WO2010042030A1 - Inhibiteurs d'aspartyl protéase - Google Patents

Inhibiteurs d'aspartyl protéase Download PDF

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WO2010042030A1
WO2010042030A1 PCT/SE2009/051105 SE2009051105W WO2010042030A1 WO 2010042030 A1 WO2010042030 A1 WO 2010042030A1 SE 2009051105 W SE2009051105 W SE 2009051105W WO 2010042030 A1 WO2010042030 A1 WO 2010042030A1
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alkyl
mmol
acid
compound
heterocyclyl
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PCT/SE2009/051105
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Stina Lundberg
Susana Ayesa
Oscar Belda
Ismet Dorange
Karolina Ersmark
Kristin Hammer
Per-Ola Johansson
Stefan LINDSTRÖM
Åsa ROSENQUIST
Bertil Samuelsson
Marcus BÄCK
Ingemar KVARNSTRÖM
Fredrik WÅNGSELL
Katarina BJÖRKLUND
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Medivir Ab
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    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • 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
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • 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
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    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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
    • C07D263/18—Oxygen atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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).
  • AD Alzheimer's disease
  • 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 is processed along two pathways, the major ⁇ - and the minor ⁇ -secretase pathway.
  • APP large transmembrane amyloid precursor protein
  • the ⁇ - secretase pathway results in non-pathogenic products known as soluble APP, whereas the ⁇ - secretase pathway produces pathogenic 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.
  • the sequential proteolytic cleavage of APP by ⁇ - and ⁇ -secretase is a key step in the production of A ⁇ .
  • the 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 absence of 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 reduce the production of A ⁇ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
  • the compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved potency in inhibiting BACE.
  • A is CR 1 or N
  • D is H, Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl or
  • R 1 is H, Ci-Cealkyl, Ci-Cealkoxy, N 3 or halo;
  • R 2 is H or Ci-C ⁇ alkyl
  • R 3 is Ci-C 6 alkyl, C 2 -C6alkenyl, C 2 -C 3 alkynyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 6 alkoxy, arylCi- C 6 alkoxy, heterocyclylCi-C 6 alkoxy, NRaRb or N 3 ;
  • R 7 is Ci-C 6 alkyl, C 3 -C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-CealkoxyCi-Qsalkyl, arylC 0 -C 3 alkoxyCi-
  • Ci-C 3 alkyl C 3 alkyl, heterocyclylC 0 -C 3 alkoxyCi-C 3 alkyl, N(Ra)(Rb)Ci -C 3 alkyl; wherein, when present, the Ci-C 3 alkyl moiety of R 7 is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-C 6 alkyl
  • R 7 and R 8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with or fluoro;
  • R 9 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C 6 alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or phenyl;
  • Q is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heterocyclyl;
  • W is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, haloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, C 3 -C 6 Cy cloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH 3 , the other is Ci-C 3 alkyl, F, OH, NRaRb, CF 3 or N 3 ; or X' and X" are both F;
  • Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached may form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro; Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocyclic ring; Rd is H or Ci-C 3 alkyl; and wherein aryl is independently phenyl, naphthyl or phenyl fused to C 4 -Cecycloalkyl or Q-Qcycloalkenyl; heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and
  • R 1 is H, Ci-Csalkyl, N 3 or halo;
  • R 2 is H or Ci-C 6 alkyl;
  • R 3 is Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 6 alkoxy, arylCi-C 6 alkoxy, heterocyclylCi-
  • R 7 is Ci-C 6 alkyl, C 3 -C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-Qsalkyl, hydroxyCi-C 3 alkyl, Ci-CealkoxyCi-Gsalkyl, Ci-C 3 alkanediyl-O-C 0 -
  • Ci -C 3 alkanediylaryl Ci -C 3 alkanediyl-0-Co-C 3 alkanediylheterocyclyl, Ci -C 3 alkanediylNRaRb; wherein the Ci-C 3 alkanediyl moiety is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-Cealkyl; or R 7 and R 8 together with the N atom to which they are attached define a heterocyclyl group;
  • R 9 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 CyC loalkyl, C 3 -C 6 CyC loalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C 6 alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 6 membered heterocyclic ring;
  • Q is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heterocyclyl;
  • W is H, Ci-C 6 alkyl, Ci-C 6 alkenyl, haloCi-C 3 alkyl, polyhaloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, C 3 -
  • X' and X" are both F;
  • Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl group;
  • Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached form a heterocyclic ring; and wherein aryl is independently phenyl, naphthyl or phenyl fused to Q-Qcycloalkyl or Q-Qcycloalkenyl;
  • heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N; and wherein each occurrence of Q-Qalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Q-Qcycloalkyl, ary
  • R 1 is H or F
  • R 2 is H
  • R 7 is Ci-C ⁇ alkyl, Cs-C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-Csalkyl, aryl, arylCi-Csalkyl, heterocyclyl, heterocyclylCi-Csalkyl; wherein, when present, the Ci-Csalkyl moiety of R 7 is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-Cealkyl
  • Q is optionally substituted aryl or optionally substituted heterocyclyl
  • W is C 3 -C 6 Cy cloalkyl, C 2 -C 6 alkenyl, aryl or heterocyclyl, any of which is optionally substituted; one of X' and X" is OH;
  • Y is O or NH
  • D is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or
  • A is CR 1 .
  • R 7 is as recited above. Typical values for R 7 include Ci-C 6 alkyl, arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein each Ci-C 6 alkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, C 1 - C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • a further configuration for R 7 include arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein the Ci-C3alkyl moiety is optionally substituted with Ci-C6alkyl.
  • Ci-C 4 alkyl such as methyl or ethyl
  • haloCi- C 4 alkyl such as trifluoromethyl
  • C 3 -C 4 cycloalkyl 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-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • favoured values for R 7 include phenylmethyl, 1-phenylethyl and 1-phenylpropyl, especially phenylmethyl and 1-phenylethyl, wherein the phenyl ring is optionally substituted. Accordingly, favoured embodiments of the invention include compounds having the partial structure shown below:
  • A is CR 1 .
  • the substituent(s) is preferably the in the para and/or ortho position of the phenyl ring.
  • R 7 is Cs-Coheteroarylmethyl, I-C 5 - C ⁇ heterarylethyl or l-Cs-C ⁇ heterarylpropyl, especially Cs-C ⁇ heterarylmethyl, wherein the heteroaryl ring is optionally substituted.
  • Suitable heteroaryl rings according to this embodiment include, but are not limited to thiazolyl, pyrazolyl, imidazolyl.
  • favoured compounds of the invention according to this embodiment include those having the partial structure shown below:
  • A is CR .
  • R 8 is as recited above, preferably hydrogen or methyl.
  • a further embodiment of the invention include compounds of formula (I) wherein R >7 and R together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6 membered cyclic amine, for example optionally substituted pyrrole, piperidine, piperazine or morpholine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro.
  • R 7 and R 8 are both Ci-C ⁇ alkyl, such as ethyl, propyl or butyl.
  • Typical values for R include Ci-C ⁇ alkyl, C 2 -Cealkenyl and C 2 -C 6 alkylnyl wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted.
  • Typical substituents according to this embodiment include Cs-C ⁇ cycloalkyl for example cyclopropyl, Ci-C4alkyl for example isopropyl or t.butyl, haloalkyl for example CH 2 F, CHF 2 or CF 3 , hydroxy and phenyl.
  • R 9 is optionally substituted C 2 -C 6 alkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF 3 . and C 3 -C 6 Cy cloalkylCi-Csalkyl, any of which is optionally substituted as defined above.
  • Typical substituents include Ci-C 3 alkyl, halo, polyhaloalkyl, hydroxy, phenyl.
  • R 9 Preferred values for R 9 include C 3 -C 6 cycloalkylCi-C 3 alkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C 3 alkyl. Specially preferred are cyclopropylmethyl and 2- methylcyclopropylmethyl. For these values of R 9 , R 10 is preferably H or methyl.
  • R 10 is typically H or Ci-C 3 alkyl, preferably H or methyl.
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6 membered cyclic amine, which cyclic amine is optionally substituted, thus giving the partial structures:
  • A is CR 1 .
  • Optional substituent to the R 9 -R 10 ring is selected from Ci-C 6 alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl and phenyl.
  • D is Ci-C 6 alkyl, C 2 -Cealkenyl or C 2 - C 6 alkynyl, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted.
  • Typical substituents according to this embodiment include Cs-C 6 CyC loalkyl for example cyclopropyl, C 1 - C 4 alkyl for example isopropyl or t.butyl, and haloalkyl for example CH 2 F, CHF 2 or CF 3 .
  • D is optionally substituted C 2 -C 6 alkynyl, such as ethynyl which is unsubstituted or, preferably, substituted with cyclopropyl or CF 3 .
  • 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 excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R 2 is attached has the stereochemistry shown in the partial structure: ⁇ ,Q
  • Z is O.
  • Z is NRa, wherein Ra is hydrogen or Ci-C 3 alkyl, 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 typically aryl or heterocyclyl, which is optionally substituted with one, two or three substituents as defined above.
  • Q is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • the heterocyclyl moiety contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • Representative bicyclic rings according to this embodiment include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl, each of which is optionally substituted.
  • 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.
  • monocyclic rings include phenyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • Typical values for Q according to this embodiment include 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-C 4 alkyl, C 3 -C 4 cycloalkyl, Ci-C 4 alkoxy, Ci-CsalkoxyCi- C ⁇ alkoxy, cyano, halo, haloCi-C 4 alkyl and arylCi-Csalkyl, heterocyclylCi-Csalkyl, C 2 - Csalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 alkynylC 3 -C 6 Cycloalkyl.
  • favoured values include halo such as mono- di or trifluoro, chloro, bromo and haloCi-C4alkyl for example trifluoromethyl.
  • Q is a monosubstituted phenyl or a 6- membered heterocyclyl
  • the substituent is preferably in the meta or para position.
  • Preferred configurations for Q according to these embodiments include meta and para substituted phenyl.
  • substituents are preferably in the two meta positions or one substituent is in the meta position and the other in the para position.
  • Preferred substituents to Q according to these embodiments are independently chloro, fluoro, bromo, methyl, optionally substituted phenyl, 5- or 6 membered heteroaryl.
  • favoured configurations for Q include optionally substituted phenyl, such as bromo substituted phenyl and mono- or difluorophenyl, especially difluorophenyl.
  • Q include phenyl which is substituted with heteroaryl, C 2 - C ⁇ alkenyl, C 2 -C 6 alkynyl, cyano or cyclopropylethynyl.
  • Q is optionally substituted phenyl, n is 0 and Z is O.
  • Q is optionally substituted pyridyl
  • n is 0 and Z is O.
  • Specially preferred compounds according to this embodiment are those wherein Q is pyrid-3-yl.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • Y is O or NH.
  • X' and X" are as defined above, preferably one of X' and X" is H and the other is F, or more preferably one of X' and X" is H and the other is OH.
  • X' and X" are both fluoro.
  • Y is NH
  • Typical values for R in compounds of formula (Ic) include optionally substituted Ci-C ⁇ alkoxy such as optionally substituted methoxy, ethoxy and propoxy, preferably R 3 is Ci-C4alkoxy, especially methoxy.
  • R 3 include optionally substituted Ci-Cealkoxy-Ci-C ⁇ alkoxy such as optionally substituted methoxypropoxy and methoxyethoxy.
  • Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di- and trifluoro.
  • Preferred compounds of formula (I) wherein p is 1 and one of X' and X" is H and the other is OH, are those having the stereochemistry indicated in formula (Id):
  • Preferred compounds of formula (I) wherein p is 0, one of X' and X" is H and the other is OH, and Y is NH are those having the stereochemistry indicated in formula (Ie):
  • R 1 is H.
  • R 1 is halo, such as fluoro.
  • R 6 includes cyclic sulphonamides, i.e. Ra and Rc together with the atoms to which they are attached form a heterocyclic ring.
  • the heterocyclic ring is a 5 or 6-membered ring, thus providing compounds of the general formula (If).
  • A is CR 1 .
  • R 6 is a cyclic sulphonamide
  • A is CH and R 1 is halo, preferably fluoro.
  • R 1 is in the ortho position of the phenyl ring.
  • R 6 examples include hydrogen and Ci-C ⁇ alkyl, especially hydrogen or methyl.
  • the group W is bonded either directly to Y, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively. In favoured embodiments of the invention W is bonded directly to Y or via a methylene moiety, i.e. q is 0 or 1 respectively.
  • the moiety linking W to Y may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
  • W is hydrogen, Ci-C ⁇ alkyl, C 2 -Cealkenyl, haloCi-Csalkyl, hydroxyCi-Csalkyl, Cs-C ⁇ cycloalkyl, aryl or heterocyclyl wherein the alkyl, alkenyl, cycloalkyl, aryl or heterocyclyl moiety is optionally substituted with one, two or three substituents.
  • One embodiment of the invention includes compounds wherein W is optionally substituted Ci- C ⁇ alkyl such as methyl, ethyl or isopropyl.
  • Preferred substituents to W according to these embodiments include halo such as mono-, di- or trifluoro.
  • a further embodiment of the invention includes compounds wherein W is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, chromanyl, dihydrobenzofuran, dihydroisobenzofuran.
  • Representative substituents to the bicyclic ring include Ci-C 4 alkyl, e.g. t.butyl and haloalkyl, e.g. trifluoromethyl.
  • a further embodiment of the invention includes compounds wherein W 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.
  • monocyclic heterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • a preferred embodiment of the invention includes compounds wherein W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl.
  • a further preferred embodiment of the invention includes compounds wherein W is optionally substituted Cs-C ⁇ cycloalkyl such as optionally substituted cyclopropyl.
  • a typical configuration for W according to this embodiment is cyclopropyl which is substituted with Ci-C 4 alkyl e.g. methyl or with C 2 -C 4 alkenyl e.g. ethenyl or propenyl.
  • 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 p- ⁇ uoro phenyl.
  • the substituents are preferably selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl and tert. butyl.
  • 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-C4CVC loalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C3-C4CVC loalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, N-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 the TV-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, /V-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, TV-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, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • 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. Accordingly, one embodiment of 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 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, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • 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 term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • 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 mentioned diseases, 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.
  • 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.
  • 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.
  • 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 compounds of the present invention may be used in combination with one or more additional compounds useful in the treatment and/or prophylaxis of Alzheimer's disease, or the symptoms thereof.
  • additional compounds include NSAIDs including ibuprofen; vitamin E; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin, cognition-enhancing drugs such as acetylcholinesterase inhibitors, e.g. donepezil, rivastigmine, tacrine and galanthamine; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. memantine; or PDE4 inhibitors, e.g. ArifloTM.
  • NSAIDs including ibuprofen; vitamin E; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin, cognition-enhancing drugs such as acetylcholinesterase inhibitors
  • Such additional compounds also include cholesterol-lowering drugs such as HMG-CoA reductase inhibitors, e.g. lovastatin and simvastatin.
  • Such additional compounds also include compounds known to modify the production or processing of A ⁇ in the brain ("amyloid modifier"), such as compounds which inhibit the secretion of A ⁇ , compounds which inhibit the aggregation of A ⁇ , and antibodies which selectively bind to A ⁇ .
  • additional compounds also include growth hormone secretagogues, e.g. such as ibutamoren, ibutamoren mesylate and capromorelin.
  • the amyloid modifiers according to this embodiment of the invention may be a ⁇ -secretase inhibitor other than any of those included in the present invention, such as any of the compounds disclosed in Recent Patents on CNS Drug Discovery, 2 (2007), 188-199; an inhibitor/modulator of ⁇ -secretase, or any other compound which inhibits the formation or release of A ⁇ .
  • the amyloid modifier may also be a GSK-3 inhibitor, particularly a GSK-3 ⁇ inhibitor, such as lithium, as disclosed by Phiel et al in Nature, 423 (2003), 435-439.
  • the amyloid modifier may also be a compound which inhibits the aggregation of A ⁇ or otherwise attenuates its neurotoxicity.
  • Suitable examples include chelating agents such as clioquinol (Gouras and Beal, Neuron, 30 (2001), 641-642) and the compounds disclosed in
  • WO99/ 16741 particularly the one known as DP- 109 (Kalendarev et al, J. Pharm. Biomed. Anal, 24 (2001), 967-975).
  • Other inhibitors of A ⁇ aggregation suitable for use in the present invention include for example ApanTM (Praecis) and in particular 3-aminopropane-l-sulphonic acid, also known as tramiprosate or AlzhemedTM.
  • the amyloid modifier may also be an anti-amyloid antibody which binds selectively to A ⁇ .
  • Said antibody may be polyclonal or, preferably, monoclonal, and is preferably human or humanized.
  • the compounds of the present invention may also be used in combination with one or more P- glycoprotein inhibitor(s).
  • Non- limiting examples of Pgp inhibitors include ketoconazole, cyclosporine A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX710, LY335979 and PSC-833.
  • the compounds of the present invention may also contain, or be co- administered (simultaneously or sequentially) with one or more additional drugs that either increase the efficacy, safety and/or convenience, or treat, prevent, control or reduce the risk for side effects or toxicity of the compounds of the present invention.
  • additional drugs that either increase the efficacy, safety and/or convenience, or treat, prevent, control or reduce the risk for side effects or toxicity of the compounds of the present invention.
  • the species may be combined in a single dosage form for simultaneous administration to the subject, or be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close or remote in time, e.g. one species is administrated in the morning and the other in the evening.
  • the separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
  • the separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of the species is preferred, where possible.
  • the additional compound is an antibody, it will typically be administered parenterally and separately from the compound of Formula I.
  • the combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol wherein one or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
  • 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.
  • '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).
  • the reference by Goodman and Gilman The Pharmacological Basis of
  • 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 parent compound.
  • 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 hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid 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, C 3 -CsCyC loalkoxycarbonyloxyCi-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 ⁇ alkoxycarbonyloxy ethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a 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 hydrolysable ester 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), dialkylamino acetyl and carboxyacetyl.
  • 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 wherein the 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 mentioned hereinabove are meant to comprise the therapeutically active 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.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic, />toluenesulphonic, cyclamic, salicylic, />amino salicylic, 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, /V-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.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
  • the TV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-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.
  • '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 excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • the terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
  • 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 diastereomeric mixtures 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 stereospecif ⁇ cally.
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral centre within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation.
  • the present invention also includes isotope- labelled compounds of formula I or any subgroup of formula I, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature.
  • isotopes examples include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 Cl, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 I, 124 I, 125 I and 131 I.
  • isotopes of hydrogen such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • phosphorus such as 31 P and 32 P
  • sulphur such
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 O will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
  • Isotope-labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotope-labelled reagent or starting material instead of the corresponding non- isotope-labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • the scientific and technological terms and nomenclature have the same meaning as commonly understand by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted.
  • Ci-C ⁇ alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • Preferred alkyl groups for use in the invention are Ci-C ⁇ alkyl groups, i.e. alkyl groups having from 1 to 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.butyl, pentyl, hexyl and the like.
  • the alkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • alkenyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkenyl means an alkenyl group having from 2 to 6 carbon atoms).
  • Preferred alkenyl groups for use in the invention are C 2 - C ⁇ alkenyl groups, i.e. alkenyl groups having from 2 to 6 carbon atoms.
  • alkenyl groups include ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like. Unless otherwise indicated the alkenyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 2 -C n alkynyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkynyl means an alkynyl group having from 2 to 6 carbon atoms).
  • Preferred alkynyl groups for use in the invention are C 2 -C 6 alkynyl, i.e. alkynyl groups having from 2 to 6 carbon atoms.
  • alkynyl groups include ethynyl, propynyl, propynyl, butynyl, and the like, especially propynyl. Unless otherwise indicated the alkynyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 3 -C n cycloalkyl as a group or part of a group defines a saturated cyclic hydrocarbon radical having the number of carbon atoms designated, e.g. Cs-C ⁇ cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl and the like, especially cyclopropyl.
  • the cycloalkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • 'C 3 -C n 'CycloalkylC m -C n alkyr represents a C m -C n alkyl radical which is substituted with a C 3 - C n 'Cycloalkyl moiety, wherein C 3 -C n 'Cycloalkyl and C m -C n alkyl are as defined for C 3 -
  • Preferred C 3 -C n 'CycloalkylC m -C n alkyl groups for use in the invention are C 3 -CycycloalkylCo-C 3 alkyl, i.e. the cycloalkyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • 'C 3 -C n 'CycloalkylC 2 -C n alkenyl' and 'C 3 -C n 'CycloalkylC 2 -C n alkynyl' have the corresponding meanings as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively, adjusted just for the link to the C 3 -C n 'Cycloalkyl moiety, as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively.
  • C 3 -C n 'CycloalkylC 2 -C n alkenyl and C 3 -C n 'CycloalkylC 2 -C n alkynyl groups for use in the invention are C 3 -C n 'CycloalkylC 2 -C 3 alkenyl and C 3 -C n 'CycloalkylC 2 -C 3 alkynyl, i.e. the C 3 - C n 'Cycloalkyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • C 3 -C n cycloalkenyl as a group or part of a group defines a cyclic hydrocarbon radical having one double bond and having the number of carbon atoms designated, e.g. C 3 - C ⁇ cycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkenyl groups include cyclobutenyl cyclopentenyl, cyclohexenyl and the like. Unless otherwise indicated the cycloalkenyl moiety is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • Ci-C n alkoxy' defines oxygen (Co) or a radical O-Ci-C n alkyl wherein Ci-C n alkyl is as defined for C m -C n alkyl above.
  • Preferred alkoxy groups for use in the invention are Ci-C ⁇ alkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like.
  • C 2 -C n alkenoxy defines a radical O-C 2 -C n alkenyl wherein C 2 -C n alkenyl is as defined above.
  • Preferred alkenoxy groups for use in the invention are C2-Cealkenoxy, i.e. alkenoxy groups having from 2 to 6 carbon atoms. Exemplary alkenoxy groups include but are not limited to ethenoxy, 1-propenoxy, 2-propenoxy, and the like.
  • C 2 -C 6 alkynoxy defines a radical O-C 2 -C n alkynyl wherein C 2 -C n alkynyl is as defined above.
  • Preferred alkynoxy groups for use in the invention are C2-C6alkynoxy, i.e. alkynoxy groups having from 2 to 6 carbon atoms. Exemplary alkynoxy groups include but are not limited to ethynoxy, 1-propynoxy, 2-propynoxy, and the like.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloC m -C n alkyr as a group or part of a group, represents a C m -C n alkyl radical which is substituted with one or more halogen atoms, 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.
  • 'Amino' as a group or part of a group, unless the context suggests otherwise, includes NH2, NHC m _C n alkyl or N(C m _C n alkyl)2, wherein m and n in the (C m -C n alkyl)2 are selected independentlly of each other, and wherein in the amino definition C m -C n alkyl is especially Ci-C 6 or Ci-C4alkyl variants.
  • 'C2-C n alkenylamino' and 'C2-C n alkynylamino' define NHC2-C n alkenyl and NHC2- C n alkynyl respectively, wherein the C 2 -C n alkenyl and C 2 -C n alkynyl are as defined above.
  • special interest for the invention are the C 2 -C 6 variants, and especially the C2-C4 variants.
  • 'Aryl' as a group or part of a group as applied herein represents an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C 6 CyC loalkyl (for example indanyl), or a C 5 -
  • 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 1 or 2, or where valence allows up to 3 substituents.
  • 'ArylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with an aryl moiety, wherein aryl and C m -C n alkyl are as defined above.
  • Preferred arylC m -C n alkyl groups for use in the invention are arylCo-Csalkyl, i.e. the aryl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • arylC 2 -C n alkenyl and arylC 2 -C n alkynyl groups for use in the invention are arylC 2 - Csalkenyl and arylC 2 -C 3 alkynyl, i.e. the aryl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • ⁇ eterocyclyl', 'heterocyclic' or heterocycle as applied herein is meant to include a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring, which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N.
  • 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,
  • ⁇ eterocylylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with a heterocyclyl moiety, wherein heterocyclyl and C m -C n alkyl are as defined above.
  • Preferred heterocyclylC m - C n alkyl groups for use in the invention are heterocyclylCo-Csalkyl, i.e. the heterocyclyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • heterocyclylC 2 -C n alkenyl' and 'heterocyclylC 2 -C n alkynyl' have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively.
  • Preferred heterocyclylC 2 -C n alkenyl and heterocyclylC 2 -C n alkynyl groups for use in the invention are heterocyclylC 2 -C 3 alkenyl and heterocyclylC 2 -C 3 alkynyl, i.e. the heterocyclyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • ⁇ eteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring 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.
  • 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.
  • 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 invention are prepared by reacting an acid of formula II
  • the coupling reaction is performed according to standard procedure used for amide bond formation in peptide synthesis.
  • General descriptions of such coupling reactions and reagents used therein can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993).
  • the starting materials are reacted in the presence of a coupling agent such as a carbodiimide like dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as N- ethyl-iV'- [(3 -dimethylamino)propyl] carbodiimide and a suitable catalyst, e.g. 1- hydroxybenzotriazole (HOBT), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 4- dimethylaminopyridine (4-DMAP).
  • a coupling agent such as a carbodiimide like dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as N- ethyl-iV'- [(3 -dimethylamino)propyl] carbodiimide and a suitable catalyst,
  • Further useful coupling agents are (benzotriazol-1-yloxy)- tris-(dimethylamino) phosphonium hexafluorophosphate (BOP), either by itself or in the presence of HOBT or 4-DMAP; or 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-7y,7V,N',N'-tetramethyluronium hexafluorophosphate (HATU) and similar.
  • BOP 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • TBTU 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium te
  • the coupling reactions are performed in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine, 7V-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like.
  • a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine, 7V-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like.
  • a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine,
  • the reaction temperature may range between 0 0 C and 50 0 C and the reaction time may range between 15 min and 24 h.
  • Acids of general formula (II) to be used in the coupling with an amine of general formula (III) are described in the literature, for example in WO06/057945, WO05/051914 and WO04/050619.
  • Amines of general formula (III) can be prepared as described in the schemes below and the in the experimental part that follows.
  • An intermediate to compounds of formula III wherein p is 1, Z is O, and the group Q is bonded via a methylene group to the oxygen, i.e. n is 1, can be prepared as outlined in scheme 1.
  • R 3' is C
  • Lg is a leaving group
  • the primary hydroxy group of the diol (Ia), achieved for example as described in Tetrahedron lett, 1987, 28, 1143, can be selectively alkylated 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 (Ib).
  • 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 (Ia) 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 (Ib) 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 (Ic).
  • the azide moiety can be introduced using the Mitsunobu conditions, i.e.
  • compounds wherein 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 (Ie).
  • a suitable alkylating agent such as an alkyl halide like, methyl iodide
  • Hydrolysis of the methyl glycoside by acidic treatment, followed by reduction effected for instance by LiBH 4 or the like then yields the linear compound (If).
  • Opening of the epoxide 2a achieved, for example, according to the procedure described by B. Samuelsson et al. in J. Med. Chem., 2004, 47, 3353-3356, with a desired nucleophile Q-OH in the presence of a base, such as potassium carbonate or the like, provides the ether derivative (2b).
  • a base such as potassium carbonate or the like
  • Inversion of the stereochemistry of the alcohol (3a), obtained as described above, 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
  • hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • the afforded primary amine can then be alkylated, conveniently by a reductive amination with a suitable aldehyde or keton using conditions known to the skilled person, or by reaction with an alkylating agent Ra-Lg, wherein Lg is a leaving group, optionally in the presence of a base.
  • the primary hydroxy group of the diol (Ia) 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 using 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 (4a) or the amine derivative (4b) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (Ia)
  • a further alternative method to obtain the amino derivative (4b) is to selectively oxidize the primary hydroxy group of the alcohol (Ia) 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) wherein the 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 (Ia) 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
  • An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (Ia) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (Ia) 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.
  • Alkylation of the primary hydroxy group of any of the previously described alcohols can be effected for example by reaction with a desired alkylating agent W-(CH 2 ) J1 -Lg, wherein Lg is a leaving group, such as a halide like bromo or iodo, or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as NaH or equivalent, to provide the ether derivative (5 a).
  • a desired alkylating agent W-(CH 2 ) J1 -Lg wherein Lg is a leaving group, such as a halide like bromo or iodo, or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as NaH or equivalent, to provide the ether derivative (5 a).
  • the Mitsunobu conditions with the alcohol of the desired group (W-(CH 2
  • 6d 6e Y' is O, S or NH
  • Selective protection of the secondary hydroxy group of any of the previously described alcohols can be effected by a using a suitable protection group strategy.
  • a benzylidene acetal of the two hydroxy groups may be formed, effected by treatment of the diol with anisaldehyde dimethylacetal in the presence of an acid like pTsOH or similar, followed by reductive opening of the acetal effected by treatment with Me 3 SiCl and NaCNBH 3 or equivalent, thus providing the p-MeO-protected compound (6b).
  • Amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is CH 2 NH, can be prepared according to the route illustrated in scheme 9.
  • Conversion of the ester function of compounds 7c or 8a to the corresponding aldehyde 9b can be performed by first protecting the free secondary alcohol with a suitable protecting group, for example a silyl group, followed by reduction of the ester to the alcohol (9a), using for instance sodium borohydride, and, finally, oxidation of the alcohol using for example Dess-Martin periodinate or any other suitable oxidation reagent.
  • a suitable protecting group for example a silyl group
  • the formed aldehyde is then reacted with a desired amine H 2 N-(CH 2 ) q -W in a reductive amination reaction, using reagents like NaCNBH 4 or the like to form the amine (9c).
  • the hydroxy group of compound 9d can be replaced by azide, thus affording amines of formula III wherein one of X' and X" is H and the other is N 3 , and Y is CH 2 NH.
  • the amino group of compound 9d is conveniently protected, for example with a Boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA.
  • the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH 2 .
  • Alkylation of the primary hydroxy group of the isopropylidene derivative (10a), prepared e.g. according to the method described by Mori, K. and Kinsho, T. in Liebigs. Ann. Chem 1991, 1309-1315, with a suitable derivative of the group Q-(CH 2 )J 1 can be performed using any suitable alkylation method such as any of those described above, for instance the Mitsunobu conditions can be used, or the alkylation may be effected by treatment with a alkylating agent Q-(CH 2 )-Lg in the presence of a base, may be used
  • Amines of formula III wherein Z is S or NH can be prepared, for example, by the Mitsunobu conditions using a thiol, (Q-(CH 2 ) n -SH) or an amine (Q-(CH 2 ) n -NH 2 ) respectively , as described above.
  • a suitable catalyst for instance Lindlar catalyst, or the like
  • the linear compound achieved after opening of the epoxide may be subjected to Mitsunobu conditions as illustrated in scheme 11.
  • the hydroxy group of compound 1Oi or 1 Ib can be replaced by azide, thus affording the corresponding amines of formula III wherein one of X' and X" is H and the other is N 3 .
  • the amino group of compound 1Oi is first protected, for example with a boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA.
  • the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH 2 .
  • Compound 12a can be prepared by alkylation of N-trityl-L-serine methyl ester with a desired group Q-(CH 2 ) J1 ZH or Q-CH 2 -Lg according to any of the methods described herein, followed by replacing the N-protecting group to a Boc group using standard conditions.
  • the Weinreb amide (12b) can then be achieved by hydrolysis of the methyl ester effected for example by treatment with LiOH, followed by reaction with N,O-dimethylhydroxylamine in the presence of NMM.
  • the group W-(CH 2 ) a - can then replace the hydroxylamine moiety by reaction with a suitable organometallic nucleophile, such as an organolithium reagent or a Grignard reagent, to afford the keton (12b).
  • a suitable organometallic nucleophile such as an organolithium reagent or a Grignard reagent
  • Benzyl derivatives Q-CH 2 - wherein Q is substituted with aryl, heterocyclyl, alkenyl or alkynyl can be prepared for example by using palladium promoted reactions, whereof many are described in the literature. A general is illustrated in scheme 14.
  • Q' is optionally substituted aryl or heterocyclyl, alkenediylcycloalkyl, alkynediylcycloalkyl, alkenediylaryl, alkynediylaryl, alkenediylheteocyclyl or alkynediylheterocyclyl
  • the desired substituent Q' can be introduced using for instance a Pd-catalyzed cross coupling reaction.
  • a Pd-catalyzed cross coupling reaction For example the Suzuki conditions may be used, i.e. reaction of the bromo derivative (14a) with the boronic acid of a desired substituent Q' in the presence of a palladium catalyst such as Pd(PPli3)4 or Pd(OAc) 2 or the like and a suitable base such as potassium carbonate or potassium fluoride or the like, thus providing the Q '-substituted compound (14b).
  • a palladium catalyst such as Pd(PPli3)4 or Pd(OAc) 2 or the like
  • a suitable base such as potassium carbonate or potassium fluoride or the like
  • Suitable reactions that can be used for the introduction of the substituent Q are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative (14a) in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative (14a) is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPlIs) 4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • a Pd catalyst such as Pd(PPlIs) 4 PdCl 2 or Pd(OAc) 2
  • a base such as triethylamine, potassium carbonate or the like.
  • the afforded alcohol can then either be used directly in the couplings to the primary hydroxy group of any of the intermediates described above, employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromomethane in the presence of triphenylphosphine, and subsequently coupled to the primary hydroxy group as described above.
  • a substituent Q' of Q as phenyl may alternatively be introduced at a later stage of the synthesis, for example as the last step, using similar conditions.
  • the free hydroxy group of compound (15a), prepared as described above, 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 (15b).
  • the monofluoro compound (15c) will be achieved by treatment of the alcohol to fluorinating conditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g.
  • the monofluoro compound (15e) having the reversed stereochemistry at the carbon atom to which the fluoro atom is attached can be achieved by reverting the stereochemistry of hydroxy compoundl5a to the hydroxy compound 15d, for example by subjecting the 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, and thereafter replace the hydroxy group with fluorine, as previously described.
  • X is a leaving group, e.g. Br or I Rc' is C r C 6 alkyl
  • 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.
  • 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.
  • Step b) 2.2-Dioxo-21ambda*6*-[1.3.21dioxathiolane-4.5-dicarboxylic acid diethyl ester
  • E-Ib Compound E-Ia (6.3 g, 25 mmol), NaIO 4 (8 g, 37.5 mmol) was suspended in acetonitrile (375 mL) and water (50 mL). RuCl3 (50 mg) was added and the mixture was stirred at ambient temperature for 30 min. Ether (400 mL) was added and the precipitated solid was removed by decantation and washed with ether. The ether fractions was combined, the volume reduced to half and filtrated through a pad of silica. Evaporation gave the title compound as yellow to reddish crystals (4 g, 60 %)
  • Triphenylphosphine (3.38 mg, 12.9 mmol) was dissolved in THF (40 mL) and the solution was cooled on an ice-bath. Diisopropyl azidocarboxylate (2.9 g, 94%, 14.2 mmol) was added slowly. After stirring for 15 min, a solution of 3, 5-difluorophenol (1.7 g, 13.1 mmol) in THF (10 ml) was added and the mixture was left stirring for another 15 min.
  • Step h) Acetic acid 2-azido-l-bromomethyl-3-(3,5-difluoro-phenoxy)-propyl ester (E-Ih)
  • the diol E-Ig was reacted according to the procedure described by T. Suzuki et al. in Tetrahedron Letters 46, (2005), 5811-5814. Purification by chromatography on silica gel (iso- hexane - diethyl ether, 5:1) gave pure title compound (90 %).
  • Step b) 2-Amino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester ( E-16b)
  • Compound E-16a 14.02 g, 29.61 mmol was dissolved in dichloromethane (72 mL) and the solution was cooled to 0 0 C.
  • TFA 58 mL was added dropwise during 5 minutes and the solution was stirred for 30 minutes at 0 0 C and for an additional 3.5 hours at room temperature.
  • the solvents were evaporated and co-evaporated three times with toluene.
  • the residue was dissolved in methanol (75 niL) and solid sodium hydrogen carbonate (7 g) was added and the slurry was stirred for 40 minutes.
  • Tetrabutylammoniumfluoride (0.664 mL, 1 M in THF) was added to a solution of compound E- 18a (240 mg, 0.53 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the afforded residue purified by column chromatography (SiO 2 , iso-hexane to isohexane-ether, 3:1) which gave the title compound (78 mg, 60 %).
  • the Epoxide (1 eq, prepared as described above) was dissolved in isopropanol/H 2 O 1 :1 (0.5 mL), the amine (2 eq) was added and the mixture was stirred at a temperature between room temperature and 83 0 C for 1 to 2Oh.
  • the reaction mixture was partitioned between DCM and H 2 O, the organic phase was dried (Na 2 SO 4 ), filtered and concentrated.
  • the afforded residue was purified by column chromatography, dissolved in MeOH (11 mL) and triphenylphosphine (1.5 eq) and two drops OfH 2 O were added to the solution.
  • the reaction mixture was stirred for 18h, and then concentrated.
  • the afforded crude product was then either purified by column chromatography, or used directly in the next step.
  • Step b) (2R3S)-3-amino-4-(3.5-difluorophenoxy)-l- ⁇ henoxybutan-2-ol (A-24)
  • the azide derivative A-24a was reduced according to the method described in Example 37 step b, which gave the title compound in quantitative yield.
  • the product was purified by column chromatography using toluene/ethyl acetate 1 :3 containing 1% MeOH saturated with NH 3 as mobile phase.
  • the title compound was prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO06/057945.
  • Acid-2 2-(((lS.2S)-2-methylcyclopropy ⁇ methylamino)-6-(N-methylmethylsulfonamido)isonicotinic acid (Acid-2) &
  • the title compound were prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO05/051914.
  • the title compound was prepared from 2,6-dichloroisonicotinic acid methyl ester using a procedure similar to the one described in WO06/057945.
  • Step b) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid methyl ester (Acid-5b) Triethylamine (one drop) was added to 5-bromo-isophthalic acid monomethyl ester (230 mg, 0.888 mmol) in SOCl 2 (3 ml). The mixture was stirred at 90 0 C for 1 h whereafter the solvent was evaporated and the residue dissolved in DCM (3 ml). Compound Acid-5a (200 mg, 1.40 mmol) in DCM (3 ml) was added and the mixture was stirred at rt. After 30 min the solvent was evaporated and the residue purified by flash chromatography using 1-2% MeOH in DCM as eluent, which gave the title compound (188 mg, 55%). MS: 383/385.
  • Step a) 2'-Trifluoromethyl-biphenyl-3.5-dicarboxylic acid dimethyl ester (Acid-6a) An oven-dried vial containing a magnetic stir bar was charged with dimethyl-5-bromo isophthalate (500 mg, 1.83 mmol), Pd(OAc> (4 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.).
  • Step c) 5-Dimethylsulfamoyl-isophthalic acid monomethyl ester (Acid IQc) 1 M NaOH (0.60 ml, 0.60 mmol) was added to Acid-lOb (181 mg, 0.600 mmol) in THF (5 ml) and MeOH (5 ml). The mixture was stirred at rt overnight whereafter the solvents were evaporated and 1 M HCl (2 ml) was added. The mixture was extracted with EtOAc, the organic layers were dried (MgSO 4 ) and evaporated. Yield: 167 mg (97%); white solid.
  • Acid-lOa (1.00 g, 3.38 mmol) was added to a solution of sodium sulphite (0.85 g, 6.8 mmol) and sodium bicarbonate (0.60 g, 7.1 mmol) in water. The mixture was heated at 50 0 C for 2 h whereafter the solvent was evaporated and the residue dried at high vacuum overnight. The material was suspended in DMF (10 ml) and MeI (1.00 ml, 16.0 mmol) was added. The mixture was stirred at rt for 3 h, EtOAc (50 ml) was added and the organic layer was washed with sat. NaHCO 3 ,water and dried (MgSO4)which gave the title compound (764 mg, 83%).
  • N-Methylethylene diamine (1.02 ml, 11.6 mmol) in dioxane (4 ml) was added dropwise to sulphamide (1.12 g, 11.6 mmol) in dioxane (10 ml) over 2 h.
  • the mixture was refluxed for 18 h, solvent evaporated and residue purified by flash chromatography using 3% MeOH in DCM as eluent which gave the title compound (259 mg, 16%) as a semisolid.
  • Step c) 5-(5-Methyl- 1.1 -dioxo- 1 lambda*6*-[ 1 ,2.51thiadiazolidin-2-ylVN-(l -phenyl-ethvO- sophthalamic acid methyl ester (Acid-12)
  • Acid-12b 83 mg, 0.243 mmol
  • Acid- 10 The compound Acid-12b (83 mg, 0.243 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (34 mg, 88%) as a pale yellow solid.
  • Step a) 5-(2-Oxo-oxazolidin-3-yl)-isophthalic acid dimethyl ester (Acid-14a) Tris(dibenzylideneacetone)palladium (58 mg, 0.063 mmol) was added to a degassed mixture of 5-bromo-isophthalic acid dimethyl ester (345 mg, 1.26 mmol), 2-oxazolidinone (220 mg, 2.52 mmol), CS2CO3 (1.03 g, 3.16 mmol) and Xantphos (109 mg, 0.189 mmol) in dioxane (10 ml). The mixture was stirred at 105 0 C under N 2 for 4 h. The solvent was evaporated and the residue taken up in DCM/water. The organic phase was separated and concentrated. The residue was purified by flash chromatography using 2% MeOH in DCM which gave the title compound (264 mg, 75%) as a beige solid.
  • Step a) 5-Methyl-N- ⁇ -phenyl-ethvD-isophthalamic acid methyl ester (Acid-15a) Triphenylphosphine (7 mg) was added to a mixture of 5-bromo-N-(l-phenyl-ethyl)- isophthalamic acid methyl ester (Acid- 7b) (164 mg, 0.452 mmol), trimethylboroxine (64 ⁇ l, 0.452 mmol) and K 2 CO 3 (191 mg, 1.36 mmol) in DMF (5 ml). The mixture was heated at 150 0 C for 15 min in microwave reactor. The solvent was evaporated and residue purified by flash chromatography using 1% MeOH in DCM which gave the title compound (87 mg, 71%).
  • Step b) 5-Methyl-N-(l-phenyl-ethyl)-isophthalamic acid (Acid-15) The compound Acid- 15a (97 mg, 0.326 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (91 mg, 99%) as a white solid.
  • Step N [I-O -Bromo-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- F(2-methyl-cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide
  • 2-Thiazole tributylstannane (0.050 ml, 0.16 mmol), CuI (0.003, 0.016 mmol), LiCl (0.013 g, 0.32 mmol), and (CySP) 2 PdCl 2 (0.009 g, 0.012 mmol) were added.
  • the reaction was degassed and stirred under N 2 at 125 0 C for 15 min.
  • the reaction mixture was diluted with CH3CN, the major Sn-residues were washed away by ⁇ o-hexane.
  • Step a) 6-(3.5-Difluorophenoxy)-3-deoxy-1.2-O-isopropylidene- ⁇ -D-glucose (9a) To a solution of the epoxide 5,6-anhydro-3-deoxy-l,2-O-isopropylidene-D-glucofuranoside (0.893 g, 4.80 mmol), prepared from 3-deoxy-l,2-O-isopropyliden-D-glucofuranoside according to the procedure described by B. Samuelsson et al. in J. Med.
  • Step b) 5-Azido-6-(3,5-difluorophenoxy)-3,5 dideoxy-l,2-O-isopropylidene- ⁇ -L-iodose 9b) The alcohol 9a (1.16 g, 3.65 mmol) and triphenylphosphine (1.44 g, 5.64 mmol) were dissolved in dry THF (19 rnL). The mixture was cooled to -15 0 C and diisopropyl azodicarboxylate (DIAD) (1.80 mL, 9.13 mmol) was added.
  • DIAD diisopropyl azodicarboxylate
  • Step d) (3£,45V4-Azido-5-(3,5-difluorophenoxy)-3-hvdroxy-pentanoic methyl ester (9d)
  • the carboxylic acid 9c was dissolved in methanol (100 mL) at 0 0 C and acetyl chloride (9 mL) was added slowly. The solution was stirred for 20 minutes at 0 0 C and for an additional 48 hours at room temperature. The solvent was evaporated and the residue co-evaporated with toluene and then purified by flash column chromatography, which gave the title compound.
  • Dibutyltin oxide (170 mg, 0.68 mmol) was added to a solution of the diol 9e (145 mg, 0.53 mmol) in toluene (40 mL), whereafter the solution was refluxed at 125 °C with a Dean-Stark adapter for 4h. The solution was allowed to cool to 90 °C followed by addition of methyl iodide (23.6 ⁇ L, 0,53 mmol) and tetrabutylammonium bromide (195 mg, 0.85 mmol). The reaction mixture was stirred at 90 °C for 16h. The solution was carefully concentrated, dissolved in DCM (3 mL) and applied to a silica column (10 g).
  • Step g) 2-Amino-l-(3,5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (9g) Polymer supported triphenylphosphine (270 mg, 1.48 mmol/g) was added to a solution of the azide 9f (23 mg, 0.08 mmol) in THF:MeOH (10:1.5, 11.5 ml) and the mixture was shaken for 16 h. The solution was filtered from the resin and concentrated which gave the title compound (15.6 mg, 0.06 mmol, 75%). MS m/z 262.2 (M+H) + .
  • Alcohol 10b (313 mg, 0.8 mmol) was dissolved in dry DMF (5 mL), cooled to 0 °C and hexane washed sodium hydride (60% oil suspension, 25.5 mg, 1.04 mmol) was added, followed by addition of methyl iodide (500 ⁇ L, 8 mmol). The reaction mixture was stirred for 1.5h, quenched with methanol, diluted with DCM and washed with water. The organic phase was collected, dried over sodium sulphate and the residue was purified by flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (226 mg, 70%).
  • the alcohol l ib (52.4 mg, 0.145 mmol), triphenylphosphine (42 mg, 0.16 mmol), DIAD (35 ⁇ L, 0.174 mmol) and p-nitrobenzoic acid (29 mg, 0.17 mmol) were dissolved in dry THF (30 mL) and cooled to 0 0 C. The reaction was allowed to reach RT during 16h. The solution was concentrated and the residues was purified by silica flash chromatography.
  • Alcohol 1 Ic (20 mg, 0.055 mmol) was dissolved in dry THF (1 mL) together with triphenylphosphine (21 mg, 0.082 mmol) and then cooled to 0 0 C. DIAD (16 ⁇ L, 0.82 mmol) was added drop wise, and the mixture was stirred at 0 0 C for 5 min, followed by drop wise addition of DPPA (36 ⁇ L, 0.165 mmol). The reaction was stirred at 0 0 C and allowed to reach RT overnight. The solution was concentrated, and purified by silica flash chromatography (hexane: ethyl acetate (100:0-75:25) which gave the title compound (9.8 mg, 46%).
  • Azide compound 10a (210 mg, 0.505 mmol) was dissolved in ethyl acetate (25 mL) together with Boc-anhydride (551 mg, 2.52 mmol) and then subjected to catalytic hydrogenation using an H-Cube equipment and a 10% Pd/C cartridge at 25 0 C. The solution was concentrated and the residue purified by silica flash chromatography (Hexane 100:0-80:20) which gave the title compound (146 mg, 59%). MS m/z 489 (M+H) + , 389 (M-Boc) +
  • Methyl ester 12a (146 mg, 0.298 mmol) was dissolved in hexane (30 mL) followed by addition of lithium borohydride (2M in THF, 600 ⁇ L, 1.2 mmol). The reaction mixture was stirred at RT for 2h, quenched with methanol, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (140 mg, 100%). MS m/z 462.5 (M+H) + .
  • DIBAL 3.74 mL, 3.74 mmol, IM in hexane
  • the reaction mixture was agitated at RT for 4h, and then quenched by addition of water.
  • the solution was diluted with DCM and washed with water.
  • the organic phase was separated, concentrated and purified by flash chromatography (hexane:ethyl acetate 100:0-75:25) which gave the title compound (136.5 mg, 25%), MS m/z 362.8 (M+H) + .
  • Step b) N- r2-(tert-Butyl-dimethyl-silanyloxy)- 1 -(3 ,5 -difluoro-phenoxymethvO-4-hvdroxy- butyll -2- r(2-methyl-cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (14b)
  • Step c) N-r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-oxo-butyll-2- [(2-methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (14c)
  • the alcohol 14b (69.2 mg, 0.1 mmol) was dissolved in dry dichloroethane (3 mL), followed by the addition of Dess- Martin reagent (59 mg, 0.14 mmol). The reaction mixture was stirred at RT for Ih, quenched with a saturated solution of sodium bicarbonate and Na 2 S 2 O 3 10% aq, diluted with DCM and washed with water. The organic phase was separated, concentrated and used in next step without further purification.
  • Boc anhydride (251mg, 1.14 mmol) and DMAP (0.57 mmol) were added to a solution of compound 12a (282 mg, 0.57 mmol) in acetonitrile (15 mL).
  • the reaction mixture was stirred at RT for 16h, concentrated and the residue was purified by silica flash chromatography which gave the title compound (86 mg, 25%). MS m/z 590.2 (M+H) + .
  • Step b) 4-(Bis-tert-butoxycarbonylamino)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro- phenoxy)-pentan-l-ol (17b)
  • Compound 17e (26.5 mg, 0.058 mmol) was dissolved in dioxanexonc. HCl (3:1, 4 mL) after Ih stirring, the solution was concentrated and co-evaporated with toluene.
  • Step l N-r3-Cvclopropylamino-l-(3,5-difluoro-phenoxymethyl)-2-hvdroxy-propyll-2-rmethyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (19)
  • the title compound was prepared from compound 30a and Acid-3, in 67% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer, according to the method described in Example 28 step b.
  • Step b) (2-Hydroxy-3-methoxy-l-phenoxymethyl-propy ⁇ -carbamic acid tert-butyl ester (33 a)
  • Epoxide E-17 was reacted according to the procedure described in Example 28 step a, which gave the title compound in 80% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
  • Step c) N-(2-Hvdroxy-3-methoxy-l-phenoxymethyl-propyl)-2-r(2-methyl-cvclopropylmethyl)- aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (33b)
  • Compound 34a and Acid-3 were reacted according to the method described in Example 28 step b, which gave the title compound in 96% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer.
  • Compound 36a 50 mg, 0.159 mmol was dissolved in THF/H 2 O/MeOH 4:2:1 (7 mL) and LiOH (23 mg, 0.960 mmol) and cesium carbonate (112 mg, 0.318 mmol) were added.
  • the epoxide E-Ii was opened with sodium hydride according to the conditions described in Example 28 step , but using ⁇ o-butanol instead of methanol.
  • the title compound was achieved in 84% yield after column chromatography using toluene/ ethyl acetate 15:1 as mobile phase.
  • Step a) 3-Azido-4-(3,5-difluoro-phenoxy)-l-fluoro-butan-2-ol (40a) Epoxide E-Ii (105.5 mg, 0.437 mmol) was dissolved in chlorobenzene (3 mL) and potassiumhydrogen fluoride (68 mg, 0.875 mmol) and TBAF (IM in THF) (0.875 mL, 0.875 mmol) were added and the mixture was stirred at 120 0 C for 90 minutes. The mixture was diluted with ethyl acetate and washed twice with brine whereafter the organic phase was dried, filtered, and concentrated.
  • the title compound was prepared from compound 4Od and Acid-1, in 88% yield according to the method described for the synthesis of compound 28b.
  • compound 42a (269 mg, 0.746 mmol) dissolved in dry ether (6 mL) at 0 0 C was added butylmagnesium chloride (2M in THF) (149 ⁇ L, 2.99 mmol) dropwise during 5 minutes.
  • the solution was stirred at 0 0 C for 1.5 hours and the reaction was subsequently quenched by the addition of saturated NH 4 Cl (aq) (15 rnL).
  • sodium borohydride (14.5 mg, 0.383 mmol) and the mixture was stirred at 0 0 C for 1 hour.
  • Saturated NH 4 Cl (aq) was added and the methanol was evaporated.
  • the mixture was extracted with ethyl acetate and washed twice with saturated NH4CI (aq) and the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ ethyl acetate 7:1) provided the title compound (106 mg, 92%) as a diastereomeric mixture; 3:1 in favor of the R isomer.
  • Compound 42d was prepared from compound 42c and Acid-1 in 90% yield as a diastereomeric mixture; 3:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • Compound 43b was prepared from compound 43a in 95% yield as a diastereomeric mixture; 5:1 in favor of the R isomer according to the method described for the synthesis of compound 42c.
  • Compound 43c was prepared from compound 43b and Acid-3 in 93% yield as a diastereomeric mixture; 5:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • the title compound was prepared from compound 44a in 90% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 42c.
  • Step c) N- [ 1 -(3.5 -Difluoro-phenoxymethylV 2-hydroxy-4-phenyl-butyr
  • the title compound was prepared from compound 44b and Acid-3 in 82% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • Diastereomer mixture 45a (218 mg, 0.480 mmol) was dissolved in a solution of 4M HCl in dioxane (8 ml). The reaction mixture was stirred at room temperature for 1 1/2 h and then concentrated under reduced pressure. The residue was dried by evaporation of added toluene (2x10 ml) and CH 3 CN (10 ml), to afford crude title compound.
  • Step c) N- [2-Hydroxy- 1 -phenoxymethyl-3 -(3 -trifluoromethyl-benzylaminoVpropyH -2- [methyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (45c)
  • the crude amine 45b and Acid-1 (171 mg, 0.480 mmol) were dissolved in dry DMF (8 ml) and diisopropylethylamine (416 ⁇ l, 2.40 mmol) was added. The solution was cooled on an ice-water bath and HATU (237 mg, 0.623 mmol) was then added.
  • pTSA 86.8 mg, 0.46 mmol, 3 equiv.
  • the mixture was stirred at rt for 15 h and then filtered which gave the title compound as a white solid.
  • LCMS m/z 341 (MH) + .
  • Step c) 2'-Trifluoromethyl-biphenyl-3.,5-dicarboxylic acid 5-([2-hydroxy-l-phenoxymethyl-3-(3- trifluoromethyl-phenylamino)-propyl "
  • HATU 68 mg, 0.18 mmol, 1.2 equiv.
  • Step a (2,3-Dihvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47a)
  • (l-phenoxymethyl-allyl)-carbamic acid tert-butyl ester 200 mg, 0.76 mmol
  • acetone:water 10:1 mL
  • a catalytic amount OfOsO 4 and NMO 0.16 mL, 1.52 mmol, 2 equiv., wt 50% in water.
  • Step c (3-Chloro-2-hvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47c)
  • acetone 11 rnL
  • LiCl 1.24 g, 29.3 mmol, 24 equiv.
  • EtOH aqueous ethanol
  • 3- (trifluoromethyl)benzyl amine 31 ⁇ L, 0.21 mmol, 3 eq.
  • the mixture was refluxed overnight, cooled down to rt and concentrated.
  • EtOAc was added and the solution was washed with a sat aq. solution of NaHCOs.
  • the organic phase was dried and evaporated and the afforded residue was used in the next step without any further purification.
  • HATU 25 mg, 0.07 mmol, 1.2 equiv.
  • PPI13 103.2 mg, 0.39 mmol, 1.5 equiv.
  • the mixture was stirred at rt overnight and concentrated. Purification by flash chromatography (toluene/npropanol/N ⁇ OH, 8/2/0.1) afforded pure title compound (73%).
  • Step b) (26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-5-methoxy-6-phenoxy-hexan-3-ol
  • DDQ (11.5 mg, 0.051 mmol, 1.3 equiv) was added at 0 0 C to a stirred solution of I- Ia (20 mg, 0.039 mmol) in DCM:H 2 0 (19:1, 10 mL). The reaction was allowed to reach room temperature then stirred for an additional 3 h.
  • Nosylchloride (177 mg, 0.8 mmol) and pyridine (194 ⁇ L, 2.4 mmol, 3 equiv) were added to a solution of 4-flouranilin (154 ⁇ L, 1.6 mmol, 2 equiv) in freshly distilled DCM (2mL).
  • the reaction was stirred at room temperature for two hours then quenched with 10% HCl (aq), the pH was set to ⁇ 1 before extracting with DCM (2x).
  • DIAD 32 ⁇ L, 0.164 mmol, 1.4 equiv
  • Ph 3 P 43 mg, 0.164 mmol, 1.4 equiv
  • reaction mixture was allowed to reach room temperature, then left stirring over night.
  • the solvent was evaporated and the crude product was used dissolved in MeCN and thiophenol (36 ⁇ L, 0.351 mmol, 3 equiv) was added followed by potassium carbonate (48 mg, 0.351 mmol, 3 equiv).
  • the reaction was heated to 50 0 C and followed by TLC. After 3h all starting material was consumed.
  • the methyl glycoside I-3b (1.449 g, 4.22 mmol) was dissolved in 1, 4-dioxane/ 0.5 M H 2 SO 4 1 :1 and heated to reflux. After complete reaction ( ⁇ 1 hour according to TLC), the reaction was cooled to room temperature and then neutralized with Na 2 CO 3 (aq). The volatile solvents were evaporated under vacuum and the afforded residue dissolved in DCM and washed with H 2 O (x 2). The organic phase was dried over Na 2 SO 4 and concentrated.
  • Step d) (2i?.46'.55)-5-Azido-6-(3.5-difluoro-phenoxyV2-methoxy-hexane-1.4-diol (I-3cD LiBH 4 (200 mg, 9.22 mmol, 2 equiv) was added under an argon atmosphere at 0 0 C to a stirred solution of compound I-3c (1.45 g, 4.61 mmol) in dry THF (20 mL). After 1 h the reaction was quenched with water, extracted with EtOAc, dried over Na 2 SO 4 and concentrated.
  • I-3cD LiBH 4 200 mg, 9.22 mmol, 2 equiv
  • Triphenyl phosphine (1.5 equiv) was added together with a drop of water to a solution of the azide (1 equiv) in MeOH. The reaction mixture was stirred for 16 h, concentrated to yield the crude compound which was used in the next step without further purification. Acid A (I equiv) was dissolved in dry DCM and pyBOP (1 equiv) was added followed by DIPEA (1 equiv). After 30 minutes the crude amine (1 equiv, dissolved in DCM) was added to the mixture, followed by DIPEA (1 equiv). After 2 h, the reaction mixture was diluted with DCM, washed with Na 2 CO 3 (sat.) and NH 4 Cl (aq).
  • TruPointTM Beta-Secretase Assay Kit was used to evaluate the enzymatic inhibition of BACEl exhibited by the compounds of the invention.
  • 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, lanthanide fluorescence 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 exhibited by the cleavage product.
  • the compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were 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 concentration of 200 nM.
  • Product TR- fluorescence was monitored during 90 min with a 1420 VICTOR and presented as Relative Fluorescence units (RFu).
  • the IC50 value was calculated with GraFit software.
  • Activity of the inhibitors was determined by measuring the TR-fluorescence at ⁇ g X 330 nm and ⁇ gm 615 nm. The inhibition is calculated as follows:
  • Example 68 which is a representative compound of the invention, exhibited an enzymatic inhibition of 6.5 nm, when tested in a BACE enzyme assay such as the one described above.
  • Table 1 shows the enzymatic inhibition represented as intervals exhibited by the compounds according to the invention.
  • Category A indicates an IC50 value of ⁇ 1 ⁇ M
  • category B indicates 1 - 5 ⁇ M
  • category C indicates > 5 ⁇ M.

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Abstract

L'invention porte sur un composé de formule (I) : N-oxydes, sels d'addition, amines quaternaires, complexes métalliques, formes stéréoisomères et métabolites de ceux-ci, formule dans laquelle A représente CR1 ou N; D représente H, alkyle en C1-C6, alcényle en C2-C6, alcynyle en C2-C6 ou Q représente alcényle en C2-C6, alcynyle en C2-C6, aryle ou hétérocyclyle; W représente H, alkyle en C1-C6, alcényle en C2-C6, haloalkyle en C1-C3, hydroxyalkyle en C1-C3, cycloalkyle en C3-C6, aryle ou hétérocyclyle; l'un de X' et X'' représente H ou CH3, l'autre représente alkyle en C1-C3, F, OH, NRaRb, CF3 ou N3 ; ou X' et X'' représentent tous deux F; Y est une liaison, CH2, NRa, O, CH2CH2, CH2NRa, CH2O ou S(=O)r; Z représente O, S(=O)r ou NRa; les autres variables sont telles que définies dans la description. Les composés de l'invention sont des inhibiteurs de BACE et sont entre autres choses utiles pour le traitement et/ou la prévention d'états associés à l'activité de BACE tels que la maladie d'Alzheimer.
PCT/SE2009/051105 2008-10-07 2009-10-05 Inhibiteurs d'aspartyl protéase WO2010042030A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
JP2014533250A (ja) * 2011-11-10 2014-12-11 アラタナ セラピューティクス エン ヴェー シクロプロパン誘導体の調製方法
WO2013093943A1 (fr) * 2011-12-20 2013-06-27 Council Of Scientific & Industrial Research Résolution cinétique phénolytique d'azido- et d'alcoxy-époxydes
US8975430B2 (en) 2011-12-20 2015-03-10 Council Of Scientific & Industrial Research Phenolytic kinetic resolution of azido and alkoxy epoxides
US10967074B2 (en) 2012-01-20 2021-04-06 Aratana Therapeutics, Inc. Eye drop composition
US11904024B2 (en) 2012-01-20 2024-02-20 Aratana Therapeutics, Inc. Eye drop composition
US10745380B2 (en) * 2016-03-09 2020-08-18 Ctxt Pty Ltd Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies

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