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WO2008119773A1 - Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases - Google Patents

Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases Download PDF

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WO2008119773A1
WO2008119773A1 PCT/EP2008/053767 EP2008053767W WO2008119773A1 WO 2008119773 A1 WO2008119773 A1 WO 2008119773A1 EP 2008053767 W EP2008053767 W EP 2008053767W WO 2008119773 A1 WO2008119773 A1 WO 2008119773A1
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mmol
methyl
compound
nmr
mhz
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Ingemar KVARNSTRÖM
Marcus BÄCK
Veronica Sandgren
Stefan Oscarson
Catarina BJÖRKLUND
Åsa ROSENQUIST
Bertil Samuelsson
Per-Ola Johansson
Ismet Dorange
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07C2601/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE). It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their in the preparation of a medicament or their use in therapy.
  • aspartyl proteases such as ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE).
  • a number of aspartic proteases are known to date, including pepsin A and C, Renin, BACE, BACE2, Napsin and Cathepsin D, which have been implicated in pathological conditions.
  • aspartyl protease BACE causesthe production of the protein ⁇ amyloid (A ⁇ ) in the brain, which is characteristic of Alzheimer's disease (AD).
  • AD is a progressive neurogdegenerative disease of the brain characterized by gradualloss of cognitive function related to memory, reasoning, orientation and judgement and eventually death.
  • Pathologicalfeatures of AD is accumulation of abnormal aggregated protein breakdown products, ⁇ -amyloid plaque and neurofibrillary tangles, in the brain.
  • Plaque relatively specific for AD is primary a result from extracellular accumulation of aggregated A ⁇ .
  • Fibrillary tangles consists mainly of hyperphosphorylated tau protein and are also found in other neurodegenerative disorders. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioural decline.
  • a ⁇ is a peptide comprised of 40-42 amino acid residues, which is formed by proteolytic cleavage of the large transmembrane amyloid precursor protein (APP).
  • APP large transmembrane amyloid precursor protein
  • APP is processed along two pathways, the major ⁇ - and the minor ⁇ -secretase pathway.
  • the ⁇ -secretase pathway results in nonpathogenic products known as soluble APP, whereas the ⁇ - secretase pathway producespathogenic A ⁇ peptides by cleavage by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , followed by cleavage by ⁇ -secretase at the C-terminus.
  • a ⁇ amyloid cascade hypothesis, supported by genetic and pathological evidence, claims that the formation of A ⁇ plays an early and vital role in all cases of AD.
  • a ⁇ forms aggregates that are thought to initiate a pathogenic cascade that leads to neuronal loss and dementia.
  • BACE was identified a few years ago as a type 1 glycosylated transmembrane homodimer with two aspartic acids at the active catalytic site.
  • BACE and BACE-2 (64 % amino acid sequence similarity to BACE) constitute a novel class of aspartic proteases closely related to the pepsin family.
  • the function of BACE-2 is relatively unknown and several studies indicate that this enzyme is not involved in the A ⁇ generation.
  • BACE knockout homozygote mice show complete absenceof producing A ⁇ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that ⁇ -secretase is expressed in all tissues but at highest levels in the neurons in the brain. Therefore, in vivo inhibition of BACE is likely to reducethe production of A ⁇ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
  • aspartyl protease inhibitors which can be represented by the formula (I):
  • R 2 is H or Ci-Cealkyl
  • R is Ci-C ⁇ alkoxy, Ci-C ⁇ alkoxyCi-C ⁇ alkoxy, -O-Co-C ⁇ lkanediylaryl, -0-Co-
  • R is Ci-C ⁇ alkyl and R is H; or R and R together with the carbonatom to which they are attached define C 3 -C6cycloalkyl;
  • Ci-C 3 alkanediylNRaRb aryl, heterocyclyl, C 3 -C6cycloalkyl, Ci-C 3 alkanediylC 3 -C6cycloalkyl, Ci-C 3 alkanediylaryl, Ci- C3alkanediylheterocyclyl, Ci-C3alkanediyl-0-Co-C3alkanediyl aryl or Ci-C 3 alkanediyl-O-C 0 - C3alkanediyl heterocyclyl; wherein the Ci-C3alkanediylmoietyis optionally substituted with Ci-C ⁇ alkyl; R 8 is H, Ci-Cealkyl; or
  • R and R together with the N atom to which they are attached define a heterocyclyl group;
  • R 9 is H, Ci-Cioalkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 3 alkyl, Ci- C6alkoxyCi-C6alkoxyCo-C3alkyl Ci-CioalkanediylC3-C6cycloalkyl, Ci-Cioalkanediylaryl or Ci- Cio alkanediylheterocyclyl;
  • E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)-, -CH(Rd)-NRd-, -NRd-NRd-, -CH(Rd)-O-, -0-CH(Rd)- -CH(Rc)-, -NRe-, or -O-;
  • Q is aryl or heterocyclyl;
  • W is H, Ci -C ⁇ alkyl, C3-C6cycloalkyl, aryl or heterocyclyl;
  • X' is H, F, OH, or NRaRb;
  • X" is H or when X' is F, X" can also be F;
  • Y is H, Ci-Cealkyl, C 0 -C 3 alkanediylaryl, C 0 -C 3 alkankediylC 3 -C 6 cycloalkyl or C 0 - C3 alkankediylheterocyclyl;
  • ring A is a saturated, partially unsaturated or aromatic ring;
  • m is O or 1 , wherebyring A defines a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or a phenyl ring;
  • n is O, 1, 2 or 3;
  • p is 0 or 1 ;
  • q is 0, 1 or 2; thereby defining a bond, methylene or ethylene, or when q is 1, the methylenemay alternatively be a 1 , 1 -cyclopropyl group;
  • r is 0, 1 or
  • Ra is independently H or Ci-C ⁇ alkyl
  • Rb is H or Ci-C ⁇ alkyl; or Ra and Rb together with the nitrogen atom to which they are attached define a heterocyclyl group;
  • Rc is H, Ci-Cyalkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 6 alkoxyCi -C 6 alkoxy, hydroxyCo-Csalkyl or C 0 -C 3 alkanediy INRaRb, O-Ci-C 5 alkanediylC 3 -C 6 cycloalkyl;
  • Rd is H, Ci-Cvalkyl, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxyCi-C 3 alkyl, hydroxyCi- C 3 alkyl or Ci-C 3 alkandiylNRaRa;
  • Re is H, Ci-Ci O alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkylnyl, Ci-Ci 0 alkoxy or Ci-Ci 0 alkanediylC 3 - C ⁇ cycloalkyl; or Re and R together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted with Ci-Ci O alkyl, C 2 -Ci 0 alkenyl, C 2 - Cioalkylnyl, C 3 -C6cycloalkyl, C 0 -C 3 alkanediylaryl or C 0 -C 3 alkanediylheterocyclyl; where aryl is independently phenyl, naphthyl or phenyl fused to Cs-C ⁇ cycloalkyl or Cs- C ⁇ cycloalkenyl; aryl
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excessof 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R is attached has the stereochemistry shown in the partial structure:
  • Z is O.
  • Z is NRa, whereinRa is hydrogen or Ci-C3alkyl, preferably hydrogen or methyl.
  • the group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively.
  • Q is bonded to Z via a methylene moiety, i.e. n is 1.
  • Q is bonded directly to Z, i.e. n is 0.
  • Q is aryl or heterocyclyl, which is optionally substituted with one, two or three substituents as defined above. Accordingto some embodiments of the invention Q is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl.
  • Q is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-C ⁇ cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclicheterocyclyl examples include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • Q is an optionally substituted monocyclicring, such as an optionally substituted 5 or 6-membered aryl or heterocyclyl,preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
  • Representative values for the optional substituents to Q include one or two substituents independently selected from Ci -C4alkyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-C3alkoxyCi- C ⁇ alkoxy, halo, haloCi-C4alkyl and Ci-C3alkanediylaryl, Currently favoured values include halo such as mono- di or trifluoro, chloro and bromo; and haloCi-C4alkyl for example trifluoromethyl.
  • Q is a monosubstituted 6-membered aryl or heterocyclyl, wherein the substituent preferably is in the meta or para position.
  • Q is meta or para substituted phenyl.
  • Preferred substituents according to this embodiment include bromo and fluoro.
  • Q is disubstituted phenyl with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position.
  • Preferred substituents to Q according to this embodiment are independently chloro, fluoro, bromo and methyl.
  • favoured configurations for Q include optionally substituted phenyl, such as bromosubstituted phenyl and mono-, di- or trifluoro substituted phenyl, especially difluorosubstituted phenyl and monobromo substituted phenyl.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • the chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
  • X" X' X' and X" are as defined above, preferably X' is fluoro, or more preferably hydroxy.
  • X' and X" are both fluoro.
  • the chiral centre wheretothe group R is attached has the stereochemistry shown in the partial structure:
  • R 3 is as defined above. Typical values for R 3 include optionally substituted C r C 6 alkoxy such as optionally substituted methoxy, ethoxy and propoxy.
  • R 3 is Q-Cgalkoxy, especially methoxy.
  • R 3 include optionally substituted Ci-C 6 alkoxy-C r C 6 alkoxy such as optionally substituted methoxypropoxy and methoxyethoxy.
  • Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di and trifluoro.
  • the invention includes compounds of general formula (I) whereinp is 0 or 1, i.e. compounds according to structures (Ia) and (Ib) respectively:
  • the invention further includes compounds wherein both p and q are 0, i.e. compounds according to the structure (Ic):
  • R is Ci-C 6 alkyl, such as isopropyl.
  • R is preferably hydrogen.
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in formula
  • ring A in general formula (I) is a six membered ring, i.e. m is 1.
  • Representative values for ring A according to these embodiments include cyclohexyl and phenyl, preferably phenyl.
  • ring A is a five membered ring, i.e. m is 0.
  • Preferred values for ring A according to these embodiments include cyclopentenyl and cyclopentyl, preferably cyclopentyl.
  • R examples include hydrogen and Ci-C ⁇ alkyl, especially hydrogen or methyl.
  • D is or
  • R is as recited above. Typical values for R include Ci-C ⁇ alkyl, Ci-C3alkanediylaryl or Ci- Csalkanediylheterocyclyl, wherein each Ci-C ⁇ alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi- C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • a further favoured configuration for R includes Ci-C3alkanediylaryl, whereinthe C 1 - Csalkanediyl moiety is optionally substituted with R , preferred values for R include C 1 - C4alkyl, such as ethyl or preferably methyl.
  • R include benzyl, 1-phenylethyl and 1-phenylpropyl, especially benzyl and 1-phenylethyl, wherein the phenyl ring is optionally substituted.
  • the substituent(s) are in the para and/or ortho position of the phenyl ring.
  • a further configuration for R include Ci-C3alkandiylaryl and Ci-C3alkanediylheterocyclyl, wherein the Ci-C3alkandiyl moiety is optionally substituted with Ci-C ⁇ alkyl.
  • Preferred configurations for the Ci-C ⁇ alkyl according to this embodiment include Ci-C4alkyl such as methyl or ethyl; haloCi-C4alkyl, such as trifluoromethyl and C3-C4cycloalkyl such as cyclopropyl.
  • the optional substituents to the aryl, heterocyclyl and alkyl moieties of R 7 are as defined above.
  • Representative values include one or two substituents independently selected from Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C4alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • R include a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include Cs-Cyalkyl, Ci-C3alkoxy-Ci-C3alkoxy, such as methoxyethoxy, or Ci-C3alkoxy- Ci-C3alkyl, such as 3-methoxypropyl or 2-methoxyethyl
  • R is as recited above, preferably hydrogen or methyl.
  • a further embodimentof the invention include compounds of formula (I) wherein R and R together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl group, for example optionally substituted pyrrole, piperidine or morpholine.
  • R and R are both Ci-C ⁇ alkyl, such as ethyl, propyl or butyl.
  • Link E between ring A and the unit CH(Y)(R 7 R 9 ) is as defined above.
  • the link E is -CH(Rc)-, -NRe- or -O-, in which case the compounds of the invention have one of the partial structures: wherein Rc, Rd, R and Y are as defined above.
  • one of R 9 and Rc in formula (Ha), one of R 9 and Re in formula (lib) and R 9 in formula (lie) is a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include C 5 -C 7 alkyl, Ci-C 3 alkoxy-Ci-C 3 alkoxy, such as methoxyethoxy, or Ci-C 3 alkoxy-Ci-C 3 alkyl, such as 3- methoxypropyl or 2-methoxyethyl.
  • the other one of Rc and R 9 in formula Ha and Re and R 9 in formula lib is preferably hydrogen or methyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
  • Typical configurations for partial structure (Ha) include those wherein Rc is Ci-C 6 alkoxy, O-Ci- C 6 alkanediylC 3 -C 6 cycloalkyl, O-Ci-C 6 alkanediylaryl or O-Ci-C 6 alkanediylheterocylyl wherein the cycloalkyl, aryl or heterocyclyl moiety is optionally substituted, R 9 is hydrogen or C r C 6 alkyl such as methyl, and Y is C 0 -C 3 alkanediylaryl or C 0 -C 3 alkanediylheterocyclyl wherein the aryl and heterocyclyl moieties are optionally substituted as defined above.
  • Rc is hydrogen
  • R is C 1 -Qalkoxy, O- C 1 -C 6 alkanediylC 3 -C 6 cycloalkyl, O-C r C 6 alkanediylaryl or O-C r C 6 alkanediylheterocylyl wherein the cycloalkyl, aryl and heterocyclyl moiety is optionally substituted
  • Y is C 0 - C 3 alkanediylaryl or C 0 -C 3 alkanediylheterocyclyl wherein the aryl and heterocyclyl moieties are optionally substituted as defined above.
  • Typical configurations for partial structure (lib) include those wherein Re and R are independently selected from Ci -Ci O alkyl, Q-Qoalkenyl, C 2 -Ci 0 alkylnyl, C r Ci 0 alkoxy and C 1 - C io alkanediylC 3 -C 6 cycloalkyl, any of which is optionally substituted as defined above.
  • Typical substituents for these configurations of (lib) include halo, hydroxy, phenyl, C r Ci 0 alkoxy and amino. Accordingto these configurations for partial structure (lib), Y is preferably H.
  • Preferred values for Re in partial structure (lib) include hydrogen and optionally substituted C 1 - Ci O alkyl;
  • R in partial structure (lib) is preferably Ci-C 3 alkyl, or Ci-C 3 alkyl substituted with C 3 - C 6 cycloalkyl, aryl or heterocyclyl; whereinthe C 3 -C 6 cycloalkyl, aryl or heterocyclyl is optionally substituted with C i-Qalkyl or halo; and Y is preferably H.
  • Further typical configurations for partial structure (lib) include those wherein R and Re together with the atoms to which they are attached form a 4-6 membered heterocyclic ring, which ring is optionally substituted as defined above, thus giving the partial structures:
  • E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)- CH(Rd)-NRd-,, NRd-NRd-, -CH(Rd)-O- or -0-CHRd-, in which case compounds of the invention have one of the partial structures:
  • Rc, Rd, R » 6 , r R. 9 and Y are as defined above.
  • one of the moieties Rc, Rd and R in each of the above partial structures is a carbon chain which chain is optionally interrupted by one or two oxygen atoms.
  • the chain length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include Ci-C3alkoxy- Ci-C3alkoxy, such as methoxyethoxy, or Ci-Csalkoxy-Ci-Csalkyl, such as 3-methoxypropyl or 2-methoxyethyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
  • Typical configurations for partial structure (Hi) include those whereinRd is hydrogen, R 9 is C 1 - C ⁇ alkyl, C2-C6alkenyl, C 2 -C6alkynyl, Ci-C ⁇ alkanediylCs-C ⁇ cycloalkyl, Ci-C ⁇ alkanediylaryl or Ci-C ⁇ alkanediylheterocyclyl, any of which is optionally substituted as described above.
  • Y is typically Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl.
  • a currently preferred value for E according to this embodiment is -CHRc-CHRc- i.e.
  • R is phenyl and Y is hydrogen.
  • a preferred embodimentof the invention includes compounds of formula (I) comprising any of the partial structures:
  • a further preferred value for E is -CH(Rd)-NRd-, i.e. corresponding to partial structure (Uf), wherein one of the Rd is C r C 6 alkyl or Q-Qalkoxy-Q-Qalkyl, such as 3-methoxypropyl or 2- methoxyethyl and the other is hydrogen or methyl.
  • Y is hydrogen, C r C 6 alkyl, C 0 -C 3 alkanediylC 3 -C 6 cycloalkyl, C 0 - C 3 alkanediylaryl or C 0 -C 3 alkanediylheterocyclyl, wherein each Ci-C 6 alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloC r C 4 alkyl, C r C 4 alkyl, C r C 4 alkoxy, hydroxy and cyano.
  • Preferred values for Y include hydrogen, C r C 6 alkyl especially methyl, ethyl or isopropyl; optionally substituted C 0 -C 3 alkanediylaryl or C 0 -C 3 alkanediylheterocyclyl,such as optionally substituted phenyl, optionally substituted benzyl or optionally substituted pyridyl.
  • the optional substituents to Y are as defined above. Representative values include C r C 4 alkyl such as methyl; halo such as fluoro; haloC r C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • the substituent(s) are conveniently in the para and/or ortho position.
  • favoured configurations for Y according to this embodiment include phenyl or pyridyl which is substituted in the para position.
  • the group W is bonded either directly to the amide nitrogen, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively.
  • W is bonded directly to the amide nitrogen or via a methylene moiety, i.e. q is 0 or 1 respectively.
  • the moiety linking W to the amide nitrogen may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
  • Preferred compounds according to this embodiment include those whereinp is 0 and W is phenyl or substituted phenyl, as shown in the structure below:
  • W is hydrogen, C r C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
  • W is optionally substituted Ci -C 6 alkyl such as methyl, ethyl or isopropyl.
  • Preferred substituents to W according to these embodiments include halo such as mono-, di- or trifluoro.
  • W is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl.
  • W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, C 3 -C 6 cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclicheterocyclyl examples include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl.
  • a further preferred value for W is cycloalkyl such as cyclopropyl.
  • W is a substituted 6-membered ring
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • Preferred configurations according to this embodiment include meta or para substituted phenyl, for example /?-fluoro phenyl.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C3 -C 4 cycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C4alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C3 -C 4 cycloalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C4alkyl such as methyl, ethyl and isopropyl.
  • 'Ci-C4alkyl' as a group or part of a group defines saturated straight or branched chain hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2 -propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl;
  • Ci-C4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-l- butyl, 2 -methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like.
  • Ci-Galkyl Ci-C 4 alkyl.
  • 'Ci -C n alkyl' whereinn is 7, 8, 9 or 10, encompasses Ci-C ⁇ alkyl radicals and the higher homologues thereof having 7, 8, 9 or 10 carbon atoms.
  • the term 'C2-C6alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one carbon-carbon double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1 - propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like.
  • C2-C6alkenyl is C2-C4alkenyl.
  • C2-C6alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one carbon-carbon triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2- propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C2-C6alkynyl is C2-C4alkynyl.
  • C3-C n cycloalkyl means a non aromatic all carbonring comprising 3 to n carbon atoms, wherein n is 3, 4 or 5, i.e. cyclopropyl, cyclobutyl or cyclopentyl.
  • the cycloalkyl may optionally be substituted with one or two substituents independently selected from Ci-C3alkyl, C2- Csalkenyl, C2-C3alkynyl and halo.
  • 'C 0 -C 3 alkanediyl' defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,2-propanediyl, and the like, especially methylene.
  • 'C 1 -C 3 alkanediyl' is a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,2-propanediyl, and the like, especially methylene.
  • 'C 2 -C 3 alkenediyl' defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1,2-propenediyl, and the like, especially vinyl ene.
  • 'C 2 -C 3 a lky ne diyl' defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
  • Ci -C ⁇ alkoxy means a radical O-Ci-C ⁇ alkyl whereinCi-C ⁇ alkyl is as defined above.
  • Ci -C ⁇ alkoxy of interest include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • Ci-C ⁇ alkyl as a group or part of a group, unless the context suggests otherwise, includes NH 2 , NHCi-C ⁇ alkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-C ⁇ alkyl is especially Ci -CA alkyl variants. Included are also radicals whereinthe two Ci-C ⁇ alkyl groups of the N(C 1 - C ⁇ -alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • 'Co-C3alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a Cs-C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1 ,3 -propanediyl group as defined for Ci-C3alkanediyl above.
  • aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a Cs-C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1 ,3
  • Suitable aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from Ci -Galkyl (optionally substituted with one or two substituents independently selected from Co- C 3 alkanediylaryl*, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-C6alkenyl, C 2 - Cealkynyl, C 3 -C 6 cyclolkyl, Ci-C 4 alkoxy, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 6 alkoxyCo- C 3 alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alky
  • 'C 2 -C 3 alkenediylaryl and 'C 2 -C 3 alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C 2 -C 3 alkenediyl' and 'C 2 _c 3 alkynediyl
  • 'Co-C 3 alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • Ci-C4alkyl optionally substituted with one, two or where valence allows three substituents independently selected from Ci -C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl*, amino, carbamoyl, amido and C 1 - C4alkoxyamido), C2-C6alkenyl, C 2 -C6alkynyl, Cs-C ⁇ cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- Csalkyl, Ci-C 4 alkoxyCi-C 6 alkoxyCo-C3alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl
  • C 2 -C 3 alkenediylheterocyclyl and 'C 2 -C 3 alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C 3 alkenediyl' and 'C 2 -C 3 alkynediyl
  • Heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclicring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • 'Co-C3alkanediylC3-C6cycloalkyl' as applied herein is meant to include a C3-C6cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2 -propanediyl or 1,3- propanediyl group as defined for Ci-C3alkanediyl above.
  • the cycloalkyl group may contain an unsaturated bond.
  • the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl*, amino, carbamoyl, amido and C 1 - C4alkoxyamido), C 2 -C6alkenyl, C 2 -C6alkynyl, C3-C6cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- C 3 alkyl, Ci-C 4 alkoxyCi-C 6 alkoxyCo-C3alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, nitro, Ci-C ⁇ alkylcarbonyl, a
  • 'C 2 -C 3 alkenediylC3-C7carbocyclyl and 'C 2 _c 3 alkynediylC3-C7carbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C 2 _c 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3 -pentyl.
  • each definition is independent.
  • prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo .
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parentcompound.
  • Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysableester is an ester, which is hydrolysed in the human or animal body to produce the parentacid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1 -cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C ⁇ alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysableester of a compound of the formula (I) containinga hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy acetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those whereinthe counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentionedhereinabove are meant to comprise the therapeuticallyactive non -toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic),malonic, succinic (i.e.
  • butanedioicacid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methane sulphonic, ethanesulphonic, benzenesulphonic,/?-toluenesulphonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceuticallyacceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) whereinone or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • Pure stereoisomeric forms of the compounds and intermediates as mentionedherein are defined as isomers substantially free of other enantiomeric or diastereomericforms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excessof 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excessof 90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomericmixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically .
  • the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as theiV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I) .
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or an prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as BACE.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N -oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the compounds of the present invention are also useful for the inhibition of BACE activity. Accordingly, a further embodimentof the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
  • the compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic! lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above mentioneddiseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • the pharmaceutical composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • the compounds of the present invention may be used in combination with one or more other pharmacological agents that treat, prevent, control ameliorate or reducethe risk for side effects or toxicity of the compounds of the present invention.
  • Such other pharmacological agents may be administered, by route and in amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention.
  • the pharmaceutical compositions of the present invention include those that contain one or more active ingredients, in addition to the compounds of the present invention.
  • the combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol whereinone or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
  • the present invention is also directed to combinations of the compounds of the invention with one or more pharmacologically active agents useful in the treatment and/or the prophylaxis of Alzheimer's disease.
  • combinations include combinations with anti -Alzheimer's agents, for example other BACE inhibitors or ⁇ -secretase inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies, including anti- amyloid humanized monoclonal antibodies; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • Scheme 1 illustratesa synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I). oxy-C-i-Cealkyl , C r C 3 alkanediylaryl or yl;
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid, such as sulphuric acid, in the presence of methanol.
  • a suitable acid such as sulphuric acid
  • the achieved free secondary hydroxy group can then be transformed into a desired group R 3 .
  • R 3 is an O-linked substituent can be prepared by alkylation of the hydroxy group, effected for example by treatment with a suitable alkylating agent such as an alkyl halide like, methyl iodide, in the presence of a base like silver oxide thus giving the ether derivative (Ic).
  • Inversion of the stereochemistry of the alcohol (Ib) can be effected for example by subjecting the alcohol to Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence Of Ph 3 P and for instance p-nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence Of Ph 3 P and for instance p-nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • lactones (IAb) whereinR is azide or the alcohol can be reacted with a thiol or alcohol to give alkylthio and alkoxy derivatives respectively.
  • Lactones (IAb) whereinR 3 is amine are conveniently achieved by reduction of the previously described azide derivative for example by treatment with Ph 3 P or by catalytic hydrogenation using a catalyst like Lindlar's catalyst, or alternatively, the Gabriel synthesis may be used, i.e.
  • the afforded primary amine can then be alkylated, conveniently by a reductive amination with a suitable aldehyde or ketone using conditions known to the skilled person, or by reaction with an alkylating agent Ra-Lg, whereinLg is a leaving group, optionally in the presence of a base. Hydrolysis of the methyl glycoside, oxidation and removal of the benzyl groups as described above, then provides the lactone.
  • Lactones obtained as described in scheme 1 and IA can then be further reacted as shown in scheme 2 to yield a linear amine which is another versatile intermediate useful for the preparation of compounds of formula (I) whereinn is 1 and Z is O.
  • Lg is a leaving group
  • the primary hydroxy group of the lactone (2a) can be selectively alkylated for example by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-CH 2 -Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide, in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2b).
  • a suitable leaving group such as a halide like bromide or iodide
  • the substituent Q-CH 2n can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1 -28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al, Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705- 4706) i.e. reaction of the primary hydroxy group of the diol (2a) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the secondary hydroxy group of the alcohol (2b) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate sulphonic anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the formed leaving group with azide for example sodium azide, thus giving the azide derivative (2c).
  • the linear compound (2e) can then be achieved by opening of the lactone with a desired amine (2d) in the presence of for example 2-hydroxypyridineand a base like isopropyl diethylamine.
  • Reduction of the azide using conditions compatible with the Q-CH 2n group, for example hydrogenation at atmospheric pressure in the presence of Lindlar 's catalyst, or treatment with Ph 3 P, then provides the amine (2f).
  • a linear intermediate amine whereinthe group Q is bonded directly to the oxygen atom, useful for the preparation of compounds of formula (I) whereinZ is O and n is O, can be prepared as shown in scheme 2A.
  • Lactones useful for the synthesis of compounds of formula (I) whereinZ is S or NH and n is 1 can be prepared from the diol 2a for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
  • the primary hydroxy group of the lactone (2a) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-CH 2 -S or Q-CH 2 -NRa.
  • a convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (2Bb) or the amine derivative (2Bc) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (2a
  • An alternative method to obtain the amino derivative (2Bc) is to selectively oxidize the primary hydroxy group of the alcohol (2a) to the corresponding aldehyde, effected for example by treatment with Dess -Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-CH 2 - NHRa in the presence of a reducing agent like NaCNBH 3 .
  • a reducing agent like NaCNBH 3
  • Intermediates for the preparations of compounds of formula (I) whereinthe group Q is linked directly to a sulphur or nitrogen atom, i.e. Z is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (2a) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the
  • An alternative method for the preparation of compounds whereinZ is S and n is 0 is to react the diol (2a) with a desired diphenyl disulphide derivative in the presence of nBu 3 P.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (2a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like.
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate. Many suitable methods for this oxidation are described in the literature for example, a peroxyacid such as AcOOH, mCPBA can be used.
  • the group Q-(CHz) n can alternatively be introduced prior to introduction of the group R 3 , as shown in scheme 3.
  • Amino derivatives used for the opening of the lactone in scheme 2 are available commercially or they can easily be prepared by the skilled person according to literature procedures. Amines useful for the preparation of compounds of the invention wherein p is 1, are conveniently prepared from the appropriate amino acid for example as illustrated in scheme 4.
  • the amino acid (4a), carrying the desired side chain R 4 and R 4 can be coupled to the amine W- (CH2) q -NH2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloro formate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • the azide derivative (5a), prepared for example as outlined in scheme 2, wherein Pg 1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlar's catalyst or the like in the presence of BoC 2 O to provide the boc protected amino derivative (5b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ) followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group, provides the primary alcohol (5c).
  • a protecting group Pg 2
  • Suitable protecting groups for the above route will be recognized by skilled person and a numerous of useful protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
  • benzyl can be used as Pg 1 and acetyl as Pg 2 .
  • the group CH 2 -Q can then be introduced as described above.
  • a Lewis acid such as BFsOEt 2 .
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • Compounds wherein n is 1 and Z is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (5 c) with a desired alcohol, Q-CH 2 -OH, thiol, Q- CH 2 -SH or amine Q-CH 2 -NHRa respectively.
  • Compounds of formula (I) whereinn is O and Z is O, S or N may be prepared by transforming the primary hydroxy group of the alcohol (5c) to a leaving group for example a derivative of sulphonic acid such as a halide like a chloride or bromide or to a derivative of sulphonic acid such as triflate, tosylate or the like which subsequently is displaced by a desired alcohol Q-OH, thiol Q-SH or amine Q-NHRa optionally in the presence of a base, for example as described hereinabove.
  • a leaving group for example a derivative of sulphonic acid such as a halide like a chloride or bromide or to a derivative of sulphonic acid such as triflate, tosylate or the like which subsequently is displaced by a desired alcohol Q-OH, thiol Q-SH or amine Q-NHRa optionally in the presence of a base, for example as described hereinabove.
  • An alternative method for the preparation of compounds wherein Z is S and n is O is to react the alcohol (5 a) with a desired derivative of diphenyl disulphide in the presence of nBusP.
  • Compounds whereinZ is NRa and n is O may alternatively be achieved by oxidation of the hydroxy group of the alcohol (5a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like. Removal of the Boc group according to standard procedures such as treatment with an acid, for example TFA, followed by removal of the hydroxy protecting group using the appropriate conditions, then provides the amine (5e).
  • Scheme 6 illustratesan example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) whereinQ is phenyl substituted with an alkoxy-alkoxy group.
  • the afforded alcohol (6b) can then either be used directly in the coupling to the primary hydroxy group of the lactone (2a) or the linear compound (5c) as described above, or the benzylic hydroxy group can be transferred to a leaving group, such as a halide like bromide, and subsequently coupled to the primary hydroxyl group of the lactone (2a) or the linear compound (5c) as described above.
  • a leaving group such as a halide like bromide
  • the free hydroxy group of compound (5a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (8a).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane
  • the monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached and thereafter replace the hydroxy group with fluorine, effected for example by subjecting the afforded inverted alcohol to fluorinatingconditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions.
  • fluorinatingconditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions.
  • Inversion of the stereochemistry of the alcohol (5 a) can be performed for example by subjectingthe alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph 3 P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • scheme 8 illustratesthe replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • Pg is an N-protecting group
  • the configuration of compound (9a), prepared as described above has to be inverted, for example as described in scheme 8.
  • the inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e. treatment with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by reaction with azide, for example diphenylphosphoryl azide (DPPA) or HN 3 to give the azido derivative (9c).
  • DPPA diphenylphosphoryl azide
  • the azido derivative (9c) can alternatively be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like.
  • a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like
  • Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d).
  • the compounds of the invention are then achieved by coupling of a suitable amine such as any of those described above to a suitable acid, as schematically outlined in scheme 10.
  • Coupling of a desired amino derivative (10a) to a suitable acid (10b or 10b') can be performed using standard peptide coupling techniques which are well known by a person skilled in the art.
  • a coupling agent like HATU or the like can be used in the presence of a tertiary amine like diisopropylethylamine or the like in a solvent like DMF to provide the amide (10c or 10c').
  • Acids (10b) to be used in the coupling with the amine (10a) are available commercially or from the literature, or they can be prepared as outlined hereinbelow. Acids (10b), wherein ring A is phenyl and E is CHRc-CHRc, can be prepared as shown in scheme 11.
  • X is a leaving group, e.g . Br
  • Rc' is CrCealkyl, CpCealkoxyCrCealkyl
  • Acids (10b) wherein ring A is phenyl, E is -NRd-CH(Rd)- can be prepared as illustrated in scheme 12.
  • Scheme 13 illustrates a route to acids (10b) wherein E is -0-CH(Rd)- and Rd is hydrogen and also an alternative route to acids whereinE is NRd-CHRd-.
  • Ether derivatives (13d) can then be achieved by hydrolysis of the methyl ester by treatment with sodium hydroxide or the like, followed by alkylation of the secondary hydroxy group using any desired alkylating agent (13c) whereinX is a leaving group such as bromide, iodide or chloride, in the presence of a base like sodium hydride.
  • Amino derivatives (13f) can be achieved by subjecting the alcohol (13b) to Mitsunobu conditions with a desired amine (13e) followed by hydrolysis of the methyl ester as described above.
  • ing group e.g. Br or I 1
  • sulphonylation of the amino group using any desired sulphonylating agent such as a sulphonylchloride, for example mesyl chloride or the like in the presence of pyridine in a solvent like dichloromethane or the like, optionally followed by alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, whereinX is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative ( 14d).
  • a sulphonylchloride for example mesyl chloride or the like in the presence of pyridine in a solvent like dichloromethane or the like
  • alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, whereinX is a leaving group such as a halide like bromide or io
  • Useful sulphamoyl chlorides can be prepared for example as described by W. L. Matier et al. in J. Med. Chem. 1972, 15, 4, 538-541.
  • X is a leaving group, e.g. B r or I n is 0 or 1
  • the diamino benzoic acid derivative (15a) can be achieved for example by removal of the fmoc group from commercially available boc-3-amino-5-(fmoc-amino)benzoic acid using standard conditions such as treatment with piperidine or morpholine or the like. Alkylation of the free amine effected for example by reaction with a desired aldehyde or ketone (15b) in the presence of a reducing agent like NaCNBH 3 or the like provides the amino derivative (15c).
  • the amine (15a) can be alkylated by reaction with an alkylating agent (15d) whereinX is a leaving group such as a halide like bromo or chloro or a derivative of sulphonic acid like a triflate or mesylate or the like, optionally in the presence of a base, which provides the amine (15e). Alkylation of the acid followed by removal of the boc group, introduction of the sulphone amide group and finally hydrolysis of the ester as described above, then provides the acid (15c).
  • an alkylating agent whereinX is a leaving group such as a halide like bromo or chloro or a derivative of sulphonic acid like a triflate or mesylate or the like, optionally in the presence of a base, which provides the amine (15e).
  • the bicyclic lactone (16a) prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanoneas described in WO2005/073195, can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (16b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature, for example the Mitsunobu conditions may be employed i.e.
  • butyl group by subjecting the diester to acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylenechloride then provides the acid (16e).
  • acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylenechloride
  • Reduction of the acid for example by a two step process of Weinreb amide formation brought about by reaction with N,0- dimethylhydroxylamine in the presence of sodium hydro gencarbonate and subsequent Dibal- reduction, gives the corresponding aldehyde (16f).
  • the afforded aldehyde can then be reacted as described above in order to get various acids which subsequentlycan be coupled to a desired amino derivative as described above.
  • X is a leaving group, e.g. Br or I
  • Useful sulphamoyl chlorides can be prepared for example as described by W. L. Matier et al. in J. Med. Chem. 1972, 15, 4, 538-541.
  • the bicyclic lactone (18a), prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanoneas described in WO2005/073195 can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (18b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature. For example the Mitsunobu conditions may be employed i.e.
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non -natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • Boc-Val-OH 500 mg, 2.30 mmol
  • benzylamine 321 mg, 2.99 mmol
  • DIPEA 0.52 mL, 2.99 mmol
  • HATU 137 mg, 2.99 mmol
  • the DMF was removed under reduced pressure and the crude residue was purified by flash column chromatography (toluene/ethyl acetate 6:1) to yield ((S)-l-benzylcarbamoyl-2-methyl- propyl)-carbamic acid tert-butyl ester (666 mg, 95 %).
  • the Boc-derivative (666 mg, 2.17 mmol) was dissolved in CH 2 Cl 2 (7.3 ml) and cooled to 0 0 C in an ice bath. Et 3 SiH (0.52 mL, 3.27 mmol) and TFA (3.5 mL) was added and the mixture were allowed to attain room temperature. After 3 hours the solution was co-evaporated with toluene (3 x 20 mL), which gave the TFA salt of the title compound as a white powder (448 mg, quant.).
  • the title compound (21 mg, 0.02 mmol, 51 %) was synthesized by reduction of compound 2g (32 mg, 0.06 mmol) followed by coupling to the acid 5-methanesulphonyl-methyl-amino)-N'-(l- phenyl -ethyl)-isophthalic acid (18mg, 0.05 mmol), according to the method described for the preparation of compound Ii.
  • Methyl 5 -azido-3.5-dideoxy-6-Q- ⁇ 4-bromopheny ⁇ -L-/vxo-hexofuranoside (3d") The title compound (752 mg, 2.10 mmol, 95%) was synthesized from compound 3c (849 mg, 2.21 mmol) according to the method described for the preparation of compoundlc.
  • Methyl 5 -azido-3.5-dideoxy-6-O-(4-bromophenviy2-O-methyl-L-/vxo-hexofuranoside (3e) The title compound (315 mg, 0.85 mmol, 90%) was synthesized from compound 3d (338 mg, 0.94 mmol) according to the method described for the preparation of compound 18.
  • the title compound (122 mg, 0.218 mmol, 96%) was synthesized by opening of the lactone 3g (80.5 mg, 0.227 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
  • the title compound (180 mg, 0.348 mmol, 97%) was synthesized by opening of the lactone 4f (112.5 mg, 0.3591 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
  • the title compound (33 mg, 0.04 mmol, 81 %) was synthesized by reduction of the azide of compound 4g (50 mg, 0.10 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (18 mg, 0.05 mmol), as described for the preparation of compound Ii.
  • the title compound (22 mg, 0.045 mmol, 30%) was synthesized by opening of the lactone 5f (43 mg, 0.155 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
  • the title compound (19 mg, 0.02 mmol, 58 %) was synthesized by reduction of the azide of compound 5g (123 mg, 0.25 mmol) followed by coupling to 5 -methanesulphonyl -methyl - amino)-7V'-(l-phenyl-ethyl)-isophthalic acid (15 mg, 0.04 mmol), according to the method described for the preparation of compound Ii.
  • the title compound (30.6 mg, 0.079 mmol, 80%) was synthesized by opening of the lactone 4f (31.1 mg, 0.099 mmol) according to the method described for the preparation of compound Ih but using isobutylamine instead of the amine Ig.
  • the title compound (20 mg, 0.03 mmol, 43%) was synthesized by reduction of the azide of compound 10a (26 mg, 0.06 mmol) followed by coupling to 5 -methanesulphonyl-methyl- amino)-iV'-(l-phenyl-ethyl)-isophthalic acid (23 mg, 0.06 mmol), according to the method described for the preparation of compound Ii.
  • the title compound (11 mg, 0.02 mmol, 30 %) was synthesized by reduction of the azide of compound 4g (50 mg, 0.10 mmol) followed by coupling to N,N-dipropyl-isophthalamic acid (13 mg, 0.05 mmol), according to the method described for the preparation of compound Ii.
  • the solution was concentrated and re-dissolved in DMF (1.2 mL).
  • the azide of compound 4g was reduced as described in Example 1, step h whereafter the formed amine (23 mg, 0.05 mmol) together with DIPEA (17 ⁇ L, 0.1 mmol) and HATU (16 mg, 0.04 mmol) were added and to the DMF solution and the reaction mixture was stirred for 2 h.
  • the solution was co -evaporated with toluene, concentrated and purified using prep. LC-MS which gave the title compound as a white powder (19 mg, 71 %).
  • Triethylsilane (11 ⁇ L, 0.07 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 3 h.
  • the solution was concentrated and re-dissolved in DMF (1.2 mL).
  • the azide of compound 4g was reduced as described in Example 1, step h whereafter the formed amine (23 mg, 0.05 mmol) together with DIPEA (18 ⁇ L, 0.1 mmol) and HATU (17 mg, 0.04 mmol) were added to the DMF solution and the reaction mixture was stirred for 2 h.
  • the solution was co -evaporated with toluene, concentrated and purified using prep. LC-MS which gave the title compound as a white powder (18 mg, 63 %).
  • the diester 13f (10 mg, 0.03 mmol) was dissolved in DCM (0.5 rnL). Triethylsilane (9.5 ⁇ L, 0.06 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2.5 h. The solution was concentrated and re-dissolved in DMF (1 mL). Benzylamine (4 ⁇ L, 0.04 mmol), TEA (12 ⁇ L, 0.09 mmol) and HOBt (5.5 ⁇ L, 0.04 mmol) were added and the mixture was cooled to 0 0 C. EDC (8.5 mg, 0.04 mmol) was added and the reaction mixture was stirred for 30 min and additional h at rt. The solution was co -evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as an oil (7 mg, 62 %).
  • the diester 13f (14 mg, 0.04 mmol) was dissolved in DCM (0.7 mL). Triethylsilane (13 ⁇ L, 0.08 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2 h. The solution was concentrated and re-dissolved in DMF (1 mL). (S)-(-)-l-(4-fluorophenyl)ethylamine (6.7 ⁇ L, 0.05 mmol), TEA (17 ⁇ L, 0.12 mmol) and HoBt (7.8 ⁇ L, 0.06 mmol) were added and the mixture was cooled to 0 0 C.
  • Phenylethylmagnesium chloride (1.0 M in THF, 0.32 mL, 0.32 mmol) was added dropwise to a cooled solution (-78 0 C) of the aldehyde 3-formyl-5-[methanesulphonyl(methyl)amino]benzoic acid methyl ester (0.26 mmol as 3.0 mL solution in 2/1 THF-Et 2 O), prepared as described in Bioorg. Med. Chem. letters, (2006), 641 -644, and the mixture was stirred for 6 h. Saturated aqueous NH 4 Cl solution (5 mL) was added, the mixture was warmed to RT, and then more NH 4 Cl solution (5 mL) was added.
  • the azide 4g was dissolved in MeOH (5 niL) triphenylphosphine and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step.
  • HATU (74 mg, 0.195 mmol) was added at O 0 C to a solution of the acid 22b (41 mg, 0.097 mmol), the amine 22c (72 mg, 0.146 mmol), and DIEA (68 ⁇ L, 0.389 mmol) in DMF (7 mL) .
  • the solution was stirred at 0 0 C for Ih and then at room temperature overnight.
  • the solvent was evaporated and the remainder was extracted with ethyl acetate and washed twice with brine.
  • the organic phase was dried, filtered, and concentrated.
  • the crude material was purified by flash column chromatography (ethyl acetate) which gave the title compound (87 mg, 100%) as a colourless solid. (M+H) + calcd: 897.4; found: 897.7; LC-MS purity: >98%.
  • the acid 23c was coupled to the amine of compound 2g according to the procedure described in
  • a oven-dried vial containinga magnetic stir bar was charged with 3 -pyridine boronic acid (500 mg, 1.83 mmol), Pd 2 (dba) 3 (10 mg, 1.0 mol%), S-Phos (15.0 mg, 2.0 mol%), 2-(trifluoromethyl)- phenyl boronic acid (695 mg, 3.66 mmol, 2 equiv.) and powdered, anhydrous KsPO 4 (LIo g, 5.49 mmol, 3 equiv.).
  • the vial was capped with a Teflon septum and then evacuated and backfilled with azote (this sequencewas repeated three times).
  • N-F(I S.2SAR V 4-(CSV 1 -Benzylcarbamoyl ⁇ -methyl-propylcarbamovO- 1 -(3.5 -difluoro- phenoxymethyl)-2-hydroxy-4-(2-methoxy-ethoxy)-butyl1-5-(methanesulfonyl-methyl-amino)- N -((R)- 1 -phenyl-ethvD-isophthalamide (28e)
  • N-FfI S.2SAR -4-((S)- 1 -Benzylcarbamoyl ⁇ -methyl-propylcarbamoylV 1 -f 3.5 -difluoro- phenoxymeth ylV2-hvdroxy-4-propyloxy-butyll -5 -f methanesulfonyl-methyl-amino VN' -((R Vl- phenyl -ethyl Visophthalamide f 30)
  • TruPointTM Beta-Secretase Assay Kit was used. The assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanidefluorescence can be measured by time- resolved fluorometry (TRF).
  • TRF time- resolved fluorometry
  • the enzyme used in the assay is recombinant BACEl (produced in house) and the substrate is a 10 amino acids long peptide with a fluorescent europium chelate coupled to one end and a quencher of europium fluorescence (QSY 7) coupled via lysine to the other end; EU- CEVNLDAEFK-QSY 7.
  • the cleavage site by BACEl is the peptide bond between L and D.
  • a spectroscopic response is generated by peptidase cleavage, and the activity was measured by a continuous detection of increased fluorescence intensity exhibitedby the cleavage product.
  • the compounds were tested at a range of concentrationswhereas the enzyme and substrate concentrationswere fixed.
  • the substrate was prepared at a 120 ⁇ M stock solution in distilled water. The stock solution was diluted to 400 nM in an amount which was needed for the day.
  • To each well of a 96-well half area polystyrene plate was added the enzyme containing reaction buffer (15 ⁇ l) and inhibitor of different concentrations in DMSO (1 ⁇ l). To control wells were added reaction buffer (15 ⁇ l) and DMSO (1 ⁇ l).
  • the enzyme with inhibitor in DMSO was preincubated at room temperature (20-25 0 C) for 30 min whereafter the reactions were started by addition of substrate, 15 ⁇ l/well, thus giving a total volume of 31 ⁇ l/well and a substrate concentrationof 200 nM.
  • Product TR-fluorescence was monitored during 90 min with a 1420 VICTOR and presented as Relative Fluorescence units (RFu).
  • RFu Relative Fluorescence units
  • the IC50 value was calculated with GraFit software.
  • Activity of the inhibitors was determined by measuring the TR-fluorescence at ⁇ ex 330 nm and ⁇ em 615 nm. The inhibition is calculated as follows:
  • Table 1 shows the enzymatic inhibition exhibitedby a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above.
  • Category A indicates an IC 50 value of ⁇ 1 ⁇ M
  • category B indicates 1 - 5 ⁇ M
  • category C indicates > 5 ⁇ M.

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Abstract

L'invention concerne des composés de formule (I). Elle concerne des N-oxydes, des sels d'addition, des amines quaternaires, des complexes métallique, des formes isomères stéréochimiques et des métabolites de ces composés. Dans la formule (I), W représente H, un alkyle en C1-C6, un cycloalkyle en C3-C6, un aryle ou un hétérocyclyle; Q représente un aryle ou un hétérocyclyle; A représente un noyau aromatique, saturé ou partiellement insaturé, à cinq ou six éléments; D représente une formule (II) ou une formule (III); les autres variables sont telles que définies dans la description. Les composés de l'invention sont des inhibiteurs de la BACE et sont, entre autres, utiles dans le traitement et/ou la prévention de troubles associés à l'activité de la BACE, notamment la maladie d'Alzheimer.
PCT/EP2008/053767 2007-03-30 2008-03-28 Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases WO2008119773A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07105328.4 2007-03-30
EP07105327.6 2007-03-30
EP07105327 2007-03-30
EP07105328 2007-03-30

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WO2008119773A1 true WO2008119773A1 (fr) 2008-10-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009110985A2 (fr) 2008-02-29 2009-09-11 Renovis, Inc. Composés amides, compositions à base de ces composés et leurs utilisations
WO2010042030A1 (fr) * 2008-10-07 2010-04-15 Medivir Ab Inhibiteurs d'aspartyl protéase
US20140336208A1 (en) * 2010-08-09 2014-11-13 Hoffmann-La Roche Inc. 1,4,5,6-tetrahydro-pyrimidin-2-ylamine compounds
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099202A2 (fr) * 2002-05-17 2003-12-04 Merck & Co., Inc. Inhibiteurs de beta-secretase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099202A2 (fr) * 2002-05-17 2003-12-04 Merck & Co., Inc. Inhibiteurs de beta-secretase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009110985A2 (fr) 2008-02-29 2009-09-11 Renovis, Inc. Composés amides, compositions à base de ces composés et leurs utilisations
US8946439B2 (en) 2008-02-29 2015-02-03 Evotec Ag Amide compounds, compositions and uses thereof
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof
WO2010042030A1 (fr) * 2008-10-07 2010-04-15 Medivir Ab Inhibiteurs d'aspartyl protéase
US20140336208A1 (en) * 2010-08-09 2014-11-13 Hoffmann-La Roche Inc. 1,4,5,6-tetrahydro-pyrimidin-2-ylamine compounds

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