WO2010107384A1 - Aspartyl protease inhibitors - Google Patents

Aspartyl protease inhibitors Download PDF

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WO2010107384A1
WO2010107384A1 PCT/SE2010/050307 SE2010050307W WO2010107384A1 WO 2010107384 A1 WO2010107384 A1 WO 2010107384A1 SE 2010050307 W SE2010050307 W SE 2010050307W WO 2010107384 A1 WO2010107384 A1 WO 2010107384A1
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alkyl
mmol
compound according
aryl
heterocyclyl
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PCT/SE2010/050307
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French (fr)
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Susana Ayesa
Oscar Belda
Ismet Dorange
Karolina Ersmark
Per-Ola Johansson
Stina Lundgren
Åsa ROSENQUIST
Bertil Samuelsson
Daniel Wiktelius
Horst Wähling
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

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
  • ⁇ amyloid A ⁇ amyloid
  • Pathological features of AD are accumulation of abnormal aggregated protein breakdown products, ⁇ -amyloid plaque and neurofibrillary tangles, in the brain. Plaque relatively specific for AD is primary a result from extracellular accumulation of aggregated A ⁇ .
  • Fibrillary tangles consist 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-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein G is NR 10 or O;
  • R 1 is H, Ci-Cealkyl, Ci-C 6 alkoxy, N 3 or halo;
  • R 2 is H or Ci-Cealkyl
  • R 3 and R 3 are independently of each other H, Ci-C ⁇ alkyl or CF 3 , or R 3 and R 3 together with the carbon atom to which they are attached form C 3 -C6Cycloalkyl or R 4 is H or Ci-C ⁇ alkyl, or when p is 1 then R 4 together with R 3 and the carbon atoms to which they are attached may form C 3 -Cecycloalkyl or
  • R 7 is Ci-Cealkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-C 6 alkoxyCi-C 3 alkyl, arylC 0 -C 3 alkoxyCi-
  • Ci-C 3 alkyl C 3 alkyl, heterocyclylC 0 -C 3 alkoxyCi-C 3 alkyl or N(Ra)(Rb)Ci-C 3 alkyl; wherein the Ci-C 3 alkyl moiety of R 7 is optionally substituted with Ci-C ⁇ alkyl;
  • R 8 is H or Ci-Cealkyl
  • R 7 and R 8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine
  • R 9 is Ci-Cealkyl, 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 or heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C ⁇ 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; wherein the cyclic amine is optionally substituted with Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -
  • Q is Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl, C 3 -Cecycloalkyl, aryl or heterocyclyl;
  • W is H, Ci-Cealkyl, C 3 -C 6 cycloalkyl, CH 2 F, CHF 2 or CF 3 ; 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;
  • Y is NRd or O
  • Ra is independently H or Ci-C ⁇ alkyl
  • Rb is independently H or Ci-C ⁇ alkyl
  • 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
  • Rc is independently Ci-C ⁇ alkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocycle; Rd is H or Ci-C 3 alkyl; and wherein aryl is independently phenyl or naphthyl, or phenyl fused to or C 4 -
  • 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,
  • C ⁇ alkynoxy, d-C ⁇ cycloalkyl, d-C ⁇ cycloalkenyl, aryl and heterocyclyl above is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C 4 alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl, Ci-C 4 alkoxy, C 1 -
  • heterocyclyl 1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence aryl 1 and heterocyclyl 1 above (including those in composite expressions such as and heterocyclyl 1 Co- C 3 alkyl), the cycloalkyl 1 , aryl 1 and heterocyclyl 1 moiety is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from C 1 - C 4 alkyl, C 3 -C 4 cycloalkyl, halo, haloCi-C 4 alkyl, hydroxy and NRaRb; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
  • R 2 is H
  • R 3' and R 3" are both H or CH 3 , or one of R 3' and R 3" is H and the other is CF 3 , or R 3' and R 3" together with the carbon atom to which they are attached form C 3 -Cecycloalkyl;
  • R 4 is H
  • R 7 is Ci-C 6 alkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl or heterocyclylCi-C 3 alkyl;
  • R 8 is H or Ci-Cealkyl
  • R 9 is Ci-Cealkyl, 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, heterocyclylor heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C ⁇ 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;
  • Q is aryl or heterocyclyl
  • W is H, Ci-Cealkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, CH 2 F, CHF 2 or CF 3 ; one of X' and X" is H and the other is OH,
  • Y is NH
  • Z is O, NH or CH 2 ; n is 0 or 1 ; p is 0 or 1 ; r is 2.
  • D is Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl, or
  • R 7 is as recited above. Typical values for R 7 include Ci-C ⁇ alkyl, arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein each Ci-C ⁇ alkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, Ci- C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • substituents to the aryl or heterocyclyl moieties of R 7 include one or two substituents independently selected from Ci-C 4 alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • a further configuration for R 7 include arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein the Ci-C3alkyl moiety is optionally substituted with Ci-C ⁇ alkyl.
  • Preferred configurations for the C 1 - C ⁇ alkyl according to this embodiment include Ci-C 4 alkyl such as methyl or ethyl; haloCi- C 4 alkyl, such as trifluoromethyl and C 3 -C 4 cycloalkyl such as cyclopropyl.
  • R 7 is phenylmethyl, 1-phenylethyl and 1- phenylpropyl, especially phenylmethyl or 1-phenylethyl, wherein the phenyl ring is optionally substituted. Accordingly, favoured embodiments of the invention include compounds having the partial structure shown below:
  • the substituent(s) is preferably the in the para and/or ortho position of the phenyl ring.
  • R 7 is Cs-C ⁇ heteroarylmethyl, I-C 5 - C ⁇ heterarylethyl or l-Cs-C ⁇ heterarylpropyl, especially Cs-C ⁇ heteroarylmethyl, 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:
  • R 8 is as recited above, preferably hydrogen or methyl.
  • a further embodiment of the invention includes compounds of formula (I) wherein R 7 and R 8 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.
  • R 7 and R 8 are both Ci-C ⁇ alkyl, such as ethyl, propyl or butyl.
  • compounds are included wherein D represents an amine moiety, i.e. compounds wherein D is
  • Typical values for R 9 according to this embodiment include d-C ⁇ alkyl, C2-Cealkenyl and C 2 - C ⁇ 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- C 4 alkyl for example isopropyl or t.butyl, haloalkyl for example CH 2 F, CHF 2 or CF 3 , hydroxy and phenyl.
  • a typical value for R 9 according to this embodiment is optionally substituted C 2 - C ⁇ alkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF3.
  • R 9 includes Cs-C ⁇ cycloalkylCi-Csalkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C 3 alkyl. Especially preferred are cyclopropylmethyl and 2-methylcyclopropylmethyl.
  • 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: opt. subst opt. subst
  • Optional substituent to the R 9 -R 10 ring is selected from Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and phenyl.
  • a preferred embodiment of the invention includes compounds wherein A is N and D represents an amine moiety NR 9 R 10 i.e. compounds having the structure (Ib):
  • Typical values for R according to this embodiment include Ci-C ⁇ alkyl, C 2 -Cealkenyl and C 2 - C ⁇ 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- C 4 alkyl for example isopropyl or t.butyl, haloalkyl for example CH 2 F, CHF 2 or CF 3 , hydroxy and phenyl.
  • a typical value for R 9 according to this embodiment is optionally substituted C 2 - C ⁇ alkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF 3 .
  • R is preferably H or methyl.
  • R 9 examples include Ci-C 3 alkoxyCi-C 4 alkyl, such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl and the like.
  • D is Ci-C ⁇ alkyl, C 2 -Cealkenyl or C 2 - C ⁇ alkynyl, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted.
  • Typical substituents according to this embodiment include Cs-C ⁇ cycloalkyl for example cyclopropyl, Ci- 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 -Cealkynyl, such as ethynyl which is unsubstituted or, preferably, substituted with cyclopropyl or CF3.
  • 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 NRd, wherein Rd is hydrogen or Ci-C 3 alkyl, preferably hydrogen or methyl.
  • Z is a bond.
  • n is 0 or 1, preferably 0.
  • 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 is an optionally substituted 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
  • Representative values for the optional substituents to Q include one or two substituents independently selected from Ci-C 4 alkyl, C 3 -C 4 cycloalkyl, Ci-C 4 alkoxy, Ci-C 3 alkoxyCi- C ⁇ alkoxy, cyano, halo, haloCi-C4alkyl and arylCi-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 according to this embodiment are compounds wherein Q is pyrid-3- yi-
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is H.
  • Y is NRd, wherein Rd is H or Ci-C 3 alkyl such as H or CH 3 .
  • Rd is H or Ci-C 3 alkyl such as H or CH 3 .
  • Y is 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.
  • one of R 3' and i T R-) 3" is H, the other is Ci-C ⁇ alkyl, such as methyl or ethyl, and R 4 is Ci-C ⁇ alkyl, such as methyl or ethyl.
  • R 3 and R 3 are both H.
  • R 3' and i T R-) 3" are both Ci -C ⁇ alkyl such as methyl.
  • one of R 3 and R 3 is H, and the other is Ci-C ⁇ alkyl or optionally substituted Ci-C ⁇ alkyl.
  • one of R 3 and R 3 is H, and the other is Ci-C ⁇ alkoxyCi-C ⁇ alkyl such as methoxy ethyl or ethoxymethyl or, preferably, methyo xymethy 1.
  • one of R 3 and R 3 is H, and the other is mono-, di- or trifluoromethyl, preferably trifluoromethyl.
  • R 3 and R 3 together with the carbon atom to which they are attached form Cs-C ⁇ cycloalkyl or thus providing compounds having partial structure Ih or Ii respectively:
  • a is 1-4.
  • E is O or NRd, and b and c are independently 0, 1, 2, 3 or 4 provided that 2 ⁇ b + c ⁇ 4.
  • Typical compounds according to this embodiment are those wherein R 3 and R 3 together with the carbon atom to which they are attached form cyclopropyl, i.e. a is 1 in partial structure Ih.
  • p is 0, Y is NH, and R 3 and R 3 are both H.
  • p is 0, Y is NH and R 3 and R 3 are methyl.
  • p is 0, Y is NH, one of R and R is H and the other is CF 3 , Ci-CsalkoxyCi-Csalkyl such as methoxymethyl or Ci-C ⁇ alkyl such as methyl or ethyl.
  • p is 0, Y is NH, and R 3 and R 3 together with the carbon atom to which they are attached form Cs-C ⁇ cycloalkyl, preferably cyclopropyl.
  • One embodiment of the invention includes compounds wherein W is H.
  • a further embodiment of the invention includes compounds wherein W is optionally substituted Ci-C ⁇ alkyl, such as methyl, ethyl, isopropyl or t.butyl.
  • a further embodiment of the invention includes compounds wherein W is Cs-C ⁇ cycloalkyl such as cyclobutyl or, preferably cyclopropyl.
  • a further embodiment of the invention includes compounds wherein W is Cs-C ⁇ cycloalkylCi- Csalkyl such as cyclopropylmethyl.
  • a further embodiment of the invention includes compounds wherein W is Ci-C3alkoxyCi- Csalkyl such as methoxymethyl.
  • a further embodiment of the invention includes compounds wherein W is haloCi-Csalkyl, such as CH 2 F, CHF 2 or CF 3 .
  • W is haloCi-Csalkyl, such as CH 2 F, CHF 2 or CF 3 .
  • a preferred configuration for W according to this embodiment is CF 3 .
  • Preferred compounds of formula (I) wherein one of X' and X" is H and the other is OH, and Y is NH are those having the stereochemistry indicated in formula (Ij):
  • R 1 is H.
  • R 1 is halo, such as fluoro.
  • R 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 (Ik):
  • R 6 is a cyclic sulphonamide
  • A is CH and R 1 is halo, preferably fluoro.
  • R 1 is preferably in the ortho position of the phenyl ring.
  • R 6 examples include hydrogen and Ci-C ⁇ alkyl, especially hydrogen or methyl.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereo chemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) as specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or an prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereo chemically 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 and are thus useful for the inhibition of bace activity.
  • 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, in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
  • the compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic! lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above 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 invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
  • the 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 stereo chemically 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/so lvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route particularly capsules or tablets is favoured.
  • the 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.
  • Such additional compounds also include cholesterol-lowering drugs such as HMG- CoA reductase inhibitors, e.g. lovastatin and simvastatin.
  • 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 stereo chemically isomeric form thereof as specified herein.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the 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, Cs-CscycloalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C ⁇ alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydro lysable 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 hydro lysable 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.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like
  • organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fum
  • 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 non- toxic 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, JV-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, trifluoro acetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereo chemically 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.
  • stereo isomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term ' stereo isomerically pure' concerns compounds or intermediates having a stereo isomeric 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.
  • 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 stereo chemically isomeric forms may also be derived from the corresponding pure stereo chemically 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 stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the 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 6 alkynyl 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 alkyl' 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 alkynyr 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 C3-C n 'Cycloalkyl moiety.
  • C3-C n 'CycloalkylC2-C n alkenyl and C3-C n 'CycloalkylC2- 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. C3- 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.
  • 'C 0 -C 3 alkanediyl' defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
  • 'C j -C 3 alkanediyr defines a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
  • 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-Cealkynoxy, 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' or 'halogen' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloC m -C n alkyl' 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 NH 2 , 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 independently of each other.
  • C m -C n alkyl is especially Ci-C 6 Or Ci-C 4 alkyl variants.
  • 'C2-C n alkenylamino' and 'C2-C n alkenylamino' 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.
  • C2-C6 variants and especially the C2-C4 variants.
  • Included are also radicals wherein the two C m -C n alkyl groups together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • 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 ⁇ cycloalkyl (for example indanyl), or a C 5 -
  • Cecycloalkenyl examples 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.
  • arylC2-C n alkenyl and arylC2-C n alkynyl groups for use in the invention are arylC2- 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, tetrahydro furanyl, 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,
  • HeterocylylC 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.
  • Heteroaryl' 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.
  • heterocyclyl 1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein the carbocyclyl 1 , aryl 1 or heterocyclyl 1 moiety is optionally substituted with 1 or 2, or where valence permits up to 3 substituents independently selected from Ci-C 4 alkyl, C 3 -C 4 Cycloalkyl, halo, haloCi-C 4 alkyl, hydroxy and NRaRb.
  • 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.
  • 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-N'-[(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-N'-[(3-dimethylamino)propyl]carbodiimide and a suitable catalyst, e.g
  • 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-l-yl)-NNN',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-NNN',N'-tetramethyluronium hexafluorophosphate (HATU) and similar.
  • a suitable base such as a tertiary amine, e.g.
  • Coupling reactions are preferably conducted in an inert solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide (DMF), dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF).
  • halogenated hydrocarbons e.g. dichloromethane, chloroform
  • dipolar aprotic solvents such as acetonitrile, dimethylformamide (DMF), dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF).
  • 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 commercially available or alternatively, they can be prepared as described in the literature, for example in J. Med. Chem., 2006, 49, 21, 6147-6150, WO06/057945, WO05/051914 and WO04/050619.
  • Amines of general formula (III) can be prepared as described in the schemes below and in the experimental part that follows.
  • Alkylation of the primary hydroxy group of the isopropylidene derivative (Ia), 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 )D can be performed using any suitable alkylation method, for instance the Mitsunobu conditions can be used (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.
  • the substituent Q-(CH 2 )D can be introduced by reaction with a suitable alkylating agent Q-(CH 2 ) n -Lg wherein Lg is a leaving group such as a halide like bromide or iodide or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as tetrabutylammonium bromide or NaH or equivalent, thus forming the ether derivative (Ib).
  • a suitable alkylating agent Q-(CH 2 ) n -Lg wherein Lg is a leaving group such as a halide like bromide or iodide or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as tetrabutylammonium bromide or NaH or equivalent, thus forming the ether derivative (Ib).
  • the epoxide (Id) can then be achieved by the reaction sequence described by T. Suzuki et al. in Tet. Lett. 46, 2005 , 5811-5814, i.e. reaction with trimethyl orthoacetate in the presence of trifluoro acetic acid and subsequent treatment with acetyl bromide to yield the acetoxybromide, followed by epoxidation effected by treatment with potassium carbonate or the like. Opening of the epoxide with a desired amino derivative (Ie) and, finally, reduction of the azide function using for instance triphenyl phosphine or the like, provides the amine of formula III (If).
  • Amines of formula III wherein Y is O can be prepared as illustrated in scheme 2.
  • Amines of formula III wherein Z is S or NH can be prepared from the alcohol Ia for example as illustrated in scheme 3.
  • Y' is NRd or O
  • a leaving such as a derivative of sulphonic acid such as a triflate, tosylate, mesylate or the like
  • the amine (3d) may alternatively be achieved by oxidizing the primary hydroxy group of the alcohol (Ia) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane, or any other suitable oxidation reagent, followed by a reductive amination with a desired amino derivative Q-CH 2 -NHRd in the presence of a reducing agent like NaCNBH3.
  • Amines of formula III wherein Z is S and n is 0, may alternatively be achieved by reaction of the alcohol (Ia) with a desired diphenyl disulphide derivative in the presence of nBusP, thus affording the thioether derivative (3a). Subsequent transformation as described above, then yields the desired amino derivative of formula III.
  • a further alternative to achieve amines of formula III wherein Z is S or NRd, is to use an aziridine intermediate as illustrated in scheme 4.
  • 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.
  • Amines of formula III wherein Z is a bond may be prepared by opening of the appropriate epoxide derivative with a desired amine (Ie) or alcohol (2a) in a procedure similar to those described in Schemes 1 and 2, as illustrated in scheme 5.
  • Epoxide derivatives 5a may be obtained from commercial suppliers or prepared according to literature procedures, e.g. by epoxidation of the corresponding olefin derivative.
  • Y is NRd, may alternatively be prepared by oxidizing the primary hydroxy group of the alcohol 6c to the corresponding aldehyde, using for instance Dess Martin periodinane or by any other suitable oxidizing agent, followed by a reductive amination with the desired amino derivative in the presence of a reducing agent like NaCNBH 3 .
  • a range of intermediate amines (Ie) and alcohols (2a) to be used in the above schemes are commercially available, or otherwise they may be prepared according to literature procedures.
  • a route to intermediate amines (Ie) and alcohols (2a) wherein W is cycloalkyl, R 3 , R 3 are both H and p is 0 is illustrated in scheme 7.
  • Lg is a leaving group e.g. a halide or a tosylate or mesylate
  • the afforded alcohol may then be used as such as in the preparation of amines of formula III wherein Y is O and W is H as depicted in scheme 2, or the hydroxy group may be converted to an amino group and the afforded amine then used in the preparation of amines of formula III wherein Y is NRd and W is H as depicted in scheme 1.
  • a substituent W may be introduced to the acetylene moiety of the afforded 1-ethynyl- cyclopropanol (9c).
  • the hydroxy group is first protected for example with a silyl group such as a t.butyldiphenylsilyl group or equivalent, thus affording the corresponding protected derivative (9d).
  • a desired group W can then be introduced for example by lithiation of the acetylene derivative (9d) with n-BuLi or the like followed by reaction with a desired alkylating agent W-Lg, wherein Lg is a leaving group for example a halide like chloro, bromo or iodo, or a derivative of sulphonic acid such as a mesylate or tosylate, to provide substituted acetylene derivative (9e).
  • Lg is a leaving group for example a halide like chloro, bromo or iodo, or a derivative of sulphonic acid such as a mesylate or tosylate
  • Removal of the hydroxy protecting group using standard conditions such as treatment with tetrabutylammonium fluoride or the like, provides the free alcohol (9e).
  • the hydroxy group can then be transformed to an amino group, using for instance the Mitsunobu conditions as described above, thus yielding the corresponding amine
  • 1-Ethynyl-C4-C6cycloalkanol may alternatively be prepared from commercially available C 4 - C ⁇ cycloalkanone according to literature procedures.
  • the l-ethynyl-C4- C ⁇ cycloalkanol may be prepared by reaction of the suitable cycloalkanone with acetylene in the presence of sodium in liquid ammonia, or with trimethylethynylaluminate in THF and toluene as described in J. Org.
  • R is H or alkyl
  • Amines, (l id) and (1 Ie) to be used in the preparation of amines of formula III wherein Y is NH can be achieved from the corresponding alcohols (1 Ib) and (1 Ic) respectively, by transforming the hydroxy group to an amino group, using for instance the Mitsunobu conditions as described above.
  • the alcohols (1 Ib) and (1 Ic) may be transformed to the corresponding amines by an oxidation-reductive amination sequence, using reagents like Dess Martin periodinane, followed by reaction with a desired amino derivative NH 2 Rd in the presence of a suitable reduction agent like NaCNBH 4 , thus providing intermediate amines Ie (scheme 1), wherein Rd is Ci-C 3 alkyl.
  • Amines of formula III wherein one of X' and X" is H and the other OH having a stereochemistry at the carbon atom the to which the hydroxy group is attached which is opposite compared to the one described above in e.g. schemes 1 and 2, may be achieved by inverting the stereochemistry at this chiral centre using Mitsunobu conditions as illustrated in Scheme 12.
  • the hydroxy group of compound 12c 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 .
  • the amino group of compound 12c 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 or NaN 3 . Removal of the N-protecting group using standard conditions then yields the desired amine of formula III.
  • the azide moiety may, if desired, be reduced to an amine, thus affording compounds of general formula I wherein one of X' and X" is NH 2 .
  • 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 route is illustrated in scheme 14.
  • Q' is optionally substituted aryl or heterocyclyl, cycloalkylalkenyl, cycloalkylalkynyl, arylalkenyl, arylalkynyl, heteocyclylalkenyl or heterocyclylalkynyl
  • 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 the 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 methods 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(PPtLs) 4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • a Pd catalyst such as Pd(PPtLs) 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 hydroxy group of the primary alcohol (Ia), employing the Mitsunobu conditions as described in Scheme 1, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromo methane in the presence of triphenylphosphine, and subsequently coupled to the hydroxy group of the primary alcohol (Ia).
  • 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).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane
  • the mono fluoro compound (15c) will be achieved by treatment of the alcohol (15a) with a fluorinating agent such as DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions.
  • a fluorinating agent such as DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions.
  • the mono fluoro 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 compound (15a) 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.
  • 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. The alcohol E-Ie (2.3 g, 12.3 mmol) in THF was added drop wise.
  • 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 %).
  • the amine EB-Ib (1.643 g, 7.11 mmol) was dissolved in dichloromethane (50 mL) and BoC 2 O (2.33 g, 10.66 mmol) and triethylamine (1.98 mL, 14.22 mmol) dissolved in 20 mL of dichloromethane were added dropwise at room temperature during 10 minutes. The solution was then stirred at room temperature for 20 hours after which saturated sodium hydrogencorbonate (aq, -120 mL) was added. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (MgSO 4 ), filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 15:1, R f -0.3) which gave the title compound (2.061 g, 87%).
  • JV-trityl-L-serine methyl ester was reacted with phenol according to method B for the preparation of epoxides, which gave the compound as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
  • 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). The amine A-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.
  • the title compound was obtaoned by reduction of Acid 5c using hydrogen (g) in the presence of 10% Pd/C.
  • the title compound was prepared from 2,6-dichloroisonicotinic acid and N-methylpropane-2- sulfonamide according to the method described in WO05/051914.
  • -isonicotinic acid tert-butyl ester A-IOb
  • Compound A-IOa (71 mg, 0.2 mmol), amine A-5a (29.2 mg, 0.2 mmol), potassium phosphate (170 mg, 0.8 mmol) and Pd[P(tBu)s]2 (15 mg, 0.02 mmol) were dissolved in dimethylamine (1.5 mL).
  • the mixture was subjected to microwave heating at 130 0 C for Ih.
  • the sample was concentrated and then purified by silica column chromatography (elution system: hexane: ethyl acetate 100:0 - 75:25) which gave the title compound (70 mg, 77%).
  • Step a) 2-Iodo-cyclopropanecarboxylic acid 4-methoxy-benzylamide A- 16a The title compound (cis, racemate) was prepared in -100% yield by coupling of the acid (lR,2R)-2-iodocyclopropanecarboxylic acid (cis, racemate) and 4-methoxybenzylamine employing the coupling conditions similar to those described in Example 1 but using HATU instead of PyBop.
  • the crude product was purified by column chromatography eluted with toluene/ ethyl acetate 2:1 to 1 :1 to ethyl acetate. [M+H] + calcd: 332.0; found: 332.0.
  • Step b) 2-Fluoro-cyclopropanecarboxylic acid 4-methoxy-benzylamide (A- 16b)
  • the iodo compound A-16a (1.478 g, 4.463 mmol, cis, racemate), potassium hydro genfluoride (670 mg, 8.926 mmol), TBAF (IM in THF) (8.926 mL, 8.926 mmol) and chlorobenzene (15 mL) were stirred at 120 0 C for 48 hours in a sealed vial. The mixture was then diluted with ethyl acetate and washed twice with brine after which the organic phase was dried, filtered, and concentrated.
  • the amide A- 16b (68 mg, 0.305 mmol, trans, racemate) was dissolved in THF (8 mL) and BH 3 - THF (1.0 M in THF) (2.44 mL, 2.44 mmol) was added. The mixture was then refluxed for 5 hours after which the reaction was quenched by the addition of methanol (5 mL) and the solvents were evaporated. The remainder was partitioned between 3M KOH and DCM and the phases were separated. The organic phase was washed with brine and was the dried, filtered, and concentrated. The remainder was then dissolved in IM HCl in dioxane (6 mL) and was stirred at 50 0 C for 1 hour.
  • 5-Methyl-N,N-dipropyl-isophthalamic acid (A-17), N-Butyl-5,N-dimethyl-isophthalamic acid (A-18), and 3-(2-Methoxymethyl-pyrrolidine- 1 -carbonyl)-5-methyl-benzoic acid (A- 19)
  • 5-Methylisophtalic acid (100-150 mg, 0.55-0.83 mmol) was dissolved in DMF (3 niL), cooled to 0 0 C and DIPEA (1 equiv) was added and the mixture was stirred until a clear solution was achieved. PyBOP (1 equiv) was added, and the stirring was continued for 30 min at 0 0 C.
  • Step b) 1 -(4-Cyclopropyl- 1 , 1 -dimethyl-but-2-ynyl)-2,2,5 ,5-tetramethyl- [l,2,5]azadisiloridine (I-2b)
  • the alkyne derivative I-2a 250 mg, 1.1 mmol
  • THF 5 ml
  • DMPU 1 ml
  • BuLi 0.85 ml, 1.1 mmol
  • Step c) 4-Cvclopropyl-l J-dimethyl-but-2-vnylamine (I-2c) The protected amine I-2b (284 mg, 1.02 mmol) was dissolved in MeOH (5 ml) and the solution was stirred for 44 h at room temperature, which gave the title compound.
  • Step b) Acetic acid 2-azido-l-bromomethyl-3-(3-bromo-phenoxy)-propyl ester
  • the diol I-3a (1.03 g, 3.4 mmol) was dissolved in DCM (25 ml) and trimethyl orthoacetate (1.1 ml) and TFA (0.280 ml) were added. The reaction mixture was stirred at room temperature over night and then concentrated. The residue was dissolved in DCM (20 ml) and acetyl bromide (2.8 ml) in DCM (5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with aq. NaHCO 3 (sat.) and extracted with DCM.
  • a solution of (l-phenoxymethyl-allyl)-carbamic acid tert-butyl ester (200 mg, 0.76 mmol), prepared in analogy to compound EB-Id but using phenol instead of 3,5-difluorophenol, in acetone:water (10:1 mL) was added a catalytic amount OfOsO 4 and NMO (0.16 mL, 1.52 mmol, 2 equiv., wt 50% in water). The mixture was stirred at rt overnight, diluted with water and extracted with CH 2 Cl 2 .
  • Step d) (3-Chloro-2-oxo-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (I-4d)
  • Dess- Martin reagent 806 mg, 1.9 mmol, 1.5 equiv.
  • the mixture was stirred at rt for 2 h and then quenched with NaHCO 3 (10%, aq.) and Na 2 S 2 O 4 .
  • the solution was washed with water, and brine.
  • pTSA.H 2 O 159.6 mg, 0.8 mmol, 3 equiv.
  • the solution was stirred for 2 h, concentrated in vacuo.
  • the residue was diluted in CH 2 Cl 2 and washed with a sat. aq. sol OfNaHCO 3 , followed by water and brine.
  • the organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography yielded the title compound in 95% yield.
  • Alcohol E-Ie 950 mg, 5 mmol
  • Sodium hydride 60% oil suspension, 204 mg, 5 mmol
  • the reaction mixture was allowed to reach room temperature and was stirred forl6h whereafter water and DCM were added.
  • the organic phase was separated and the aqueous phase extracted with ethyl acetate.
  • Compound I-22b (238 mg, 1.36 mmol) was dissolved in dry DCM (6 rnL) and trimethylorthoacetate (429 ⁇ L) was added followed by trifluoroacetic acid (113.5 ⁇ L). The solution was stirred at room temperature for 18h and then concentrated to vacuum. The resulting crude was dissolved in dry DCM (20 mL) and acetyl bromide (1.1 mL, 15 mmol) dissolved in DCM was added drop wise to the solution. The reaction mixture was stirred at room temperature for 4 h.
  • Compound I-22c (128 mg, 0.45 mmol) was dissolved in methanol (5 mL), lithium hydroxide (11 mg, 0.45 mmol) was added, and the solution was stirred at 50 ° C for 1.5 h. Water and ethyl acetate were added. The organic phase was separated and the aqueous layer was extrated with DCM. The combined organic layers was dried over anhydrous sodium sulfate and filtrated and the filtrate was concentrated at vacuum.
  • Alkyne derivative I-2a (0.50 g, 2.22 mmol) was dissolved in THF (7.5 mL) and DMPU (1.8 mL) was added. The solution was cooled to -78 0 C and stirred in a N 2 atmosphere. Butyllithium (2.33 mmol, 1.7 mL of a 1.4 M solution in hexanes) was added dropwise, and the solution was warmed to -15 0 C and aged 30 min, then cooled to -78 0 C. l-Bromo-3-chloropropane (2.44 mmol, 384 mg) was added and the reaction was allowed to warm to -15 0 C and was stirred for 1.5 h.
  • Step b) [l-Benzyl-3-(l,l-dimethyl-prop-2-ynylamino)-2-hydroxy-propyll-carbamic acid tert- butyl ester (I-25b).
  • Step c) 3-Amino-l-(l,l-dimethyl-prop-2-ynylamino)-4-phenyl-butan-2-ol (I-25c), 3-Amino- 1 -(6-chloro- 1 , 1 -dimethyl-hex-2-ynylamino)-4-phenyl-butan-2-ol (I-26c) and
  • Step b) [l-Benzyl-2-hydroxy-3-(4-methyl-pent-2-ynylamino)-propyll-carbamic acid tert- butyl ester (I-28b)
  • tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate 50 mg, 0.19 mmol
  • PrOH/H2O 1 :1 1 :1, 1 mL
  • the mixture was stirred over night at r.t. until all epoxide was consumed according LC-MS. Water (10 mL) and DCM (10 mL) were added and the phases were separated.
  • the acid A-3 (27 mg, 0.080 mmol) was dissolved in DMF (0.5 mL) and the solution was stirred and cooled to 0 0 C.
  • DIEA Diisopropylethylamine
  • PyBOP 42 mg, 0.080 mmol
  • Example 47-a The procedure described in Example 47-a was followed, but using 2-methoxyethanol (120 ⁇ l, 1.5 mmol) instead of 2-methylcyclopropanemethanol, which gave the title compound (104 mg, 63%).
  • LC/MS confirmed the structure with a major positive peak at 333.1 (M+l).
  • Example 47-la The procedure described in Example 47-la was followed, but using 3-methoxy-l-propanol (145 ⁇ l, 1.5 mmol) instead of 2-methylcyclopropanemethanol, which gave the title compound (105 mg, 61%).
  • LC/MS confirmed the structure with a major positive peak at 347.0 (M+l).
  • Step b) N- [ 1 -Benzyl-3 -(3 -cyclopropyl- 1 , 1 -dimethyl-prop-2-ynylamino)-2-hydroxy-propyl "
  • Step b) N- ⁇ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-3-fluoro-5-[(2- methyl-cyclopropylmethyD-aminol-benzamide (55b)
  • n-butyl lithium in hexanes was added drop wise at 0 0 C to a solution of cyclopropylacetylen (70% in toluene, 3.7 g, 38.7 mmol ) in dry diethyl ether (30 ml) during about 15 min, then a solution of butyraldehyde (3.35 g, 46.4 mmol ) in diethyl ether (5 ml) was added drop wise at about 5 0 C. The mixture was stirred for 1.5 hours on an ice bath whereafter the reaction was quenched with a cold solution of 5% citric acid. Diethyl ether was added, the phases were separated and the water phase was extracted twice with diethyl ether.
  • the title compound was prepared in 76% yield (0.62 g) from the Azido compound 59b, according to the method described in Example 58 step c.
  • the boc protected amine 58d (69 mg, 0172 mmol) was dissolved in DCM (2 ml) and triethylsilane (55 ⁇ l, 0.34 mmol) was added followed by TFA (2 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co- evaporated with toluene 3 times to give a crude amine salt, which was dissolved in DMF (1.5 ml) and DIPEA (164 ⁇ l, 0.94 mmol).
  • a Biotage vial of 0.5-2.0 ml (for MW irradiation using a Biotage MW synthesizer) was filled with the compound of Example 50 (30.0 mg, 0.062 mmol), benzeneboronic acid (11.4 mg, 0.093 mmol), bis(triphenylphosphine)palladium(II) chloride (4.4 mg, 0.006 mmol), N 5 N- diisopropylethylamine (54 ⁇ l, 0.31 mmol) and a solution of l,2-dimethoxyethane-H2 ⁇ -ethanol (7:3:2 v/v, 2 ml).
  • the mixture was degassed with N 2 (g), sealed, and irradiated at 120 0 C for 20 minutes in a Biotage MW synthesizer.
  • the reaction mixture was diluted with CH 2 Cl 2 (4 ml) and washed with saturated aqueous NH 4 Cl (2 ml). The aqueous layer was washed with CH 2 Cl 2 (3 ml). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • Amine I-17b was dissolved in dry DMF (1.5 ml). 2,6-Difluoropyridine-4-carboxylic acid (14.1 mg, 0.089 mmol) and N,N-diisopropylethylamine (0.078 ml, 0.45 mmol) were added and the solution was cooled on an ice-water bath. HATU (35.6 mg, 0.094 mmol) was added and the reaction mixture was then stirred at ca 0 0 C for 1 h, and concentrated under reduced pressure. The residue was taken up into ethyl acetate (10 ml) and washed with saturated aqueous NaHCOs (20 ml).
  • Step b) N-[ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-fluoro-6-[(2- methyl-cyclopropylmethyD-aminol-isonicotinamide (65b)
  • Step a) 2-Chloro-6-(((lR,2S)-2-chlorocyclopropyl)methoxy)isonicotinic acid (68a) The alcohol [(lR,2S)-2-chlorocyclopropyl]methanol, prepared from methyl acrylate as disclosed in J. Org. Chem. 2005, 70, 4162-4165, (106 mg, 1.0 mmol) was dissolved in dioxane (5 ml), NaH (60% in mineral oil, 40 mg, 1.0 mmol) was added and the solution was heated to 80 0 C.
  • Lithium acetylide ethylenediamine complex (2.9 Ig, 30 mmol) was dissolved in DMSO (20 ml) and THF (10 ml) and cooled to 0 0 C.
  • (Bromomethyl)cyclopropane (1.76 g, 13 mmol) in THF (7.5 ml) was added in one portion and the reaction mixture was kept stirring at 20 0 C.
  • the reaction mixture was poured on water (250 ml) and treated with aqueous disodium tartrate, aqueous citric acid and brine.
  • Et 2 O (appr. 80 ml) was added and the slurry was filtrated through celite.
  • the organic phase was dried with MgSO 4 , filtered, diluted with Et 2 O to a volume of 100 ml and stored over molecular sieves. This solution was used directly in the next step.
  • Step a) l-(l-Ethynylcyclohexyl)-2,2,5,5-tetramethyl-l,2,5-azadisilolidine
  • 1-Ethynylcyclohexylamine (665 mg, 5.4 mmol) and Et 3 N (1.88 ml, 13.5 mmol) was dissolved in DCM (25 ml) and stirred at 0 0 C under N2-atmosphere.
  • a solution of 1,2- bis(chlorodimetylsilyl)ethane (1.22 g, 5.67 mmol) in DCM (5 ml) was slowly added.
  • Step b) 1 -( 1 -Q-Cyclopropylprop- 1 -ynyl)cyclohexyl)-2,2,5 ,5-tetramethyl- 1,2,5- azadisilolidine
  • Compound 71a (965 mg, 3.64mmol) and l,3-dimethyl-3,4,5,6,-tetrahydro-2(lH)-pyriminidone (2 ml, 16.5 mmol) was dissolved in THF (11 ml) and stirred at -70 0 C under N2-atmosphere.
  • n- BuLi 1.6 M in hexane, 3.0 ml, 4.8 mmol
  • Example 30 The following compounds were prepared in an analogous manner to the procedure described for the preparation of Example 30 using the appropriate alkylating agent in the step corresponding to Example 22 step a.
  • Examples 76 and 77 were prepared in a manner analogous to the procedure described for the preparation of Example 1, using acid A-3 and the appropriate intermediate, the intermediate being prepared by reaction of epoxide I- 17a with the appropriate amine according to the method described for the preparation of intermediate I- 17b.
  • TruPointTM Beta-Secretase Assay Kit was used. The assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, 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 ⁇ e X 330 nm and ⁇ em 615 nm. The inhibition is calculated as follows:
  • Table 1 shows the enzymatic inhibition exhibited by a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above.
  • Category A indicates an IC50 value of ⁇ 0.02 ⁇ M
  • category B indicates 0.02 - 1 ⁇ M
  • category C indicates > 1 ⁇ M.

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Abstract

A compound of formula (I) N-oxides, addition salts, quaternary amines metal complexes stereochemically isomeric forms and metabolites thereof, wherein A is CR1 Or N; formula (A) or formula (B) D is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, G is NR10 or O Q is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6Cycloalkyl, aryl or heterocyclyl; W is H, C1-C6alkyl, C3-C6Cycloalkyl, CH2F, CHF2 or CF3; one of X' and X" is H or CH3, the other is C1-C3alkyl, F, OH, NRaRb, CF3 or N3; or X' and X" are both F; Y is NRd or O; Z is O, NRa, CHRd, CF2 or S(=0)r or a bond; the other variables are as defined in the specification. The compounds of the invention are inhibitors of BACE and are among other things useful for the treatment and/or prevention of conditions associated with BACE activity such as Alzheimer's disease.

Description

Aspartyl protease inhibitors
Technical field
This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as β-secretase (β-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.
Background to the invention
A number of aspartic proteases are known to date, including pepsin A and C, Renin, BACE, BACE2, Napsin and Cathepsin D, which have been implicated in pathological conditions. For example the aspartyl protease BACE causes the production of the protein β amyloid (Aβ) in the brain, which is characteristic of Alzheimer's disease (AD). AD is a progressive neurodegenerative disease of the brain characterized by gradual loss of cognitive function related to memory, reasoning, orientation and judgement and eventually death. Pathological features of AD are accumulation of abnormal aggregated protein breakdown products, β-amyloid plaque and neurofibrillary tangles, in the brain. Plaque relatively specific for AD is primary a result from extracellular accumulation of aggregated Aβ. Fibrillary tangles consist mainly of hyperphosphorylated tau protein and are also found in other neurodegenerative disorders. It is believed that Aβ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioural decline. Aβ 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 α- and the minor β-secretase pathway. The α-secretase pathway results in non-pathogenic products known as soluble APP, whereas the β- secretase pathway produces pathogenic Aβ peptides by cleavage by β-secretase at the position corresponding to the N-terminus of Aβ, followed by cleavage by γ-secretase at the C-terminus. The sequential proteolytic cleavage of APP by β- and γ-secretase is a key step in the production of Aβ. The amyloid cascade hypothesis, supported by genetic and pathological evidence, claims that the formation of Aβ plays an early and vital role in all cases of AD. Aβ 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 Aβ generation. BACE knockout homozygote mice show complete absence of producing Aβ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that β-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 Aβ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
Presently there are no known effective treatments for preventing, delaying or reversing the progression of AD. Current available therapies for mild to moderate AD are safe but of limited benefit to most of the patients since they treat the symptoms and do not affect the progression of aggregated protein breakdown products underlying the pathology of the disease. In view of the fact that amyloid β peptides are formed as a result of BACE activity, inhibition of BACE is an attractive therapeutic approach to the treatment and prevention of AD and other cognitive and degenerative diseases caused by Aβ plaque deposition. Desirable characteristics for inhibitors of BACE include low molecular weight and features that would allow them to cross the blood-brain barrier.
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.
Brief description of the Invention In accordance with the present invention, there is provided novel compounds which are aspartyl protease inhibitors. Accordingly, in one aspect of the invention, there is provided compounds represented by general formula (I):
Figure imgf000003_0001
wherein
A is CR1 or N;
D is H, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl,
Figure imgf000004_0001
wherein G is NR10 or O;
R1 is H, Ci-Cealkyl, Ci-C6alkoxy, N3 or halo;
R2 is H or Ci-Cealkyl;
R3 and R3 are independently of each other H, Ci-Cβalkyl or CF3, or R3 and R3 together with the carbon atom to which they are attached form C3-C6Cycloalkyl or
Figure imgf000004_0002
R4 is H or Ci-Cβalkyl, or when p is 1 then R4 together with R3 and the carbon atoms to which they are attached may form C3-Cecycloalkyl or
Figure imgf000004_0003
R6 is R1 or aryl, N(Ra)S(=O)rRc, N(Ra)S(=O)rNRaRb, S(=O)rCi-C6alkyl, N(Ra)C(=O)Rc,
N(Ra)C(=O)ORc, N(Ra)C(=O)NRaRc or cyano;
R7 is Ci-Cealkyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl, hydroxyCi-C3alkyl, Ci-C6alkoxyCi-C3alkyl, arylC0-C3alkoxyCi-
C3alkyl, heterocyclylC0-C3alkoxyCi-C3alkyl or N(Ra)(Rb)Ci-C3alkyl; wherein the Ci-C3alkyl moiety of R7 is optionally substituted with Ci-Cβalkyl;
R8 is H or Ci-Cealkyl; or
R7 and R8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine;
R9 is Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl or heterocyclylCi-C3alkyl;
R10 is H or Ci-Cβalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine; wherein the cyclic amine is optionally substituted with Ci-Cβalkyl, C2-Cealkenyl, C2-
Cβalkynyl or phenyl;
Q is Ci-Cβalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Cecycloalkyl, aryl or heterocyclyl;
W is H, Ci-Cealkyl, C3-C6cycloalkyl, CH2F, CHF2 or CF3; one of X' and X" is H or CH3, the other is Ci-C3alkyl, F, OH, NRaRb, CF3 or N3; or X' and X" are both F;
Y is NRd or O;
Z is O, NRa, CHRd, CF2 or S(=O)r or a bond; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; r is 0, 1 or 2;
Ra is independently H or Ci-Cβalkyl; Rb is independently H or Ci-Cβalkyl; 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;
Rc is independently Ci-Cβalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocycle; Rd is H or Ci-C3alkyl; and wherein aryl is independently phenyl or naphthyl, or phenyl fused to
Figure imgf000005_0001
or C4-
Cβcycloalkenyl; 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 d-Cβalkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cβalkoxy, C2-Cealkenoxy, C2-
Cβalkynoxy, d-Cβcycloalkyl, d-Cβcycloalkenyl, aryl and heterocyclyl above (including those in composite expressions such as arylalkyl or heterocyclylalkyl) unless otherwise specified is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C4alkoxy, C1-
C4alkoxyCi-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, NRaRb, NRaRbCi-
C4alkyl, NRaRbC(=O), RbC(=O)N(Ra), cyano, azido, nitro, Ci-C4alkylcarbonyl, C3- Cecycloalkyl'Co-Csalkyl, ary^Co-dalkyl, heterocyclyl1 C0-C3alkyl, C3-C6cycloalkyl1C2-
C3alkenyl, aryl1C2-C3alkenyl, heterocyclyl1 C2-C3alkenyl, C3-Cecycloalkyl1C2-C3alkynyl, aryl1C2-C3alkynyl or heterocyclyl1 C2-C3alkynyl, or a 3 to 6 membered cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl, Ci-C3alkoxyCi-C4alkyl or fluoro); wherein aryl1 is independently phenyl, naphthyl, or phenyl fused to C4-C6Cycloalkyl or C4-
Cβcycloalkenyl; heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence
Figure imgf000006_0001
aryl1 and heterocyclyl1 above (including those in composite expressions such as
Figure imgf000006_0002
and heterocyclyl1 Co- C3alkyl), the cycloalkyl1, aryl1 and heterocyclyl1 moiety is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from C1- C4alkyl, C3-C4cycloalkyl, halo, haloCi-C4alkyl, hydroxy and NRaRb; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
In typical embodiments of the invention compounds of formula (I) are included wherein R1 is H or F;
R2 is H;
R3' and R3" are both H or CH3, or one of R3' and R3" is H and the other is CF3, or R3' and R3" together with the carbon atom to which they are attached form C3-Cecycloalkyl;
R4 is H R6 is H, Ci-Cealkyl, aryl, N(Ra)S(=O)2Rc, N(Ra)S(=O)2NRaRb, halo or cyano;
R7 is Ci-C6alkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl or heterocyclylCi-C3alkyl;
R8 is H or Ci-Cealkyl;
R9 is Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclylor heterocyclylCi-C3alkyl;
R10 is H or Ci-Cβalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine;
Q is aryl or heterocyclyl;
W is H, Ci-Cealkyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, CH2F, CHF2 or CF3; one of X' and X" is H and the other is OH,
Y is NH;
Z is O, NH or CH2; n is 0 or 1 ; p is 0 or 1 ; r is 2.
As indicated above, D is Ci-Cβalkyl, C2-Cealkenyl, C2-Cealkynyl, or
Figure imgf000007_0001
Consequently, according to some embodiments of the invention, compounds are included wherein D represents an amide moiety, thus giving compounds according to formula Ia.
Figure imgf000007_0002
R7 is as recited above. Typical values for R7 include Ci-Cβalkyl, arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein each Ci-Cβalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, Ci- C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
Representative values for the substituents to the aryl or heterocyclyl moieties of R7 include one or two substituents independently selected from Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C4alkyl such as fluoromethyl and trifluoromethyl; and cyano.
A further configuration for R7 include arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein the Ci-C3alkyl moiety is optionally substituted with Ci-Cβalkyl. Preferred configurations for the C1- Cβalkyl according to this embodiment include Ci-C4alkyl such as methyl or ethyl; haloCi- C4alkyl, such as trifluoromethyl and C3-C4cycloalkyl such as cyclopropyl.
In a currently favoured embodiment of the invention, R7 is phenylmethyl, 1-phenylethyl and 1- phenylpropyl, especially phenylmethyl or 1-phenylethyl, wherein the phenyl ring is optionally substituted. Accordingly, favoured embodiments of the invention include compounds having the partial structure shown below:
opt.
Figure imgf000007_0003
If present, the substituent(s) is preferably the in the para and/or ortho position of the phenyl ring.
In a further favoured embodiment of the invention, R7 is Cs-Cβheteroarylmethyl, I-C5- Cβheterarylethyl or l-Cs-Cβheterarylpropyl, especially Cs-Cβheteroarylmethyl, wherein the heteroaryl ring is optionally substituted. Suitable heteroaryl rings according to this embodiment include, but are not limited to thiazolyl, pyrazolyl, imidazolyl.
Accordingly, favoured compounds of the invention according to this embodiment include those having the partial structure shown below:
Figure imgf000008_0001
R8 is as recited above, preferably hydrogen or methyl.
A further embodiment of the invention includes compounds of formula (I) wherein R7 and R8 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.
According to a further embodiment of the invention, R7 and R8 are both Ci-Cβalkyl, such as ethyl, propyl or butyl.
According to a further embodiment of the invention, compounds are included wherein D represents an amine moiety, i.e. compounds wherein D is
R9
R10 > thus giving compounds according to formula Ib:
Figure imgf000009_0001
Typical values for R9 according to this embodiment include d-Cβalkyl, C2-Cealkenyl and C2- Cβalkylnyl wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted. Typical substituents according to this embodiment include Cs-Cβcycloalkyl for example cyclopropyl, Ci- C4alkyl for example isopropyl or t.butyl, haloalkyl for example CH2F, CHF2 or CF3, hydroxy and phenyl. A typical value for R9 according to this embodiment is optionally substituted C2- Cβalkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF3.
Further typical values for R9 according to this embodiment include Cs-CβcycloalkylCi-Csalkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C3alkyl. Especially preferred are cyclopropylmethyl and 2-methylcyclopropylmethyl. For these values of R9, R10 is preferably H or methyl.
R , 10 is typically H or Ci-C3alkyl, preferably H or methyl.
In a further configuration according to this embodiment of D, R9 and R10 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: opt. subst opt. subst
Figure imgf000009_0002
Figure imgf000009_0004
Figure imgf000009_0003
Optional substituent to the R9-R10 ring is selected from Ci-Cβalkyl, C2-C6alkenyl, C2-C6alkynyl and phenyl. A preferred embodiment of the invention includes compounds wherein A is N and D represents an amine moiety NR9R10 i.e. compounds having the structure (Ib):
Figure imgf000010_0001
According to a further embodiment of the invention, compounds are included wherein D represents an alkoxy moiety, thus giving compounds according to formula Ic:
Figure imgf000010_0002
Typical values for R according to this embodiment include Ci-Cβalkyl, C2-Cealkenyl and C2- Cβalkylnyl wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted. Typical substituents according to this embodiment include Cs-Cβcycloalkyl for example cyclopropyl, Ci- C4alkyl for example isopropyl or t.butyl, haloalkyl for example CH2F, CHF2 or CF3, hydroxy and phenyl. A typical value for R9 according to this embodiment is optionally substituted C2- Cβalkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF3.
Further typical values for R according to this embodiment include Cs-CβcycloalkylCi-Csalkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C3alkyl. Specially preferred are ccyycclloopprroopp}ylmethyl and 2-methylcyclopropylmethyl. For these values of R9, R10 is preferably H or methyl.
Further typical values for R9 according to this embodiment include Ci-C3alkoxyCi-C4alkyl, such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl and the like. According to a further embodiment of the invention, D is Ci-Cβalkyl, C2-Cealkenyl or C2- Cβalkynyl, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted. Typical substituents according to this embodiment include Cs-Cβcycloalkyl for example cyclopropyl, Ci- C4alkyl for example isopropyl or t.butyl, and haloalkyl for example CH2F, CHF2 or CF3. Typically according to this embodiment, D is optionally substituted C2-Cealkynyl, such as ethynyl which is unsubstituted or, preferably, substituted with cyclopropyl or CF3.
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. In typical embodiments of the invention, the chiral centre whereto the group R2 is attached has the stereochemistry shown in the partial structure: ψ ,Q
Figure imgf000011_0001
According to preferred embodiments of the invention, Z is O.
According to alternative embodiments Z is NRd, wherein Rd is hydrogen or Ci-C3alkyl, preferably hydrogen or methyl.
According to a further embodiment of the invention, Z is a bond. Typically according to this embodiment, n is 0 or 1, preferably 0.
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. In favoured embodiments of the invention Q is bonded to Z via a methylene moiety, i.e. n is 1. In further favoured embodiments, 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.
In some embodiments of the invention Q is an optionally substituted bicyclic aryl or heterocyclyl moiety. Typically, 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.
According to a further embodiment of the invention, Q is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-Cβcycloalkyl 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. Representative values for 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 is an optionally substituted 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
Representative values for the optional substituents to Q include one or two substituents independently selected from Ci-C4alkyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-C3alkoxyCi- Cβalkoxy, cyano, halo, haloCi-C4alkyl and arylCi-Csalkyl,
Figure imgf000012_0001
C2- Csalkenyl, C2-C3alkynyl, C2-C3alkynylC3-C6Cycloalkyl. Currently favoured values include halo such as mono- di- or trifluoro, chloro, bromo and haloCi-C4alkyl for example trifluoromethyl.
According to embodiments of the invention wherein 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.
According to embodiments of the invention wherein Q is a disubstituted phenyl or a 6-membered heterocyclyl, the 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.
Currently favoured configurations for Q include optionally substituted phenyl, such as bromo substituted phenyl and mono- or difluorophenyl, especially difluorophenyl.
Further favoured configurations for Q include phenyl which is substituted with heteroaryl, C2- Cβalkenyl, C2-C6alkynyl, cyano or cyclopropylethynyl. In preferred embodiments of the invention, Q is optionally substituted phenyl, n is 0 and Z is O.
In further preferred embodiments of the invention, Q is optionally substituted pyridyl, n is 0 and Z is O. Specially preferred according to this embodiment are compounds wherein Q is pyrid-3- yi-
R2 is Ci-Cβalkyl such as methyl or ethyl, or preferably R2 is H.
In typical embodiments of the invention Y is NRd, wherein Rd is H or Ci-C3alkyl such as H or CH3. Preferably Y is 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.
In an alternative embodiment of the invention X' and X" are both fluoro.
In compounds of formula (I) wherein Y is NH, one of X' and X" is OH and the other is H, the chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
Figure imgf000013_0001
In one embodiment of the invention, compounds of general formula (I) are included wherein p is 0, thus giving compounds of general formula (Id):
Figure imgf000013_0002
In alternative embodiments of the invention, compounds of general formula (I) are included wherein p is 1, 2 or 3, thus giving compounds having the partial structures (Ie), (If) and (Ig) respectively:
Figure imgf000014_0001
In one configuration of compounds of formula (Ie), i.e. wherein p is 1, R3 is H and R3 and R4 together with the carbon atoms to which they are attached form a Cs-Cβcarbocyclyl, preferably cyclopropyl, thus providing compounds of formula Ie' and Ie" respectively:
Figure imgf000014_0002
In a further configuration of compounds of formula
Figure imgf000014_0003
and R4 together with the carbon atoms to which they are attached form a Cs-Cβheterocyclyl, which heterocyclyl is optionally substituted such as with one or two Ci-C3alkyl groups, for example one or tho methyl groups.
In an alternative configuration of compounds of formula Ie, one of R 3' and i T R-) 3" is H, the other is Ci-Cβalkyl, such as methyl or ethyl, and R4 is Ci-Cβalkyl, such as methyl or ethyl.
In typical embodiments of the invention, R3 and R3 are both H.
In an alternative embodiment of the invention, R 3' and i T R-) 3" are both Ci -Cβalkyl such as methyl.
In a further embodiment of the invention, one of R3 and R3 is H, and the other is Ci-Cβalkyl or optionally substituted Ci-Cβalkyl. Typically according to this embodiment, one of R3 and R3 is H, and the other is Ci-CβalkoxyCi-Cβalkyl such as methoxy ethyl or ethoxymethyl or, preferably, methyo xymethy 1. In a further embodiment of the invention, one of R3 and R3 is H, and the other is mono-, di- or trifluoromethyl, preferably trifluoromethyl.
In a further embodiment of the invention R3 and R3 together with the carbon atom to which they are attached form Cs-Cβcycloalkyl or
Figure imgf000015_0001
thus providing compounds having partial structure Ih or Ii respectively:
Figure imgf000015_0002
In partial structure Ih, a is 1-4. In partial structure Ii, E is O or NRd, and b and c are independently 0, 1, 2, 3 or 4 provided that 2 < b + c < 4.
Typical compounds according to this embodiment are those wherein R3 and R3 together with the carbon atom to which they are attached form cyclopropyl, i.e. a is 1 in partial structure Ih.
In typical embodiments of the invention, p is 0, Y is NH, and R3 and R3 are both H.
In further typical embodiments of the invention, p is 0, Y is NH and R3 and R3 are methyl.
In further typical embodiments of the invention, p is 0, Y is NH, one of R and R is H and the other is CF3, Ci-CsalkoxyCi-Csalkyl such as methoxymethyl or Ci-Cβalkyl such as methyl or ethyl.
In further typical embodiments of the invention, p is 0, Y is NH, and R3 and R3 together with the carbon atom to which they are attached form Cs-Cβcycloalkyl, preferably cyclopropyl.
One embodiment of the invention includes compounds wherein W is H.
A further embodiment of the invention includes compounds wherein W is optionally substituted Ci-Cβalkyl, such as methyl, ethyl, isopropyl or t.butyl. A further embodiment of the invention includes compounds wherein W is Cs-Cβcycloalkyl such as cyclobutyl or, preferably cyclopropyl.
A further embodiment of the invention, includes compounds wherein W is Cs-CβcycloalkylCi- Csalkyl such as cyclopropylmethyl.
A further embodiment of the invention, includes compounds wherein W is Ci-C3alkoxyCi- Csalkyl such as methoxymethyl.
A further embodiment of the invention includes compounds wherein W is haloCi-Csalkyl, such as CH2F, CHF2 or CF3. A preferred configuration for W according to this embodiment is CF3.
Preferred compounds of formula (I) wherein one of X' and X" is H and the other is OH, and Y is NH are those having the stereochemistry indicated in formula (Ij):
Figure imgf000016_0001
In typical embodiments of the invention, R1 is H.
In alternative embodiments of the invention, R1 is halo, such as fluoro.
According to one embodiment of the invention R6 is N(Ra)S(=O)2Rc. Typical configurations for R6 according to this embodiment include N(Co-C2alkyl)S(=0)2Rc, wherein Re typically is C1- C4alkyl, preferably methyl or isopropyl.
Further typical values for R according to this embodiment include cyclic sulphonamides, i.e. Ra and Rc together with the atoms to which they are attached form a heterocyclic ring. Preferably according to this configuration of R6, the heterocyclic ring is a 5 or 6-membered ring, thus providing compounds of the general formula (Ik):
Figure imgf000017_0001
Typically, in embodiments of the invention wherein R6 is a cyclic sulphonamide, A is CH and R1 is halo, preferably fluoro. According to these embodiments, R1 is preferably in the ortho position of the phenyl ring.
Further typical values for R6 include hydrogen and Ci-Cβalkyl, especially hydrogen or methyl.
The invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereo chemically isomeric forms thereof.
One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) as specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
The invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
The invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament. Or the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or an prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereo chemically 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 and are thus useful for the inhibition of bace activity.
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, in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
The compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease. For example, 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 β-secretase. Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic! lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis. In a further embodiment, 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 invention relates to 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.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
The compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereo chemically 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/so lvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, 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 pharmaceutical 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. For these purposes 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. Examples of such 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; muscarinic ml or m2 agonists; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. memantine; or PDE4 inhibitors, e.g. Ariflo™. 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 Aβ in the brain ("amyloid modifier"), such as compounds which inhibit the secretion of Aβ, compounds which inhibit the aggregation of Aβ, and antibodies which selectively bind to Aβ. Such 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 β-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 γ-secretase, or any other compound which inhibits the formation or release of Aβ. The amyloid modifier may also be a GSK-3 inhibitor, particularly a GSK-3α 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 Aβ 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 Aβ aggregation suitable for use in the present invention include for example Apan™ (Praecis) and in particular 3-aminopropane-l-sulphonic acid, also known as tramiprosate or Alzhemed™.
The amyloid modifier may also be an anti-amyloid antibody which binds selectively to Aβ. 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.
Additionally, 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. The foregoing list of anti- Alzheimer's agents suitable for combinations is illustrative only and not intended to be limiting in any way.
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. When 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 stereo chemically isomeric form thereof as specified herein.
It is to be understood that the above defined subgroups of compounds of formula (I) are meant to also comprise any prodrugs, JV-oxides, addition salts, quaternary amines, metal complexes and stereo chemically isomeric forms of such compounds.
Furthermore, it is to be understood that whenever expressions like 'compounds of formula (I)', or 'the present compounds' or similar terms are used above and hereinafter it is meant to include the compounds of formula (I) and any subgroups of the compounds of formula (I), their prodrugs, //-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
In the context of the present specification, the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary. The terms 'therapeutic' and 'therapeutically' should be construed accordingly.
The term '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 Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. 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.
Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group. An in vivo 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-Cβalkoxymethyl esters for example methoxymethyl, Ci-Cβalkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi-Cβalkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-Cβalkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which may be formed at any carboxy group in the compounds of this invention.
An in vivo hydro lysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy. A selection of in vivo hydro lysable 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. Examples of 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.
For therapeutic use, salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, 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 non- toxic 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, JV-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.
The term 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.
The term '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. Other 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, trifluoro acetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
The iV-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 iV-oxide.
The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre. The presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereo chemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
Pure stereo isomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ' stereo isomerically pure' concerns compounds or intermediates having a stereo isomeric 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). For instance, 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. Examples of optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereo chemically isomeric forms may also be derived from the corresponding pure stereo chemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecific 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. Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.
It will be appreciated that 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 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. Examples of isotopes that may be incorporated into the compounds of formula I or any subgroup of formula I, include but are not limited to isotopes of hydrogen, such as 2H and 3H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11C, 13C and 14C, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 31P and 32P, sulphur, such as 35S, fluorine, such as 18F, chlorine, such as 36Cl, bromine such as 75Br, 76Br, 77Br and 82Br, and iodine, such as 123I, 124I, 125I and 131I.
The choice of 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 3H or 14C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11C, 18F, 13N or 15O will be useful. The incorporation of a heavier isotope, such as deuterium, i.e. 2H, 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. As used in the foregoing and hereinafter, 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.
As used herein 'Cm-Cnalkyl' as a group or part of a group defines a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g. Ci-Cβalkyl means an alkyl group having from 1 to 6 carbon atoms). Preferred alkyl groups for use in the invention are Ci-Cβalkyl 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. Unless otherwise indicated the alkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
The term 'C2-Cnalkenyl' 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. C2-Cealkenyl means an alkenyl group having from 2 to 6 carbon atoms). Preferred alkenyl groups for use in the invention are C2- Cβalkenyl groups, i.e. alkenyl groups having from 2 to 6 carbon atoms. Exemplary 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.
The term 'C2-Cnalkynyl' 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. C2-C6alkynyl means an alkynyl group having from 2 to 6 carbon atoms). Preferred alkynyl groups for use in the invention are C2-C6alkynyl, i.e. alkynyl groups having from 2 to 6 carbon atoms. Exemplary 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.
The term C3-Cncycloalkyl as a group or part of a group defines a saturated cyclic hydrocarbon radical having the number of carbon atoms designated, e.g. Cs-Cβcycloalkyl 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. Unless otherwise indicated the cycloalkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
'C3-Cn'CycloalkylCm-Cnalkyl' represents a Cm-Cnalkyl radical which is substituted with a C3- Cn'Cycloalkyl moiety, wherein C3-Cn'Cycloalkyl and Cm-Cnalkyl are as defined for C3-
Cncycloalkyl and Cm-Cnalkyl respectively above. Preferred C3-Cn'CycloalkylCm-Cnalkyl groups for use in the invention are C3-CycycloalkylCo-C3alkyl, i.e. the cycloalkyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
'C3-Cn'CycloalkylC2-Cnalkenyl' and 'C3-Cn'CycloalkylC2-Cnalkynyr have the corresponding meanings as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively, adjusted just for the link to the C3-Cn'Cycloalkyl moiety. Preferred C3-Cn'CycloalkylC2-Cnalkenyl and C3-Cn'CycloalkylC2- Cnalkynyl groups for use in the invention are C3-Cn'CycloalkylC2-C3alkenyl and C3- Cn'CycloalkylC2-C3alkynyl, i.e. the C3-Cn'Cycloalkyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
The term C3-Cncycloalkenyl 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. C3- Cβcycloalkenyl 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.
'C0-C3alkanediyl' defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
'Cj-C3alkanediyr defines a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
'Ci-Cnalkoxy' defines a radical O-Ci-Cnalkyl wherein Ci-Cnalkyl is as defined for Cm-Cnalkyl above. Preferred alkoxy groups for use in the invention are Ci-Cβalkoxy, 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.
C2-Cnalkenoxy, defines a radical O-C2-Cnalkenyl wherein C2-Cnalkenyl 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.
C2-C6alkynoxy, defines a radical O-C2-Cnalkynyl wherein C2-Cnalkynyl is as defined above. Preferred alkynoxy groups for use in the invention are C2-Cealkynoxy, 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.
The term 'halo' or 'halogen' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
The term 'haloCm-Cnalkyl' as a group or part of a group, represents a Cm-Cnalkyl 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. In case more than one halogen atom is attached to an alkyl group within the definition of haloCm-Cnalkyl, the halogen atoms may be the same or different.
As used herein, the term '(=O)' or 'oxo' forms a carbonyl moiety when attached to a carbon atom, a sulphoxide moiety when attached to a sulphur atom and a sulphonyl moiety when two of said terms are attached to a sulphur atom. It should be noted that an atom can only be substituted with an oxo group when the valency of that atom so permits.
'Amino' as a group or part of a group, unless the context suggests otherwise, includes NH2, NHCm_Cnalkyl or N(Cm-Cnalkyl)2, wherein m and n in the (Cm-Cnalkyl)2 are selected independently of each other. Cm-Cn alkyl is especially Ci-C6 Or Ci-C4alkyl variants. Included are also radicals wherein the two Cm-Cnalkyl groups of the N(Cm-Cnalkyl)2 together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. The terms 'Cm-Cnalkylamino' and '(Cm-Cnalkyl)2amino' as used herein has the same meaning as NHCm_Cnalkyl and N(Cm-Cn-alkyl)2 respectively as defined above.
The terms 'C2-Cnalkenylamino' and 'C2-Cnalkenylamino' define NHC2-Cnalkenyl and NHC2- Cnalkynyl respectively, wherein the C2-Cnalkenyl and C2-Cnalkynyl are as defined above. Among special interest for the invention are the C2-C6 variants, and especially the C2-C4 variants.
'Amido' as a group or part of a group represents a radical -C(=O)NH2, -C(=O)NHCm-Cnalkyl and -C(=O)N(Cm-Cnalkyl)2, especially C(=O)NHCi-C4alkyl and C(=O)N(Ci-C4alkyl)2. Included are also radicals wherein the two Cm-Cnalkyl groups together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. Also included are radicals -NHC(=O)H, -NH(C=O)Cm- Cnalkyl, -N(Cm-Cnalkyl)(C=O)H, -N(Cm-Cnalkyl)(C=O)Cm-Cnalkyl, especially NH(C=O)Ci- C4alkyl and -N(Ci-C4alkyl)(C=O)Ci-C4alkyl. The term 'alkoxyamido' is meant to include - NHC(=O)Ci-C6alkoxy, such as tert.butoxycarbonylamino.
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-Cβcycloalkyl (for example indanyl), or a C5-
Cecycloalkenyl. Examples of 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.
'ArylCm-Cnalkyl' represents a Cm-Cnalkyl radical which is substituted with an aryl moiety, wherein aryl and Cm-Cnalkyl are as defined above. Preferred arylCm-Cnalkyl 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.
'ArylC2-Cnalkenyl' and 'arylC2-Cnalkynyl' have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively. Preferred arylC2-Cnalkenyl and arylC2-Cnalkynyl groups for use in the invention are arylC2- Csalkenyl and arylC2-C3alkynyl, i.e. the aryl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
Ηeterocyclyl', '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. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydro furanyl, 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, piperazinyl, morpholinyl, thiomorpholinyl, triazinyl, 1 ,4-dioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzo thiazinolyl, benziso thiazinolyl, benzo thiazolyl, benzoxadiazolyl, benzo- 1,2,3-triazolyl, benzo- 1,2,4-triazolyl, benzotetrazolyl, benzo furanyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl, indanyl, pyrrolopyridine, etc. Unless otherwise indicated the heterocyclyl group is optionally substituted with one, two or where valence allows three substituents.
'HeterocylylCm-Cnalkyl' represents a Cm-Cnalkyl radical which is substituted with a heterocyclyl moiety, wherein heterocyclyl and Cm-Cnalkyl are as defined above. Preferred heterocyclylCm- Cnalkyl 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.
'HeterocyclylC2-Cnalkenyl' and 'heterocyclylC2-Cnalkynyl' have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively. Preferred heterocyclylC2-Cnalkenyl and heterocyclylC2-Cnalkynyl groups for use in the invention are heterocyclylC2-C3alkenyl and heterocyclylC2-C3alkynyl, i.e. the heterocyclyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
'Heteroaryl' as applied herein means an aromatic heterocyclyl moiety. Typically 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.
Unless otherwise specified, the alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, aryl and heterocyclyl (including those in composite expressions such as arylalkyl or heterocyclylalkyl) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from: Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi- C4alkyl, NRaRb, NRaRbC i-C4alkyl, NRaRbC(=O), RbC(=O)NRa, cyano, azido, nitro, Ci-
Cβalkylcarbonyl, oxo, mercapto,
Figure imgf000032_0001
aryl1 Co-C3alkyl, heterocyclyl1 Co- C3alkyl, C3-C6cycloalkyl1C2-C3alkenyl, aryl1C2-C3alkenyl, heterocyclyl1 C2-C3alkenyl, C3- C6Cycloalkyl1C2-C3alkynyl, aryl1C2-C3alkynyl, heterocyclyl1 C2-C3alkynyl, a 3 to 6 membered cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), where aryl1 is independently phenyl, naphthyl, or phenyl fused to C4-Cecycloalkyl or C4- Cβcycloalkenyl;
heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein the carbocyclyl1, aryl1 or heterocyclyl1 moiety is optionally substituted with 1 or 2, or where valence permits up to 3 substituents independently selected from Ci-C4alkyl, C3-C4Cycloalkyl, halo, haloCi-C4alkyl, hydroxy and NRaRb.
It should be noted that the 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. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1- pentyl, 2-pentyl and 3 -pentyl.
When any variable occurs more than one time in any constituent, each definition is independent. General synthetic methodology
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.
Generally, the compounds of the invention are prepared by reacting an acid of formula II
Figure imgf000033_0001
or an activated and optionally protected derivative thereof, wherein A, D, R1 and R6 are as defined above, with an amine of formula III
Figure imgf000033_0002
wherein Q, X', X", Y, Z, W, R , R , R , n and p are as defined above. Typically, 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). Typically, 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-N'-[(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). 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-l-yl)-NNN',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-NNN',N'-tetramethyluronium hexafluorophosphate (HATU) and similar. Normally, the coupling reactions are performed in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), JV-methyl-morpholine, JV-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like. Coupling reactions are preferably conducted in an inert solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide (DMF), dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF). The reaction temperature may range between 0 0C and 50 0C 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 commercially available or alternatively, they can be prepared as described in the literature, for example in J. Med. Chem., 2006, 49, 21, 6147-6150, WO06/057945, WO05/051914 and WO04/050619. Amines of general formula (III) can be prepared as described in the schemes below and in the experimental part that follows.
A route to amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is NRd, is illustrated in scheme 1. H3
Figure imgf000034_0001
1d
Scheme 1
Alkylation of the primary hydroxy group of the isopropylidene derivative (Ia), 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-(CH2)D can be performed using any suitable alkylation method, for instance the Mitsunobu conditions can be used (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 alcohol (Ia) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine, followed by displacement with a desired alcohol Q-(CH2)n-OH. Alternatively, the substituent Q-(CH2)D can be introduced by reaction with a suitable alkylating agent Q-(CH2)n -Lg wherein Lg is a leaving group such as a halide like bromide or iodide or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as tetrabutylammonium bromide or NaH or equivalent, thus forming the ether derivative (Ib). Removal of the acetal group by subjecting the compound to acidic conditions provides the diol (Ic). The epoxide (Id) can then be achieved by the reaction sequence described by T. Suzuki et al. in Tet. Lett. 46, 2005 , 5811-5814, i.e. reaction with trimethyl orthoacetate in the presence of trifluoro acetic acid and subsequent treatment with acetyl bromide to yield the acetoxybromide, followed by epoxidation effected by treatment with potassium carbonate or the like. Opening of the epoxide with a desired amino derivative (Ie) and, finally, reduction of the azide function using for instance triphenyl phosphine or the like, provides the amine of formula III (If).
Amines of formula III wherein Y is O can be prepared as illustrated in scheme 2.
Figure imgf000035_0001
1d 2b
Scheme 2 Opening of the epoxide (Id) with a suitable alcohol (2a) in the presence of a base such as sodium hydride or the like, followed by reduction of the azide to the amine using for instance triphenylphosphine or equivalent, provides the amine of formula III wherein Y is O (2b).
Amines of formula III wherein Z is S or NH, can be prepared from the alcohol Ia for example as illustrated in scheme 3.
Figure imgf000036_0001
Y' is NRd or O
Scheme 3
Transformation of the primary hydroxy group of the alcohol (Ia) to a leaving, such as a derivative of sulphonic acid such as a triflate, tosylate, mesylate or the like, by treatment of the alcohol with an appropriate sulphonylating agent such as the anhydride or halide of the desired sulphonyl derivative, in a solvent like dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or the like, followed by displacement of the formed leaving group with the desired thiol Q-(CH2)D-SH or amine Q-(CH2)D-NHRa, optionally in the presence of a base such as NaH or the like, provides the thioether derivative (3a) or the amino derivative (3b) respectively. Removal of the acetal group by treatment with acid, followed by formation of the epoxide, epoxide opening with a desired amine or alcohol, and finally reduction of he azido group, as described above, yields the amines of formula III wherein Z is S or NRd (3c) and (3d) respectively.
The amine (3d) may alternatively be achieved by oxidizing the primary hydroxy group of the alcohol (Ia) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane, or any other suitable oxidation reagent, followed by a reductive amination with a desired amino derivative Q-CH2-NHRd in the presence of a reducing agent like NaCNBH3.
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 O, may alternatively be prepared using the Mitsunobu conditions, i.e. reaction of the alcohol Ia with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine, followed by displacement of the thus formed leaving group with the desired thioether derivative Q-SH or amino derivative Q-NHRd, thus providing the thioether derivative (3a) or the amino derivative (3b) respectively.
Amines of formula III wherein Z is S and n is 0, may alternatively be achieved by reaction of the alcohol (Ia) with a desired diphenyl disulphide derivative in the presence of nBusP, thus affording the thioether derivative (3a). Subsequent transformation as described above, then yields the desired amino derivative of formula III.
A further alternative to achieve amines of formula III wherein Z is S or NRd, is to use an aziridine intermediate as illustrated in scheme 4.
Figure imgf000037_0001
1a 4a 4b
Figure imgf000037_0002
Scheme 4
Reduction of the azide function of the acetal derivative (Ia) and subsequent protection of the formed amine using any convenient N-protecting group such as a nosyl group or the like, provides the amino protected compound (4a). Conversion of the hydroxy group to a leaving group for example a derivative of sulphonic acid as described above, and finally ring closure, provides the aziridine derivative (4c). The formed aziridine can then be opened with a desired nucleophile, Q-(CH2)D-SH or Q-(CH2)D-NHRd, thus yielding the ether or amine derivative (4d) respectively. Removal of the acetal group by treatment with acid, followed by formation of the epoxide, alkylation with a desired amino derivative and finally reduction of he azido group, as described above, yields the amines of formula III (4e).
Amines of formula III wherein Z is a sulphone i.e. S(=O)2 may be obtained by oxidation of the sulphur of the corresponding thioether derivative. 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.
Amines of formula III wherein Z is a bond may be prepared by opening of the appropriate epoxide derivative with a desired amine (Ie) or alcohol (2a) in a procedure similar to those described in Schemes 1 and 2, as illustrated in scheme 5.
Figure imgf000038_0001
Scheme 5
Epoxide derivatives 5a may be obtained from commercial suppliers or prepared according to literature procedures, e.g. by epoxidation of the corresponding olefin derivative.
An alternative route to amines of formula III wherein Z is a bond is outlined in scheme 6.
Figure imgf000038_0002
Scheme 6 Alkylation of 2,3-bis-(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulphinamide, prepared from 2,3-dihydroxypropyl 4-methoxybenzoate as described in WO07/061670, with a suitable alkylating agent Q-(CH2)D-X wherein X is chloro, bromo or iodo, by way of a Grignard reaction or the like, for example as described in WO08/147547, provides the alkylated derivative (6b). Hydrolysis of the sulphinylamide group and the primary silyl group by treatment with acid, followed by protection of the afforded primary amino group with for example a boc group provides the protected amino derivate (6c). The amine or alcohol (6d), wherein Y is NRd or O respectively, can then be introduced for example by using the Mitsunobu conditions, i.e. treatment with an azodicarboxylate such as DIAD or the like in the presence of PH3P, and subsequent displacement with the amine or alcohol and thus provide the amine or ether derivative respectively. Removal, finally, of the Boc group by treatment with acid, then gives the primary amine of formula III (6e). The amino derivative 6e, i.e. Y is NRd, may alternatively be prepared by oxidizing the primary hydroxy group of the alcohol 6c to the corresponding aldehyde, using for instance Dess Martin periodinane or by any other suitable oxidizing agent, followed by a reductive amination with the desired amino derivative in the presence of a reducing agent like NaCNBH3.
A range of intermediate amines (Ie) and alcohols (2a) to be used in the above schemes are commercially available, or otherwise they may be prepared according to literature procedures. A route to intermediate amines (Ie) and alcohols (2a) wherein W is cycloalkyl, R3 , R3 are both H and p is 0 is illustrated in scheme 7.
Figure imgf000039_0001
Hydroxymethylation of the cycloalkylethynyl derivative (7a) using para formaldehyde in the presence of a base such as butyllithium or the like provides the alcohol (7b). The alcohol can then be used as such in the preparation of compounds of formula I wherein Y is O, or it can be converted to the corresponding amine and subsequently used in the preparation of compounds of formula I wherein Y is NRd. Accordingly, reaction of the alcohol 7a with diphenylphosphoryl azide (DPPA) in the presence of a base such as DBU, provides the corresponding azide derivative. Reduction of the azide group using a reagent like triphenylphosphine or the like, then provides the amine (7c). The hydroxy group of alcohol 7b may alternatively be converted to the azide by reaction with DPPA using the Mitsunobu conditions, i.e. in the presence of an azodicarboxylate such as DIAD or the like.
Intermediate amines (Ie) and alcohols (2a) wherein W is CF3, R3 and R3 are both H and p is 0 can be prepared from commercially available ethyl 4,4,4-trifluorobut-2-ynoate, as illustrated in scheme 8.
Figure imgf000040_0001
Scheme 8
Reduction of the ester function of the acetylene derivative (8a) using a suitable reducing agent, provides the corresponding alcohol (8b). The afforded alcohol can then be used as such in the preparation of compounds of formula I wherein Y is O, or it can be converted to the corresponding amine as described above, and subsequently used in the preparation of compounds of formula I wherein Y is NRd.
Intermediate amines (Ie) and alcohols (2a) wherein R3 and R3 together with the carbon atom to which they are attached form a Cs-Cβcycloalkyl are commercially available, or they can be prepared according to literature procedures. In scheme 9, a route to amines and alcohols wherein R3 and R3 together with the carbon atom to which they are attached form a cyclopropyl group useful for the preparation of compounds of formula I wherein Y is NH or O respectively, is illustrated.
Figure imgf000040_0002
tBDPSiCI
Figure imgf000040_0003
Lg is a leaving group e.g.
Figure imgf000040_0004
a halide or a tosylate or mesylate
9f
9g
Scheme 9 1-Ethynylcyclopropanol (9c) can be obtained for example as described in Synthesis, 2007, No. 22, pp. 3574-3588, i.e. treatment of hemiacetal (9a) with methylmagnesium chloride in THF followed by alkynylation with [(trimethylsilyl)ethynyl] lithium, and finally removal of the silyl group by treatment with ammonium fluoride. The afforded alcohol may then be used as such as in the preparation of amines of formula III wherein Y is O and W is H as depicted in scheme 2, or the hydroxy group may be converted to an amino group and the afforded amine then used in the preparation of amines of formula III wherein Y is NRd and W is H as depicted in scheme 1. If desired, a substituent W, may be introduced to the acetylene moiety of the afforded 1-ethynyl- cyclopropanol (9c). To effect this introduction, the hydroxy group is first protected for example with a silyl group such as a t.butyldiphenylsilyl group or equivalent, thus affording the corresponding protected derivative (9d). A desired group W can then be introduced for example by lithiation of the acetylene derivative (9d) with n-BuLi or the like followed by reaction with a desired alkylating agent W-Lg, wherein Lg is a leaving group for example a halide like chloro, bromo or iodo, or a derivative of sulphonic acid such as a mesylate or tosylate, to provide substituted acetylene derivative (9e). Removal of the hydroxy protecting group using standard conditions such as treatment with tetrabutylammonium fluoride or the like, provides the free alcohol (9e). If desired the hydroxy group can then be transformed to an amino group, using for instance the Mitsunobu conditions as described above, thus yielding the corresponding amine
(9g).
1-Ethynyl-C4-C6cycloalkanol may alternatively be prepared from commercially available C4- Cβcycloalkanone according to literature procedures. For example, the l-ethynyl-C4- Cβcycloalkanol may be prepared by reaction of the suitable cycloalkanone with acetylene in the presence of sodium in liquid ammonia, or with trimethylethynylaluminate in THF and toluene as described in J. Org. Chem., 1996, pp.4472-4475, or by treatment with acetylene in the presence of a base like tBuOK, BuLi or the like, or with trimethylsilylethyn in the presence of BuLi or the like.
Intermediate amines (Ie) wherein p is 1, R3 is H and R3 and R4 together with the carbon atom to which they are attached form a Cs-Cβcycloalkyl can be prepared as generally outlined in Scheme 10.
Figure imgf000042_0001
R is H or alkyl
Figure imgf000042_0002
Scheme 10
Aldehyde (10b) can be obtained from the corresponding commercially available mono or di- protected di-acid (10a) by reduction of one of the carboxyl functions according to literature proceedures. Subjection of the achieved aldehyde to a Wittig reaction e.g. as described in J. Org. Chem. 1980, 45, 173-174, using a desired reagent WBrC=PPh3 provides the olefin (10c). Elimination of HBr effected by treatment with a base followed by removal of the t.butoxy group provides acid (1Od). The amine (1Of) can then be achieved by a Curtius rearrangement, i.e. transformation of the acid function to the corresponding acyl azide for example in a two-step procedure by treatment with thionyl chloride or ethyl chloroformate or the like, followed by displacement with sodium azide, or directly by treatment with DPPA in the presence of an amine such as triethylamine and, decomposition finally, of the acyl azide then yields the desired amine (1Of).
An alternative method to prepare intermediate amines (Ie) and alcohols (2a) for use in the preparation of amines of formula III, wherein Y is NH or O, R3 is H and R3 and R4 together with the carbon atom to which they are attached form a Cs-Cβcycloalkyl is illustrated in scheme 11.
Figure imgf000042_0003
11d 11e
Scheme 11 2-((Trimethylsilyl)ethynyl)C4-C5Cycloalkanol (1 Ib) can be prepared from
Figure imgf000043_0001
oxide, which is available from commercial sources or from the literature, by opening of the epoxide with lithiotriethylacetylide followed by treatment with K2CO3 in MeOH as described in J. Org. Chem., 2002, pp. 5727-5732. The afforded alcohol (1 Ib) can then be used as such in the preparation of amines of formula III wherein Y is O and W is H, or the acetylene group may, after protection of the hydroxy group, be alkylated with a desired group W as described above. Amines, (l id) and (1 Ie) to be used in the preparation of amines of formula III wherein Y is NH, can be achieved from the corresponding alcohols (1 Ib) and (1 Ic) respectively, by transforming the hydroxy group to an amino group, using for instance the Mitsunobu conditions as described above. Alternatively, the alcohols (1 Ib) and (1 Ic) may be transformed to the corresponding amines by an oxidation-reductive amination sequence, using reagents like Dess Martin periodinane, followed by reaction with a desired amino derivative NH2Rd in the presence of a suitable reduction agent like NaCNBH4, thus providing intermediate amines Ie (scheme 1), wherein Rd is Ci-C3alkyl.
The above described intermediate amines and alcohols, are then further transformed as described above in schemes 1 and 2, in order to obtain amines of formula III.
Amines of formula III wherein one of X' and X" is H and the other OH having a stereochemistry at the carbon atom the to which the hydroxy group is attached which is opposite compared to the one described above in e.g. schemes 1 and 2, may be achieved by inverting the stereochemistry at this chiral centre using Mitsunobu conditions as illustrated in Scheme 12.
Figure imgf000043_0002
Q
Figure imgf000043_0003
Scheme 12 Reaction of alcohol (12a), obtained as described above, with Ph3P, and an azodicarboxylate such as DIAD and for example p-nitrobenzylic acid followed by hydrolysis of the afforded p- nitrobenzoic ester by treatment with for example methanolic methanolate or the like, provides the alcohol (12b) with the reversed stereochemistry. Reduction, finally of the azide function then provides the corresponding amine (12c).
If desired, the hydroxy group of compound 12c can be replaced by azide, thus affording amines of formula III wherein one of X' and X" is H and the other is N3. To effect this replacement, the amino group of compound 12c 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 or NaN3. Removal of the N-protecting group using standard conditions then yields the desired amine of formula III. Once the afforded amine of formula III is coupled to the acid of formula I, the azide moiety may, if desired, be reduced to an amine, thus affording compounds of general formula I wherein one of X' and X" is NH2.
A method to prepare a substituted phenyl derivative useful for the preparation of amines of formula (III) wherein Q is phenyl substituted an alkoxy-alkoxy group is illustrated in scheme 13.
DIBAL
Figure imgf000044_0001
Scheme 13
Alkylation of the phenolic hydroxy group of ester (13a) using for example the Mitsunobu, such as in the presence OfPh3P, an azodicarboxylate like DIAD and the suitable alcohol followed by reduction of the ester function using any convenient reduction method known in the art provides benzylic alcohol (13c). The afforded alcohol (13c) can then either be used directly in the coupling to the primary hydroxyl group employing the Mitsunobu conditions, or the a hydroxy group can be transferred to a leaving group, such as a halide like bromide, and subsequently coupled to the primary hydroxy group as described in scheme 1. Even though the strategy in scheme 13 is illustrates the introduction of a methoxy-ethoxy substituent to the phenyl ring, the skilled person will easily realise that the same methodology can be applied for the introduction of other O-linked substituents, such as substituents with other chain lengths. Furthermore, despite the fact that scheme 13 is illustrated with a 1,3 substituted phenyl derivative as starting compound, the skilled person will realise that the same methodology is also applicable to other phenyl derivatives, for example the corresponding 1,2- or 1 ,4-disubstituted derivatives.
Benzyl derivatives Q-CH2- 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 route is illustrated in scheme 14.
Figure imgf000045_0001
Figure imgf000045_0002
14c, R = OH 14d, R = Br
Q' is optionally substituted aryl or heterocyclyl, cycloalkylalkenyl, cycloalkylalkynyl, arylalkenyl, arylalkynyl, heteocyclylalkenyl or heterocyclylalkynyl
Scheme 14
The desired substituent Q' can be introduced using for instance 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 the 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). Other suitable methods 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(PPtLs)4 PdCl2 or Pd(OAc)2 and a base such as triethylamine, potassium carbonate or the like. Reduction of the ester function of compound 14b using any convenient reduction method known in the art, such as treatment with DIBAL-H, provides benzylic alcohol (14c). The afforded alcohol can then either be used directly in the couplings to the hydroxy group of the primary alcohol (Ia), employing the Mitsunobu conditions as described in Scheme 1, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromo methane in the presence of triphenylphosphine, and subsequently coupled to the hydroxy group of the primary alcohol (Ia). 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.
An intermediate towards amines of formula (III) wherein X' is F and X" is H or X' and X" are both F can be prepared by replacement of the hydroxy with fluoro or difluoro as exemplified in scheme 15.
Figure imgf000046_0001
15d 15e
Scheme 15
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 mono fluoro compound (15c) will be achieved by treatment of the alcohol (15a) with a fluorinating agent such as DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions. The mono fluoro 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 compound (15a) 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 Ph3P 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.
A route to acids of general formula (II) wherein A is CH, R is NRaS(=O)2Ci-Cealkyl and D is C(=O)NR7R8 can be prepared according to the procedure described by Stachel et al. in J. Med. Chem., 47, 2004, 6447-6450 as depicted in scheme 16.
Figure imgf000047_0001
X is a leaving group, e.g. Br or I Rc' is CrC6alkyl
Figure imgf000047_0002
Scheme 16
Sulphonylation of the amino group of commercially available 5-amino isophthalic ester (16a) with a desired sulphonylating agent such as a sulphonyl chloride, for example methane sulphonylchloride, in the presence of pyridine in a solvent like dichloromethane or the like followed optionally by alkylation of the nitrogen effected by a displacement reaction with a desired alkylating agent Ra-X, wherein X is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (16b). Mono hydro lysis of the bis-ester (16b) to the mono acid, for example by treatment with sodium hydroxide, followed by a peptide coupling of the amino derivative R7R8NH using any convenient method for amide bond formation such as using a reagent like BOP or the like provides the amide (16c). Subsequent hydrolysis of the methyl ester then affords the acid (16d).
Acids of formula (II) wherein the A is CH and the phenyl ring is substituted with a sulphamoyl amide group, i.e. R6 is NRaS(=O)2NRaRb, can be prepared according to the above scheme but using sulphamoyl chloride instead of a sulphonyl chloride in the reaction of the amino group of aniline (16c). 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. For example functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups depend upon the reaction conditions. 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.
Detailed Description
Various embodiments of the compounds of the invention and key intermediates towards such compounds will now be described by way of illustration only with reference to the following non- limiting examples.
Method A for the preparation of epoxides: Epoxide 1
Figure imgf000048_0001
E-1a E-1b E-1c
Figure imgf000048_0002
O
E-1f E-1g, R' = H, R" = OH = Br
Figure imgf000048_0003
E-11
Step a) 2-Oxo-21ambda*4*-|"l,3,2]dioxathiolane-4,5-dicarboxyric acid diethyl ester (E-Ia) Diethyl (D)-tartrate (25 g, 121 mmol) and pyridine (29 g, 367 mmol) was dissolved in dichloromethane (1200 ml). Thionyl chloride (12.4 ml) was added slowly at O 0C. The reaction mixture was stirred for 2 h and the solvent was then removed by reduced pressure. The crude product was taken up in ether and purified by filtration through a pad of silica gel. Yield ~90 %. GC-MS: 253 (M+)
Step b) 2,2-Dioxo-21ambda*6*-|"l,3,2]dioxathiolane-4,5-dicarboxyric acid diethyl ester (E-
Ib)
Compound E-Ia (6.3 g, 25 mmol), NaIO4 (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 %)
Step c) 2-Azido-3-hydroxy-succinic acid diethyl ester (E-Ic) Compound E-Ib (9.4 g, 35 mmol) was dissolved in acetone (125 mL) and water (25 mL). Sodium azide (4.6 g, 70 mmol) was added. The mixture was left with stirring at ambient temperature for 1.5 h or until complete reaction. The solvent was removed by reduced pressure. Ether (200 mL) was added followed by 20 % aqueous sulphuric acid (200 mL) and the mixture was left with stirring at ambient temperature over night. The ether phase was collected and the aqueous phase extracted with ether. The combined organic phases were washed with water and dried over sodium sulphate. Purification by Flash chromatography (ώo-hexane-ethyl acetate, 5:1) gave the pure title compound (5.8 g, 70%)
Step d) 3-Azido-butane-1.2.4-triol (E-Id) Compound E-Ic (3.3 g, 14.2 mmol) and sodium borohydride (1.1 g, 29 mmol) was stirred at 0 0C in ethanol (25 mL) for 3 hours. The solution was acidified to pH~7 by addition of aqueous hydrochloric acid whereafter the solvent was removed under reduced pressure. The residue was purified by flash chromatography (4% EtOH in EtOAc to 25% EtOH in EtOAc) which gave the crude title compound 4 (1.44 g, 68%) of sufficient purity.
Step e) 2-Azido-2-(2.2-dimethyl-ri.31dioxolan-4-yl)-ethanol (E-Ie)
The triol E-Id (4g, 27.2 mmol), dimethoxypropane (20 mL) and camphorsulphonic acid (5 mol %) were stirred at room temperature for 20 h. The solvent was then removed and the mixture of camphorsulphonic acid and 1,2- and 1,4- protected triol was dissolved in acetone and re fluxed for 24 h. Neutralization using solid sodium hydrogen carbonate followed by filtration and chromatography on silica gel (Toluene - EtOAc, 10:1) gave pure title compound (3.9 g, 76%). GC-MS: 172 (M+ - Me).
4-r 1 -Azido-2-(3.5-difluoro-phenoxy)-ethyl1-2.2-dimethyl-r 1.31dioxolane (E- 1 f)
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. The alcohol E-Ie (2.3 g, 12.3 mmol) in THF was added drop wise. The ice-bath was removed and the reaction mixture was left at room temperature for 3 h, or until the reaction was complete (TLC, toluene-ethyl acetate, 15:1 or GC). After complete reaction the mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The solvent was removed, the crude product was purified by flash chromatography on silica gel (toluene) which gave the pure title compound (2.65 g, 72 %). GC- MS (m/z) 284 (M+- 15).
3-Azido-4-(3,5-difluoro-phenoxy)-butane- 1 ,2-diol (E- 1 g)
Compound E-If (2.65 g, 21, 7 mmol) was dissolved in acetic acid (30 ml) and water (20 ml). The mixture was then heated to 60 0C for 3-4 h. The solvent was the evaporated which gave crude title compound (98 %), which was used without further purification. HPLC-MS: 318.1 (M + OAc)"
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 i) 2-[l-Azido-2-(3,5-difluoro-phenoxy)-ethyl"|-oxirane (E-2i)
The title compound was prepared in 86 % yield from compound E-Ih according to the procedure described by T. Suzuki et al. in Tetrahedron Letters 46, (2005), 5811-5814.
1H NMR (400 MHz CDCl3): δ 6.46 (m, 3H), 4.11 (m, 2H), 3.66 (m, IH), 3.22 (m, IH), 2.89 (m, IH), 2.81 (m, IH). The following epoxides were prepared by reaction of Intermediate E-Ie with the appropriate phenol derivative according to the procedure described for the preparation of Epoxide 1 :
Figure imgf000051_0002
Method B for the preparation of epoxides:
Epoxide EB-I
H H H
R N-A O
Boc-N -^ Boc^ /<? Boc-N - ^ ~-~--\
Figure imgf000051_0001
r EB-Ia, R = Ph3C EB-Id TΕB-Ib, EB-Ie R = H ^EB-Ic, R = Boc
Step a) 3-(3,5-Difluoro-phenoxy)-2-(tritylamino)-propionic acid methyl ester (EB-Ia)
To a solution of JV-trityl-L-serine methyl ester (5.333 g, 14.75 mmol), 3,5-difluorophenol (2.111 g, 16.225 mmol), and triphenylphosphine (4.256 g, 16.225 mmol) in toluene (55 mL) under nitrogen atmosphere was added DIAD (3.195 mL, 16.225 mmol) dropwise during 20 minutes at room temperature. The solution was then allowed to stir at 80 0C for 24 hours after which the solvent was evaporated. The crude product was purified with flash column chromatography (toluene, Rf -0.6) which gave the title compound (5.081 g, 73%).
Step b) 2-Amino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester (EB-Ib)
Compound EB-Ia (14.02 g, 29.61 mmol) was dissolved in dichloromethane (72 mL) and the solution was cooled to 0 0C. TFA (58 mL) was added dropwise during 5 minutes and the solution was stirred for 30 minutes at 0 0C 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 mL) and solid sodium hydrogen carbonate (7 g) was added and the slurry was stirred for 40 minutes. The methanol was then evaporated and the mixture was extracted with ethyl acetate and washed twice with saturated sodium hydrogen carbonate (aq) and once with brine. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified using flash column chromatography (ethyl acetate +1% MeOH saturated with NH3, Rf -0.3) which gave the title compound (4.81 g, 70%).
Step c) 2-tert-Butoxycarbonylamino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester
(EB-Ic)
The amine EB-Ib (1.643 g, 7.11 mmol) was dissolved in dichloromethane (50 mL) and BoC2O (2.33 g, 10.66 mmol) and triethylamine (1.98 mL, 14.22 mmol) dissolved in 20 mL of dichloromethane were added dropwise at room temperature during 10 minutes. The solution was then stirred at room temperature for 20 hours after which saturated sodium hydrogencorbonate (aq, -120 mL) was added. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf -0.3) which gave the title compound (2.061 g, 87%).
Step d) [l-(3,5-Difluoro-phenoxymethyl)-allyl"|-carbamic acid tert-butyl ester (EB-Id) Preparation of the Wittig reagent: Methyltripenylphosphonium bromide (8.182 g, 22.90 mmol) was added to dry THF (68 mL) under nitrogen atmosphere and the slurry was cooled to 0 0C. KHMDS (0.5 M in toluene) (45.4 mL, 22.685 mmol) was added during 5 minutes and the slurry was stirred for 1.5 hours at 0 0C.
Reduction of the ester to the aldehyde: Compound EB-Ic (3.596 g, 10.854 mmol) was dissolved in dry toluene (45 mL) under nitrogen atmosphere and the solution was cooled to -78 0C. DIBAL (1.0 M in hexane) (14.11 mL, 14.11 mmol) was added dropwise during 5 minutes. The reaction mixture was stirred at -78 0C until the starting material had been consumed according to TLC (approximately 20 minutes).
The above mentioned Wittig mixture was cooled to -78 0C and the aldehyde mixture was added directly (without workup) by syringe during 3 minutes and the mixture was allowed to stir at -78 0C under nitrogen atmosphere for 25 minutes, at room temperature for 1 hour, and then the mixture was heated to 40 0C for 20 hours. The reaction allowed to attain room temperature and was then quenched by the addition of 25 mL of MeOH. The mixture was transferred to a separatory funnel and ethyl acetate and a 1 : 1 mixture of saturated Roche lie salts (aq) and water were added. The phases were separated and the aqueous phase was extracted one more time with ethyl acetate. The combined organic phases were washed once with water and once with brine and were then dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf ~0.4) which gave the title compound (1.296 g, 40%).
Step e) [2-(3,5-Difluoro-phenoxy)-l-oxiranyl-ethyl"|-carbamic acid tert-butyl ester (EB-Ie) Compound E-5d (287 mg, 0.959 mmol) was dissolved in dichloromethane (15 mL) and 3- chloroperoxybenzoic acid (mCPBA) (77%) (860 mg, 3.835 mmol) was added and the mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with diethyl ether and was transferred to a separatory funnel. The organic phase was washed with 0 0C 10% Na2SO3 (aq), saturated sodium hydrogencarbonate (aq), and brine. The organic phase was then dried (MgSO4), filtered and, concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf ~0.3) which gave the title compound (229 mg, 76%) as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
Epoxide EB-2
Figure imgf000053_0001
(l-Oxiranyl-2-phenoxy-ethyD-carbamic acid tert-butyl ester (EB-2)
JV-trityl-L-serine methyl ester was reacted with phenol according to method B for the preparation of epoxides, which gave the compound as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
Figure imgf000054_0001
Acid 5
Figure imgf000054_0002
5b, R = CH3 5c, R = H
Step a) Methyl-(4-methyl-thiazol-2-ylmethyl)-amine (A-5a)
Methylamine (4.7 ml, 9.3 mmol, 2 M in THF) was added to a solution of (4-methyl-2-thiazole carboxaldehyde (200 μl, 1.86 mmol) in DCM (5 ml) and the mixture was stirred at rt. After 3 days, the solvent was evaporated and the residue dissolved in MeOH (20 ml) and reduced using an H-cube with a 10% Pd on C cartridge, which gave the title compound (200 mg). Step b) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid methyl ester (A-5b)
Triethylamine (one drop) was added to 5-bromo-isophthalic acid monomethyl ester (230 mg, 0.888 mmol) in SOCl2 (3 ml). The mixture was stirred at 90 0C for 1 h whereafter the solvent was evaporated and the residue dissolved in DCM (3 ml). The amine A-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 c) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid (A-5c) 1 M NaOH (1.5 ml) was added to the methyl ester (A-5b) (188 mg, 0.491 mmol) in MeOH (5 ml) and THF (5 ml). The mixture was stirred at rt for 3 d. whereafter most of the solvent was evaporated, and IM HCl (2.5 ml) and brine was added. The mixture was extracted with EtOAc, the organic layers were combined, dried (MgSO4) and evaporated, which gave the title compound (178 mg, 98%) as a yellow solid. MS: m/z = 369/371.
Acid 6
Figure imgf000055_0001
N-Methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid (A-6)
The title compound was obtaoned by reduction of Acid 5c using hydrogen (g) in the presence of 10% Pd/C.
Acid 7
Figure imgf000055_0002
2-(l ,2-Dimethyl-propylamino)-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinic acid (A-
TL A mixture of (S)-2-amino-3-methylbutane (200 μL) and 2-Chloro-6-[methyl-(propane-2- sulfonyl)-amino]-isonicotinic acid tert-butyl ester (59 mg, 0.17 mmol) was heated in a sealed tube at 150 0C for 10 days. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography (5% MeOH/NH3 in CH2Cl2) to give the 15 mg of the tert- butyl ester protected acid that were taken into TFAiCH2Cl2 (1 :1) to afford the title compound as the TFA salt. Used without further purification.
Acid 8
Figure imgf000056_0001
2-(N,l-dimethylcyclopropanesulfonamido)-6-(((lS,2S)-2-methylcyclopropyl)- methylamino)isonicotinic acid
The title compound was prepared from 2,6-dichloroisonicotinic acid, N,l-dimethylcyclopropane- 1-sulfonamide and ((lS,2S)-2-methylcyclopropyl)methanamine according to the procedure described in WO05/051914. Yield 26%, [M+l] = 594.
Acid 9
Figure imgf000056_0002
2-chloro-6-((2-methylcyclopropyl)methoxy)isonicotinic acid (A-9)
A Commercial cis/trans mixture of 2-methylcyclopropane (10 mmol) was dissolved in 1,4- dioxane (3 mL) under nitrogen and the resulting solution cooled to 0 0C. To the stirred solution was added drop-wise a 3M solution of methyl lithium in DME (leq.). The reaction was stirred for 10 min whereafter 2,6-dichloro-isonicotinic acid methyl ester (0.9 eq.) was added as a solution in 1 ,4-dioxane (3 mL) and the reaction was heated to reflux until completion according to LC-MS. The solution was then cooled to 0 0C and lithium hydroxide (2 eq.) was added as a solution in water (3 mL). The reaction was heated at reflux for Ih after which LC-MS showed complete hydrolysis of the ester. The mixture was diluted with ethyl acetate and neutralized with 4M HCl. Preparative HPLC afforded the title compound (30 mg). Acid 10
A-10a A-10b, R = t.Bu A-10c, R = H
Step a) 2-Chloro-6-(N-methylpropan-2-ylsulfonamido)isonicotinic acid (A-IOa) The title compound was prepared from 2,6-dichloroisonicotinic acid and N-methylpropane-2- sulfonamide according to the method described in WO05/051914.
Step b) 2- [Methyl-(4-methyl-thiazol-2-ylmethyl)-amino] -6- [methyl-(propane-2-sulfonyO- amino"|-isonicotinic acid tert-butyl ester (A-IOb) Compound A-IOa (71 mg, 0.2 mmol), amine A-5a (29.2 mg, 0.2 mmol), potassium phosphate (170 mg, 0.8 mmol) and Pd[P(tBu)s]2 (15 mg, 0.02 mmol) were dissolved in dimethylamine (1.5 mL). The mixture was subjected to microwave heating at 130 0C for Ih. The sample was concentrated and then purified by silica column chromatography (elution system: hexane: ethyl acetate 100:0 - 75:25) which gave the title compound (70 mg, 77%).
Step c) 2- [Methyl-(4-methyl-thiazol-2-ylmethyl)-aminol -6- [methyl-(propane-2-sulfonyD- amino"|-isonicotinic acid (A-IOc)
Compound A-IOb (70 mg, 0.15 mmol) was dissolved in a mixture of TFA/ DCM/ water 0/1/1 (2.5 ml) and stirred at room temperature for 2 h. The solution was co-evaporated with toluene twice which gave the title compound in quantitative yield.
Acid 11
Figure imgf000057_0002
A-11b, R = H Step a) 2-(Benzyl-cyclopropylmethyl-amino)-6- [methyl-(propane-2-sulfonyl)-aminol - isonicotinic acid tert-butyl ester (A-I Ia)
To acid A-IOa (0.091 g, 0.26 mmol), N-benzyl-1-cyclopropylmethanamine (0.061 g, 0.38 mmol) and K3PO4 (0.118 g, 0.56 mmol) was added degassed DMA (3 mL) in a pyrex tube. The solution was degassed with argon, and then Pd[P(tBu)s]2 (0.009 g, 0.017 mmol) was added. The solution was further degassed and was then heated at 130 0C for 90 minutes using microwave heating. After cooling down, the reaction mixture was extracted with DCM/H2O. The organic phase was, dried, filtered and concentrated and the afforded residue was purified by column chromatography using hexane:EtOAc 10:1 and then DCM as eluent, which gave the title compound (16.3 mg, 13%).
1H-NMR (CDCl3): 7.32-7.19 (m. 3 H) 6.90 (d, J= 6.90 Hz, 2 H) 5.30 (s, 1 H) 4.87 (s, 1 H) 3.76- 3.64 (m. 1 H) 3.41 (d, J= 6.52 Hz, 2 H) 3.35 (s, 3 H) 1.56 (s, 9 H) 1.15 (d, J= 6.89 Hz, 6 H) 0.57-0.46 (m, 2 H) 0.28-0.14 (m, 2 H).
Step b) 2-(Benzyl-cyclopropylmethyl-amino)-6-[methyl-(propane-2-sulfonyl)-aminol- isonicotinic acid (A-I Ib)
Compound 11-a (16.3 mg, 0.034 mmol) was dissolved in MeOH (40 mL) and EtOAc (10 mL) and the subjected to reduction using an H-cube over a PdOH cartridge (20 bar, 60 0C, 0.7 mL/min). The solvent was removed in vacuo and the transparent compound was dissolved in DCM (0.8 mL) and TFA (0.8 mL). After stirring for 1 h, the sample was frozen and the solvent was removed under reduced pressure which gave the title compound as a TFA salt.
Figure imgf000058_0001
Acid 15
Figure imgf000059_0001
2-(2-Methyl-cyclopropylmethoxy)-isonicotinic acid (A- 15)
To a solution of 2-methylcyclopropane-methanol (943 μL, 9.52 mmol, mixture of cis, trans isomers) in dioxane (20 mL) was added NaH (381 mg, 9.52 mmol, 60% in mineral oil) and the mixture was stirred for 1.5 hours at room temperature. 2-Chloropyridine-4-carboxylic acid (150 mg, 0.952 mmol) was added and the mixture was stirred at 90 0C for 24 hours. The dioxane was evaporated and the remainder was partitioned between saturated NH4Cl (aq) and DCM and the phases were separated. The aqueous phase was extracted twice with DCM and the combined organic phases were dried, filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 3:1 containing 0.6% acetic acid) which gave the title compound (134 mg, 68%, mixture of cis, trans isomers). (M+H)+ calcd: 208.1; found: 208.1.
Acid 16
Figure imgf000059_0002
A-16a A-16b
O O
Figure imgf000059_0003
A-16
Step a) 2-Iodo-cyclopropanecarboxylic acid 4-methoxy-benzylamide A- 16a The title compound (cis, racemate) was prepared in -100% yield by coupling of the acid (lR,2R)-2-iodocyclopropanecarboxylic acid (cis, racemate) and 4-methoxybenzylamine employing the coupling conditions similar to those described in Example 1 but using HATU instead of PyBop. The crude product was purified by column chromatography eluted with toluene/ ethyl acetate 2:1 to 1 :1 to ethyl acetate. [M+H]+ calcd: 332.0; found: 332.0. Step b) 2-Fluoro-cyclopropanecarboxylic acid 4-methoxy-benzylamide (A- 16b) The iodo compound A-16a (1.478 g, 4.463 mmol, cis, racemate), potassium hydro genfluoride (670 mg, 8.926 mmol), TBAF (IM in THF) (8.926 mL, 8.926 mmol) and chlorobenzene (15 mL) were stirred at 120 0C for 48 hours in a sealed vial. The mixture was then diluted with ethyl acetate and washed twice with brine after which the organic phase was dried, filtered, and concentrated. The crude material was purified by flash column chromatography toluene/ ethyl acetate 3:1 to 2:1 which gave the title compound (70 mg, 7%, trans, racemate). (M+H)+ calcd: 224.1; found: 224.1.
Step c) (2-Fluoro-cyclopropylmethyl)-(4-methoxy-benzyl)-amine (A- 16c)
The amide A- 16b (68 mg, 0.305 mmol, trans, racemate) was dissolved in THF (8 mL) and BH3- THF (1.0 M in THF) (2.44 mL, 2.44 mmol) was added. The mixture was then refluxed for 5 hours after which the reaction was quenched by the addition of methanol (5 mL) and the solvents were evaporated. The remainder was partitioned between 3M KOH and DCM and the phases were separated. The organic phase was washed with brine and was the dried, filtered, and concentrated. The remainder was then dissolved in IM HCl in dioxane (6 mL) and was stirred at 50 0C for 1 hour. The mixture was concentrated and the remainder was partitioned between saturated NaHCO3 (aq) and chloroform and the phases were separated. The aqueous phase was then extracted twice with chloroform and the combined organic phases were dried, filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 1 :3 containing 1% MeOH saturated with NH3) which gave the title compound (58 mg, 91%, trans, racemate). (M+H)+ calcd: 210.1; found: 210.1.
Step d) 2- [(2-Fluoro-cyclopropylmethyl)-aminol -6- [methyl-(propane-2-sulfonyl)-aminol - isonicotinic acid (A- 16)
The title compound (trans, racemate) was prepared by coupling of the amine A- 16c to the acid 2- chloro-6-[methyl-(propane-2-sulfonyl)-amino]-isonicotinic acid in 36% yield using the conditions described in WO05/051914. (M+H)+ calcd: 346.1; found: 346.1. Acid 17. 18 & 19
Figure imgf000061_0001
5-Methyl-N,N-dipropyl-isophthalamic acid (A-17), N-Butyl-5,N-dimethyl-isophthalamic acid (A-18), and 3-(2-Methoxymethyl-pyrrolidine- 1 -carbonyl)-5-methyl-benzoic acid (A- 19) 5-Methylisophtalic acid (100-150 mg, 0.55-0.83 mmol) was dissolved in DMF (3 niL), cooled to 0 0C and DIPEA (1 equiv) was added and the mixture was stirred until a clear solution was achieved. PyBOP (1 equiv) was added, and the stirring was continued for 30 min at 0 0C. A solution of amine (dipropylamine, butylmethylamine and i?-(methoxymethyl)pyrrolidine for A- 17, A-18 and A-19 respectively, 1.1 equiv) and DIPEA (1 equiv) in DMF (3 mL) was added dropwise to the activated ester solution and the reaction was stirred for 1 h. Et2O (30 mL) was added followed by 1 M NaOH (10 mL) and the phases were separated. The organic layer was extracted with 2 X 10 mL 1 M NaOH. The combined aqueous phases were acidified to pH 1 with 3 M HCl and extracted with 3 X 10 mL DCM. The combined organic layers were concentrated in vacuo and the product was purified by gradient column chromatography (1 :1 hexanes/ EtOAc - EtOAc with 1% AcOH throughout. This gave the title compounds with some minor contaminants and the products were used as such without further purification. A-17: 40%, m/z ES+ 264.2 [M+H]+; A-18: 38% m/z ES+ 250.2 [M+H]+; A-19: 42%, m/z ES+ 278.2 [M+H]+.
Acid 20
Figure imgf000061_0002
2- [Methyl-(2-methyl-cyclopropylmethyl)-aminol -6- [methyl-(propane-2-sulfonyl)-aminol - isonicotinic acid (A-20)
The title compound was prepared as described in WO06/057945. Intermediate 1
Figure imgf000062_0001
S-cyclopropylprop-l-yn- 1 -amine (I- 1 )
The title compound was prepared from commercially available ehynylcyclopropan according to the procedure described in WO2004/056806.
Intermediate 2
Figure imgf000062_0002
l-2a, R = H l-2c l-2b, R = cycloprpylmethyl
Step a) l-(l,l-Dimethyl-prop-2-ynyl)-2,2,5,5-tetramethyl-[l,2,51azadisilolidine I-2a) To an ice cold solution of l,l-dimethyl-prop-2-ynylamine (0.5 g, 6.01 mmol) in DCM (10 ml) under an atmosphere of nitrogen was added EtsN (2.1 ml, 15 mmol) followed by a solution of l,2-bis(chlorodimethylsilyl)ethane (1.42 g, 6.62 mmol) in DCM (2ml) and the solution was stirred at room temperature for 18h.. A precipitate was formed which was fϊlterer off and washed with Et20, thus forming an oil. The afforded oil was distilled in a Kϋgelrohr at 2.4x102 mbar, 58-62 C, which gave the title compound (997 mg, 74%). MS 210.
Step b) 1 -(4-Cyclopropyl- 1 , 1 -dimethyl-but-2-ynyl)-2,2,5 ,5-tetramethyl- [l,2,5]azadisiloridine (I-2b) The alkyne derivative I-2a (250 mg, 1.1 mmol) was dissolved in THF (5 ml)/DMPU (1 ml). The solution was cooled to -72 0C, then BuLi (0.85 ml, 1.1 mmol) was added and the temperature was allowed to raise to -15 0C. The reaction mixture was stirred for 30 min at -15 0C whereafter the temperature was lowered to -72 0C and bromomethylcyclopropane was added (180 mg, 1.33 mmol). The temperature was allowed to raise slowly to room temperature. After 18 h the reaction was quenched by addition OfEt2O (10 ml) and NH4OAc (10 ml). The phases were separated and the water phase was extracted with Et2O (2x10 ml). The organic phases were combined, washed with brine (10 ml), dried (Na2SO4) filtered and concentrated, which gave a crude product (284 mg) that was used in the next step without further purification. MS 264.
Step c) 4-Cvclopropyl-l J-dimethyl-but-2-vnylamine (I-2c) The protected amine I-2b (284 mg, 1.02 mmol) was dissolved in MeOH (5 ml) and the solution was stirred for 44 h at room temperature, which gave the title compound.
Intermediate 3
Figure imgf000063_0001
Step a) 3-Azido-4-(3-bromo-phenoxy)-butane-l,2-diol (I-3a)
The alcohol E-Ie (1.0 g, 5.3 mmol) was dissolved in dry THF (16 ml). The solution was cooled to 0 0C and DIAD (1.22 ml, 5.9 mmol) was added. After stirring for 5 min m-bromophenol (0.971 g, 5.6 mmol) in THF (2.8 ml) was added. The reaction mixture was stirred at 0 0C for 15 min and then at room temperature for 2.5 h. The mixture was extracted between Et2O and aq. NaHCO3 (sat.). The organic layer was dried (Na2SO4) and concentrated and the residue was purified by flash column chromatography (ώo-Hexane/toluene, 1 :0-0:1). The residue was dissolved in 60% aq. HOAc (24 ml) and stirred at 60 0C for 3 h and then concentrated. Purification of the crude product by flash column chromatography (ώo-Hexane/EtOAc, 1 :0-4: 1- 1 :1-0:1) gave the title compound ( 1.03 g, 64%) .
1H-NMR (CDCl3) δ 7.19-7.08 (m, 3H), 6.86 (m, IH), 4.32 (m, IH), 4.15 (m, IH), 3.87-3.71 (m, 4H), 3.19 (br s, IH), 2.67 (br s, IH).
Step b) Acetic acid 2-azido-l-bromomethyl-3-(3-bromo-phenoxy)-propyl ester (I-3b) The diol I-3a (1.03 g, 3.4 mmol) was dissolved in DCM (25 ml) and trimethyl orthoacetate (1.1 ml) and TFA (0.280 ml) were added. The reaction mixture was stirred at room temperature over night and then concentrated. The residue was dissolved in DCM (20 ml) and acetyl bromide (2.8 ml) in DCM (5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with aq. NaHCO3 (sat.) and extracted with DCM. The organic layer was washed with brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography (ώo-Hexane/EtOAc, 10:1) gave the title compound (1.23 g, 89%). 1H-NMR (CDCl3) δ 7.18-7.03 (m, 3H), 6.84 (m, IH), 5.05 (m, IH), 4.22-4.02 (m, 3H), 3.72-3.63 (m, 2H), 2.11 (s, 3H). Intermediate 4
Figure imgf000064_0001
l-4a, R = OH l-4d l-4e l-4b, R = OTs l-4c, R = Cl
Step a) (2,3-Dihydroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (I-4a) To a solution of (l-phenoxymethyl-allyl)-carbamic acid tert-butyl ester (200 mg, 0.76 mmol), prepared in analogy to compound EB-Id but using phenol instead of 3,5-difluorophenol, in acetone:water (10:1 mL) was added a catalytic amount OfOsO4 and NMO (0.16 mL, 1.52 mmol, 2 equiv., wt 50% in water). The mixture was stirred at rt overnight, diluted with water and extracted with CH2Cl2. The organic phase was washed with brine, dried and concentrated. Purification by flash chromatography (EtOAc/n-Heptane, 6/4) afforded the pure title compound in 89% yield. LCMS m/z 198 (MH-Boc)+.
Step b) Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-2-hydroxy-4-phenoxy-butyl ester (I-4b) To a solution of compound I-4a (364 mg, 1.22 mmol) in CH2Cl2 (2.6 mL) were added n-
(dibutyltin)oxide (61 mg, 0.02 eq.), tosylchloride (231 mg, 1 equiv.) and triethylamine (169 μL, 1 equiv.). The mixture was stirred at rt overnight, filtered and concentrated in vacuo which gave the title compound. LCMS m/z 352 (MH-Boc)+.
Step c) (3-Chloro-2-hydroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (I-4c)
To a solution of compound I-4b (550.8 mg, 1.22 mmol) in acetone (11 mL) was added LiCl (1.24 g, 29.3 mmol, 24 equiv.) and the mixture was refluxed overnight. After cooling down to rt, the mixture was concentrated, diluted with CH2Cl2 and washed with water. The organic phase was dried and evaporated, which gave the title compound which was used in the next step without further purification. LCMS m/z 216 (MH-Boc)+.
Step d) (3-Chloro-2-oxo-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (I-4d) To a solution of compound I-4c (385 mg, 1.22 mmol) in CH2Cl2 (12 mL) was added Dess- Martin reagent (806 mg, 1.9 mmol, 1.5 equiv.). The mixture was stirred at rt for 2 h and then quenched with NaHCO3 (10%, aq.) and Na2S2O4. The solution was washed with water, and brine. The organic phase was dried and evaporated and the afforded residue was purified by flash chromatography (EtOAc/n-Heptane, 2/8) which gave the title compound in 92% yield. LCMS m/z 214 (MH-BoC)+.
Step e) 3-Chloro-2-hydroxy-2-methyl-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (I-4e)
To a solution of compound I-4d (100 mg, 0.32 mmol) in THF (0.8 mL) methylmagnesium bromide (0.32 mL, 3 equiv., 3 M in Et2O) was added dropwise at -78 0C. The mixture was stirred 1 h at -78 0C, and then slowly warmed up to rt overnight. The reaction was then quenched with a sat aqueous, solution of sodium chloride and extracted with EtOAc. The organic phase was dried and evaporated and the afforded residue was purified by flash chromatography (EtO Ac/n- Heptane, 2/8) which gave the title compound in 55% yield). LCMS m/z 230 (MH-Boc)+.
General method for preparation of Intermediates 5-16
Epoxide Intermediate #
The Epoxide (1 eq, prepared as described above) was dissolved in EtOH (0.5 mL), the amine (4 eq) was added and the mixture was heated to reflux until HPLC indicated complete opening of the Epoxide. The reaction mixture was diluted with EtOAc, sat aq NaHCO3 was added and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with sat aq NaHCO3, dried (Na2SO4), filtered and evaporated. The afforded residue was dissolved in MeOH (11 mL) and triphenylphosphine (1.5 eq) and two drops OfH2O were added. The reaction was stirred over night, whereafter the solvent was removed by rotary evaporation. The afforded crude product was then either purified by column chromatography, or used directly in the next step.
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0002
Intermediate 17
Figure imgf000068_0001
Step a) tert-butyl 4-(3-cyclopropylprop-2-ynylamino)-3 -hydroxy- l-phenylbutan-2- ylcarbamate (I- 17a)
To a solution of tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate (500 mg, 1.9 mmol) in ethanol (6 mL) was added 3-cyclopropylprop-2-yn-l-amine (362 mg, 3.8 mmol, 2 eq.). The mixture was refluxed 4 h, cooled down to rt, concentrated in vacuo. The slurry was diluted in EtOAc, washed with water and brine, dried and concentrated. Purification by flash chromatography (EtO Ac/Heptane, 6/4 to 8/2) gave the title compound as a colourless oil in 60% yield. LCMS m/z 359 (MH)+.
Step b) 3-amino-l-(3-cyclopropylprop-2-ynylamino)-4-phenylbutan-2-ol (I- 17b) To a solution of I-17a (100 mg, 0.3 mmol) in 1.4 mL of CH3CN was added pTSA.H2O (159.6 mg, 0.8 mmol, 3 equiv.). The solution was stirred for 2 h, concentrated in vacuo. The residue was diluted in CH2Cl2 and washed with a sat. aq. sol OfNaHCO3, followed by water and brine. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography yielded the title compound in 95% yield. LCMS m/z 259 (MH)+. Intermediate 18
Figure imgf000069_0001
(2R,3 S)-3-amino-4-phenyl- 1 -(prop-2-ynylamino)butan-2-ol (I- 18)
The procedures described for the preparation of Intermediate 17 was followed but using prop-2- yn-1 -amine instead of 3-cyclopropylprop-2-yn-l -amine, which gave the title compound. LCMS m/z 219 (MH)+.
Intermediate 1-19
Figure imgf000069_0002
3-Amino- 1 -(3-cyclopropyl-prop-2-ynylamino)-4-pyridin-3-yl-butan-2-ol (I- 19)
The procedures described for the preparation of Intermediate 17 was followed but using (1- oxiranyl-2-pyridin-3-yl-ethyl)-carbamic acid tert-butyl ester (prepared as described in WO05 064008) instead of tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate, which gave the title compound. LCMS m/z 260 (MH)+.
Intermediate 1-20
Figure imgf000069_0003
3-Amino- 1 -(I -ethynyl-cyclohexylamino)-4-phenyl-butan-2-ol (1-20) The procedures described for the preparation of Intermediate 17 was followed but using 1- ethynyl-cyclohexylamine instead of 3-cyclopropylprop-2-yn-l -amine, which gave the title compound. LCMS m/z 287 (MH)+. Intermediate 21
Figure imgf000070_0001
3 -Amino- 1 -(3 -cyclopropyl-prop-2-ynylamino)-5 -methyl- hexan-2-ol (1-21) The procedures described for the preparation of Intermediate 17 was followed but using (3- methyl-l-oxiranyl-butyl)-carbamic acid tert-butyl ester instead of tert-butyl (S)-l-((S)-oxiran-2- yl)-2-phenylethylcarbamate, which gave the title compound. LCMS m/z 225 (MH)+.
Intermediate 22
Figure imgf000070_0002
Step a) 4-(l-Azido-2-ethoxy-ethyl)-2.2-dimethyl-ri.31dioxolane (I-22a) Alcohol E-Ie (950 mg, 5 mmol) was dissolved in dry DMF (4 mL). Sodium hydride (60% oil suspension, 204 mg, 5 mmol) was added and the mixture was stirred at room temperature for 1 h. The solution was cooled down to -5 ° whereafter iodoethane (400 μL, 5 mmol) was added slowly. The reaction mixture was allowed to reach room temperature and was stirred forl6h whereafter water and DCM were added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and then the crude residue was purified by column chromatography on silica (elution system: hexane: ethyl acetate 100:0 - 75:25) which gave the title compound (591 mg, 54%) as a color less oil.
Step b) 3-Azido-4-ethoxy-butane-1.2-diol (I-22b)
Compound I-22a (591 mg, 2.74 mmol) was dissolved in a solution of 60% aqueous acetic acid (35 mL) and heated at 60 0C for 2.5 h. After concentration under vacuum, the crude was dissolved in hexane and purified by flash chromatography (hexane: ethyl acetate 100:0-60:40) which gave the title compound (452 mg, 2.53 mmol, 94%). Step c) Acetic acid 2-azido-l-bromomethyl-3-ethoxy-propyl ester (I-22c) Compound I-22b (238 mg, 1.36 mmol) was dissolved in dry DCM (6 rnL) and trimethylorthoacetate (429 μL) was added followed by trifluoroacetic acid (113.5 μL). The solution was stirred at room temperature for 18h and then concentrated to vacuum. The resulting crude was dissolved in dry DCM (20 mL) and acetyl bromide (1.1 mL, 15 mmol) dissolved in DCM was added drop wise to the solution. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with DCM. The organic phase was washed with brine, dried and concentrated to vacuum. The crude was dissolved in hexane and purified by flash chromatography (hexane: ethyl acetate 100:0-70:30) which gave the title compound (317 mg, 83%).
Step d) 3-Azido-l-(3-cyclopropyl-prop-2-ynylamino)-4-ethoxy-butan-2-ol (I-22d) Compound I-22c (128 mg, 0.45 mmol) was dissolved in methanol (5 mL), lithium hydroxide (11 mg, 0.45 mmol) was added, and the solution was stirred at 50 ° C for 1.5 h. Water and ethyl acetate were added. The organic phase was separated and the aqueous layer was extrated with DCM. The combined organic layers was dried over anhydrous sodium sulfate and filtrated and the filtrate was concentrated at vacuum. The resulting epoxide was dissolved in water: isopropanol 1 : 1 (6 mL), and then amine 1-1 (86 mg, 0.9 mmol) was added. The solution was stirred at room temperature for 16 h then the concentrated and the resulting crude product was purified by silica column chromatography (elution system: MeOH:DCM, 0:100 to 15:85) which gave the title compound (78 mg, 65%). MS m/z 253.4 (M+H)+.
The following intermediates were prepared according to the general method described above:
Figure imgf000071_0001
Figure imgf000072_0002
Intermediates 25, 26 and 27
Figure imgf000072_0001
l-27b, R = Boc step c \~ ' -"'25b, R = Boc l-26b, R = Boc step c r '" step c \_^_ μ2 l-25c ■ 2TFA, R = H -"r ' <-~ l-26c ■ 2TFA, R = H ^ ' l"-:27c ■ 2TFA, R = H Step a) l-(6-Chloro-lJ-dimethyl-hex-2-vnyl)-2,2,5,5-tetramethyl-ri,2,51azadisilolidine (I- 26a) and
1 -(3-Cyclopropyl- 1 , 1 -dimethyl-prop-2-ynyl)-2,2,5,5-tetramethyl-|" 1 ,2,51azadisilolidine (I- 27a)
Alkyne derivative I-2a (0.50 g, 2.22 mmol) was dissolved in THF (7.5 mL) and DMPU (1.8 mL) was added. The solution was cooled to -78 0C and stirred in a N2 atmosphere. Butyllithium (2.33 mmol, 1.7 mL of a 1.4 M solution in hexanes) was added dropwise, and the solution was warmed to -15 0C and aged 30 min, then cooled to -78 0C. l-Bromo-3-chloropropane (2.44 mmol, 384 mg) was added and the reaction was allowed to warm to -15 0C and was stirred for 1.5 h. GC/MS indicated approx 66% conversion to I-26a. Freshly prepared LDA (2.49 mmol in 1 mL THF) was added and the solution stirred for 2 h. GC/MS indicated approx 50% conversion of I-26a into I- 27a. The reaction was quenched by adding 20 mL of sat aq NH4Cl. Et2O (10 mL) was added and the phases were separated. The aqueous phase was extracted with Et20 (2 x 10 mL), and the combined organic extracts were washed with H2O and brine (10 mL), dried (Na2SO4), filtered and evaporated which gave 628 mg of a crude mixture of I-2a, I-26a, and I-27a in an approximate ratio of 1 : 1 : 1 by GC/MS. m/z (EI) 210, 286 and 250 (M-Me of the three products respectively). The crude mixture was used as such in the following step without further purification.
Step b) [l-Benzyl-3-(l,l-dimethyl-prop-2-ynylamino)-2-hydroxy-propyll-carbamic acid tert- butyl ester (I-25b).
[ 1 -Benzyl-S-fβ-chloro- 1 , 1 -dimethyl-hex-2-ynylamino)-2-hydroxy-propyll-carbamic acid tert-butyl ester (I-26b) and
[ 1 -Benzyl-S-Q-cyclopropyl- 1 , 1 -dimethyl-prop-2-ynylamino)-2-hydroxy-propyll-carbamic acid tert-butyl ester Q-27b)
The crude mixture from the previous step (628 mg, approx 1.8 mmol) was dissolved in MeOH (5 mL) and stirred for 8 h, which resulted in the removal of the silyl protective group from the three intermediates. The solvent volume was reduced by gentle rotary evaporation. MeOH (2 mL) and tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate (100 mg, 0.38 mmol) was added followed by H2O (1 mL). The reaction was heated to 60 0C for 4 h and then cooled to rt. Et2O (10 mL) and sat aq NaHCO3 (10 mL) was added and the phases were separated. The aqueous phase was extracted with 2 x 10 mL EtOAc, and the combined organic phases were washed with sat aq NaHCO3 (10 mL), dried (Na2SO4), filtered and evaporated which gave I-25b, I-26b and I- 27b as a crude mixture. The products were separated by preparative HPLC (20-80% MeCN/0.01 M NH4OAc) which gave I-25b (28 mg, m/z ES+ 347.2 [M+H]+), I-26b (27 mg, m/z ES+ 423.3 [M+H]+) and I-27b (30 mg, m/z ES+ 387.3). The combined yield was 59% (epoxide was limiting reagent).
Step c) 3-Amino-l-(l,l-dimethyl-prop-2-ynylamino)-4-phenyl-butan-2-ol (I-25c), 3-Amino- 1 -(6-chloro- 1 , 1 -dimethyl-hex-2-ynylamino)-4-phenyl-butan-2-ol (I-26c) and
3-Amino- 1 -(3-cyclopropyl- 1 , 1 -dimethyl-prop-2-ynylamino)-4-phenyl-butan-2-ol (I-27c)
The three carbamates I-25b (28 mg, 0.081 mmol), I-26b (27 mg, 0.064 mmol) and I-27b (30 mg,
0.078 mmol), were separately dissolved in DCM (3 mL), stirred and cooled to 0 0C. 1.5 equiv of triethylsilane was added, and immediately thereafter TFA (3 mL). The reaction was stirred for 1 h and then evaporated in vacuo to dryness. The residue was redisolved in a small volume of
MeOH and then toluene (approx 10 mL) was added, and the mixture was concentrated by rotary evaporation. This process was repeated thrice, followed by drying under vacuum. The bis-TFA salts of amines I-25c (m/z ES+ 247.1 [M+H]+), I-26c (m/z ES+ 323.2 [M+H]+) and I-27c (m/z ES+ 287.2 [M+H]+), were isolated in 89, >99 and 99% yield respectively. Intermediate 28
Figure imgf000074_0001
Step a) 4-Methyl-pent-2-ynylamine (I-28a)
3-Methyl-butyne (600 mg, 8.83 mmol) was dissolved in dry THF(5 mL) and the mixture was cooled to -78 0C before dropwise addition of BuLi (1.6 M in hexanes, 5.5 mL, 8.83 mmol). The reaction mixture was slowly heated and stirred at r.t. for one hour. The mixture was cooled to -78 0C whereafter paraformaldehyde (370 mg, 12.4 mg) was added in one portion. The reaction mixture was slowly heated over night to r.t. NH4Cl (sat, 1.5 mL) and Na2SO4 (3 g) were added. Et2O (30 mL) was added and the solids were filtered off. The solution was concentrated in vacuo. The remaining oil was dissolved in dry Et2O (10 mL). Et3N (10.3 mmol, 950 μL) was added and the mixture was cooled to -78 0C whereafter of MsCl (10.6 mmol, 824 μL)was added dropwise. The reaction mixture was stirred for 2.5 h. and then H2O (2.5 mL) was added. The phases were separated, the organic phase was dried and concentrated under vacuum. The residue was dissolved in dry DMF (7 mL). NaN3 (25.7, 1.67 g) was added and the resulting suspension was heated to 60 0C for 2.5 h. H2O (3 mL) was added and the mixture was extracted with Et2O (3x10 mL). PPh3 (2.54, 9.6 mmol) was added to the ether phase and after 1 h H2O(3 mL) was added and the resulting mixture was stirred over night. Solid OPPh3 was filtered off and the mixture was concentrated. The crude amine was used without further purification in the next step.
Step b) [l-Benzyl-2-hydroxy-3-(4-methyl-pent-2-ynylamino)-propyll-carbamic acid tert- butyl ester (I-28b) To a solution of tert-butyl (S)-l-((S)-oxiran-2-yl)-2-phenylethylcarbamate (50 mg, 0.19 mmol) in 1PrOH/H2O 1 :1 (1 :1, 1 mL) was added an excess of amine I-28a. The mixture was stirred over night at r.t. until all epoxide was consumed according LC-MS. Water (10 mL) and DCM (10 mL) were added and the phases were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (DCM: NH3 in MeOH 1 :0 to 7:3), which gave the title compound (39%). LCMS m/z 361.1 (MH)+.
Intermediate 29
Figure imgf000075_0001
[l-Benzyl-2-hydroxy-3 -(5 -methyl- hex-3-ynylamino)-propyl"|-carbamic acid tert-butyl ester
(1-29)
The procedures described for the preparation of Intermediate 28 was followed but using oxirane instead of paraformaldehyde in step a, which gave the title compound in 49% yield calculated from the epoxide. LCMS m/z 375.1 (MH)+.
Intermediate 30
Figure imgf000075_0002
[l-Benzyl-2-hydroxy-3-(6-methyl-hept-4-ynylamino)-propyll-carbamic acid tert-butyl ester (1-30)
The procedures described for the preparation of Intermediate 28 was followed but using oxetane instead of paraformaldehyde in step a, which gave the title compound in 82% yield calculated from the epoxide. LCMS m/z 389.1 (MH)+.
Example 1
Figure imgf000075_0003
N-((2S,3S)-l-(3,5-difluorophenoxy)-3-hydroxy-4-(2-methylbut-3-yn-2-ylamino)butan-2-yl)- 2-(((lS,2S)-2-methylcyclopropyl)methylamino)-6-(N-methylpropan-2- ylsulfonamido)isonicotinamide (1)
The acid A-3 (27 mg, 0.080 mmol) was dissolved in DMF (0.5 mL) and the solution was stirred and cooled to 0 0C. Diisopropylethylamine (DIEA) (0.12 mmol, 20 μL) and PyBOP (42 mg, 0.080 mmol) were added, and the reaction was allowed to warm to rt, stirred for 1 h and then cooled to 0 0C again. In a separate flask, DIEA (0.08 mmol, 15 μL) was added to the amine 1-5 (24 mg, 0.080 mmol) in DMF (0.5 mL) and the entire solution was added in one portion to the first flask, and the reaction was stirred for 15 min. Et2O (10 mL) and sat aq NaHCOs (10 mL) were added, and the phases were separated. The aqueous phase was extracted with EtOAc (2 X 10 mL) and the combined organic phases were washed with a 1 : 1 mixture of brine and sat aq NaHCO3 (10 mL). The solvents were evaporated and the product was purified by preparative HPLC (50-65% MeCN in 0.01 M NH4OAc) which gave the title compound (11 mg, 22%) of The purity was determined by HPLC with a DAD-detector to be >99%. LC/MS [M+H]+ (ES+) 622.3; 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J= 8.4, IH), 6.80 (d, J= 0.9, IH), 6.54 - 6.39 (m, 4H), 4.74 (s, IH), 4.45 - 4.30 (m, 2H), 4.11 (dd, J= 4.3, 9.2, IH), 3.93 - 3.86 (m, IH), 3.86 - 3.76 (m, IH), 3.40 (s, 3H), 3.24 - 3.16 (m, IH), 3.13 - 3.04 (m, IH), 2.98 (dd, J= 4.1, 12.5, IH), 2.90 (dd, J= 4.8, 12.6, IH), 2.44 (br s, 3H), 2.29 (s, IH), 2.09 (br s, IH), 1.41 (s, 3H), 1.39 (s, 3H), 1.38 - 1.32 (m, J= 4.1, 6.9, 6H), 1.06 (d, J= 6.0, 3H), 0.85 - 0.74 (m, IH), 0.72 - 0.61 (m, IH), 0.44 - 0.36 (m, IH), 0.33 - 0.25 (m, IH).
The following examples were prepared in an analogous manner to the procedure described for the preparation of Example 1 using the appropriate acid and amine.
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Example 47
Figure imgf000087_0001
Step a) 2-(2-Methyl-cyclopropylmethoxy)-6-[methyl-(propane-2-sulfonyl)-aminol- isonicotinic acid (47a)
A mixture of 2-methylcyclopropanemethanol (150 μl, 1.5 mmol), 60% sodium hydride in mineral oil (60 mg, 1.5 mmol) and 2-chloro-6-[methyl-(propane-2-sulfonyl)-amino]-isonicotinic acid (146 mg, 0.5 mmol) in dioxane (5 ml) was heated at +80 0C for 12 hours. Thereafter the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with sat ammonium chloride. The organic phase was evaporated and the residue purified on a silica gel column eluting with isohexane 2 and ethyl acetate 1 containing 1% of acetic acid to give 119 mg (70%) of the title compound. LC/MS confirmed the structure with a major positive peak at 343.1 (M+l).
Step b) N- [ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-(2-methyl- cyclopropylmethoxy)-6- [methyl-(propane-2-sulfonyl)-aminol -isonicotinamide (47b) Boc protected amine I-17a (143 mg, 0.4 mmol) was dissolved in DCM (5 ml) at 0 0C and triethyl silane (95 μl, 0.4 mmol) was added followed by TFA (5 ml). The reaction mixture was stirred at 0 0C for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene 3 times to give a crude amine salt which was dissolved in DMF (2 ml) and DIPEA (140 μl). In a separate flask, the acid 47a (119 mg, 0.35 mmol) was dissolved in DMF (2 ml) and the solution was stirred and cooled to 0 0C. Dϋsopropylethylamine (DIEA) (125 μl, 0.7 mmol) and HATU (133 mg, 0.35 mmol) were added, and the reaction was stirred at 0 0C for 1 hour. This reaction mixture was then added drop wise to the above amine salt and the reaction mixture was stirred at 0 0C for 2 hours. Then, the reaction mixture was poured into ethyl acetate and sat sodium bicarbonate. The organic phase was evaporated and the residue purified on a silica gel column eluting with isohexane 1 and ethyl acetate 1 containing 1% of sat ammonia in methanol to give 73 mg of the title product with a LC purity of about 80%. A final purification on preparative HPLC gave the title compound (27 mg, 13%). The purity was determined by HPLC with a DAD-detector to be >98% and LC/MS confirmed the structure with a M+l peak at 583.2. Example 48
Figure imgf000088_0001
Step a) 2-(2-Methoxy-ethoxy)-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinic acid (48a)
The procedure described in Example 47-a was followed, but using 2-methoxyethanol (120 μl, 1.5 mmol) instead of 2-methylcyclopropanemethanol, which gave the title compound (104 mg, 63%). LC/MS confirmed the structure with a major positive peak at 333.1 (M+l).
Step b) N- [ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-(2-methoxy- ethoxy)-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (48b) Boc protected amine I-17a (125 mg, 0.35 mmol) was dissolved in DCM (5 ml) at 0 0C and triethyl silane (85 μl, 0.53 mmol) was added followed by TFA (5 ml). The reaction mixture was stirred at 0 0C for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene 3 times to give a crude amine salt which was dissolved in DMF (2 ml) and DIPEA (130 μl). In a separate flask, the acid 48a (104 mg, 0.3 mmol) was dissolved in DMF (2 ml) and the solution was stirred and cooled to 0 0C. DIPEA (125 μl, 0.7 mmol) and HATU (114 mg, 0.3 mmol) were added, and the reaction was stirred at 0 0C for 1 hour. This reaction mixture was then added drop wise to the above amine salt and the reaction mixture was stirred at 0 0C for 2 hours followed by stirring at room temperature over the weekend. Then, the reaction mixture was poured into ethyl acetate and sat sodium bicarbonate. The organic phase was evaporated and the residue purified on a silica gel column eluting with DCM containing 2% of methanol followed by DCM containing 4% methanol to give 26 mg of the title product contaminated by a DIPEA salt as indicated by NMR. A final purification on preparative HPLC gave the title compound (10 mg, 6%). The purity was determined by HPLC with a DAD-detector to be >98% and LC/MS confirmed the structure with a M+l peak at 573.3. Example 49
Figure imgf000089_0001
Step a) 2-(3-Methoxy-propoxy)-6-[methyl-(propane-2-sulfonyl)-amino]-isonicotinic acid (49a)
The procedure described in Example 47-la was followed, but using 3-methoxy-l-propanol (145 μl, 1.5 mmol) instead of 2-methylcyclopropanemethanol, which gave the title compound (105 mg, 61%). LC/MS confirmed the structure with a major positive peak at 347.0 (M+l).
Step b) N- [ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-(3-methoxy- propoxy)-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (49b) Boc protected amine I- 17a (108 mg, 0.3 mmol) was dissolved in DCM (2.5 ml) at 0 0C and triethyl silane (72 μl, 0.45 mmol) was added followed by TFA (2.5 ml). The reaction mixture was stirred at 0 0C for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene 3 times to give a crude amine salt which was dissolved in DMF (2 ml) and DIPEA (105 μl). In a separate flask, the acid 49a (105 mg, 0.3 mmol) was dissolved in DMF (2 ml) and the solution was stirred and cooled to 0 0C. DIPEA (157 μl, 0.9 mmol) and PyBOP (156 mg, 0.3 mmol) were added, and the reaction was stirred at 0 0C for 1 hour. This reaction mixture was then added drop wise to the above amine salt and the reaction mixture was stirred at 0 0C for 1 hour. Then, the reaction mixture was poured into ethyl acetate and sat sodium bicarbonate. The organic phase was evaporated and the residue purified on a silica gel column eluting with DCM containing 2% of methanol followed by DCM containing 3% methanol to give 75 mg of the title product but not pure enough. A final purification on preparative HPLC gave the title compound (43 mg, 24%). The purity was determined by HPLC with a DAD-detector to be >98% and LC/MS confirmed the structure with a M+l peak at 587.3. Example 50
Figure imgf000090_0001
N-[l-Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-chloro-6-[(2-methyl- cyclopropylmethyD-aminol-isonicotinamide (50)
A mixture of the compound of Example 24 (8 mg, 0.019 mmol) and C-(2-methyl-cyclopropyl)- methylamine (0.5 mL, 50% in Et2O) was heated in a sealed tube at 70 0C for 3 days. The reaction mixture was purified by preparative HPLC (50 to 70% acetonitrile in 1OmM aq. NH4OAC) which gave the title compound as a white solid (1.8 mg, 20%). m/z 481 (MH)+.
Example 51
Figure imgf000090_0002
Step a) N- [ 1 -Benzyl-3 -(3 -cyclopropyl- 1 , 1 -dimethyl-prop-2-ynylamino)-2-hydroxy-propyll -
2,6-dichloro-isonicotinamide (5 Ia)
Compound I-27c was coupled to 2,6-dichloropyridine-4-carboxylic acid using a procedure analogous to the one described for the preparation of Example 1, which gave the title compound in 80% yield. [M+H]+ 460.1.
Step b) N- [ 1 -Benzyl-3 -(3 -cyclopropyl- 1 , 1 -dimethyl-prop-2-ynylamino)-2-hydroxy-propyl"|- 2-chloro-6-isobutylamino-isonicotinamide (51-b)
A solution of compound 51a (20 mg, 0.043 mmol) in isobutylamine (0.5 mL) was heated to 90 0C in a sealed tube for 24 h. The reaction mixture was concentrated under vacuum and the residue was taken into EtO Ac/sat, aq. NaHCO3. The organic phase was washed with sat. aq. NaHCOs, dried (Na2SO4) and evaporated which gave the title compound (19.2 mg, 90%), [M+H]+ 497.2.
Example 52-54
The following compounds were prepared by reaction of compound 51a with the appropriate amine according to the method described in Ex. 51b:
Figure imgf000091_0001
Figure imgf000092_0001
Step a) Λ/-[l-Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-3,5-difluoro- benzamide (55 a)
3,5-Difluorobenzoic acid and I-17b were reacted as described in Example 1 but HATU was used instead of PyBOP. Purification by preparative HPLC gave the title compound in 33% yield. LCMS ES+ 399.2, ES- 397.2.
Step b) N-\ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-3-fluoro-5-[(2- methyl-cyclopropylmethyD-aminol-benzamide (55b)
A mixture of rac-trans-2-methylcyclopropylmethylamine (300 μL solution in MeOHZEt2O, approx 20 equiv) and 55a (20 mg, 0.050 mmol) was prepared in a tube which was sealed and cooled to -78 0C, and the tube was evacuated carefully. The reaction was heated to 90 0C and stirred for 9 days. The tube was allowed to cool and MeCN (1 mL) was added, followed by a few drops of 0.1 M NH4OAc. The mixture was evaporated to dryness and the product was purified by preparative HPLC (30-75% MeCN in H2O with 0.01 M NH3 throughout). This gave 1.4 mg of the title compound (6%). The purity was determined to be 95% by HPLC/DAD. LCMS ES+ 464.2 [M+H+], ES- 522.2 [M+AcO"].
Example 56-57
The following compounds were prepared by reaction of compound 55a with the appropriate amine according to the method described in Ex. 55b:
Figure imgf000093_0001
Example 58
Figure imgf000093_0002
58c, R = NH2 58d
Figure imgf000093_0003
Step a) l-Cyclopropyl-hex-l-yn-3-ol (58a)
1.6 M n-butyl lithium in hexanes was added drop wise at 0 0C to a solution of cyclopropylacetylen (70% in toluene, 3.7 g, 38.7 mmol ) in dry diethyl ether (30 ml) during about 15 min, then a solution of butyraldehyde (3.35 g, 46.4 mmol ) in diethyl ether (5 ml) was added drop wise at about 5 0C. The mixture was stirred for 1.5 hours on an ice bath whereafter the reaction was quenched with a cold solution of 5% citric acid. Diethyl ether was added, the phases were separated and the water phase was extracted twice with diethyl ether. The combined organic phases were washed with brine and dried with sodium sulphate. The solvent was evaporated under reduced pressure and the afforded residue was purified by silica gel chromatography eluted with isohexane: ethyl acetate, which gave the title compound (3.52 g, 65%).
Step b) (3-Azidohex-l-ynyl Vcyclopropane (58b)
DPPA (8.37 g, 30.4 mmol ) and then drop wise DBU (4.63 g, 30,4 mmol) were added to an ice cooled solution of the alcohol 58a (3.5 g, 25.32 mmol) in toluene (40 ml ). The mixture was stirred at room temperature for 1.5 hour whereafter DPPA (1.1 ml) and DBU (0,91 ml) were added and the stirring was continued. After 2h DPPA (1,1 ml ) and DBU (0,91 ml) were added and the mixture was left with stirring at room temperature over night. Ethyl acetate (100 ml) and isohexane (100 ml) were added, the phases separated and the organic phase was washed four times with water. The combined organic phases were dried with sodium sulphate, the solvent was evaporated under reduced pressure and the afforded residue was purified by silica gel chromatography eluted with isohexane: ethyl actate, which gave the title compound (2.86 g, 69%).
Step c) 1-Cyclopropylethynyl-butylamine (58c)
To a solution of the azide 58b (2.84 g, 17.39 mmol) in THF (80 ml ) was added water (0,9 ml) and triphenylphosphine (6.9 g, 26 mmol) and the mixture was stirred at room temperature for 72h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The phases were separated and the organic phase was extracted with cold 0.5 M HCl (3x 50 ml). The water phase was washed once with ethyl acetate and then made alkalic by addition of a 5 M solution of sodium hydroxide. The alkalic water phase was extracted four times with DCM, and then the combined organic phases were dried over sodium sulphate and the solvent was evaporated under reduced pressure (bath temperature below 30° C), which gave the title compound, (1.64g, 68%).
Step d) [l-Benzyl-3-(l-cyclopropylethynyl-butylamino)-2-hydroxy-propyll-carbamic acid tert-butyl ester (58d) A solution of (2S,3S )-l,2-epoxy-(3-boc-amino)-4-phenylbutane (527 mg, 2 mmol) and the amine 58c (550 mg, 4 mmol) in EtOH was stirred for four hours at 65 0C. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluted with isohexane: ethyl acetate, which gave the title compound, (0.52 g, 62%). Step e) N- [ 1 -Benzyl-3 -( 1 -cyclopropylethynyl-butylamino)-2-hydroxy-propyll -2- [(2-methyl- cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (58e) To a solution of compound 58d (40 mg, 0.1 mmol ) in DCM (1 ml ) was added triethylsilane (23.2 mg, 0.2 mmol) and TFA and the mixture was stirred for one hour at room temperature. The mixture was evaporated under reduced pressure and co evaporated twice with toluene. The residue was dissolved in DMF (2.5 ml) and Acid-3 (34 mg, 0,1 mmol ) and DIEA (77 mg, 0,6mmol ) were added. The mixture was cooled to 0 0C and HATU (38 mg, 0,1 mmol ) was added and the mixture was stirred for one hour. The mixture was then diluted with ethyl acetate, the phases were separated and the organic phase was washed twice with a saturated solution of sodium hydrogencarbonate and twice with brine. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Purification of the afforded residue by chromatography on silica gel eluted with DCM: MeOH (2%), gave the title compound, (34 mg, 54%). Purity as determined by HPLC > 95%. LC-MS [M+H]+ 624.
Example 59
Figure imgf000095_0001
Step a) l-Cylobutyl-4-cyclopropylbut-3-yn-2-ol (Ex. 59a)
The title compound was prepared in 28% yield (1.8 g) according to the method described in Example 58 step a, but using cylobutylcarboxaldehyd instead of butyraldehyde.
Step b) (2-Azido-4-cyclopropylbut-3-ynyl Vcyclobutane (59b)
To an ice cold solution of triphenylphosphine (4.1 g, 15.5 mmol ) in dry THF (60 ml) was added drop wise DIAD (3.15 g, 15.5 mmol). The mixture was stirred for 15 minutes at 5 0C whereafter an ice cooled solution of alcohol 59a (1.78 g, 10.8 mmol) in dry THF (40 ml) was added. DPPA (4.84 g, 17.6 mmol) was added and the mixture was stirred for 3 hours at 5 0C. The reaction was quenched with brine, ethyl acetate was added, the phases were separated and the water phase extracted three times with ethyl acetate. The combined organic phases were dried with sodium sulphate and the solvent was evaporated under reduced pressure. The afforded residue was purified by chromatography on silica gel eluted with isohexane: ethyl acetate, which gave the title compound (0.96g, 47%).
Step c) l-Cyclobutylmethyl-3-cyclopropyl-2-ynylamine (59c)
The title compound was prepared in 76% yield (0.62 g) from the Azido compound 59b, according to the method described in Example 58 step c.
Step d) [ 1 -Benzyl-3 -( 1 -cyclobutylmethyl-3 -cyclopropylprop-2-ynylamino)-2-hydroxy- propyll-carbamic acid tert-butyl ester (59d)
A solution of (2S, 3S)-l,2-epoxy- (3-boc-amino)-4-phenylbutane (490 mg, 3.0 mmol) and the amine 58c (395 mg, 1.5 mmol in EtOH (15 ml) was stirred for four hours at 70 0C. The solvent was removed under reduced pressure and the product was isolated in 76% yield (490 mg) by chromatography on silica gel eluted with isohexane: ethyl acetate.
Step e) N- [ 1 -Benzyl-3 -( 1 -cyclobutylmethyl-3 -cyclopropylprop-2-ynylamino)-2-hydroxy- propyl] -2- [(2-methyl-cyclopropylmethyl)-aminol -6- [methyl-(propane-2-sulfonyl)-aminol - isonicotinamide (59e)
Compound 59d was reacted according to the procedure described in Example 58 step 3, which gave the title compound (52 %, 34 mg). LC-MS [M+H]+ 650. Purity as determined by HPLC > 95%.
Example 60
Figure imgf000096_0001
N- [ 1 -Benzyl-3 -( 1 -cyclopropylethynyl-3 -methyl-butylamino)-2-hydroxypropyll -2- \(2- methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide
(60) The title compound was prepared in 20 % yield (45 mg) according to the procedure described in example 59, but using isovaleraldehyde instead of cylobutylcarboxaldehyd in step a. LC-MS [M+H]+ 638. Purity as determined by HPLC > 95%.
Example 61
Figure imgf000097_0001
Step a) 5-Cyclopropyl-l-phenylpent-4-yn-2-ol (61a)
A solution of n-butyllithium (2.5 M in hexane, 24 ml, 60.8 mmol) was added drop wise at -20 0C to a solution of cyclopropylacetylene (70% in toluene, 5.7 g, 60 mmol). The mixture was stirred for additional 15 minutes at -20 0C, then cooled to -78 0C and bortifluoride etherate (5.25 g, 37 mmol was added dropwise. After stirring for 10 minutes at -78 0C, (2,3-epoxypropyl)-l -benzene (5.2 g, 38 mmol) in THF (5 ml) was added drop wise and then the mixture was stirred for additional 2.5 hours at -78 0C. The mixture was added to a cooled solution of saturated ammonium chloride and stirred for 15 minutes. The phases were separated and the water phase was extracted twice with ethyl acetate. The combined organic phases were dried with sodium sulphate and concentrated under reduced pressure. The title compound was isolated in 65% yield (5.0 g) by chromatography on silica gel eluted with isohexane: ethyl acetate.
Step b) N-[l-Benzyl-3-(l-benzyl-4-cyclopropyl-but-3-ynylamino)-2-hydroxy-propyll- isonicotinamide (61b)
The title compound was prepared in 16 % yield (34 mg) from alcohol 61a according to the method described in Example 59 steps b, c, d and e, but using isonicotinic acid instead of Acid- 3 in step e. LC-MS [M+H]+ 468. Purity as determined by HPLC > 95%.
Exempel 62
Figure imgf000097_0002
Step a) N- [( 1 S ,2R)- 1 -benzyl-3 - [ 1 -(2-cyclopropylethynyDbutylaminol -2-hydroxy-propyl] -
2,6-dichloropyridine-4-carboxamide (62a)
The boc protected amine 58d (69 mg, 0172 mmol) was dissolved in DCM (2 ml) and triethylsilane (55 μl, 0.34 mmol) was added followed by TFA (2 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co- evaporated with toluene 3 times to give a crude amine salt, which was dissolved in DMF (1.5 ml) and DIPEA (164 μl, 0.94 mmol). 2,6-Dichloroisonicotinic acid (30 mg, 0.156 mmol) was added and to the resulting solution HATU (62 mg, 0.163 mmol) was added and the reaction was stirred at room temperature for 15 minutes. Then the reaction mixture was poured into ethyl acetate and saturated sodium bicarbonate. The organic phase was evaporated and the residue purified on a silica gel column eluted with 1 - 2% methanol / dichloromethane, containing 1% of 2.3M ammonia in methanol which gave the title compound (61 mg, 83%). LC/MS [M+H]+ 475.1.
Step b) N- |Y 1 S ,2R)- 1 -benzyl-3 - [ 1 -(2-cyclopropylethynyl)butylaminol -2-hydroxy-propyl] -2- chloro-6-|Yl S)- 1 ,2-dimethylpropyl"|pyridine-4-carboxamide (62b)
A mixture of (2S)-3-methylbutan-2-amine (150 μL) and N-[(lS,2R)-l-benzyl-3-[l-(2- cyclopropylethynyl)butylamino]-2-hydroxy-propyl]-2,6-dichloropyridine-4-carboxamide (6.1 mg, 0.013 mmol) was heated in a sealed tube at 90 0C for 3 days. The reaction mixture was evaporated under vacuum and the residue was purified by semi-preparative HPLC eluted with a water/acetonitrile gradient at pH 10 which gave the title compound (2.1 mg, 30%). LC/MS [M+H]+ 526.3. Purity as determined by HPLC >98%.
Example 63
Figure imgf000098_0001
N-[(l S,2R)- 1 -benzyl-3-[ 1 -(2-cyclopropylethynyl)butylaminol-2-hydroxy-propyll-2-chloro-
6-[(1R)- 1 ,2-dimethylpropyl"|pyridine-4-carboxamide (63)
The title compound was prepared in 78% yield (13 mg) from of (2R)-3-methylbutan-2-amine (350 μL) and N- [( 1 S ,2R)- 1 -benzyl-3 - [ 1 -(2-cyclopropylethynyl)butylamino] -2-hydroxy-propyl] - 2,6-dichloropyridine-4-carboxamide (15 mg, 0.032 mmol) according to the method described in Example 62 step b. LC/MS [M+H]+ 526.3. Purity as determined by HPLC >99%. Example 64
Figure imgf000099_0001
N-[l-Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-[(2-methyl- cyclopropylmethyD-aminol-β-phenyl-isonicotinamide (64)
A Biotage vial of 0.5-2.0 ml (for MW irradiation using a Biotage MW synthesizer) was filled with the compound of Example 50 (30.0 mg, 0.062 mmol), benzeneboronic acid (11.4 mg, 0.093 mmol), bis(triphenylphosphine)palladium(II) chloride (4.4 mg, 0.006 mmol), N5N- diisopropylethylamine (54 μl, 0.31 mmol) and a solution of l,2-dimethoxyethane-H2θ-ethanol (7:3:2 v/v, 2 ml). The mixture was degassed with N2 (g), sealed, and irradiated at 120 0C for 20 minutes in a Biotage MW synthesizer. The reaction mixture was diluted with CH2Cl2 (4 ml) and washed with saturated aqueous NH4Cl (2 ml). The aqueous layer was washed with CH2Cl2 (3 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue purified first by silica gel column chromatography (a short column using ethyl acetate, containing 1% saturated methanolic ammonia, as eluent) and then by preparative LC on a RP (Gemini-NX C 18, 100x21.20 mm, 5 μm particles) column using a gradient of 50- 90% CH3CN in H2O (containing 0.1% NH4OH, pH 10) during 8 minutes (flow rate: 20 ml/min) which gave the title compound (6.8 mg, 21%) as an off-white powder after freeze-drying from 1,4-dioxane. The purity was determined by HPLC with DAD-detector to be 97.6%. LC/MS [M+H]+ (ES+) 523.3;
Figure imgf000099_0002
Step a) N-[ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2,6-difluoro- isonicotinamide (65 a)
Amine I-17b was dissolved in dry DMF (1.5 ml). 2,6-Difluoropyridine-4-carboxylic acid (14.1 mg, 0.089 mmol) and N,N-diisopropylethylamine (0.078 ml, 0.45 mmol) were added and the solution was cooled on an ice-water bath. HATU (35.6 mg, 0.094 mmol) was added and the reaction mixture was then stirred at ca 0 0C for 1 h, and concentrated under reduced pressure. The residue was taken up into ethyl acetate (10 ml) and washed with saturated aqueous NaHCOs (20 ml). The aqueous layer was washed with ethyl acetate (10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (stepwise gradient of 2-4% CH3OH in CH2Cl2 containing 0.025% triethylamine) which gave the title compound as a white solid (31 mg, 87%). LC/MS [M+H]+ (ES+) 400.1;
Step b) N-[ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-fluoro-6-[(2- methyl-cyclopropylmethyD-aminol-isonicotinamide (65b)
A solution of compound 65a (30 mg, 0.075 mmol) in rac-trans-2-methylcyclopropylmethylamine (0.6 ml) and dry DMF (0.2 ml) was heated at 70 0C for 2 Vi h. The product was isolated by preparative LC on a RP (Gemini-NX C 18, 100x21.20 mm, 5 μm particles) column using a gradient of 50-90% CH3CN in H2O (containing 0.1% NH4OH, pH 10) during 8 minutes (flow rate: 20 ml/min) (18 mg, 52%) as a white powder after freeze-drying from 1,4-dioxane. The purity was determined by HPLC with DAD-detector to be 98.8%. LC/MS [M+H]+ (ES+) 465.3;
Example 66
Figure imgf000100_0001
N-[l-Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-(2-chloro- cyclopropylmethoxy)-6-fluoro-isonicotinamide (66)
Rac-trans-(2-chlorocyclopropyl)-methanol, prepared from methyl acrylate as described in J. Org Chem. 2005, 70, 4162-4165 (53 mg, 0.50 mmol) was treated with sodium hydride, 60% dispersion in mineral oil (16 mg, 0.40 mmol) in dry DMSO (0.93 ml) at 70 0C for 30 minutes. An aliquot (0.23 ml) of the solution was added to a solution of compound 65-a (31 mg, 0.078 mmol) in dry DMSO (1 ml), and the resulting reaction mixture was then stirred at room temperature for 20 h. The reaction was quenched by addition of 10 mM NH4OAc in CH3CH- H2O (9:1 v/v, 1 ml). The product was isolated by preparative LC on a RP (XBridgePrepPhenyl, 100x19 mm, 5 μm particles) column using a gradient of 50-90% CH3CN in H2O (containing 10 mM NH4OAc, pH 7) during 15 minutes (flow rate: 20 ml/min) which gave the title compound (6 mg, 16%) as a white powder after freeze-drying from 1,4-dioxane. The purity was determined by HPLC with DAD-detector to be 97.3%. LC/MS [M+H]+ (ES+) 486.0.
Example 67
Figure imgf000101_0001
Step a) 2-Chloro-6-(((lS,2R)-2-chloro-l-methylcyclopropyl)methoxy)isonicotinic acid & 2-chloro-6-((( 1 R,2S)-2-chloro- 1 -methylcyclopropyl)methoxy)isonicotinic acid (67a) A racemic mixture of the alcohol 2-chloro-l-methylcyclopropyl)methanol (291 mg, 2.41 mmol) was dissolved in dioxane (10 ml), NaH, (60% in mineral oil, 60 mg, 2.41 mmol) was added and the solution was heated to 70 0C. After 10 min. 2,6-dichloropyridine-4-carboxylic acid (157 mg, 0.82 mmol) was added. The solution was kept at 70 0C for 16 h, then further NaH, (60% in mineral oil, 70 mg, 2.81 mmol) was added. When the reaction was completed the reaction mixture was extracted between aqueous citric acid (10%, 40 ml) and EtOAc (50 ml). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc containing 0.1% acetic to give the title product. MS (LC-MS, ES" ): [M-H]" =274.0
Step b) 2-Chloro-6-((2-chloro-l-methylcvclopropynmethoxy)-N-((2S.3R)-4-(3- cyclopropylprop-2-ynylamino)-3 -hydroxy- 1 -phenylbutan-2-yl)isonicotinamide (67b) Acid 67a (50 mg, 0.18 mmol) was dissolved in DMF (2 ml), and DIPEA (100 μl, 0.6 mmol) was added and the reaction mixture was cooled to 0 0C. HATU (87.5 mg, 0.23 mmol) was then added. To this solution was added a solution of the amine I- 17b and DIPEA (100 μl, 0.6 mmol) in DMF (2 ml) at 0 0C in one portion. The reaction was monitored by LC-MS. When the reaction was rendered complete the reaction mixture was extracted between EtOAc (30 ml) and aqueous NaHCO3 (10 ml). The organic phase was washed with water (10 ml), dried over MgSO4, filtered and concentrated. The residue was purified by preparative LC-MS to give the title compound (3 mg, 3.%). MS (LC-MS, ES+):[M+H]+ =516.1
Example 68
Figure imgf000102_0001
Step a) 2-Chloro-6-(((lR,2S)-2-chlorocyclopropyl)methoxy)isonicotinic acid (68a) The alcohol [(lR,2S)-2-chlorocyclopropyl]methanol, prepared from methyl acrylate as disclosed in J. Org. Chem. 2005, 70, 4162-4165, (106 mg, 1.0 mmol) was dissolved in dioxane (5 ml), NaH (60% in mineral oil, 40 mg, 1.0 mmol) was added and the solution was heated to 80 0C. After 40 min 2,6-dichloropyridine-4-carboxylic acid (64 mg, 0.33 mmol) was added and the solution was kept at 80 0C for 2 h. After cooling, the reaction mixture was extracted between aqueous citric acid (10%, 10 ml) and EtOAc (30 ml). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography eluted with EtOAc/isohexane, 50/50, containing 0.5% acetic acid which gave the title compound (84mg, 97%). MS (LC-MS, ES"): [M-H]" 260.0.
Step b) 2-Chloro-6-(((lR.2S)-2-chlorocvclopropyl)methoxy)-N-((2S.3R)-4-(3- cvclopropytorop-2-vnylamino)-3-hvdroxy- 1 -phenylbutan-2-yl)isonicotinamide (68b) Compound I- 17b (0.4 mmol) was reacted with acid 68-a (84 mg, 0.32 mmol) according to the procedure described in Example 67 step b, which gave the title compound (67mg, 42 %). MS (LC-MS, ES+): [M+H]+ = 502.1
Example 69
Figure imgf000103_0001
2-(((lR,2S)-2-Chlorocyclopropyl)methoxy)-N-((2S,3R)-4-(3-cyclopropylprop-2-ynylamino)- 3 -hydroxy- 1 -phenylbutan-2-yl)-6-(N-methylpropan-2-ylsulfonamido)isonicotinamide (69) The alcohol [(lR,2S)-2-chlorocyclopropyl]methanol, prepared from methyl acrylate as disclosed in J. Org. Chem. 2005, 70, 4162-4165, was reacted with Acid-1 and subsequently with I-17b according to the procedure described in Example 68, which gave the title compound. MS (LC- MS, ES ): [M+H]+ 603.3.
Example 70
Figure imgf000104_0001
70b, R = NO2 70c, R = NH2
Figure imgf000104_0002
7Od
Figure imgf000104_0003
Step a) Prop-2-ynylcyclopropane (70a)
Lithium acetylide ethylenediamine complex (2.9 Ig, 30 mmol) was dissolved in DMSO (20 ml) and THF (10 ml) and cooled to 0 0C. (Bromomethyl)cyclopropane (1.76 g, 13 mmol) in THF (7.5 ml) was added in one portion and the reaction mixture was kept stirring at 20 0C. After 2Oh, the reaction mixture was poured on water (250 ml) and treated with aqueous disodium tartrate, aqueous citric acid and brine. Et2O (appr. 80 ml) was added and the slurry was filtrated through celite. The organic phase was dried with MgSO4, filtered, diluted with Et2O to a volume of 100 ml and stored over molecular sieves. This solution was used directly in the next step.
Step b) (lR,2S)-l-(3-Cyclopropylprop-l-ynyl)-2-nitrocyclohexane &
(lS,2R)-l-(3-cyclopropylprop-l-ynyl)-2-nitrocyclohexane (70b)
A solution of compound 70a in Et2O (50ml,) was cooled to -60 0C. n-BuLi (1.6 M in hexane, 2.85 ml, 4.5 mmol) was added slowly. After Ih 1-nitro-l-cyclohexene 500 μl, (4.5 mmol) in THF (20 ml) was added slowly. After Ih the reaction mixture was slowly heated to 20 0C and 1.5h later the reaction was quenched with glacial acetic acid (1 ml). The reaction mixture was extracted with water. The organic phase was washed with aqueous NaHCO3 , brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using Et2O /isohexane which gave the title compound (618 mg, 66%), predominately cis isomers. MS (LC-MS, ES+): [M+Na]+ = 225.1. The afforded isomeric mixture was dissolved in a mixture of CH3CN (4 ml) and Et3N (840 μl, 6.0 mmol) and the solution was stirred at 35 0C. After 18h sat. aqueous NH4Cl (10 ml) was added and the reaction mixture was extracted with Et2O (40 ml). The organic phase was washed with, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography using Et2O /isohexane, 3/97, which gave the title compound (211 mg, 35%). MS (LC-MS, ES+): [M+Na]+ = 225.1
Step c) (lS,2R)-2-(3-cyclopropylprop-l-ynyl)cyclohexanamine & ( 1 R,2S)-2-(3 -cyclopropylprop- 1 -ynyDcyclohexanamine (70c)
To a stirred of compound 70b (21 lmg, 1.0 mmol) in EtOH (25 ml) Zn-dust (333 mg, 5.1 mmol) was added followed by aqueous IM HCl (5 ml, 5 mmol). Additional Zn-dust (260 mg, 4.1 mmol) and aqueous IM HCl (4 ml, 4 mmol) was added after Ih. After 16h, the reaction mixture was filtered, concentrated, extracted between EtOAc (50 ml) and aqueous NaHCO3 (10 ml). The organic phase was washed with aqueous NaHCO3 (10 ml), dried over MgSO4, filtered and carefully evaporated which gave the title product (162 mg, 90%). MS (LC-MS, ES+): [M+H]+ = 178.2.
Step d) Tert-butyl (2S.3R)-4-((lR.2S)-2-(3-cvclopropylprop-l-vnvncvclohexylamino)-3- hydroxy- 1 -phenylbutan-2-ylcarbamate & tert-butyl (2S,3R)-4-((l S, 2R)-2-(3 -cyclopropylprop- 1 -ynyl)cyclohexylamino)-3-hydroxy- 1 - phenylbutan-2-ylcarbamate (7Od)
A solution of compound 70c (162 mg, 0.91 mmol) and (2S,3S)-l,2-epoxy-3-(Boc-amino)-4- phenylbutane (156 mg, 0.59 mmol) in EtOH (10 ml) was heated to 65 0C for 8h. The reaction mixture was evaporated on silica and purified by column chromatography using
EtOAc/isohexane, 50/50, which gave the title compound (103 mg, 39%). MS (LC-MS, ES+): [M+H]+ = 441.3
Figure imgf000105_0001
2-(((lR,2S)-2-Chlorocyclopropyl)methoxy)-6-fluoroisonicotinic acid (7Oe) The alcohol [(lR,2S)-2-chlorocyclopropyl]methanol, prepared from methyl acrylate as disclosed in J. Org. Chem. 2005, 70, 4162-4165, (41mg, 0.38mmol) was dissolved in dioxane (1.5 ml). NaH (60% in mineral oil, 15 mg, 0.38 mmol) was added and the solution was heated to 800C for 15 minutes and then cooled to 20 0C. In a separate flask 2,6-difluoropyridine-4-carboxylic acid (50mg, 0.31mmol) and DIPEA (54 μl, 0.31 mmol) was dissolved in dioxane (1.5ml). The two solutions were mixed and stirred at 20 0C. After 3 h additionally NaH (60% in mineral oil, 15 mg, 0.38 mmol) was added and the solution was heated to 700C for 30 minutes whereby only traces of starting material remained. After cooling the reaction mixture was extracted between EtOAc and 0.2M aqueous HCl. The organic phase was evaporated and the crude product was purified by preparative LC-MS which gave the title compound (46 mg, 60%). MS (LC-MS, ES"): [M-H]" 244.0.
Step f) 2-(((lR.2S)-2-chlorocvclopropyl)methoxy)-N-((2S.3R)-4-((lR.2S)-2-(3- cyclopropylprop- 1 -ynyl)cyclohexylamino)-3 -hydroxy- 1 -phenylbutan-2-yl)-6- fluoroisonicotinamide (7Of-I) &
2-(((lR.2S)-2-chlorocvclopropyl)methoxy)-N-((2S.3R)-4-((lS.2R)-2-(3-cvclopropylprop-l- ynyl)cyclohexylamino)-3-hydroxy-l-phenylbutan-2-yl)-6-fluoroisonicotinamide(70f-2) The title compounds were obtained by removal of the Boc group of compound 70-d (59 mg, 0.134 mmol) followed by coupling of the afforded amine to the acid 70-e (24.5mg, O.lmmol) according to the procedure described in Example 67 step b. The two enantiomers were separated by preparative LC-MS which gave the title compounds, 7Of-I (12.6mg, 22%, first eluting peak) and 70f-2 (8.0 mg, 14%, second eluting peak). MS (LC-MS, ES+): [M+H]+ 178.2.
Example 71
Figure imgf000107_0001
Step a) l-(l-Ethynylcyclohexyl)-2,2,5,5-tetramethyl-l,2,5-azadisilolidine (71a) 1-Ethynylcyclohexylamine (665 mg, 5.4 mmol) and Et3N (1.88 ml, 13.5 mmol) was dissolved in DCM (25 ml) and stirred at 0 0C under N2-atmosphere. A solution of 1,2- bis(chlorodimetylsilyl)ethane (1.22 g, 5.67 mmol) in DCM (5 ml) was slowly added. The reaction mixture was kept at 0 0C for Ih and then slowly heated to 20 0C for Ih. Et2O (approx. 100 ml) was added and the slurry was filtrated. The filtrate was evaporated and the crude product was purified by kugelrohr distillation which gave the title compound (981mg, 68%). MS (GC- MS, EI): M/Z = 265, 222 (100%)
Step b) 1 -( 1 -Q-Cyclopropylprop- 1 -ynyl)cyclohexyl)-2,2,5 ,5-tetramethyl- 1,2,5- azadisilolidine (71b) Compound 71a (965 mg, 3.64mmol) and l,3-dimethyl-3,4,5,6,-tetrahydro-2(lH)-pyriminidone (2 ml, 16.5 mmol) was dissolved in THF (11 ml) and stirred at -70 0C under N2-atmosphere. n- BuLi (1.6 M in hexane, 3.0 ml, 4.8 mmol) was slowly added. The solution was kept at -70 0C for 2 h, slowly heated to -20 0C and then cooled to -70 0C. (Bromomethyl)cyclopropane (470 μl, 4.9 mmol) in THF (2 ml) was added slowly and the reaction mixture was slowly heated to 20 0C and left stirred for 2Oh. Et2O (50 ml) was added followed by saturated aqueous NH4Cl. To this mixture additional water was added and the phases were separated. The aqueous phase was extracted with Et2O (2x15 ml). The pooled organic phases were washed with brine (2x15 ml) dried over MgSO4, filtered and evaporated which gave a mixture (1.46 g) of starting material 26% and the title compound 74%. This crude material was used without further purification in the next step. MS (GC-MS, EI): M/Z = 319, 276(100%). Step c) l-(3-Cyclopropylprop-l-ynyl)cyclohexanamine (71c)
Crude 71b (1.46 g) was dissolved in Et2O (20 ml). Water (10 ml) was added and the reaction mixture was cooled to 0 0C. 2M aqueous HCl (2.2 ml, 4.4 mmol) was added slowly. The reaction was monitored by GC-MS. After 30 min the phases were separated. The aqueous phase was washed with Et2O (10 ml) , pH adjusted to 8-9 with cone. NH3 and then extracted with Et2O (2x20 ml). The pooled organic phases were dried over MgSO4, filtered and carefully evaporated which gave the crude title product (738mg). GC-MS analyses showed that this material contained 79% product, 16% 1-ethynyl-cyclohexylamine and 5% byproducts. The afforded crude material was used in without further purification the next step. MS (GC-MS, EI): M/Z = 177, 134 (100%) .
Step d) Tert-butyl (2S,3R)-4-(l-(3-cyclopropylprop-l-ynyl)cyclohexylamino)-3-hydroxy-l- phenylbutan-2-ylcarbamate (7Id) A solution of compound 71c (438 mg, 2.47 mmol) and (2S,3S)-l,2-epoxy-3-(Boc-amino)-4- phenylbutane (423 mg, 1.61 mmol) in EtOH (25ml)was heated to 65 0C for 5h and then 75 0C for 2h. The reaction mixture was evaporated and the crude product was purified by preparative LC-MS which gave the title compound (173 mg, 24%). MS (LC-MS, ES+): [M+H]+ = 441.3.
Step e) 2-(((lR.2S)-2-Chlorocvclopropyl)methoxy)-N-((2S.3R)-4-(l-(3-cvclopropylprop-l- ynyl)cyclohexylamino)-3-hydroxy- 1 -phenylbutan-2-yl)-6-fluoroisonicotinamide (71 e) The title compound was obtained by a reaction sequence analogous to the one described in Example 67 step b, using the acid 70-e (24.5 mg, 0.10 mmol) and compound 71-d (48.5 mg, 0.11 mmol). The crude product was purified by preparative LC-MS which gave the title compound (19 mg, 33%). MS (LC-MS, ES+): [M+H]+ = 568.3
Example 72
Figure imgf000108_0001
Step a) 2,2,5,5-Tetramethyl-l-(prop-2-ynyl)-l,2,5-azadisilolidine (72a) Propargylamine (4.98 ml, 72.6 mmol) and Et3N (24.3 ml, 174 mmol) was dissolved in DCM (100 ml) and stirred at 0 0C under N2-atmosphere. A solution of 1,2- bis(chlorodimetylsilyl)ethane (16.4 g, 76.2 mmol) was slowly added. The reaction mixture was kept at 0 0C for Ih and then slowly heated to 20 0C for Ih. Et2O (approx. 100 ml) was added and the slurry was filtrated. The filtrate was evaporated and the crude product was purified by distillation at diminished pressure which gave the title compound (12.0 g, 84%). MS (GC-MS, EI): M/Z = 197, 182 (100%).
Step b) l-(4-Cvclopropylbut-2-vnyl)-2.2.5.5-tetramethyl-1.2.5-azadisilolidine (72b)
Compound 72a (2.0 g, 10.1 mmol) and l,3-dimethyl-3,4,5,6,-tetrahydro-2(lH)-pyriminidone (3 ml, 24.8 mmol) was dissolved in THF (15 ml) and stirred at -70 0C under N2-atmosphere. n-BuLi (1.6 M in hexane, 8.9 ml, 14.2 mmol) was added slowly. The solution was kept at -70 0C for 1 h, slowly heated to -20 0C and then cooled to -70 0C. (Bromomethyl)cyclopropane (1.26 ml, 13.2 mmol) was slowly added and the reaction mixture was slowly heated to 20 0C and left stirred for 2Oh, then heated to 65 0C for 7h. Work-up of the reaction mixture was performed as described in Example 71 step b which gave a mixture (2.56 g) of product (40%), starting material (56%) and byproducts (4%). This crude material was used in the next step without further purification. MS (GC-MS, EI): M/Z = 251, 236(100%).
Step c) 2-(((lR.2S)-2-chlorocvclopropyl)methoxy)-N-((2S.3R)-4-(4-cvclopropylbut-2- ynylamino)-3 -hydroxy- 1 -phenylbutan-2-yl)-6-fluoroisonicotinamide (72c) Compound 72b was reacted according to the procedure described in Example 71 steps c, d and e which gave the title compound (1.2 mg, 0.8%). MS (LC-MS, ES+): [M+H]+ = 500.2
The following compounds were prepared in an analogous manner to the procedure described for the preparation of Example 30 using the appropriate alkylating agent in the step corresponding to Example 22 step a.
Figure imgf000110_0001
The compounds of Examples 76 and 77 were prepared in a manner analogous to the procedure described for the preparation of Example 1, using acid A-3 and the appropriate intermediate, the intermediate being prepared by reaction of epoxide I- 17a with the appropriate amine according to the method described for the preparation of intermediate I- 17b.
Figure imgf000111_0002
Example 78
Figure imgf000111_0001
Step a) 2-(4-Methoxy-but-2-enyloxy)-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinic acid (78a)
A mixture of cis-4-methoxy-but-2-en-l-ol (153 mg, 1.5 mmol), prepared according Organic Letters 2006, p 5437-39 (suppl material), 60% sodium hydride in mineral oil (60 mg, 1.5 mmol) and 2-chloro-6-[methyl-(propane-2-sulfonyl)-amino]-isonicotinic acid (146 mg, 0.5 mmol) in dioxan (5 ml) was heated at +80 0C for 12 hours. Thereafter the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with sat ammonium chloride. The organic phase was evaporated and the residue purified on a silica gel column eluting with isohexane 2 and ethyl acetate 1 containing 1% of acetic acid to give 144 mg (80%) of the title compound. LC/MS confirmed the structure with a major positive peak at 359.0 (M+l). Step b) N- [ 1 -Benzyl-3-(3-cyclopropyl-prop-2-ynylamino)-2-hydroxy-propyll-2-(4-methoxy- cis-but-2-enyloxy)-6-[methyl-(propane-2-sulfonyl)-amino]-isonicotinamide (78b) Boc protected amine from Ex I- 17a (72 mg, 0.2 mmol) was dissolved in DCM (2.5 ml) at 0 0C and TFA (2.5 ml) was added. The reaction mixture was stirred at 0 0C for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene 3 times to give a crude amine salt which was dissolved in DMF (1.5 ml) and DIPEA (70 μl, 0.4 mmol). In a separate flask, the acid from step a above (72 mg, 0.2 mmol) was dissolved in DMF (2 ml) and the solution was stirred and cooled to 0 0C. Diisopropylethylamine (DIEA) (70 μl, 0.4 mmol) and HATU (76 mg, 0.2 mmol) were added, and the reaction was stirred at 0 0C for 1 hour. This reaction mixture was then added drop wise to the above amine salt and the reaction mixture was stirred at 0 0C for 1 hour. Then, the reaction mixture was poured into ethyl acetate and sat sodium bicarbonate. The organic phase was evaporated and the residue purified on a silica gel column eluting with dichloromethane with increasing amounts of methanol 2 , 3 and 4% to give 19 mg of the title product. A final purification on preparative HPLC gave 12 mg (10%) of the title product. The purity was determined by HPLC with a DAD-detector to be >98% and LC/MS confirmed the structure with a M+l peak at 599.2.
1HNMR data for a selection of compounds Ex. 6: (400 MHz, CDCl3) δ 8.36 (s, IH), 8.25 (s, IH), 7.30 (s, 2H), 6.83 (s, IH), 6.49 (s, IH), 4.75 (s, IH), 4.54 - 4.33 (m, 2H), 4.17 (s, IH), 3.97 (s, IH), 3.80 (dt, J= 6.9, 13.7, IH), 3.49 (s, 2H), 3.41 (s, 3H), 3.20 (m, IH), 3.10 (m, IH), 2.96 (s, 2H), 2.02 (s, IH), 1.36 (dd, J= 1.7, 6.8, 6H), 1.06 (d, J= 5.9, 3H), 0.88 - 0.74 (m, IH), 0.65 (dd, J= 7.8, 15.6, IH), 0.39 (dd, J= 6.8, 10.9, IH), 0.29 (dt, J= 4.9, 9.4, IH). Ex. 7: (400 MHz, CDCl3) δ 8.36 (s, IH), 8.25 (s, IH), 7.30 (s, 3H), 6.83 (s, IH), 6.50 (s, IH),
4.73 (t, J= 4.5, IH), 4.43 (m, 3H), 4.17 (dd, J= 4.2, 8.9, IH), 3.95 (m, IH), 3.87 - 3.76 (m, IH), 3.43 (m, 2H), 3.42 (s, 3H), 3.20 (dd, J= 6.3, 12.6, IH), 3.10 (td, J= 6.2, 13.1, IH), 2.92 (m, 2H), 1.36 (dd, J= 1.2, 6.8, 6H), 1.06 (d, J= 5.9, 3H), 0.79 (m, IH), 0.71 (m, 2H), 0.69 - 0.63 (m, IH), 0.60 (m, 2H), 0.46 - 0.34 (m, IH), 0.34 - 0.24 (m, IH). Ex. 10: (400 MHz, CDCl3) δ 7.95 - 7.83 (m, IH), 7.44 (ddd, J = 3.1, 6.4, 9.3, IH), 7.29 (br s, IH), 6.87 (dd, J = 3.5, 8.9, IH), 6.83 (s, IH), 6.52 (s, IH), 4.75 (br m, IH), 4.40 (m, 2H), 4.16 (dd, J = 4.4, 9.0, IH), 3.95 (dd, J = 5.2, 10.5, IH), 3.85 - 3.72 (m, IH), 3.42 (br m, 6H), 3.26 - 3.15 (m, IH), 3.09 (m, IH), 2.99 - 2.83 (m, 2H), 1.36 (dd, J = 1.8, 6.9, 7H), 1.28 - 1.13 (m, 2H), 1.06 (d, J = 6.0, 3H), 0.89 - 0.75 (m, IH), 0.75 - 0.63 (m, 3H), 0.62 - 0.56 (m, 2H), 0.44 - 0.35 (m, IH), 0.29 (m, IH). Ex. 17: (400 MHz, CDCl3) δ 8.26-8.19 (m, 2H), 7.38 (m, IH), 7.32 (m, IH), 6.82 (app. s, IH),
6.50 (app. s, IH), 4.75 (m, IH), 4.45-4.38 (m, 2H), 4.18 (m, IH), 3.93 (m, IH), 3.80 (m, IH), 3.43-3.39 (m, 4H), 3.19 (m, IH), 3.09 (m, IH), 2.99-2.81 (m, 2H), 1.38-1.33 (m, 6H), 1.19 (m, IH), 1.06 (m, 3H), 0.79 (m, IH), 0.74-0.56 (m, 5H), 0.39 (m, IH), 0.29 (m, IH). Ex. 18: (500 MHz, CDCl3) δ 8.25-8.21 (m, 2H), 7.39 (m, IH), 7.32 (m, IH), 6.82 (app. s, IH),
6.51 (app. s, IH), 4.76 (m, IH), 4.46-4.37 (m, 2H), 4.19 (m, IH), 3.93 (m, IH), 3.81 (m, IH), 3.45-3.39 (m, 5H), 3.20 (m, IH), 3.10 (m, IH), 2.95 (m, IH), 2.87 (m, IH), 1.39-1.32 (m, 6H), 1.20 (m, IH), 1.09-1.02 (m, 3H), 0.79 (m, IH), 0.75-0.63 (m, 3H), 0.62-0.57 (m, 2H), 0.40 (m, IH), 0.29 (m, IH). Ex. 31 : (CDCU δ 7.38-7.19 (m, 5 H) 6.91 (d, J= 8.61 Hz, 1 H) 6.66 (s, 1 H) 6.37 (s, 1 H) 4.77- 4.67 (m, 1 H) 4.42-4.31 (m, 1 H) 3.87-3.78 (m, 1 H) 3.77-3.71 (m, 1 H) 3.70-3.63 (m, 1 H) 3.42- 3.39 (m, 2 H) 3.38 (s, 3 H) 3.15-3.09 (m, 2 H) 3.07-2.94 (m, 2 H) 2.94-2.74 (m, 2 H) 1.38-1.33 (dd, J= 3.44, 6.83 Hz, 6 H) 1.30-1.15 (m, 1 H) 1.14-1.03 (m, 1 H) 0.77-0.69 (m, 2 H) 0.65-0.59 (m, 2 H) 0.58-0.50 (m, 2 H) 0.27-0.20 (q, J= 4.92, 4.94 Hz, 2 H), Ex. 37: 1H NMR (SOO MHz, CDCl3) δ 7.38 - 7.19 (m, 5H), 6.67 (d, J= 8.6, IH), 6.63 (s, IH), 6.33 (s, IH), 4.68 (t, J= 5.1, IH), 4.40 - 4.31 (m, IH), 3.81 (hept, J= 6.9, IH), 3.65 (dd, J= 5.3, 9.7, IH), 3.37 (s, 3H), 3.20 - 3.12 (m, IH), 3.09 - 3.00 (m, 2H), 2.92 (dd, J= 3.6, 12.2, IH), 2.82 (dd, J= 5.2, 12.2, IH), 2.28 (s, IH), 2.14 (br s, OH, NH), 1.44 - 1.32 (m, 12H), 1.06 (d, J= 6.0, 3H), 0.78 (qd, J= 3.6, 7.2, IH), 0.70 - 0.61 (m, J= 5.1, 10.3, IH), 0.42 - 0.36 (m, IH), 0.32 - 0.25 (m, IH).
Ex. 57: 1H NMR (500 MHz, cdcl3) δ 7.37 - 7.18 (m, 5H), 6.71 (s, IH), 6.60 (d, J= 8.4 Hz, IH), 6.54 (t, J= 8.5 Hz, IH), 6.42 (dd, J= 11.9, 2.0 Hz, IH), 4.43 - 4.34 (m, IH), 3.86 (td, J= 7.6, 3.9 Hz, IH), 3.67 (d, J= 2.8 Hz, IH), 3.47 - 3.37 (m, 4H), 3.36 (s, 2H), 3.26 - 3.20 (m, IH), 3.16 - 3.05 (m, 3H), 3.01 (dd, J= 14.0, 5.4 Hz, IH), 2.93 - 2.74 (m, 2H), 2.12 - 1.90 (m, 4H), 1.88 - 1.46 (br s, 2H), 1.24 - 1.15 (m, IH), 0.76 - 0.68 (m, 2H), 0.64 - 0.58 (m, 2H).
Biological Examples
To evaluate the enzymatic inhibition of BACEl exhibited by the compounds of the invention, a TruPoint™ Beta-Secretase Assay Kit was used. The assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanide fluorescence can be measured by time-resolved fluorometry (TRF). 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 assay used employs the enzyme at a concentration of 10 nM in a reaction buffer consisting of 50 mM sodium acetate, CHAPS, 0.05% Triton X-100 and EDTA at pH=4.5. The substrate was prepared at a 120 μM 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 μl) and inhibitor of different concentrations in DMSO (1 μl). To control wells were added reaction buffer (15 μl) and DMSO (1 μl). The enzyme with inhibitor in DMSO was preincubated at room temperature (20-25 0C) for 30 min whereafter the reactions were started by addition of substrate, 15 μl/well, thus giving a total volume of 31 μl/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 λeX 330 nm and λem 615 nm. The inhibition is calculated as follows:
RFuinhlbltor-RFubackground
100 - x 100 = % inhibition
( ) enzyme controll ^^^ background
For example, Table 1 shows the enzymatic inhibition exhibited by a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above. Category A indicates an IC50 value of < 0.02 μM, category B indicates 0.02 - 1 μM and category C indicates > 1 μM. TABLE 1
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003

Claims

Claims
1. A compound of formula (I) :
Figure imgf000116_0001
wherein
A is CR1 or N;
O
R* R
D is H, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or
R7 wherein G is NR 10 or O; R1 is H, Ci-Cealkyl, Ci-C6alkoxy, N3 or halo; R2 is H or Ci-Cealkyl;
R3 and R3 are independently of each other H, Ci-Cβalkyl or CF3, or R3 and R3 together with the carbon atom to which they are attached form C3-C6Cycloalkyl or C4- Cβheterocyclyl;
R4 is H or Ci-Cβalkyl, or when p is 1 then R4 together with R3 and the carbon atoms to which they are attached may form C3-C6Cycloalkyl or C4-Ceheterocyclyl; R6 is R1 or aryl, N(Ra)S(=O)rRc, N(Ra)S(=O)rNRaRb, S(=O)rCi-C6alkyl, N(Ra)C(=O)Rc, N(Ra)C(=O)ORc, N(Ra)C(=O)NRaRc or cyano;
R7 is Ci-Cealkyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl, hydroxyCi-C3alkyl, Ci-C6alkoxyCi-C3alkyl, arylCo- C3alkoxyCi-C3alkyl, heterocyclylC0-C3alkoxyCi-C3alkyl or N(Ra)(Rb)Ci-C3alkyl; wherein the Ci-C3alkyl moiety of R7 is optionally substituted with Ci-Cβalkyl; R8 is H or Ci-Cealkyl; or
R7 and R8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine;
R9 is Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl or heterocyclylCi-C3alkyl;
R10 is H or Ci-Cβalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine; wherein the cyclic amine is optionally substituted with Ci-C4alkyl, Ci-C2alkoxyCi- C4alkyl, haloCi-C4alkyl or halo;
Q is Ci-Cβalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C6Cycloalkyl, aryl or heterocyclyl; W is H, Ci-C6alkyl, C3-C6cycloalkyl, CH2F, CHF2 or CF3; one of X' and X" is H or CH3, the other is Ci-C3alkyl, F, OH, NRaRb, CF3 or N3; or
X' and X" are both F; Y is NRd or O;
Z is O, NRa, CHRd, CF2 or S(=O)r or a bond; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; r is 0, 1 or 2;
Ra is independently H or Ci-Cβalkyl;
Rb is independently H or Ci-Cβalkyl; 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;
Rc is independently Ci-Cβalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocycle; Rd is H or Ci-C3alkyl; and wherein aryl is independently phenyl or naphthyl, or phenyl fused to C4-Cecycloalkyl or C4-
Cβcycloalkenyl; 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 Ci-Cβalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cβalkoxy, C2-C6alkenoxy, C2-C6alkynoxy, C3-Cecycloalkyl, C3-Cecycloalkenyl, aryl and heterocyclyl above (including those in composite expressions such as arylalkyl or heterocyclylalkyl) unless otherwise specified is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, C2-C6alkenyl, C2-
Cβalkynyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, NRaRb, NRaRbC i-C4alkyl, NRaRbC(=O), RbC(=O)N(Ra), cyano, azido, nitro, Ci-C4alkylcarbonyl, C3-C6Cycloalkyl1Co-C3alkyl, aryl1Co-C3alkyl, heterocyclyl1 Co-C3alkyl, C3-C6cycloalkyl1C2-C3alkenyl, aryl1C2-C3alkenyl, heterocyclyl1C2-C3alkenyl, C3-C6Cycloalkyl1C2-C3alkynyl, aryl1C2-C3alkynyl or heterocyclyl1C2-C3alkynyl, or a 3 to 6 membered cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl, Ci-C3alkoxyCi-C4alkyl or fluoro); wherein aryl1 is independently phenyl, naphthyl, or phenyl fused to
Figure imgf000118_0001
or C4-
Cβcycloalkenyl; heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence of C3-C6cycloalkyl1, aryl1 and heterocyclyl1 above (including those in composite expressions such as C3-C6Cycloalkyl1Co-C3alkyl, aryl1Co-C3alkyl and heterocyclyl1 Co-C3alkyl), the cycloalkyl1, aryl1 and heterocyclyl1 moiety is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, C3-C4cycloalkyl, halo, haloCi-C4alkyl, hydroxy and NRaRb; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
2. A compound according to claim 1, wherein A, D, Ra, Rb and Rc are as defined in claim 1, R1 is H or F;
R2 is H;
R3 and R3 are both H or CH3, or one of R3 and R3 is H and the other is CF3, or R3 and
R3 together with the carbon atom to which they are attached form C3-Cecycloalkyl;
R4 is H R6 is H, Ci-Cealkyl, aryl, N(Ra)S(=O)2Rc, N(Ra)S(=O)2NRaRb, halo or cyano;
R7 is Ci-C6alkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl or heterocyclylCi-C3alkyl;
R8 is H or Ci-Cealkyl;
R9 is Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl or
Figure imgf000118_0002
R10 is H or Ci-Cβalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine; wherein the cyclic amine is optionally substituted with Ci-Cβalkyl, C2-C6alkenyl, C2- Cβalkynyl or phenyl; Q is aryl or heterocyclyl;
W is H, Ci-Cealkyl, C3-C6cycloalkyl, C3-C6CycloalkylCi-C3alkyl, CH2F, CHF2 or CF3; one of X' and X" is H and the other is OH, Y is NH; Z is O, NH or CH2; n is 0 or 1 ; p is 0 or 1 ; r is 2.
3. A compound according to claim 1, wherein R1 and/or R2 is H.
4. A compound according to any preceding claim, wherein R6 is N(Co-C2alkyl)S(=0)2Rc and Rc is Ci-C4alkyl, preferably methyl or isopropyl.
5. A compound according to any of claims 1-3, wherein R6 is NRaS(=O)2Rc, and Ra and Rc together with the atoms to which they are attached form a heterocyclic ring.
6. A compound according to any preceding claim, wherein one of X' and X" is OH.
7. A compound according to any preceding claim, wherein n is 0.
8. A compound according to any preceding claim, wherein n is 0 and Z is a bond.
9. A compound according to any preceding claim, wherein Z is O.
10. A compound according to any of the preceding claims, wherein Q is an optionally substituted 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
11. A compound according to any preceding claim, wherein Q is optionally substituted phenyl.
12. A compound according to any preceding claim, wherein Q is mono- or di- halophenyl, such as mono- or di- fluorophenyl or mono- or di-bromophenyl.
13. A compound according any of claims 1-10, wherein Q is optionally substituted pyridyl.
14. A compound according to any preceding claim, wherein p is 0.
15. A compound according to any preceding claim, wherein Y is NH.
16. A compound according to any preceding claim, wherein R and R are both H.
17. A compound according to any one of claims 1-15, wherein one of R3 and R3 is H and the other is CF3.
18. A compound according to any one of claims 1-15, wherein R3 and R3 together with the carbon atom to which they are attached form C3-C6cycloalkyl, preferably cyclopropyl.
19. A compound according to any one preceding claim, wherein W is C3-C6Cycloalkyl, such as cyclopropyl.
20. A compound according to any one of claims 1-18, wherein W is Ci-Cβalkyl, such as methyl, ethyl, isopropyl or t.butyl.
21. A compound according to any one of claims 1-18, wherein W is CF3.
22. A compound according to any preceding claim, wherein D is
Figure imgf000120_0001
23. A compound according to claim 22, wherein R7 is arylCi-C3alkyl such as phenylmethyl or 1-phenylethyl, or C5-C6heterocyclylCi-C3alkyl, and wherein the Ci-C3alkyl moiety and the phenyl or heterocyclyl ring is optionally substituted.
24. A compound according to any of claims 1-21, wherein D is R1
,N
-,10 V.
25. A compound according to claim 24, wherein A is N.
26. A compound according to claim 24 or 25, wherein R9 is Cs-CβcycloalkylCi-Csalkyl, and the cycloalkyl moiety is optionally substituted with Ci-C3alkyl.
27. A compound according to claim 24 or 25, wherein R9 is cyclopropylmethyl or 2- methylcyclopropylmethyl, and R10 is H or methyl.
28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of the preceding claims in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a therapeutically effective amount of a cholinesterase inhibitor or a muscarinic ml or m2 agonist in a pharmaceutically acceptable adjuvant, diluent or carrier.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a therapeutically effective amount of an N-methyl-D-aspartate receptor antagonist, gamma secretase inhibitor/modulator, HMG-CoA reductase inhibitor or a non-steroidal antiinflammatory agent.
31. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 27, for use in therapy.
32. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 27, in the manufacture of a medicament for use in the treatment or prevention of Alzheimer's disease.
33. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 27, for use in the treatment or prevention of Alzheimer's disease.
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Citations (5)

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WO2003040096A2 (en) * 2001-11-08 2003-05-15 Elan Pharmaceuticals, Inc. N, n'-substituted-1,3-diamino-2-hydroxypropane derivatives
WO2003043975A1 (en) * 2001-11-19 2003-05-30 Elan Pharmaceuticals, Inc. Amine 1,2- and 1,3-diol compounds and their use for treatment of alzheimer's disease
WO2003072535A2 (en) * 2002-02-27 2003-09-04 Elan Pharmaceuticals, Inc. Substituted hydroxyethylamines
WO2005065195A2 (en) * 2003-12-19 2005-07-21 Merck & Co., Inc. Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002512A2 (en) * 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Compounds to treat alzheimer's disease
WO2003040096A2 (en) * 2001-11-08 2003-05-15 Elan Pharmaceuticals, Inc. N, n'-substituted-1,3-diamino-2-hydroxypropane derivatives
WO2003043975A1 (en) * 2001-11-19 2003-05-30 Elan Pharmaceuticals, Inc. Amine 1,2- and 1,3-diol compounds and their use for treatment of alzheimer's disease
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