include solvate and/or salts of the depicted compound. Compounds in the disclosure may exist in different crystal forms known as polymorphs. Practitioners of the art will recognize that certain chemical groups may exist in multiple tautomeric forms. The scope of this disclosure is meant to include all such tautomeric forms. For example, a tetrazole may exist in two tautomeric forms, 1- H tetrazole and a 2-H tetrazole. This is depicted in figure below. This example is not meant to be limiting in the scope of tautomeric forms.
Figure imgf000034_0001
[0187] Practitioners of the art will recognize that certain electrophilic ketones, may exist in a hydrated form. The scope of this disclosure is to include all such hydrated forms. For example, a trifluoromethyl ketone may exist in a hydrated form via addition of water to the carbonyl group. This is depicted in figure below. This example is not meant to be limiting in the scope of hydrated forms.
Figure imgf000034_0002
General Reaction Schemes
[0188] In certain embodiments, the tetrasubstituted benzene compounds may be prepared and/or substituted in the manner described in PCT Application No. PCT/US2008/087968, the content of which is herein incorporated by reference in its entirety.
[0189] The 1 -position acetic acid moiety common to compounds of Formulas I and II, as the free acid itself or as an ester derivative thereof, is already present in the case of a 4- hydroxyphenyl acetic acid or 4-hydroxyphenyl acetic acid ester starting material. In the case of a 4-fluoronitrobenzene starting materials or intermediates, the acetic acid moiety can be introduced by standard nucleophilic aromatic substitution of the 4-fluoro group with an
unsubstituted malonic ester (e.g., diethyl malonate) or a malonic ester derivative already bearing an P i group (e.g., diethyl 2-isobutylmalonate). Introduction of the X-R3 and Y-R4 groups or intermediate groups that are further elaborated to X-R3 and Y-R4 can be carried out by substitution or manipulation of suitable 3 or 4-position functional groups in appropriate starting materials or intermediates en route to Formulas I and II respectively. In cases where X or Y is a bond, a 3 or 4- position halogen or triflate group is replaced with an aryl or heteroaryl group by carbon-carbon bond forming reaction typically a Suzuki coupling reaction. In cases where X or Y is O, S or N, a 3 or 4-position halogen (e.g., the corresponding 2-fluoro group of a 2,4-difluoronitrobenzene starting material) substitution reaction is performed using HO-R3 or HS-R3 or H2N-R3 and a base (e.g., NaH, K2CO3) in a suitable solvent (e.g., DMF). Compounds where X or Y is -S(O)- or - S(02)- are prepared by oxidation of compounds where X or Y is S. Compounds where X or Y is - S(0)2N(H)-, -S(0)2N(R5)- can be prepared by conversion of a 3 or 4-position nitro group (e.g., the nitro group of the nitrobenzene starting material) to a sulfonyl chloride via Sandmeyer reaction followed by addition of the corresponding amine. Compounds where X or Y is
N(H)S(0)2- or -N(R5)S(0)2- can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding sulfonylchloride. Compounds where X or Y is NHC(O)- or -N(R5)C(0)- can be prepared by reduction of a 3 or 4- position nitro group to the corresponding aniline followed by reaction with the corresponding carboxylic acid chloride. Compounds where X or Y is a -C(O)- can be prepared by addition of an organometallic reagent (e.g., a Grignard reagent or organolithium) to a 3 or 4-position cyano group directly or in a 2-step sequence by addition of an organometallic reagent to a 3 or 4- position
carboxaldehyde group followed by oxidation. Compounds where X or Y is -C(0)NH- or
C(0)N(Rs)- can be prepared by addition of a corresponding amine to a 3 or 4-position carboxylic acid which in turn may be prepared by hydrolysis of a 3 or 4-position cyano group. Either aromatic nucleophilic substitution of a 2-fluoro-l -nitrobenzene intermediate or alkylation of a 3 or 4-hydroxybenzene intermediate with the corresponding alkyl bromide or triflate may be used to prepare compounds of Formulas I and II where the R4 group is OCH2CF3, C2-C4 alkoxy, or cyclopropyloxymethyl. Compounds wherein the R4 group is an alkyl, aryl or heteroaryl group attached by a carbon-carbon bond may be prepared by a Suzuki coupling reaction. In this process an aryl or heteroaryl boronic acid or borate ester is reacted with an intermediate compound having a 3 or 4-position halogen or triflate group. This method results in replacement of the halogen or triflate group with an aryl or heteroaryl group which is then bonded to the intermediate at the carbon atom previously bearing the boronic acid or ester group. Compounds wherein the R4 group is a heteroaryl group attached by a carbon-nitrogen bond may be prepared by reacting a 3 or 4-iodo intermediate with a heteroaromatic heterocycle having an acidic N-H group under Ulman reaction or copper catalyzed reaction conditions.
[0190] Compounds of Formulas I and II wherein A = tetrazole may be prepared from their corresponding nitriles A = CN which are available via dehydration of the corresponding primary amides A = CONH2 whose preparation is described above. Thus, the nitrile may be treated with an azide, such as sodium azide or tributylstanyl azide (Bu3SnN3) at a temperature of 20-100 °C, optionally with a solvent such as DMF, THF or DMSO. [0191] Compounds of the disclosure of Formula III in which Ri is Rg an alkyl, cycloalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, Y is O, X is a bond, R3 is Z, R4 and R5 are as described previously and thus having general Formula XXIV may be prepared generally as depicted in Scheme 1.
Figure imgf000036_0001
[0192] Thus, as depicted in Scheme 1 an alkyl, cycloalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl or arylalkyl Rg group is introduced in the first step by treating ethyl 4- benzyloxyphenylacetate one equivalent of a suitable deprotonating base such as sodium hydride in an appropriate organic solvent followed by the addition of the corresponding reactive alkyl bromide RgBr such as isobutylbromide to yield XX where R9 is hydrogen. In cases where a second alkyl or aralkyl group is present this alkylation step is repeated using R9Br as an alkylating agent. In cases where a spirocyclic ring is formed by Rg and R9 (e.g., cyclopropyl) then the appropriate dibromide is used (e.g., dibromoethane in the case of cyclopropyl). The benzyl group is then removed under standard catalytic hydrogenation conditions and the resulting phenol is treated with bromine in acetic acid to give the bromophenol intermediate XXI. Nitration of XXI then yields nitrophenol intermediate XXII which then us subjected to a standard base mediated aliphatic or aromatic nucleophilic substitution reaction with an alkyl or aryl halide R4-X to give intermediate XXIII where R4 is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl. This is then followed by introduction of the Z group by standard reactions. Such reactions are exemplified by the well- established Suzuki coupling of a substituted aryl or heteroaryl boronic acid derivative Z-B(OH)2 using a suitable palladium(O) catalyst typically bearing with phosphine ligands (e.g., Pd(PPh3)4 or tetrakistriphenylphosphine) in the case where Z is linked by a carbon-carbon bond and by copper
(e.g., Cul) mediated Ulman type coupling of a heteroaryl ring bearing an active N-H group where Z is a heteroaryl ring linked by a nitrogen-carbon bond.
Figure imgf000037_0001
[0193] After introduction of the Z group, the nitro group is converted to the corresponding aniline by any number of standard reduction conditions (e.g., SnCl2 reduction). This is followed by conversion of the resulting aniline to the diazonium salt which is then converted "in situ" either directly to R5 either directly in the case where R5 is F, CI, Br, CN, OH, C1-C4 alkoxy or SR6, by using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol or in a subsequent step e.g., oxidation (e.g., with MCPBA) of the product of thiol coupling when R5 is S(0)2R6 ; e.g., Suzuki coupling of the bromide product when R5 is heteroaryl e.g., treatment of an intermediate sulfonylchloride obtained via CuCl/S02 conditions with an amine
HN(R7)2, when R5 is S(0)2N(R7)2, e.g., Burton trifluoromethylation reaction of the iodide product (Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014 and 1986, 108, 832; Miller, J.A., Coleman, M. C; Matthews, R. S. J. Org. Chem. 1993, 58, 2637) when R5 is CF3 Standard ester hydrolysis yields compounds of Formula XXIV.
Figure imgf000037_0002
[0194] Compounds of the disclosure of Formula III and IV in which Ri is R8 an alkyl, cycloalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, X and Y are a bond, R3 and R4 are respectively Zi and Z2 representing independently chosen Z groups as defined above and R5 is as described previously and thus having general Formula XXX may be prepared generally as depicted in Scheme 3 starting from compounds of general Formula XXII which can be prepared as described in Scheme 1.
[0195] Compounds of Formula V in which Ri is Rg an alkyl, cycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is Q = O, S, or S02; R5 is F or CI; R3 and Z are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 4. Accordingly, the 4-halo group of 2,4,5- trifluoronitrobenzene or 2,4,5-trichloronitrobenzene is selectively displaced by reaction with a 2- substituted diethylmalonate R8YCH(C02Et)2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXI. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R3-J-H compound (wherein J is O, S) under basic conditions (e.g., NaH/DMF) followed by reduction and Sandmeyer reaction to give iodide XXXII.
Figure imgf000039_0001
[0196] Suzuki coupling then gives intermediates of general formula XXXIII. Introduction of an R9 group may be conducted using alkylation conditions described above. Compounds wherein J is S02 may be prepared by standard oxidation of intermediates XXXIII wherein J is S. Final products having general Formula XXXIV are then prepared by standard ester hydrolysis. Compounds of Formula IV in which Ri is R8 an alkyl, cycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is O; R5 is CI; R3 and Z are as described previously and thus having general Formula XXXVIII may be prepared generally as depicted in Scheme 5. Accordingly, the 4-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R8CH2(C02Et)2 under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXV. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R3-O- H compound under basic conditions (e.g., NaH/DMF) followed by reduction and chlorination reaction (e.g., with N-chlorosuccinimide) to give chloroaniline intermediates of general formula XXXVI. Sandmeyer iodination reaction to followed by Suzuki coupling then gives intermediates of general formula XXXVII. Introduction of an R9 group may be conducted using alkylation conditions described above. Final products having general Formula XXXVIII are then prepared by standard ester hydrolysis.
Figure imgf000040_0001
[0197] Compounds of Formula IV in which R1 is R8 an alkyl, cycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J= O, S; R5 is NO2, NH2, CN, SR6, SO2R6, SO2N(R7)2 F, CI, Br; R3 and Z are as described previously and thus having general Formula XLII may be prepared generally as depicted in Scheme 6. Accordingly, the 2- fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a an alcohol or thiol of formula R3-J-H under basic conditions (e.g., NaH/DMF). The 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XXXIX. Reduction of the nitro group of XXXIX followed by nitration of the resulting aniline give nitroaniline intermediates of Formula XL. Sandmeyer iodination reaction, followed by Suzuki coupling and finally alkylation reaction to introduce Rs then gives intermediates of general Formula XLI. The nitro group of XLI may be optionally reduced via any number of standard reduction conditions
(e.g., SnCl2) to an aniline which may in turn optionally be converted to diverse other R5 groups either directly or in multistep procedures. Thus, in the case where R5 is F, CI, Br, CN, OH, Ci-
C4 alkoxy or SR6, diazotization of the aniline is followed by direct "in situ" conversion to R5 using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol.
Intermediates where R5 is S(0)2R6 may be prepared by subsequent step oxidation (e.g., with
MCPBA) of the above products of thiol coupling wherein R5 is SR6. Intermediates where R5 is e.g., heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R5 is Br or I. Intermediates where R5 is CF3 may be prepared by
Burton reaction of the above products wherein R5 is I. Intermediates where R5 is S(0)2N(R7)2, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via
CuCl/S02 conditions ) with an amine HN(R7)2, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.
Figure imgf000041_0001
[0198] Compounds of Formula VII in which Ri is Rg an alkyl, cycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J= O, S; R5 is N02, NH2, CN, SR5, SO2R5, S02N(Rv)2 F, CI, Br; R3 and Z are as described previously and thus having general Formula XLV may be prepared generally as depicted in Scheme 7. Reduction of the nitro group of XXXIX followed by bromination (e.g., with NBS) of the resulting aniline and prepared by 1 alkylation reaction to introduce R9 gives bromoaniline intermediates of Formula XLIII Suzuki coupling reaction substitutes Z groups for the Br group to give intermediates of general Formula XLIV. The aniline group in intermediates of Formula Formula XLIV may in turn optionally be converted to diverse other R5 groups either directly or in multistep procedures. Thus, in the case where R5 is F, CI, Br, CN, OH, C1-C4 alkoxy or SR^, diazotization of the aniline is followed by direct "in situ" conversion to R5 using the appropriate copper salt i.e., CuCl, CuBr, CuCN or nucleophile i.e., water, alcohol or thiol. Intermediates where R5 is S(0)2R6 may be prepared by subsequent step oxidation (e.g., with MCPBA) of the above products of thiol coupling wherein R5 is SR6. Intermediates where R5 is e.g., heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R5 is Br or I. Intermediates where R5 is CF3 may be prepared by Burton reaction of the above products wherein R5 is I.
Intermediates where R5 is S(0)2N(Rv)2, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/S02 conditions) with an amine HN(R7)2, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.
Figure imgf000043_0001
[0199] Compounds of Formula IV in which Ri is R8 an alkyl, cycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X-R3 and R5 are identical (J- R3 in Scheme 8) and are either C1-C4 alkoxy or SR6 groups; and Z is as described previously and thus having general Formula L may be prepared generally as depicted in Scheme 8. Accordingly, the 2 and 6- fluoro groups of 2,4,6-trifluoronitrobenzene are selectively displaced by reaction with a an alcohol or thiol of formula R3-J-H under basic conditions (e.g., NaH/DMF). The 4- fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (e.g., NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XLVIIL Reduction of the nitro group of followed by Sandmeyer iodination reaction of the resulting aniline gives intermediates of Formula XLVIII. Suzuki coupling and followed by alkylation reaction to introduce R8 then gives intermediates of general Formula XLIX. Final products having general Formula L are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.
[0200] In addition, compounds wherein R1 is -SR6 may be prepared using the following general reaction scheme (Scheme 9), e.g., wherein -SR6 is represented by -SR:
Figure imgf000044_0001
Scheme 9
III. Pharmaceutical Compositions
[0201] The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas I - IX, a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
[0202] The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt. [0203] In another embodiment, the compound can be administered parenterally, such as intravenous (i.v.) administration. The formulations for administration will commonly comprise a solution of the compound of the Formulas I - IX dissolved in a pharmaceutically acceptable carrier.
Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.
These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formulas I - IX in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For i.v. administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally- acceptable diluent or solvent, such as a solution of 1,3-butanediol.
[0204] In one embodiment, a compound of Formulas I - IX can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of
Formulas I - IX dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formulas I - IX is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formulas I -IX is introduced intraocullarly, to thereby contact retinal ganglion cells.
[0205] The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization. [0206] In one embodiment, the pharmaceutical composition comprising a compound of
Formulas I -IX is administered into a subject intrathecally. As used herein, the term "intrathecal administration" is intended to include delivering a pharmaceutical composition comprising a compound of Formulas I - IX directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebro ventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al., Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al, Cancer Drug Delivery, 1 : 169-179, the contents of which are incorporated herein by reference). The term "lumbar region" is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term "cisterna magna" is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term "cerebral ventricle" is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formulas
I -IX to any of the above mentioned sites can be achieved by direct injection of the
pharmaceutical composition comprising the compound of Formulas I - IX or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re- dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
[0207] In one embodiment, the pharmaceutical composition comprising a compound of Formulas I - IX is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
[0208] In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
[0209] For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
[0210] Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formulas I - IX with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
[0211] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
[0212] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0213] For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0214] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl -pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
[0215] The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[0216] The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
[0217] The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formulas I - IX in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolality.
[0218] Oil suspensions can be formulated by suspending a compound of Formulas I -IX in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
[0219] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0220] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
[0221] For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0222] In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
[0223] The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.
[0224] Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. ("Remington's"). After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formulas I - IX, such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.
EXEMPLIFICATION
[0225] The present invention is illustrated by the following examples, which are not intended to be limiting in any way.
Example 1
Experimental procedures for rat primary cortical culture-based Abetax→42/i→xELISAs
[0226] Rat primary neocortical cultures are established through the dissection of the neocortices from 10-12 El 7 embryos harvested from time-pregnant SD (Sprague Dawley) rats (Charles River Laboratories). Following dissection, the combined neocortical tissue specimen volume is brought up to 5mL with dissection medium (DM; lxHBSS (Invitrogen Corp., cat#14185-052) /lOmM HEPES (Invitrogen Corp., cat# 15630-080)/ ImM Sodium Pyruvate (Invitrogen Corp., cat# 11360-070)) supplemented with lOOuL Trypsin (0.25%; Invitrogen Corp., cat# 15090-046) and lOOuL DNase I (0.1% stock solution in DM, Roche Diagnostics Corp., cat# 0104159), undergoing digestion via incubation at 37°C for 10 minutes. Digested tissue is washed once in plating medium (PM; NeuroBasal (Invitrogen Corp., cat# 21103-049) / 10%) Horse Serum (Sigma-Aldrich Co., cat# HI 138) / 0.5mM L-Glutamine (Invitrogen Corp., cat# 25030-081)), then resuspended in a fresh lOmL PM volume for trituration. Trituration consists of 18 cycles with a 5mL-serological pipet, followed by 18 cycles with a flame-polished glass Pasteur pipet.
[0227] The volume is elevated to 50mL with PM, the contents then passed over a 70um cell-strainer (BD Biosciences, cat# 352350) and transferred directly to a wet-ice bath. The cell- density is quantified using a hemacytometer, and diluted to allow for the plating of 50000 cells/well/ lOOuL in pre-coated 96-well PDL-coated plates (Corning, Inc., cat# 3665). Cells are incubated for 4-5 hours at 37°C/5% C02, after which time the entire volume is exchanged to feeding medium (FM; NeuroBasal/2% B-27 Serum- free supplement (Invitrogen Corp., cat# 17504-044)/ 0.5mM L- Glutamine/ 1% Penicillin-Streptomycin (Invitrogen Corp., cat# 15140- 122)). The cultures undergo two 50% fresh FM exchanges, after 3 days in vitro (DIV3), and again at DIV7.
[0228] C-terminal recognition-site Abetax→42 and Rat N-terminal recognition-site Abetai→x capture-antibodies, diluted 1 :300 in 0.05M Carbonate-Bicarbonate buffer (Sigma-Aldrich Co., C-3041), are used to coat (lOOuL/well) flat-bottomed F96 MicroWell™ (MaxiSorp™ surface) plates (Nalge Nunc International, cat# 439454), and incubated overnight at 4°C for eventual use in the ELISA assay. Compounds to be screened are solubilized in dimethyl sulphoxide (DMSO, Sigma-Aldrich Co., cat# 15493-8), and further diluted in DMSO in an eight-point dose-response format. Into 96-well plates, dose-response compound dilutions (lOOOx the desired final concentration) are stamped out at 2 μΐ ννεΐΐ, in duplicate (up to 3 compounds/plate), as a daughter plate. In addition, DMSO and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor (GSI), are incorporated as solvent and positive controls, respectively. With the assistance of liquid-handling automation, the compound daughter plate is diluted 1 :500 with warmed FM, and two DIV8 culture plates are leveled to 60uL/well, and immediately overlaid with 60μΙ ννε11 of the 2x diluted daughter plate. The plates are returned to the 37°C/5% C02-incubator for 24 hours.
[0229] Each coated capture-antibody ELISA plate undergoes 4x 250uL/well Phosphate- buffered saline with 0.05% Tween®-20 SigmaUltra (PBS-T; Fluka, cat# 79383/Sigma- Aldrich Co., cat# P7949) washes. The ELISA plates are then overlaid with 120uL/well PBS-T
supplemented with 1% Bovine Serum Albumin Diluent/Blocking solution (BSA; Kirkegaard & Perry Laboratories (KPL), Inc., cat# 50-61-01) and incubate at room-temperature on an orbital shaker for a minimum of 2 hours.
[0230] Rat Abetai→42 and rat Abetai→40 peptide (American Peptide Co., cat# 62-0-84/62-0- 86A) DMSO stock solutions are serially-diluted 1 :2 in FM yielding a final concentration range of 0- 500pg/mL, to be plated on the respective ELISA plates for determination of the corresponding standard curve, from which concentrations of specific or total Abeta peptides in the presence of a particular drug concentration can be calculated. The conditioned medium from the duplicate culture plates are collected and combined into one round-bottom 96-well transfer plate which is incubated on wet-ice. The culture plates are rinsed once with 120ul/well FM, and replenished immediately with ΙΟΟμΕΛνεΙΙ FM, being returned to the incubator for 10 minutes. Cell-viability is evaluated by adding 20uL/well of warmed CellTiter 96® Aqueous One Solution (MTS/PES; Promega Corp., cat# G3581), and returning the plates to the incubator for 30-90 minutes. Plate absorbance at 492nm is read on a spectrophotometer, and from which, the ratio of absorbance of compound-treated cells to absorbance of solvent (DMSO)-treated control cells is calculated. The calculation of the corresponding EC50 values is performed following non-linear curve-fitting using GraphPad Prism® software.
[0231] For each ELISA plate, a corresponding transfer-plate is created containing 120μΕΛνε11 of either the rat Abetai→42 or rat Abetai→40 peptide standard solutions, in duplicate, and 110- 115μΕΛνε11 of the collected conditioned-medium plate, half designated for the Abetax→42 ELISA, and the other half for the Abetai→x ELISA. The ELISA plates undergo a second set of 4x 250uL/well PBS-T washes, immediately followed by being overlaid with their designated transfer-plate. The ELISA plates incubate on an orbital-shaker for 16-18 hours at 4°C.
[0232] Detection antibody solution is prepared by diluting beta- Amyloid 17-24 (4G8) biotinylated monoclonal antibody (Covance, Inc., cat# SIG-39240-200) 1 : 1500 in PBS-T supplemented with 0.67% BSA. The ELISA plates undergo 4x 250uL/well PBS-T washes, and are overlaid with lOOuL/well of 4G8 diluted detection-antibody solution. The Abetax→42 ELISA plates are incubated on an orbital-shaker at room-temperature for 90 minutes, the Abetai→x ELISA plates for 60 minutes.
[0233] In order to conjugate the biotinylated monoclonal 4G8 antibody, following 4x 250uL/well PBS-T washes, the ELISA plates undergo a one-hour incubation at lOOul/well with a 1 : 15000 dilution of Streptavidin-HRP conjugate (Jackson ImmunoResearch Laboratories, Inc., cat# 016-030-0840) on an orbital-shaker at room temperature.
[0234] Following a final set of 4x 250uL/well PBS-T washes, the ELISA plates are overlaid with lOOul/well SureBlue 3,3', 5, 5' - Tetramethylbenzidine (TMB) Microwell
Peroxidase substrate solution (Kirkegaard & Perry Laboratories, Inc., cat# 52-00-02), protected from light, and incubate for 20-45 minutes at room temperature. At the point the desired level of development is attained, lOOul/well of TMB Stop solution (Kirkegaard & Perry Laboratories, Inc., cat# 50-85-05) is added, and the plate thoroughly shaken in preparation for reading on a spectrophotometer. SureBlue TMB Microwell Substrate develops a deep blue color in the presence of a peroxidase-labeled conjugate, and turns yellow when stopped by acidification, allowing for plate absorbance at 450nm to be read. From the calculation of the standard curve, the compound dose-response curves, normalized to DAPT performance, are plotted as %DMSO using
GraphPad Prism® software, and the corresponding EC50 values are calculated.
Example 2
Experimental procedures for human H4 glioma cell line stably expressing human APP
Abeta1→42/i→x ELISAs
A. Measurement of Αβ in vitro
[0235] The Αβ peptide is proteolytically derived from a larger integral membrane amyloid precursor protein (APP). The production of Αβ is derived from proteolytic cleavages at its N- and C- termini within β-ΑΡΡ by the β and γ-secretase activities, respectively. Transfected cells overexpressing β-ΑΡΡ or its equivalent producing the Αβ peptide can be used to monitor the effects of synthetic compounds on the production of Αβ.
[0236] To analyze a compound's effects on the concentrations of the various products of the γ- secretase cleavage activity, the Αβ peptides, various methods known to a person skilled in the art are available. Examples of such methods, but not limited to, include mass-spectrometric identification as described by Wang et al, 1996, J. Biol. Chem. 271 :31894-31902, or detection
by specific antibodies using, for example, ELISA's.
[0237] Examples of such assays for measuring the production
Figure imgf000053_0001
Αβ40 and Αβ42 by ELISA include but are not limited to those described by Vassar et al, 1999, Science 286:735- 741. Suitable kits containing the necessary antibodies and reagents for such an analysis are available, for example, but not limited to the Genetics Company, Wako, Covance, and Innogenetics. The kits are essentially used according to the manufacturers recommendations similar to the assay that is described by Citron et al, (1997) Nature Medicine 3:67-72 and the original assay described by Seubert et al, (1992) Nature 359:325-327.
[0238] Screening was carried out using the human glioma H4 cell line (American Type Culture Collection #HTB-148) stably overexpressing human amyloid precursor protein (APP) transgene, grown in Pro-293a CDM media (Lonza, cat#12-764Q). Cells were plated at a density of 15000 cells/well (96-well tissue culture plate, Corning #3997) and incubated for 6 hours before the addition of test compounds. The growth media was aspirated or removed, the cells washed, and replaced with 100 of compound, serially diluted in serum free media. The plates are then incubated for 16-18 hours at 37°C.
[0239] Conditioned Medium samples are removed for analysis/quantitation of the various Αβ peptide levels by differential ELISA's, e.g., as described in accompanying instructions to the kits. Those compounds examined which do not demonstrate any overt toxicity (determined by
CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS); Promega #G3582), or nonspecific inhibitory properties are investigated further for their Αβ inhibitory effects and form the basis of medicinal chemistry efforts and to study the effect of the compounds in different experimental conditions and configurations.
[0240] Representative compounds are shown in the table below. A compound with the value "A" had an IC50 value less than or equal to 100 nM. A compound with the value "B" had an IC50 value greater than 100 nM and less than 500 nM:
Figure imgf000054_0001
Example 3
Experimental procedures for glucuronidation assay
A. Glucuronidation protocols
[0241] Microsomal glucuronidation reactions were conducted using the UGT Reaction Mix solutions (A and B) from BD Biosciences and following the vendor's protocol. 10 μΜ of test article or control compound was incubated with 0.5 mg/mL of human or rat liver microsomes. Samples were taken at 0 and 60 minutes and acetonitrile was added to terminate the reactions. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide. Control reactions were run for each compound substituting water for the glucuronic acid solution to monitor for any loss of parent compound due to degradation or unanticipated microsomal reactions.
[0242] Hepatocyte experiments were run using cryopreserved human hepatocytes (single donor) obtained from Celsis/In Vitro Technologies. Cells were thawed and counted according to the vendor's protocols using the trypan blue exclusion method to obtain the count of live cells. Test article and control compounds were incubated at a concentration of 5 uM in KHB buffer (Celsis/In Vitro Technologies) containing 1 million cells per mL. Samples were taken at 0, 60 and 120 minutes. The reactions were terminated with addition of acetonitrile. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide.
B. LC-MS/MS analysis
[0243] Samples were analyzed by LC-MS/MS using a Shimadzu LC system consisting of two LC-10AD pumps and a SIL-HTc autosampler connected to an Applied Biosystems MDS/Sciex API 3200 QTRAP mass spectrometer.
[0244] For chromatographic separation, a Phenomenex Luna C-18 3 μΜ (2 x 20 mm) column was used with an acetonitrile-based gradient mobile phase. The two mobile phase components were:
Mobile phase A: water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide; and
Mobile phase B: 95:5 acetonitrile/ water with 0.05%> (v/v) formic acid and 0.05%> (v/v) 5 N ammonium hydroxide.
[0245] The gradient for each analysis was optimized for the specific compound, but generally, the run started with between 0% and 40% of mobile phase B, ramped up to 100% of mobile phase B over 1-2 minutes, then held there for 2-3 minutes before returning to the initial conditions for 4 minutes to re-equilibrate.
[0246] The API 3200 QTRAP mass spectrometer was used in MRM mode with negative electrospray ionization. MRM transitions and mass spec settings were optimized for each compound.
[0247] Standard curves were created by quadratic or linear regression with l/x*x weighting. Calibration standards were prepared 1-10,000 ng/mL, but the highest (and sometimes lowest) standards were often not acceptable for quantitation and only those standards with reasonable back- calculated accuracies were included in the calibration curve. Ideally, only standards with
+/-15% of nominal concentration would be included in the fitted standard curve, but occasionally larger deviations were accepted after careful consideration. Sample concentrations below the quantitation range were reported as "BQL". Concentrations above the curve were usually re-run with larger sample dilutions
C. Pharmacology
[0248] Compounds of the disclosure are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Αβ peptides produced by γ-secretase. In certain embodiments the compounds alter the relative levels of Αβ peptides produced by γ-secretase without
significantly changing the total level of Αβ peptides produced. Certain compounds of the disclosure modulate γ-secretase activity with respect to APP proteolytic processing and in so doing lower the production of Αβ42 both in vitro in cells and in vivo in animals. In some cases this effect occurs at concentrations that do not significantly impair the viability of cells in vitro and at doses that are well tolerated in vivo. Certain compounds of the disclosure lower Αβ42 secretion in native neuronal and cellular construct assay systems with EC50 values that are below 1 micromolar (Class A compounds, Table 14) while others have EC50 values from 1-5 micromolar (Class B
compounds, Table 14) and others have EC50 values greater than 5 micromolar (Class C
compounds). Certain compounds of the disclosure do not appear to significantly interfere with γ- secretase related Notch processing activity. Compounds that significantly interfere with γ-secretase related Notch processing activity have been associated with toxic side-effects. Certain compounds of the disclosure have favorable pharmacokinetic (PK) properties in animals. Thus, certain of the compounds are orally bioavailable, penetrate into the brain and have favorable PK parameters including half-life and clearance supporting pharmaceutical application in humans. In turn, certain compounds of the disclosure significantly lower Αβ42 production in the brains of non-transgenic and transgenic animals after single dose and multi-dose oral administration with no overt side effects. For certain compounds of the disclosure single oral doses of <30 milligrams/kilogram are efficacious at lowering Αβ42 production in the brains of rats (e.g., Sprague-Dawley) and wild type mice (e.g., C57BL/6). Certain compounds of the disclosure which lower Αβ42 at doses of <30 milligrams/kilogram appear to be well tolerated and show no overt or clinical chemical toxicity after subchronic 14- day administration at doses >30 milligrams/kilogram/day. Certain compounds of the disclosure have favorable absorption-distribution-metabolism and excretion (ADME) properties. Moreover, certain compounds of the disclosure do not appear to significantly bio- accumulate in tissues especially in the brain. Compounds of Formulas I-IX wherein A = C02H show favorable profiles with respect to acylglucoronide (A = C02Glu) metabolite formation. The potential for acylglucoronide metabolites to cause of toxicity has been described particularly for non-steroidal anti-inflammatory drugs (NSAIDs) containing carboxylic acid groups (Ebner et al Drug Metabolism and Disposition 1999,27(10),1143-49). Several such NSAIDs have been removed from the market due to idiosyncratic toxicity in humans and it has been speculated that NSAID idiosyncratic toxicity is related to the relative load and relative reactivity of
acylglucoronide metabolites. Therefore, carboxylic acid compounds which are less prone to acylgluconoride formation are expected to be less toxic. As measured using established in vitro assay systems, certain desirable compounds of the disclosure are less prone to acylglucoronidation than NSAID compounds that remain on the market are regarded as safe (e.g., flurbiprofen).
Example 4
Synthesis of 2-( 5-chloro-6-(2,2,2-trifluoroethoxy)-4 '-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl-
2-methyl propanoic acid
A. Ethyl 2-(3-chloro-4-hvdroxyphenyl) acetate
[0249] To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g) in 250 ml of DCM were added sulfuryl chloride (9.48 mL) and diethyl ether (19.6 mL) at 0 °C under nitrogen atmosphere and the resultant mixture was stirred for 1 h. After complete consumption of stating material, the reaction mixture was poured into crushed ice and extracted with DCM (2x100 mL). The combined organic layers were washed with 10% NaHC03 (50 mL) solution followed by water (50 mL), dried over Na2S04, filtered and evaporated under vacuum to afford ethyl 2-(3- chloro- 4-hydroxyphenyl) acetate (18.6 g, 62%) as an off white solid.
B. Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl) acetate
[0250] To a stirred solution of ethyl 2-(3-chloro-4-hydroxyphenyl) acetate (56 g) in 700ml of CC14 at -10 °C, was slowly added solution of bromine (13.4 mL) in 150 mL of CC14 at -10 °C over 30min. The reaction mixture was stirred for a further hour at -10°C and after complete consumption of starting material, the reaction mixture was quenched with saturated Na2S203 and extracted with DCM (3x200 mL). The combined organic layers were washed with water (100 mL), dried over Na2S04 filtered and evaporated under reduced pressure to afford ethyl 2-(3- bromo-5- chloro-4-hydroxyphenyl) acetate (47.1 g, 62%>) as a white solid.
C. Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate
[0251] To a room temperature stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl) acetate (15 g,), potassium carbonate (17.12 g) in dry DMF (75 mL), was slowly added
trifluoroethyl iodide (25 mL). The reaction mixture was heated to 100 °C for 24 h and after complete consumption of starting material, the reaction mixture was poured into ice water and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water (35 mL), dried over Na2S04 and evaporated under reduced pressure. The crude material was purified by column chromatography over silica gel (hexane/EtOAc) to afford ethyl 2-(3-bromo- 5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (8.11 g, 43 % yield) as an off white solid.
D. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)acetate
[0252] To a room temperature stirred solution of ethyl 2-(3-bromo-5-chloro-4-(2,2,2- trifluoroethoxy)phenyl)-acetate (5.1 g) in 1 ,2-dimethoxyethane (50 ml) were added 4- trifluoromethyl phenylboronic acid (5.14 g), Pd (PPh3)4 (1.57 g), cesium fluoride (5.13 g) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After complete consumption of starting material, the reaction mixture was filtered through celite bed, the filtrate was diluted with water and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by column chromatography over silica gel (hexane/EtOAc) to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl- 3-yl)acetate (4.0 g, 72 % yield) as a white solid.
E. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)-3- cvclobutyl propanoate
[0253] To a -10°C stirred suspension of NaH (60% wt. in paraffin oil, 1.09 g) in anhydrous DMF (75 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)bipheny 1-3 -yl) acetate (10 g) and cyclobutane methyl bromide (2.8 mL) under a nitrogen atmosphere. The reaction mixture was stirred an additional 2 h at -10 °C. and after complete consumption of starting material, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x30mL). The combined organic layers were washed with water (2x25mL), brine (20mL), dried over MgS04, filtered and evaporated under reduced pressure to give a colorless oil. The oil was purified by flash column chromatography to yield ethyl 2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl propanoate (8 g, 70% yield) as a thick colorless syrup..
F. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutyl-2-methylpropanoate
[0254] To a 0°C stirred suspension of NaH (60%> wt. in paraffin oil, 12.79 g) in anhydrous DMF (350 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-
(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl propanoate (65 g) and methyl iodide (45.42 g) under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0 °C and allowed to warm up to room temperature and stirred for an additional 12 h. The reaction mixture was then diluted with water (25 mL) and extracted with EtOAc (3xl50mL). The combined organic layers were washed with water (2xl00mL), brine (100 mL), dried over MgS04, filtered and evaporated under reduced pressure to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-
(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl-2-methylpropanoate (46 g) as thick colorless syrup, which was used to next step without further purification.
G. 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)-3-cvclobutyl-2- methyl propanoic acid
[0255] To a stirred solution of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl-2-methylpropanoate (35 g) in MeOH/THF/Water (1 : 1 : 1) (600 mL) was added lithium hydroxide monohydrate (28.16 g, 670 mmol) at room temperature. The reaction mixture was heated to 80 °C for 4 h and then the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2x500 mL). The combined organic layers were washed with water, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography to yield 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl-2-methyl propanoic acid (28.24 g, 85%) as a white solid. The enantiomers were separated using chiral preparative HPLC purification: Enantiomer 1 : 1H-NMR (DMSO-D6, 500MHz): 12.56 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.46 (d, 1H); 7.26 (d, 1H); 4.30 (q, 2H); 2.23-2.20 (m, 1H); 2.10-1.98 (m, 2H); 1.90- 1.85 (m, 1H); 1.82- 1.70 (m, 2H); 1.68- 1.60 (m, 2H); 1.58- 1.50 (m, 1H); 1.45 (s, 3H); Chiral HPLC: >98% ee at 9.66 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes). Enantiomer 2: 1H-NMR (DMSO-D6, 500MHz): 12.56 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.46 (d, 1H); 7.26 (d, 1H); 4.30 (q, 2H); 2.30-2.20 (m, 1H); 2.12-1.98 (m, 2H); 1.96- 1.89 (m, 1H); 1.84- 1.70 (m, 2H); 1.69- 1.62 (m, 2H); 1.60- 1.52 (m, 1H); 1.45 (s, 3H); Chiral HPLC: >98% ee at 12.44 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes). Example 5
Synthesis of 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4 '-(trifluoromethyl)-[l,l '- biphenyl]-3-yl)-2-(cyclobutylmethyl)butanoic acid
A. 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy
propanoic acid
[0256] To a stirred solution of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl propanoate (7.5 g) in MeOH/THF/Water (1 : 1 : 1) (75 mL) was added lithium hydroxide monohydrate (3.1 g) at room temperature. The reaction mixture was stirred for 3 h at room temperature and then the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HC1 solution and extracted with ethyl acetate (2x35 mL). The combined organic layers were washed with water, dried with Na2S04, filtered and evaporated. The residue was washed with pentane to yield 2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl propanoic acid (5.5 g, 79 %) as a white solid: 1H-NMR (CDC13, 400MHz): 7.73 (d, 2H), 7.68 (d, 2H), 7.41 (d, IH); 7.21 (d, IH); 3.98 (q, 2H); 3.5 (t, IH); 2.29-2.18 (m, 2H); 2.10-1.75 (m, 4H); 1.70- 1.52 (m, 3H); Mass: 481 [M+l].
B. 2-(5-Chloro-6-(2,2,2-trifluoroethoxy -4,-(trifiuoromethvn-r 1.1 '-biphenyl1-3-yl)-2- (cyclobutylmethyl)butanoic acid
[0257] To a -78°C stirred solution of DIPEA (0.231 g) in THF (10 mL) was added n-BuLi (2.5 M, 0.912 mL) under nitrogen atmosphere. The reaction mixture was warmed to -30 °C and stirred for 45 min. The reaction mixture was then cooled back to -78 oC and 2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutyl propanoic acid (0.550 g, 1.14 mmol) in THF (5 mL) was added. The reaction mixture was then stirred at -78 °C for additional 45 minutes before ethyl iodide (0.354 g, 2.29 mmol) was added. The resulting mixture was then stirred for 4 h at room temperature and then quenched with sat. NH4C1 and extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water, dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC yield 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-3-yl)-2- (cyclobutylmethyl)butanoic acid (0.1 g, 17 %) as a white solid: 1H-NMR (CDC13,
500MHz):7.70 (d, 2H); 7.58 (d, 2H), 7.40 (d, IH); 7.18(d, IH); 3.48 (q, 2H); 2.30-2.18 (m, 2H); 2.10-2.00 (m, IH); 1.99- 1.85 (m, 3H); 1.83- 1.76 (m, 2H); 1.70- 1.58 (m, 3H); 1.82 (t, 3H). Example 6
Synthesis of 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4 '-(tri fluoromethyl)biphenyl-3- yl)-3-cyclopropyl-2-methylpropanoic acid
A. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)-3- cyclopropyl propanoate
[0258] To a -10°C stirred suspension of NaH (60% wt. in paraffin oil, 0.109 g) in anhydrous DMF (50 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (1.0 g) and cyclopropyl methyl bromide (0.24 mL, 2.5 mmol) under a nitrogen atmosphere. The reaction mixture was stirred an additional 2 h at -10 °C and then diluted with water (25 mL) and extracted with EtOAc (3x30mL). The combined organic layers were washed with water (2x25mL), brine (20mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to yield ethyl 2- (5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropyl propanoate (0.68 g, 57%) as thick syrup.
B. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethvnbiphenyl-3-vn-3- cyclopropyl -2 -methylpropanoate
[0259] To a 0°C stirred suspension of NaH (60%> wt. in paraffin oil, 1.012 g) in anhydrous DMF (50 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3 -cyclopropyl propanoate (5 g) and methyl iodide (3.59 g) under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0 °C and then stirred at an additional 12 h at RT. The reaction mixture was then diluted with water (25 mL) and extracted with EtOAc (3x35mL). The combined organic layers were washed with water
(2x20mL), brine (20 mL), dried over MgS04, filtered and concentrated in vacuo to yield ethyl 2- (5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropyl-2- methylpropanoate (4 g) as thick colorless syrup, which was used to next step without further purification.
C. 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethynbiphenyl-3-yl)-3-cyclopropyl- 2-methylpropanoic acid
[0260] To a room temperature stirred solution of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3 -cyclopropyl -2 -methylpropanoate (1 g) in MeOH/THF/Water (1 : 1 : 1) (35 mL) was added lithium hydroxide monohydrate (0.413 g). The reaction mixture was stirred for 4 h at 80 °C and then the volatiles were removed under reduced pressure. The residue was then diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate
(2x25 mL). The combined organic layers were washed with water, dried with Na2S04, filtered and then concentrated in vacuo. The residue was purified by flash column chromatography to yield 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropyl-2- methylpropanoic acid (850 mg, 90%) as a white solid. The enantiomers were separated using chiral preparative HPLC purification. Enantiomer 1 : 1H-NMR (CDC13, 500MHz): 7.72 (d, 2H); 7.63 (d, 2H), 7.42 (d, 1H); 7.22 (d, 1H); 3.98 (q, 2H); 2.98-2.86 (m, 2H); 1.68 (s, 3H); 0.61-0.59 (m, 1H); 0.50-0.48 (m, 2H); 0.10.05( m, 2H); Chiral HPLC: >98% ee at 10.50 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes). Enantiomer 2: 1H-NMR (CDC13, 500MHz): 7.72 (d, 2H); 7.63 (d, 2H), 7.42 (d, 1H); 7.22 (d, 1H); 3.98 (q, 2H); 2.98-2.86 (m, 2H); 1.68 (s, 3H); 0.61-0.59 (m, 1H); 0.50-0.48 (m, 2H); 0.10.05( m, 2H); Chiral HPLC: >98% ee at 10.50 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ ; (n-Hexane: IPA (98:2); 0.1% TFA in n-Hexanes).
Example 7
Synthesis of 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4 '-(trifluoromethyl)biphenyl-3-yl)-2- cyclopentyl propanoic acid
A. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy -4,-(trifluoromethvn-r 1.1 '-biphenyl1-3-yr)-2- cvclopentylacetate
[0261] To a -10°C stirred suspension of NaH (60%> wt. in paraffin oil, 1.09 g) in anhydrous DMF (75 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (10 g) and cyclopentyl bromide (2.67 mL) under a nitrogen atmosphere. The reaction mixture was stirred a further 2 h at -10 °C and then diluted with water (25 mL) and extracted with EtOAc (3x30mL). The combined organic layers were washed with water (2x25mL), brine (20mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to yield ethyl 2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-3-yl)-2-cyclopentylacetate (8 g, 70%> yield) as thick colorless syrup.
B. Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy -4,-(trifluoromethvn-r 1.1 '-biphenyl1-3-vn-2- cyclopentylpropanoate
[0262] To a 0°C stirred suspension of NaH (60%> wt. in paraffin oil, 0.35 g) in anhydrous DMF (20 mL) was added a mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)- [Ι,Γ- biphenyl]-3-yl)-2-cyclopentylacetate (1.5 g) and methyl iodide (45.42 g) under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0 °C and then an additional 36 h at
RT. Then the reaction mixture was diluted with water (10 mL) and extracted with EtOAc
(2x20mL). The combined organic layers were washed with water (2x1 OmL), brine (10 mL), dried over MgSC^, filtered and concentrated in vacuo to yield ethyl 2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)-[l, -biphenyl]-3-yl)-2-cyclopentylpropanoate (1 g) as a thick colorless syrup, which was used to next step without further purification.
C. 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4,-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentyl propanoic acid
[0263] To a room temperature stirred solution of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)-[l, -biphenyl]-3-yl)-2-cyclopentylpropanoate (1.5 g) in MeOH/THF/Water (1 : 1 : 1) (50 mL) was added lithium hydroxide monohydrate (1.2 g). The reaction mixture was heated to 80 °C for 4 h and then all the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography to yield 2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentyl propanoic acid (1 g) as a white solid. The enantiomers were separated using chiral preparative HPLC purification: Enantiomer 1 : 1H-NMR (DMSO-D6, 500MHz): 12.60 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.57 (d, 1H); 7.37 (d, 1H); 4.30 (q, 2H); 2.78-2.70 (m, 1H); 1.72-1.63 (m, 1H); 1.58- 1.48 (m, 4H); 1.46 (s, 3H); 1.41- 1.30 (m, 2H); 1.18- 0.90 (m, 1H); Chiral HPLC: >98% ee at 5.7 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ; (n-Hexane: IPA (95:5); 0.1% TFA in n-Hexanes). Enantiomer 2: 1H- NMR (DMSO-D6, 500 MHz): 12.60 (s, 1H); 7.82 (d, 2H); 7.74 (d, 2H), 7.57 (d, 1H); 7.37 (d, 1H); 4.30 (q, 2H); 2.78-2.70 (m, 1H); 1.72-1.63 (m, 1H); 1.58- 1.48 (m, 4H); 1.46 (s, 3H); 1.41- 1.30 (m, 2H); 1.18- 0.90 (m, 1H); Chiral HPLC: >98% ee at 12.77 min. Column; Chiral Pak IA, 250x4.6 mm, 5 μ; (n-Hexane: IPA (95.5); 0.1% TFA in n-Hexanes).
Incorporation By Reference
[0264] The patent and scientific literature referred to herein establishes knowledge that is available to those of skill in the art. The issued U.S. patents, allowed applications, published foreign applications, and references, including database sequences, that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference.
Equivalents
[0265] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents were considered to be within the scope of this invention and are covered by the following claims. Moreover, any numerical or alphabetical ranges provided herein are intended to include both the upper and lower value of those ranges. In addition, any listing or grouping is intended, at least in one embodiment, to represent a shorthand or convenient manner of listing independent embodiments; as such, each member of the list should be considered a separate embodiment.

Claims

What is claimed is:
1. A compound of Formula I or II
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof,
wherein:
A is C02H;
Ri is selected from the group consisting of (Ci-C6)alkyl, (C3-Cy)cycloalkyl, -(CH2)0_iOR6 and -(CH2)o_iSR6,
R2 is independently selected from the group consisting of: (a) (Ci-C6)alkyl, (b) (C0- C3)alkyl-(C3-Cy)cycloalkyl, (c) a Ci-C6 alkyl that is independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, (d) (C3-C7)cycloalkyl, (e) (Co-C3)alkyl-(C3-C7)cycloalkyl, (f) heterocycloalkylalky, and (g) (CH2)nQ wherein n= 0-2 and wherein Q is a monocyclic or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from the group consisting of alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio and alkylsulfonyl,
wherein each alkyl or cycloalkyl of Ri and R2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, or C1-C4 alkyl;
R6 is selected from the group consisting of H, Ci-C6 alkyl and (C3-C7)cycloalkyl;
each R7 is independently selected from the group consisting of Ci-C6 alkyl, alkoxyethyl, (C3-C7)cycloalkyl, (Co- C3)alkyl-(C3-C7)cycloalkyl, heterocycloalkylalkyl and (CH2)nQ, wherein n= 0-2 and wherein Q is a mono or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C and wherein Q is optionally substituted with up to 3 groups independently selected from the group consisting of alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, N02, alkylthio, and alkylsulfonyl; or in the case when two R7 are attached to the same N and are both alkyl, they can be taken together to form a 5- membered or 6-membered ring optionally containing O, S, N(H) or N-alkyl;
X is a bond or a divalent linking group selected from the group consisting of -0-,
-OCH2-, -OCH(R7)-, - CH(R7)0-, - OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-,
-CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-,
-C(0)N(R7)-, -NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-,
-N(H)S(0)2-, and -N(R7)S(0)2- wherein the point of attachment of divalent linking
groups, X, to R3 in the Formulas I and II is to the right;
Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -OCH(R7), -CH(R7)0-, -OCH2CH2-, -CH2-, -C(O)-, -CH=CH-, -CH2CH2-, -CH20-, -CH2OCH2-, -CH2CH20-, -S-, -SCH2-, -CH2S-, -CH2SCH2-, -C(0)NH-, -C(0)N(R7)-, -NHC(O)-, -N(R7)C(0)-, -S(O)-, -S(02)-, -S(0)2N(H)-, -S(0)2N(R7)-, -N(H)S(0)2- and -N(R7)S(0)2-, wherein the point of attachment of divalent linking groups, Y, to R4 in the Formulas I and II is to the right;
R3 is selected from the group consisting of:
(a) Ci-C7 alkyl optionally and independently interrupted by one or more -0-, -S-, -S(O)-, and -S(0)2- groups,
(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl, and
(d) Z, wherein Z is a mono-or bi-cyclic ring system having 3 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6;
R4 is selected from the group consisting of:
(a) Ci-C7 alkyl group optionally and independently interrupted by one or more - 0-, -S-, -S(O)-, or -S(0)2- groups,
(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,
(c) heterocycloalkylalkyl, and (d) Z, wherein Z is a mono-or bi-cyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, R6, CF3, CN, N02, OH, Ci-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRs, S(0)R6, S(0)2Rs, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6; and
R5 is selected from the group consisting of N02, NH2, aryl, heteroaryl, F, CI, Br, CN, OH, C1-C4 alkoxy, SR6, S(0)2R6, S(0)2N(R7)2, (C1-C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, -O(C0- C3alkyl)(C3- C7)cycloalkyl and (C2-C4) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl,
provided that one or both of R3 and R4 is Z.
2. The compound of claim 1 having a formula selected from the group consisting of Formula III, Formula IV, Formula V Formula VI, Formula VII, Formula VIII and Formula IX
Figure imgf000067_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 having Formula III, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 having Formula IV, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 2 having Formula V, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 2 having Formula VI, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 2 having Formula VII, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 2 having Formula VIII, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 2 having Formula IX, or a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1-9 wherein Ri is (Ci-C6)alkyl or (C3- C7)cycloalkyl, or a pharmaceutically acceptable salt thereof.
11. The compound of any one of claims 1-10 wherein Ri is (Ci-C6)alkyl, or a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1-10 wherein Ri is (Ci-C3)alkyl, or a pharmaceutically acceptable salt thereof.
13. The compound of any one of claims 1-10 wherein Ri is methyl or ethyl, or a
pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1- 10 wherein Ri is -SR6 or -OR6, or a pharmaceutically acceptable salt therof.
15. The compound of any one of claims 1-13 wherein R2 is (Co-C3)alkyl-(C3- C7)cycloalkyl, or a pharmaceutically acceptable salt thereof.
16. The compound of any one of claims 1-13 wherein R2 is -(C3-Cy)cycloalkyl or -CH2-(C3-
Cy)cycloalkyl, or a pharmaceutically acceptable salt thereof.
17. The compound of any one of claims 1-13 wherein R2 is selected from the group consisting of cyclopentyl, cyclopropylmethyl and cyclobutylmethyl, or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1-17 wherein R3 is a C1-C7 alkyl independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, or a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1-17 wherein R4 is a C1-C7 alkyl group independently interrupted by one or more -0-, -S-, -S(O)-, or -S(0)2- groups, or a pharmaceutically acceptable salt thereof.
20. The compound of any one of claims 1-17 wherein R3 is (Co-C3)alkyl-(C3- C7)cycloalkyl or heterocycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1-17 wherein R4 is (Co-C3)alkyl-(C3- C7)cycloalkyl or heterocycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
22. The compound of any one of claims 1-17 wherein R3 is (Co-C3)alkyl-(C3- C7)cycloalkyl or heterocycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
23. The compound of any one of claims 1-17 wherein R4 is (Co-C3)alkyl-(C3- C7)cycloalkyl or heterocycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
24. The compound of any one of claims 1-19 and 21 wherein:
R3 is Z, wherein Z is a monocyclic or bibcyclic ring system having 3 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRe, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6,
N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6,
or a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 1-20 and 22 wherein:
R4 is Z, wherein Z is a monocyclic or bicyclic ring system having 5 to 10 ring atoms independently selected from the group consisting of C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, OC(0)NHR7, OC(0)N(R7)2, SRe, S(0)R6, S(0)2R6, S(0)2NHR7, S(0)2N(R7)2, NHR7, N(R7)2, NHC(0)R6, N(R7)C(0)R6, NHC(0)OR6, N(R7)C(0)OR6 N(R7)C(0)NH(R7), N(R7)C(0)NH(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C02H, C02R6 and COR6,
or a pharmaceutically acceptable salt thereof.
26. The compound of any one of claims 1-25 wherein Z is monocyclic, or a pharmaceutically acceptable salt thereof.
27. The compound of any of claims 1-25 wherein Z is bicylic, or a pharmaceutically acceptable salt thereof.
28. The compound of any of claims 1-25 wherein Z is an aryl group, or a pharmaceutically acceptable salt thereof.
29. The compound of claim 28 wherein Z is an optionally substituted phenyl, or a
pharmaceutically acceptable salt thereof.
30. The compound of any one of claims 1-25 wherein Z is a heteroaryl group, or a
pharmaceutically acceptable salt thereof.
31. The compound of any one of claims 1-30 wherein X is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -CH2-, -C(O)-, -CH20-, -S-, -SCH2- and -CH2S-, wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I, II IV, V and VIII is to the right, or a pharmaceutically acceptable salt thereof.
32. The compound of any one of claims 1-30 wherein Y is a bond or a divalent linking group selected from the group consisting of -0-, -OCH2-, -CH2-, -C(O)-, -CH20-, -S-, -SCH2- and -CH2S-, wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I, II, III, VI, VII and IX is to the right, or a pharmaceutically acceptable salt thereof.
33. The compound of any one of claims 1-30 wherein Y is -0-, or a pharmaceutically acceptable salt thereof.
34. The compound of any one of claims 1-30 wherein Y is -S-, or a pharmaceutically acceptable salt thereof.
35. The compound of any one of claims 1-30 wherein Y is a bond, or a pharmaceutically acceptable salt thereof.
36. The compound of any one of claims 1-35 wherein X is -0-, or a pharmaceutically acceptable salt thereof.
37. The compound of any one of claims 1-35 wherein X is -S-, or a pharmaceutically acceptable salt thereof.
38. The compound of any one of claims 1-35 wherein X is a bond, or a pharmaceutically acceptable salt thereof.
39. The compound of any one of claims 1-38 wherein R5 is N02, NH2 , F, CI, Br, CN, OH, Ci- C4 alkoxy, (Co-C3)alkyl-(C3-C7)cycloalkyl, or (Ci-C4) alkyl, wherein each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, or Ci-C4 alkyl, or a pharmaceutically acceptable salt thereof.
40. The compound of any one of claims 1-38 wherein R5 is N02, NH2 , F, CI, Br, CN, OH, Ci- C4 alkoxy, (Co-C3)alkyl-(C3-C7)cycloalkyl, or (Ci-C4) alkyl, wherein each alkyl is optionally independently singly or multiply substituted with halo, or a pharmaceutically acceptable salt thereof.
41. The compound of any one of claims 1-38 wherein R5 is selected from the group consisting of F, CI, C1-C4 alkoxy and (C1-C4) alkyl, wherein each alkyl is optionally multiply and independently substituted with halo,
or a pharmaceutically acceptable salt thereof.
42. The compound of any one of claims 1 and 18-41 wherein one of Ri is (Ci-C6)alkyl and R2 is (Co-C3)alkyl-(C3-Cy)cycloalkyl, or a pharmaceutically acceptable salt thereof.
43. The compound of any one of claims 1 and 18-41 wherein one of Ri is (Ci-C6)alkyl and R2 is -(C3-Cy)cycloalkyl, or a pharmaceutically acceptable salt thereof.
44. The compound of any one of claims 1 and 18-41 wherein Ri is (Ci-C6)alkyl and R2 is -CH2- (C3-Cy)cycloalkyl, or a pharmaceutically acceptable salt thereof.
45. The compound of any one of claims 42-44 wherein Ri is (Ci-C3)alkyl, or a pharmaceutically acceptable salt thereof.
46. The compound of any one of claims 42-44 wherein Ri is methyl or ethyl, or a
pharmaceutically acceptable salt thereof.
47. The compound of claim 43 wherein R2 is cyclopentyl, or a pharmaceutically acceptable salt thereof.
48. The compound of claim 44 wherein R2 is cyclopentyl, cyclopropylmethyl or
cyclobutylmethyl, or a pharmaceutically acceptable salt thereof.
49. The compound of any one of claims 1 and 18-41 wherein Ri is -SCH3 and R2 is -CH2-(C3- Cy)cycloalkyl, or a pharmaceutically acceptable salt thereof.
50. The compound of any one of claims 1-49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6, SRg, NHRy, N(R7)2C02H, C02R6 and COR6, or a pharmaceutically acceptable salt thereof.
51. The compound of any one of claims 1 -49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of halogen, Κ , CF3, CN, N02, C1-C4 alkoxy, aryloxy, OCH2CH2OCH3i OC(0)R<5, OC(0)OR<5 and SR^, or a pharmaceutically acceptable salt thereof.
52. The compound of any one of claims 1-49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of halogen, 5, CF3, CN, N02, C1-C4 alkoxy, OCH2CH2OCH3, OC(0)R6, OC(0)OR6 and SR6.
53. The compound of any one of claims 1 -49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of halogen, Ci-C6 alkyl, (C0-C3)alkyl- (C3-Cy)cycloalkyl, CF3, C1-C4 alkoxy and SR6, or a pharmaceutically acceptable salt thereof.
54. The compound of any one of claims 1-49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C3 alkyl, (C3- C6)cycloalkyl, CF3, C1-C4 alkoxy, S-(Ci-C4)alkyl and S-(C0-C3)alkyl-(C3-C7)cycloalkyl, or a pharmaceutically acceptable salt thereof.
55. The compound of any one of claims 1-49 wherein Z is optionally substituted with up to 3 substituents independently selected from the group consisting of F, CI, Ci-C3 alkyl, (C3- C6)cycloalkyl, CF3, C1-C4 alkoxy and S-(Ci-C3)alkyl, or a pharmaceutically acceptable salt thereof.
56. The compound of any one of claims 1-49 wherein Z is substituted with up to 3
substituents independently selected from the group consisting of CF3, OCF3, OCH2CF3, F, CI, SMe, Me, Et and i-Pr, or a pharmaceutically acceptable salt thereof.
57. The compound of any one of claims 1-49 wherein Z is substituted once with CF3, OCF3, OCH2CF3, F, CI, SMe, Me, Et or iPr, or a pharmaceutically acceptable salt thereof.
58. The compound of any of claims 1-26, 28-29 and 31-57 wherein Z is a 4-substituted phenyl, or a pharmaceutically acceptable salt thereof.
59. The compound of example 4, 5, 6 or 7, or a pharmaceutically acceptable salt thereof.
60. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt of any one of claims 1-59 and a pharmaceutically acceptable carrier or excipient.
61. A method for treating a neurodegenerative disorder comprising administering to a patient and effective amount of the pharmaceutical composition of claim 60.
62. The method of claim 61 wherein the disorder is Alzheimer's disease.
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