+

WO2008119773A1 - Amide derivatives as inhibitors of aspartyl proteases - Google Patents

Amide derivatives as inhibitors of aspartyl proteases Download PDF

Info

Publication number
WO2008119773A1
WO2008119773A1 PCT/EP2008/053767 EP2008053767W WO2008119773A1 WO 2008119773 A1 WO2008119773 A1 WO 2008119773A1 EP 2008053767 W EP2008053767 W EP 2008053767W WO 2008119773 A1 WO2008119773 A1 WO 2008119773A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
methyl
compound
nmr
mhz
Prior art date
Application number
PCT/EP2008/053767
Other languages
French (fr)
Inventor
Ingemar KVARNSTRÖM
Marcus BÄCK
Veronica Sandgren
Stefan Oscarson
Catarina BJÖRKLUND
Åsa ROSENQUIST
Bertil Samuelsson
Per-Ola Johansson
Ismet Dorange
Original Assignee
Medivir Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivir Ab filed Critical Medivir Ab
Publication of WO2008119773A1 publication Critical patent/WO2008119773A1/en

Links

Classifications

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

Definitions

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

Landscapes

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

Abstract

The invention provides compounds of the formula (I). N-oxides, addition salts, quaternary amines, metal complexes, stereochemically isomeric forms and metabolites thereof, wherein W is H,C 1-C 6 alkyl, C 3-C 6 cycloalkyl, aryl or heterocyclyl; Q is aryl or heterocyclyl; A is a five or six membered saturated, partially unsaturated or aromatic ring; D is (II) or (III) 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

AMIDE DERIVATIVES AS INHIBITORS OF ASPARTYL PROTEASES
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 causesthe production of the protein β amyloid (Aβ) in the brain, which is characteristic of Alzheimer's disease (AD).
AD is a progressive neurogdegenerative disease of the brain characterized by gradualloss of cognitive function related to memory, reasoning, orientation and judgement and eventually death. Pathologicalfeatures of AD is accumulation of abnormal aggregated protein breakdown products, 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 consists 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 nonpathogenic products known as soluble APP, whereas the β- secretase pathway producespathogenic 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 absenceof 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 reducethe 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 reversingthe 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.
Brief description of the Invention
In accordance with the present invention, there is provided aspartyl protease inhibitors which can be represented by the formula (I):
Figure imgf000003_0001
wherein
R2 is H or Ci-Cealkyl;
R is Ci-Cβalkoxy, Ci-CβalkoxyCi-Cβalkoxy, -O-Co-C^lkanediylaryl, -0-Co-
Csalkanediylheterocyclyl, azide, amine, S(=O)rCi-C6alkyl;
R is Ci-Cβalkyl and R is H; or R and R together with the carbonatom to which they are attached define C3-C6cycloalkyl;
R6 is hydrogen, Ci-C6alkyl,
Figure imgf000003_0002
-C6alkyl, N(Ra)S(=O)rNRaRb, S(=O)rCi-C6alkyl, halo or cyano;
Figure imgf000003_0003
, hydroxyCi-C3alkyl, Ci-C3alkanediylNRaRb, aryl, heterocyclyl, C3-C6cycloalkyl, Ci-C3alkanediylC3-C6cycloalkyl, Ci-C3alkanediylaryl, Ci- C3alkanediylheterocyclyl, Ci-C3alkanediyl-0-Co-C3alkanediyl aryl or Ci-C3alkanediyl-O-C0- C3alkanediyl heterocyclyl; wherein the Ci-C3alkanediylmoietyis optionally substituted with Ci-Cβalkyl; R8 is H, Ci-Cealkyl; or
R and R together with the N atom to which they are attached define a heterocyclyl group; R9 is H, Ci-Cioalkyl, C2-Ci0alkenyl, C2-Ci0 alkynyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C3alkyl, Ci- C6alkoxyCi-C6alkoxyCo-C3alkyl Ci-CioalkanediylC3-C6cycloalkyl, Ci-Cioalkanediylaryl or Ci- Cio alkanediylheterocyclyl;
E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)-, -CH(Rd)-NRd-, -NRd-NRd-, -CH(Rd)-O-, -0-CH(Rd)- -CH(Rc)-, -NRe-, or -O-; Q is aryl or heterocyclyl;
W is H, Ci -Cβalkyl, C3-C6cycloalkyl, aryl or heterocyclyl; X' is H, F, OH, or NRaRb; X" is H or when X' is F, X" can also be F;
Y is H, Ci-Cealkyl, C0-C3alkanediylaryl, C0-C3 alkankediylC3-C6cycloalkyl or C0- C3 alkankediylheterocyclyl; Z is O, S(=O)r or NRa; ring A is a saturated, partially unsaturated or aromatic ring; m is O or 1 , wherebyring A defines a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or a phenyl ring; n is O, 1, 2 or 3; p is 0 or 1 ; q is 0, 1 or 2; thereby defining a bond, methylene or ethylene, or when q is 1, the methylenemay alternatively be a 1 , 1 -cyclopropyl group; r is 0, 1 or 2;
Ra is independently H or Ci-Cβalkyl;
Rb is H or Ci-Cβalkyl; or Ra and Rb together with the nitrogen atom to which they are attached define a heterocyclyl group;
Rc is H, Ci-Cyalkyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C3alkyl, Ci-C6alkoxyCi -C6alkoxy, hydroxyCo-Csalkyl or C0-C3 alkanediy INRaRb, O-Ci-C5alkanediylC3-C6cycloalkyl; Rd is H, Ci-Cvalkyl, Ci-C6alkoxyCi-C3alkyl, Ci-C6alkoxyCi-C6alkoxyCi-C3alkyl, hydroxyCi- C3alkyl or Ci-C3alkandiylNRaRa;
Re is H, Ci-CiOalkyl, C2-Ci0 alkenyl, C2-Ci0alkylnyl, Ci-Ci0alkoxy or Ci-Ci0alkanediylC3- Cβcycloalkyl; or Re and R together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted with Ci-CiOalkyl, C2-Ci0alkenyl, C2- Cioalkylnyl, C3-C6cycloalkyl, C0-C3alkanediylaryl or C0-C3 alkanediylheterocyclyl; where aryl is independently phenyl, naphthyl or phenyl fused to Cs-Cβcycloalkyl or Cs- Cβcycloalkenyl; aryl is phenyl, naphthyl, or phenyl fused to Cs-Cβcycloalkyl or Cs-Cβcycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; and whereineach occurrence of Ci-Cβalkyl, C2-C6alkenyl, C2-Cβalkynyl, Cs-Cβcycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as alkoxy or alkanediylaryl) is optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl , amino, carbamoyl, amido and Ci- C4alkoxyamido), C2-C6alkenyl, C2-Cβalkynyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- Csalkyl, Ci-C4alkoxyCi-C6alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, Ci- C4alkylcarbonyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co-C3alkanediylC3-C6cycloalkyl, Co-C3alkanediylaryl , Co-C3alkanediylheterocyclyl , C2-C3alkenediylC3-C6cycloalkyl, C2-C3alkenediylaryl , C2-C3alkenediylheterocyclyl , C2- C3alkynediylC3-C6cycloalkyl, C2-C3alkynediylaryl , C2-C3alkynediylheterocyclyl ; and wherein each occurrence of the Ci-Cioalkyl, C2-Cioalkenyl, C2-Cioalkynyl, Ci -C 10 alkoxy or Ci- CioalkanediylC3-C6cycloalkyl moieties are optionally substituted with 1, 2 or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, aryl, heterocyclyl, C3- Cβcycloalkyl, C1-C10 alkoxy, haloCi-C4alkyl, halo, hydroxy, cyano, amino, and a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; and whereineach occurrence of aryl and heterocyclyl above (including those in composite expressions such as alkanediylaryl and alkanediylheterocyclyl ) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, halo and haloCi-C4alkyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
As indicated above, D is
Figure imgf000005_0001
Consequently, according to some embodiments of the invention, compounds are included wherein D is YCH(R9)E, thus giving compounds according to formula Iaa.
Figure imgf000006_0001
Accordingto other embodiments of the invention, compounds are included whereinD is (R )(R )NC(=O), i.e an amide moiety, thus giving compounds according to formula laa'.
Figure imgf000006_0002
The compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excessof 95%, enantiomeric purity at each of the chiral centres. In typical embodiments of the invention, the chiral centre whereto the group R is attached has the stereochemistry shown in the partial structure:
Figure imgf000006_0003
Accordingto preferred embodiments of the invention, Z is O.
According to other embodiments Z is NRa, whereinRa is hydrogen or Ci-C3alkyl, preferably hydrogen or methyl.
The group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively. 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 aryl or heterocyclyl, which is optionally substituted with one, two or three substituents as defined above. Accordingto some embodiments of the invention Q is an optionally substituted bicyclic aryl or heterocyclyl moiety. Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl.
Accordingto other embodiments 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 monocyclicheterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
Preferably Q is an optionally substituted monocyclicring, such as an optionally substituted 5 or 6-membered aryl or heterocyclyl,preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
Representative values for the optional substituents to Q include one or two substituents independently selected from Ci -C4alkyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-C3alkoxyCi- Cβalkoxy, halo, haloCi-C4alkyl and Ci-C3alkanediylaryl, Currently favoured values include halo such as mono- di or trifluoro, chloro and bromo; and haloCi-C4alkyl for example trifluoromethyl.
Accordingto some embodiments of the invention Q is a monosubstituted 6-membered aryl or heterocyclyl, wherein the substituent preferably is in the meta or para position. In a preferred configuration according to this embodiment, Q is meta or para substituted phenyl. Preferred substituents according to this embodiment include bromo and fluoro.
Accordingto further embodiments, Q is disubstituted phenyl with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position. Preferred substituents to Q according to this embodimentare independently chloro, fluoro, bromo and methyl.
Currently favoured configurations for Q include optionally substituted phenyl, such as bromosubstituted phenyl and mono-, di- or trifluoro substituted phenyl, especially difluorosubstituted phenyl and monobromo substituted phenyl.
R2 is Ci-Cβalkyl such as methyl or ethyl, or preferably R2 is hydrogen. The chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
X" X' X' and X" are as defined above, preferably X' is fluoro, or more preferably hydroxy.
In an alternative embodimentof the invention X' and X" are both fluoro.
In typical embodiments of the invention, the chiral centre wheretothe group R is attached has the stereochemistry shown in the partial structure:
Figure imgf000008_0001
R3 is as defined above. Typical values for R3 include optionally substituted CrC6alkoxy such as optionally substituted methoxy, ethoxy and propoxy.
Preferably R3 is Q-Cgalkoxy, especially methoxy.
Further typical values for R3 include optionally substituted Ci-C6alkoxy-CrC6alkoxy such as optionally substituted methoxypropoxy and methoxyethoxy. Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di and trifluoro.
The invention includes compounds of general formula (I) whereinp is 0 or 1, i.e. compounds according to structures (Ia) and (Ib) respectively:
H
Figure imgf000008_0002
Ia Ib
The invention further includes compounds wherein both p and q are 0, i.e. compounds according to the structure (Ic):
Figure imgf000009_0001
In compounds of formula (Ib), i.e. whereinp is 1, the chiral centre wheretoR4 and R4 are attached typically has the configuration shown in the partial structure below.
Figure imgf000009_0002
Thus, when R is hydrogen, the configuration typically corresponds to that of an L- amino acid
Preferably R is Ci-C6alkyl, such as isopropyl.
R is preferably hydrogen.
Preferred compounds of formula (I) are those having the stereochemistry indicated in formula
(Id):
Figure imgf000009_0003
Accordingto some embodiments of the invention ring A in general formula (I) is a six membered ring, i.e. m is 1. Representative values for ring A according to these embodiments include cyclohexyl and phenyl, preferably phenyl.
According further embodiments of the invention ring A is a five membered ring, i.e. m is 0. Preferred values for ring A according to these embodiments include cyclopentenyl and cyclopentyl, preferably cyclopentyl.
In embodiments of the invention whereinring A is cyclopentyl, the stereochemistry is typically as indicated in the partial structures below:
Figure imgf000010_0001
The chiral centre to which R > 6 attached has typically the configuration as shown in the partial structure below:
Figure imgf000010_0002
R6
R6 is as defined above, typical values for R6 include N(Co-C2alkyl)S(=0)2Ci -C4alkyl, preferably NHS(O)2CH3.
Further typical values for R include hydrogen and Ci-Cβalkyl, especially hydrogen or methyl.
As indicated above, D is
Figure imgf000010_0003
or
R is as recited above. Typical values for R include Ci-Cβalkyl, Ci-C3alkanediylaryl or Ci- Csalkanediylheterocyclyl, wherein each Ci-Cβalkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi- C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
A further favoured configuration for R includes Ci-C3alkanediylaryl, whereinthe C1- Csalkanediyl moiety is optionally substituted with R , preferred values for R include C1- C4alkyl, such as ethyl or preferably methyl.
Currently favoured values for R include benzyl, 1-phenylethyl and 1-phenylpropyl, especially benzyl and 1-phenylethyl, wherein the phenyl ring is optionally substituted. Preferably the substituent(s) are in the para and/or ortho position of the phenyl ring.
Favoured compounds according to this embodiment include those having the partial structures shown below:
Figure imgf000011_0001
A further configuration for R include Ci-C3alkandiylaryl and Ci-C3alkanediylheterocyclyl, wherein the Ci-C3alkandiyl moiety is optionally substituted with Ci-Cβalkyl. Preferred configurations for the Ci-Cβalkyl according to this embodiment include Ci-C4alkyl such as methyl or ethyl; haloCi-C4alkyl, such as trifluoromethyl and C3-C4cycloalkyl such as cyclopropyl.
The optional substituents to the aryl, heterocyclyl and alkyl moieties of R7 are as defined above. Representative values include one or two substituents independently selected from Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C4alkyl such as fluoromethyl and trifluoromethyl; and cyano.
Further typical values for R include a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms. Preferred configurations for such a chain include Cs-Cyalkyl, Ci-C3alkoxy-Ci-C3alkoxy, such as methoxyethoxy, or Ci-C3alkoxy- Ci-C3alkyl, such as 3-methoxypropyl or 2-methoxyethyl
R is as recited above, preferably hydrogen or methyl.
A further embodimentof the invention include compounds of formula (I) wherein R and R together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl group, for example optionally substituted pyrrole, piperidine or morpholine.
Accordingto a further embodimentof the invention, R and R are both Ci-Cβalkyl, such as ethyl, propyl or butyl.
Link E between ring A and the unit CH(Y)(R7R9) is as defined above.
Accordingto some embodiments of the invention, the link E is -CH(Rc)-, -NRe- or -O-, in which case the compounds of the invention have one of the partial structures:
Figure imgf000012_0001
wherein Rc, Rd, R and Y are as defined above.
Preferably, one of R9 and Rc in formula (Ha), one of R9 and Re in formula (lib) and R9 in formula (lie) is a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms. Preferred configurations for such a chain include C5-C7alkyl, Ci-C3alkoxy-Ci-C3alkoxy, such as methoxyethoxy, or Ci-C3alkoxy-Ci-C3alkyl, such as 3- methoxypropyl or 2-methoxyethyl. The other one of Rc and R9 in formula Ha and Re and R9 in formula lib is preferably hydrogen or methyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
Typical configurations for partial structure (Ha) include those wherein Rc is Ci-C6alkoxy, O-Ci- C6alkanediylC3-C6cycloalkyl, O-Ci-C6alkanediylaryl or O-Ci-C6alkanediylheterocylyl wherein the cycloalkyl, aryl or heterocyclyl moiety is optionally substituted, R9 is hydrogen or Cr C6alkyl such as methyl, and Y is C0-C3alkanediylaryl or C0-C3alkanediylheterocyclyl wherein the aryl and heterocyclyl moieties are optionally substituted as defined above.
In a further typical configuration for partial structure (Ha), Rc is hydrogen, R is C1 -Qalkoxy, O- C1 -C6 alkanediylC3-C6 cycloalkyl, O-CrC6alkanediylaryl or O-CrC6alkanediylheterocylyl wherein the cycloalkyl, aryl and heterocyclyl moiety is optionally substituted, and Y is C0- C3alkanediylaryl or C0-C3alkanediylheterocyclyl wherein the aryl and heterocyclyl moieties are optionally substituted as defined above.
Typical configurations for partial structure (lib), include those wherein Re and R are independently selected from Ci -CiOalkyl, Q-Qoalkenyl, C2-Ci0alkylnyl, CrCi0alkoxy and C1- C io alkanediylC3-C6 cycloalkyl, any of which is optionally substituted as defined above. Typical substituents for these configurations of (lib) include halo, hydroxy, phenyl, CrCi0alkoxy and amino. Accordingto these configurations for partial structure (lib), Y is preferably H.
Preferred values for Re in partial structure (lib) include hydrogen and optionally substituted C1- CiOalkyl; R in partial structure (lib) is preferably Ci-C3alkyl, or Ci-C3alkyl substituted with C3- C6 cycloalkyl, aryl or heterocyclyl; whereinthe C3-C6cycloalkyl, aryl or heterocyclyl is optionally substituted with C i-Qalkyl or halo; and Y is preferably H. Further typical configurations for partial structure (lib), include those wherein R and Re together with the atoms to which they are attached form a 4-6 membered heterocyclic ring, which ring is optionally substituted as defined above, thus giving the partial structures:
subst
Figure imgf000013_0001
Figure imgf000013_0003
Figure imgf000013_0002
According further embodiments of the invention, E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)- CH(Rd)-NRd-,, NRd-NRd-, -CH(Rd)-O- or -0-CHRd-, in which case compounds of the invention have one of the partial structures:
Figure imgf000013_0004
wherein Rc, Rd, R » 6 , r R. 9 and Y are as defined above.
Conveniently, one of the moieties Rc, Rd and R in each of the above partial structures is a carbon chain which chain is optionally interrupted by one or two oxygen atoms. Preferably the chain length is 5, 6 or 7 atoms. Preferred configurations for such a chain include Ci-C3alkoxy- Ci-C3alkoxy, such as methoxyethoxy, or Ci-Csalkoxy-Ci-Csalkyl, such as 3-methoxypropyl or 2-methoxyethyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
Typical configurations for partial structure (Hi) include those whereinRd is hydrogen, R9 is C1- Cβalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-CβalkanediylCs-Cβcycloalkyl, Ci-Cβalkanediylaryl or Ci-Cβalkanediylheterocyclyl, any of which is optionally substituted as described above. Y is typically Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl. A currently preferred value for E according to this embodiment is -CHRc-CHRc- i.e. corresponding to partial structure (Hd), wherein one Rc is H or methyl and the other is H or Ci- Csalkoxy Ci-Cβalkoxy such as 2-methoxyethoxy or 3-methoxypropoxy. Preferably according to this embodiment, R is phenyl and Y is hydrogen.
A preferred embodimentof the invention includes compounds of formula (I) comprising any of the partial structures:
Figure imgf000014_0001
A further preferred value for E is -CH(Rd)-NRd-, i.e. corresponding to partial structure (Uf), wherein one of the Rd is CrC6alkyl or Q-Qalkoxy-Q-Qalkyl, such as 3-methoxypropyl or 2- methoxyethyl and the other is hydrogen or methyl.
As recited above, Y is hydrogen, CrC6alkyl, C0-C3alkanediylC3-C6cycloalkyl, C0- C3alkanediylaryl or C0-C3alkanediylheterocyclyl, wherein each Ci-C6alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCrC4alkyl, CrC4alkyl, CrC4alkoxy, hydroxy and cyano.
Preferred values for Y include hydrogen, CrC6alkyl especially methyl, ethyl or isopropyl; optionally substituted C0-C3alkanediylaryl or C0-C3alkanediylheterocyclyl,such as optionally substituted phenyl, optionally substituted benzyl or optionally substituted pyridyl.
The optional substituents to Y are as defined above. Representative values include CrC4alkyl such as methyl; halo such as fluoro; haloCrC4alkyl such as fluoromethyl and trifluoromethyl; and cyano.
In embodiments wherein, in the definition of Y, the aryl or heterocyclyl moiety of of C0- C3alkanediylaryl or C0-C3alkanediylheterocyclyl is a substituted 6-membered ring, the substituent(s) are conveniently in the para and/or ortho position. Currently favoured configurations for Y according to this embodiment include phenyl or pyridyl which is substituted in the para position. The group W is bonded either directly to the amide nitrogen, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively. In favoured embodiments of the invention W is bonded directly to the amide nitrogen or via a methylene moiety, i.e. q is 0 or 1 respectively.
Alternatively, when q is 1, the moiety linking W to the amide nitrogen may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
Figure imgf000015_0001
Preferred compounds according to this embodiment include those whereinp is 0 and W is phenyl or substituted phenyl, as shown in the structure below:
Figure imgf000015_0002
As stated above, W is hydrogen, CrC6alkyl, C3-C6cycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
Accordingto some embodiments of the invention, W is optionally substituted Ci -C6alkyl such as methyl, ethyl or isopropyl. Preferred substituents to W according to these embodiments include halo such as mono-, di- or trifluoro.
Accordingto further embodiments of the invention W is an optionally substituted bicyclic aryl or heterocyclyl moiety. Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl.
Accordingto furthther embodiments of the invention, W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, C3-C6cycloalkyl 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 monocyclicheterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted. Preferably, W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl.
A further preferred value for W is cycloalkyl such as cyclopropyl.
In embodiments wherein W is a substituted 6-membered ring, the ring is preferably mono substituted with the substituent in the meta or para position. Preferred configurations according to this embodimentinclude meta or para substituted phenyl, for example /?-fluoro phenyl.
In embodiments wherein the ring W is disubstituted the substituents are preferably in the two meta positions or in the meta and para positions.
Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C3 -C4 cycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C4alkyl such as methyl, ethyl and isopropyl.
It is to be understood that the above defined subgroups of compounds of formulae (I) are meant to also comprise any prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds.
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 'Ci-C4alkyl' as a group or part of a group defines saturated straight or branched chain hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2 -propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl;
'Ci -CβalkyP encompasses Ci-C4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-l- butyl, 2 -methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like. Of interest amongst Ci-Galkyl is Ci-C4 alkyl.
'Ci -Cnalkyl' whereinn is 7, 8, 9 or 10, encompasses Ci-Cβalkyl radicals and the higher homologues thereof having 7, 8, 9 or 10 carbon atoms. The term 'C2-C6alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one carbon-carbon double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1 - propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest amongst C2-C6alkenyl is C2-C4alkenyl.
'C2-Cnalkenyl' whereinn is 7, 8, 9 or 10, encompasses C2-C6alkenyl radicals and the higher homologues thereof having 7, 8, 9 or 10 carbon atoms.
The term 'C2-C6alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbonbonds and at least one carbon-carbon triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2- propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. Of interest amongst C2-C6alkynyl is C2-C4alkynyl.
'C2-Cnalkynyl' whereinn is 7, 8, 9 or 10, encompasses C2-C6alkynyl radicals and the higher homologues thereof having 7, 8, 9 or 10 carbon atoms.
The term C3-Cncycloalkyl means a non aromatic all carbonring comprising 3 to n carbon atoms, wherein n is 3, 4 or 5, i.e. cyclopropyl, cyclobutyl or cyclopentyl. The cycloalkyl may optionally be substituted with one or two substituents independently selected from Ci-C3alkyl, C2- Csalkenyl, C2-C3alkynyl and halo.
'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.
'C1 -C3alkanediyl' is a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,2-propanediyl, and the like, especially methylene.
'Co-Cnalkanediyl' whereinn is 4, 5, 6, 7, 8, 9 or 10, encompasses Co-C3alkanediyl and the higher homologues thereof having 4, 5, 6, 7, 8, ,9 or 10 carbon atoms.
'C2-C3alkenediyl' defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1,2-propenediyl, and the like, especially vinyl ene. 'C2-C3 alkynediyl' defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
'Ci -Cβalkoxy' means a radical O-Ci-Cβalkyl whereinCi-Cβalkyl is as defined above. Ci -Cβalkoxy of interest include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy.
The term 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
The term 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of haloCi-Cβalkyl, the halogen atoms may be the same or different.
As used herein, the term '(=0)' 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, NHCi-Cβalkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-Cβalkyl is especially Ci -CA alkyl variants. Included are also radicals whereinthe two Ci-Cβalkyl groups of the N(C1- Cβ-alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
'Carbamoyl' includes C(=0)NH2, and mono- and dialkylcarbamoyl, such as C(=O)NHCi -C6 alkyl and C(O)N(C i-C6alkyl)2, especially C(=O)NHCrC4alkyl and C(O)N(Ci-C4alkyl)2. Included are also radicals wherein the two Ci-Cβalkyl groups of the dialkylcarbamoyl together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl .
'Amido' includes NHC(=O)H, alkanoylamino such as NH(C=O)C i-C6alkyl especially NH(C=O)C i-C4alkyl, and N-alkyl alkanoylamino such as N(Ci-C6alkyl)(C=O)CrC6alkyl especially N(Ci-C4alkyl)(C=O)Ci -C4alkyl. The term 'alkoxyamido' is meant to include NHC(=O)Ci-C6alkoxy, such as tert.butoxycarbonylamino.
'Co-C3alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-Cβcycloalkyl (for example indanyl), or a Cs-Cβcycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1 ,3 -propanediyl group as defined for Ci-C3alkanediyl above. 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 one, two or where valence allows three substituents independently selected from Ci -Galkyl (optionally substituted with one or two substituents independently selected from Co- C3alkanediylaryl*, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-C6alkenyl, C2- Cealkynyl, C3-C6 cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C6alkoxyCo- C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-Qalkyl, carbamoyl, amido, cyano, azido, nitro, Ci-Cβalkylcarbonyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), oxo, mercapto, Co-C3alkanediylC3- Cycarbocyclyl, Co-C3alkanediylaryl*, Co-C3alkanediylheterocyclyl*, C2-C3alkenediylC3- Cycarbocyclyl C2-C3alkenediylaryl*, C2-C3alkenediylheterocyclyl*, C2-C3alkynediylC3- Cycarbocyclyl C2-C3alkynediylaryl*, C2-C3alkynediylheterocyclyl*, whereinthe asterisked aryl or heterocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino . 'Aryl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
'C2-C3alkenediylaryl and 'C2-C3 alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C2-C3alkenediyl' and 'C2_c3alkynediyl
'Co-C3alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, triazinyl, 1,4-dioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo-l,2,3-triazolyl, benzo-l,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl etc, Said heterocyclyl is bonded either directly (i.e. Co), or through an intermediate methylene, ethylene or propanediyl group as defined for Ci-C3alkanediyl above. Unless otherwise indicated the ring system is optionally substituted with one, two or where valence allows three substituents independently selected from Ci -C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl*, amino, carbamoyl, amido and C1- C4alkoxyamido), C2-C6alkenyl, C2-C6alkynyl, Cs-Cβcyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- Csalkyl, Ci-C4alkoxyCi-C6alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, nitro, Ci-Cβalkylcarbonyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), oxo, mercapto, Co-C3alkanediylC3-Cycarbocyclyl, Co-C3alkanediylaryl*, Co- C3alkanediylheterocyclyl*, C2-C3alkenediylC3-Cycarbocyclyl C2-C3alkenediylaryl*, C2- C3alkenediylheterocyclyl*, C2-C3alkynediylC3-C7carbocyclyl C2-C3alkynediylaryl*, C2- C3alkynediylheterocyclyl*, wherein the asterisked aryl or heterocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino .. 'Heterocyclyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
C2-C3alkenediylheterocyclyl and 'C2-C3alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C2-C3alkenediyl' and 'C2-C3alkynediyl
'Heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
Typically aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclicring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
'Co-C3alkanediylC3-C6cycloalkyl' as applied herein is meant to include a C3-C6cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2 -propanediyl or 1,3- propanediyl group as defined for Ci-C3alkanediyl above. The cycloalkyl group may contain an unsaturated bond. Unless otherwise indicated the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl*, amino, carbamoyl, amido and C1- C4alkoxyamido), C2-C6alkenyl, C2-C6alkynyl, C3-C6cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- C3alkyl, Ci-C4alkoxyCi-C6alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, nitro, Ci-Cδalkylcarbonyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), oxo, mercapto, Co-C3alkanediylC3-Cycarbocyclyl, Co-C3alkanediylaryl*, Co- Csalkanediylheterocyclyl*, C2-C3alkenediylC3-Cycarbocyclyl C2-C3alkenediylaryl*, C2- C3alkenediylheterocyclyl*, C2-C3alkynediylC3-Cycarbocyclyl C2-C3alkynediylaryl*, C2- C3alkynediylheterocyclyl*, wherein the asterisked aryl or heterocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino . 'Cs-Cβcycloalkyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
'C2-C3alkenediylC3-C7carbocyclyl and 'C2_c3alkynediylC3-C7carbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C2_c3alkenediyr and 'C2-C3alkynediyl
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.
Whenever used hereinafter, the term 'compounds of formula (I)', or 'the present compounds' or similar terms, it is meant to include the compounds of formula (I), their prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemical^ isomeric forms.
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 parentcompound. Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group. An in vivo hydrolysableester is an ester, which is hydrolysed in the human or animal body to produce the parentacid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci-Cδalkoxymethyl 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-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysableester of a compound of the formula (I) containinga hydroxy group includes inorganic esters such as phosphate esters and 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 hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy acetyl. 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 whereinthe 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 mentionedhereinabove are meant to comprise the therapeuticallyactive non -toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic),malonic, succinic (i.e. butanedioicacid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methane sulphonic, ethanesulphonic, benzenesulphonic,/?-toluenesulphonic, cyclamic, salicylic, /^-aminosalicylic, pamoic acids and the like. Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
The compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
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. Pharmaceuticallyacceptable counterions include chloro, bromo, iodo, trifluoroacetate 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) whereinone or several nitrogen atoms are oxidized to the so-called iV-oxide.
The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre. The presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof. Pure stereoisomeric forms of the compounds and intermediates as mentionedherein are defined as isomers substantially free of other enantiomeric or diastereomericforms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excessof 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excessof 90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomericexcess, 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 diastereomericmixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species. 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 stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically . When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecifϊc 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 invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof. One embodimentcomprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as theiV-oxides, salts, as the possible stereoisomeric forms thereof.
The invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I) .
The invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament. 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 stereochemically isomeric form thereof in therapy.
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 compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as BACE.
The invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof. A therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
The invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N -oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
The compounds of the present invention are also useful for the inhibition of BACE activity. Accordingly, a further embodimentof the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
The compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease. 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 mentioneddiseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
For the above -mentionedtherapeutic 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 stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 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.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove. Additionally, the compounds of the present invention may be used in combination with one or more other pharmacological agents that treat, prevent, control ameliorate or reducethe risk for side effects or toxicity of the compounds of the present invention. Such other pharmacological agents may be administered, by route and in amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more active ingredients, in addition to the compounds of the present invention. The combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol whereinone or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
The present invention is also directed to combinations of the compounds of the invention with one or more pharmacologically active agents useful in the treatment and/or the prophylaxis of Alzheimer's disease. Examples of combinations include combinations with anti -Alzheimer's agents, for example other BACE inhibitors or γ-secretase inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies, including anti- amyloid humanized monoclonal antibodies; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonists; neuronalnicotinic agonists; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduceunwanted 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.
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.
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.
Scheme 1 illustratesa synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
Figure imgf000029_0001
oxy-C-i-Cealkyl , CrC3alkanediylaryl or yl;
Figure imgf000029_0002
Scheme 1
The isopropylidene derivative (Ia) achieved for example as described in Tetrahedron lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid, such as sulphuric acid, in the presence of methanol. The achieved free secondary hydroxy group can then be transformed into a desired group R3. For example, compounds wherein R3 is an O-linked substituent can be prepared by alkylation of the hydroxy group, effected for example by treatment with a suitable alkylating agent such as an alkyl halide like, methyl iodide, in the presence of a base like silver oxide thus giving the ether derivative (Ic). Hydrolysis of the methyl glycoside by treatment with sulphuric acid followed by oxidation of the formed alcohol effected by any convenient oxidation reagent, for example pyridinium dichromate or mCPBA, affords the lactone (Id). Removal of the benzyl groups using any suitable conditions well known to the skilled person, such as catalytic hydrogenation, provides the diol (Ie).
Further intermediate lactones, useful for the preparation of compounds of formula (I) whereinR3 is azide, amine, alkylthio or alkoxy can be prepared by first inverting the stereochemistry of the steric center wheretothe hydroxy group is attached, and then replace the hydroxy group with the desired group as shown in scheme IA.
Figure imgf000030_0001
Scheme IA
Inversion of the stereochemistry of the alcohol (Ib) can be effected for example by subjecting the alcohol to Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence Of Ph3P and for instance p-nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like. The afforded alcohol (IAa) with the reversed stereochemistry can then be reacted in a Mitsunobu reaction with azide like sodium azide or DPPA or the like, to give lactones (IAb) whereinR is azide or the alcohol can be reacted with a thiol or alcohol to give alkylthio and alkoxy derivatives respectively. Lactones (IAb) whereinR3 is amine are conveniently achieved by reduction of the previously described azide derivative for example by treatment with Ph3P or by catalytic hydrogenation using a catalyst like Lindlar's catalyst, or alternatively, the Gabriel synthesis may be used, i.e. reaction of the alcohol (IAa) with phthalimide followed by hydrolysis of the phthalimido group effected for example by treatment with hydrazine hydrate or the like. If desired, the afforded primary amine can then be alkylated, conveniently by a reductive amination with a suitable aldehyde or ketone using conditions known to the skilled person, or by reaction with an alkylating agent Ra-Lg, whereinLg is a leaving group, optionally in the presence of a base. Hydrolysis of the methyl glycoside, oxidation and removal of the benzyl groups as described above, then provides the lactone.
Lactones obtained as described in scheme 1 and IA, can then be further reacted as shown in scheme 2 to yield a linear amine which is another versatile intermediate useful for the preparation of compounds of formula (I) whereinn is 1 and Z is O.
Figure imgf000031_0001
Lg is a leaving group
2e 2F
Scheme 2
The primary hydroxy group of the lactone (2a) can be selectively alkylated for example by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-CH2 -Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide, in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2b). Alternatively, the substituent Q-CH2n can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1 -28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al, Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705- 4706) i.e. reaction of the primary hydroxy group of the diol (2a) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol. Replacement of the secondary hydroxy group of the alcohol (2b) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate sulphonic anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the formed leaving group with azide for example sodium azide, thus giving the azide derivative (2c). The linear compound (2e) can then be achieved by opening of the lactone with a desired amine (2d) in the presence of for example 2-hydroxypyridineand a base like isopropyl diethylamine. Reduction of the azide using conditions compatible with the Q-CH2n group, for example hydrogenation at atmospheric pressure in the presence of Lindlar 's catalyst, or treatment with Ph3P, then provides the amine (2f).
A linear intermediate amine whereinthe group Q is bonded directly to the oxygen atom, useful for the preparation of compounds of formula (I) whereinZ is O and n is O, can be prepared as shown in scheme 2A.
Figure imgf000032_0001
as above
Figure imgf000032_0002
2Ac
Scheme 2 A
Treatment of the diol (2a) with triphenylphosphine and an azodicarboxylate for example DIAD provides the epoxide (2Aa). Opening of the epoxide with a desired nucleophileQ-OH in the presence of a base, such as potassium carbonate or the like, provides the ether derivative (2Ab). Subsequent replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, provides the linear amine (2Ac).
Lactones useful for the synthesis of compounds of formula (I) whereinZ is S or NH and n is 1 , can be prepared from the diol 2a for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
Figure imgf000032_0003
Scheme 2B
The primary hydroxy group of the lactone (2a) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-CH2-S or Q-CH2-NRa. A convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (2Bb) or the amine derivative (2Bc) respectively. Alternatively, the amine (2Ac) may be achieved by using an azide derivative, such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (2a), followed by reduction of the azide to the primary amine and subsequent alkylation of the amine with a suitable alkylating agent Q-CH2-Lg, or by performing a reductive amination with a suitable aldehyde Q-CH(=O). An alternative method to obtain the amino derivative (2Bc) is to selectively oxidize the primary hydroxy group of the alcohol (2a) to the corresponding aldehyde, effected for example by treatment with Dess -Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-CH2- NHRa in the presence of a reducing agent like NaCNBH3. Replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, then provides the linear amines (2Bd and 2Be).
Intermediates for the preparations of compounds of formula (I) whereinthe group Q is linked directly to a sulphur or nitrogen atom, i.e. Z is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (2a) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base. An alternative method for the preparation of compounds whereinZ is S and n is 0 is to react the diol (2a) with a desired diphenyl disulphide derivative in the presence of nBu3P. Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (2a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH4 or the like.
Compounds of formula (I) whereinZ 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.
The group Q-(CHz)n can alternatively be introduced prior to introduction of the group R3, as shown in scheme 3.
Figure imgf000034_0001
Figure imgf000034_0002
Scheme 3
Selectivealkylation of the primary alcohol of the diol (3a) for example by activation with dibutyltin oxide and subsequent displacement with the desired group Q-CH2-Lg as described above, provides the ether derivative (3b) whereinn is 1, whereas treatment of the diol (3a) with Ph3P and DIAD or the like followed by opening of the afforded epoxide with a desired nucleophilein the presence of a base such as K2CO3 as described above, provides the ether derivative (3b) whereinn is O. Displacement of the secondary alcohol with azide as described in scheme 2 provides the azide derivative (3c). Hydrolysis of the acetal followed by introduction of the group R3 and finally hydrolysis of the methyl glycoside and oxidation as described in scheme 1 and IA, provides the lactone (3f).
Amino derivatives used for the opening of the lactone in scheme 2 are available commercially or they can easily be prepared by the skilled person according to literature procedures. Amines useful for the preparation of compounds of the invention wherein p is 1, are conveniently prepared from the appropriate amino acid for example as illustrated in scheme 4.
Figure imgf000034_0003
4a 4b
Scheme 4 The amino acid (4a), carrying the desired side chain R4 and R4 , can be coupled to the amine W- (CH2)q-NH2 using any convenient method for peptide coupling known in the art. For example, a coupling agent like HATU or isobutylchloro formate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used. Subsequent removal of the N-protecting group using the appropriate conditions according to the protecting group used, such as acidic treatment in the case of a Boc -group, provides the amine (4b).
An alternative route to linear amines whereinn is 1, is shown in scheme 5.
Pg1 Pg1
OH R3 H o P 2) BOC2° H OH R3 H Q P
5a 5b
Figure imgf000035_0001
group , OH, SH or NHRa orthogonal protecting g roups
Figure imgf000035_0002
5B
Scheme 5
The azide derivative (5a), prepared for example as outlined in scheme 2, wherein Pg1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlar's catalyst or the like in the presence of BoC2O to provide the boc protected amino derivative (5b). Protection of the secondary hydroxy group, using a protecting group (Pg2) which is orthogonal to the one used for the primary hydroxy group (Pg1) followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group, provides the primary alcohol (5c). Suitable protecting groups for the above route will be recognized by skilled person and a numerous of useful protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981). For example benzyl can be used as Pg1 and acetyl as Pg2.
The group CH2-Q can then be introduced as described above. For example, compounds wherein Z is O and n is 1 can be prepared by reaction of the primary alcohol (5 c) with an alkylating agent Q-CH2-Lg whereinLg is a halide like a bromide, chloride or iodide or a derivative of sulphonic acid such as a triflate or mesylate or the like in the presence of a base like NaH or the like, or a trichloroacetimidate of a desired group, Q-CH2-O-C(=NH)CCl3 may be reacted with the primary alcohol (5c) in the in the presence of a Lewis acid such as BFsOEt2. Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH. Compounds wherein n is 1 and Z is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (5 c) with a desired alcohol, Q-CH2-OH, thiol, Q- CH2-SH or amine Q-CH2-NHRa respectively.
Compounds of formula (I) whereinn is O and Z is O, S or N may be prepared by transforming the primary hydroxy group of the alcohol (5c) to a leaving group for example a derivative of sulphonic acid such as a halide like a chloride or bromide or to a derivative of sulphonic acid such as triflate, tosylate or the like which subsequently is displaced by a desired alcohol Q-OH, thiol Q-SH or amine Q-NHRa optionally in the presence of a base, for example as described hereinabove. An alternative method for the preparation of compounds wherein Z is S and n is O is to react the alcohol (5 a) with a desired derivative of diphenyl disulphide in the presence of nBusP. Compounds whereinZ is NRa and n is O may alternatively be achieved by oxidation of the hydroxy group of the alcohol (5a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH4 or the like. Removal of the Boc group according to standard procedures such as treatment with an acid, for example TFA, followed by removal of the hydroxy protecting group using the appropriate conditions, then provides the amine (5e).
Scheme 6 illustratesan example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) whereinQ is phenyl substituted with an alkoxy-alkoxy group.
Figure imgf000036_0001
Scheme 6
Alkylation of the phenolic hydroxy group of ester (6a) using for example the Mitsunobu conditions, 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, such as treatment with DIBAL or the like, provides benzylic alcohol (6c). The afforded alcohol (6b) can then either be used directly in the coupling to the primary hydroxy group of the lactone (2a) or the linear compound (5c) as described above, or the benzylic hydroxy group can be transferred to a leaving group, such as a halide like bromide, and subsequently coupled to the primary hydroxyl group of the lactone (2a) or the linear compound (5c) as described above.
Even though the strategy in scheme 6 is illustratesthe 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 5 is illustratedwith a 1,3 substituted phenyl derivative as starting compound, the skilled person will realize that the same methodology also is applicable to other phenyl derivatives, for example the corresponding 1,2- or 1,4-disubstituted derivatives.
An intermediate towards compounds of formula (I) whereinX' is F and X" is H or X' and X" are both F can be prepared by replacement of the hydroxy group of compound 5 a with fluoro or difluoro as exemplified in scheme 8.
Figure imgf000037_0001
5a δa
1 ) DIAD, Ph3P, p-NO2-benzoic acid
2) NaOMe
Figure imgf000037_0002
Scheme 8
The free hydroxy group of compound (5a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (8a). The monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached and thereafter replace the hydroxy group with fluorine, effected for example by subjecting the afforded inverted alcohol to fluorinatingconditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions. Inversion of the stereochemistry of the alcohol (5 a) can be performed for example by subjectingthe alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph3P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
Even though scheme 8 illustratesthe replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
Compounds of formula (I) whereinX' is amino may be prepared from the corresponding alcohol. A variety of methods for the transformation of an alcohol to an amine are described in the literature. For example, the hydroxy group can be transformed into a leaving group which subsequentlyis displaced by azide, and the azide is thereafter reduced to the amine, as illustrated scheme 9.
Figure imgf000039_0001
9a 9b
Figure imgf000039_0002
9c 9d
Pg is an N-protecting group
Scheme 9
In order to get the desired configuration at the steric centre wheretothe X' is attached in the final compound, the configuration of compound (9a), prepared as described above, has to be inverted, for example as described in scheme 8. The inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e. treatment with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by reaction with azide, for example diphenylphosphoryl azide (DPPA) or HN3 to give the azido derivative (9c). The azido derivative (9c) can alternatively be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like. Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d).
Even though scheme 9 illustratesthe conversion of the hydroxy group to amine as the last step of the synthesis, the skilled person will realise that this transformation is also applicable at any other suitable stage of the synthesis for example on any of the intermediates described above.
The compounds of the invention are then achieved by coupling of a suitable amine such as any of those described above to a suitable acid, as schematically outlined in scheme 10.
Figure imgf000040_0001
Scheme 10
Coupling of a desired amino derivative (10a) to a suitable acid (10b or 10b') can be performed using standard peptide coupling techniques which are well known by a person skilled in the art. For example a coupling agent like HATU or the like can be used in the presence of a tertiary amine like diisopropylethylamine or the like in a solvent like DMF to provide the amide (10c or 10c').
Acids (10b) to be used in the coupling with the amine (10a) are available commercially or from the literature, or they can be prepared as outlined hereinbelow. Acids (10b), wherein ring A is phenyl and E is CHRc-CHRc, can be prepared as shown in scheme 11.
Figure imgf000040_0002
X is a leaving group, e.g . Br
Rc' is CrCealkyl, CpCealkoxyCrCealkyl
Figure imgf000040_0003
Scheme 11 Reaction of an aldehyde (1 Ia), prepared for example according to the procedure described by S. J. Stachel et al. in Med. Chem. Lett., 16 (2006) 641-644, in a Grignard reaction or equivalent, with a suitable reagent such as an alkylmagnesium bromide, provides the alcohol (1 Ib). Hydrolysis of the methyl ester using for instance sodium hydroxide or the like, followed by alkylation of the tertiary hydroxy group with an alkylating agent Rc'-X, wherein Rc' is C1- Cβalkyl or Ci-CβalkoxyCi-Cβalkyl and X is a leaving group for example a halogen like chloride, bromide or iodide, in the presence of a base like sodium hydride or the like gives the acid (1 Ib).
Acids (10b) wherein ring A is phenyl, E is -NRd-CH(Rd)- can be prepared as illustrated in scheme 12.
Figure imgf000041_0001
Scheme 12
Reaction of aldehyde (1 Ia) in a reductive amination reaction with an amino derivative (12a), using of a reducing agent like sodium cyanoboro hydride or the like, and subsequent hydrolysis of the methyl ester provides the amine containing acid (12b). Although the method in scheme 12 illustrates the preparation of an acid wherein the benzylic carbonis unsubstituted, the skilled person will realize that the corresponding acid which is substituted at the benzylic carbon can be obtained according to the same procedure by using the appropriate ketone instead of the aldehyde (1 Ia) as starting material.
Scheme 13 illustrates a route to acids (10b) wherein E is -0-CH(Rd)- and Rd is hydrogen and also an alternative route to acids whereinE is NRd-CHRd-.
Figure imgf000042_0001
Scheme 13
The aldehyde or keto derivative (13a), prepared for example as described by S. J. Stachel et al. in Med. Chem. Lett., 16 (2006) 641-644, can be reduced to the corresponding alcohol (13b) for example by treatment with sodium borohydride, or any other appropriate reagent. Ether derivatives (13d) can then be achieved by hydrolysis of the methyl ester by treatment with sodium hydroxide or the like, followed by alkylation of the secondary hydroxy group using any desired alkylating agent (13c) whereinX is a leaving group such as bromide, iodide or chloride, in the presence of a base like sodium hydride. Amino derivatives (13f) can be achieved by subjecting the alcohol (13b) to Mitsunobu conditions with a desired amine (13e) followed by hydrolysis of the methyl ester as described above.
It should be appreciated that in any functional groups that optionally may be present on any of the constituent compounds are appropriately protected where necessary during the reaction sequence and deprotected afterwards.
Scheme 14 illustrates a route to acids (10b) useful for the preparation of compounds wherein ring A is phenyl, R6 is NRaS(=O)2CH3 and E is -O- or -CH(Rd)-O-.
Figure imgf000043_0001
ing group, e.g. Br or I 1
Figure imgf000043_0002
Scheme 14
Alkylation of the phenolic hydroxy group of commercially available 3-tert- butoxycarbonylamino -5 -hydroxy-benzoic acid with a desired alkylating agent (14a) in the presence of a base such as NaOH, followed by transforming the acid function into an ester using Standard conditions such as treatment with methyl iodide in the presence of a base like cesium carbonate, provides the ester (14b). Removal of the boc group by treatment with acid, for example TFA in dichloromethane, provides the aniline (14c). Subsequent sulphonylation of the amino group using any desired sulphonylating agent such as a sulphonylchloride, for example mesyl chloride or the like in the presence of pyridine in a solvent like dichloromethane or the like, optionally followed by alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, whereinX is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative ( 14d). Alternatively, the primary amino group of aniline (14c) can be reacted with a sulphamoyl chloride instead of a sulphonyl chloride thus affordingcompounds wherein ring A is substituted with a sulphamoyl amide group, i.e. R is NRaS(=0)2NRaRb. 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.
Scheme 15 illustrates a route to acids (10b) useful for the preparation of compounds wherein ring A is phenyl, R6 is NRaS(=O)2CH3 and E is -CH(Rd)-NH- or -NH-.
Figure imgf000044_0001
X is a leaving group, e.g. B r or I n is 0 or 1
Scheme 15
The diamino benzoic acid derivative (15a) can be achieved for example by removal of the fmoc group from commercially available boc-3-amino-5-(fmoc-amino)benzoic acid using standard conditions such as treatment with piperidine or morpholine or the like. Alkylation of the free amine effected for example by reaction with a desired aldehyde or ketone (15b) in the presence of a reducing agent like NaCNBH3 or the like provides the amino derivative (15c). Alternatively, the amine (15a) can be alkylated by reaction with an alkylating agent (15d) whereinX is a leaving group such as a halide like bromo or chloro or a derivative of sulphonic acid like a triflate or mesylate or the like, optionally in the presence of a base, which provides the amine (15e). Alkylation of the acid followed by removal of the boc group, introduction of the sulphone amide group and finally hydrolysis of the ester as described above, then provides the acid (15c).
A typical route to acids (10b) to be coupled to the amine as schematically shown in scheme 10 wherein ring A is a cyclopentane and R6 is NRaS(=O)2CH3 is shown in Scheme 16.
Figure imgf000045_0001
Scheme 16
The bicyclic lactone (16a), prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanoneas described in WO2005/073195, can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (16b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature, for example the Mitsunobu conditions may be employed i.e. treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate derivative, in combination with triphenylphosphine, followed by reaction with azide for example DPPA, subsequent reduction of the azido group effected for example by catalytic hydrogenation in the presence of a suitable catalyst, for example Lindlar's catalyst or by treatment with triphenylphosphine provides amino derivative (16c). Mesylation of the afforded amine using for example methanesulphonyl chloride or any other corresponding sulphonylating agent in the presence of pyridine and in a solvent like dichloromethane or the like followed optionally by alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, whereinX is a leaving group such as a halide like bromide or iodide, in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (16d). Selectiveremoval of the tert. butyl group by subjecting the diester to acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylenechloride then provides the acid (16e). Reduction of the acid for example by a two step process of Weinreb amide formation brought about by reaction with N,0- dimethylhydroxylamine in the presence of sodium hydro gencarbonate and subsequent Dibal- reduction, gives the corresponding aldehyde (16f). The afforded aldehyde can then be reacted as described above in order to get various acids which subsequentlycan be coupled to a desired amino derivative as described above.
Acids (1Ob') to be used in the coupling with the amine (10a) are available either commercially or in the literature. Acids wherein ring A is phenyl and R is NRaS(=O)2CH3 can be prepared according to the procedure described by Stachel et al. in J. Med. Chem., 47, 2004, 6447-6450 as depicted in scheme 17.
Figure imgf000046_0001
X is a leaving group, e.g. Br or I
Figure imgf000046_0002
Scheme 17
Sulphonylation of the amino group of commercially available 5 -amino isophthalic ester (17a) 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, whereinX is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (17b). Monohydro lysis of the bis -ester (17b) to the mono acid, for example by treatment with sodium hydroxide, followed by a peptide coupling of the amino derivative (17c) using any convenient method such as using a reagent like BOP or the like provides the amide (17d). Subsequent hydrolysis of the methyl ester then affords the acid (17e).
Compounds of the invention whereinring A 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 (17c). 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. A typical route to acids 10b' to be used in the preparation of compounds of formula (I) wherein ring A is a cyclopentane, D is C(=O)NR7R8 and R6 is NRaS(=O)2CH3 is shown in Scheme 18.
Figure imgf000047_0001
Scheme 18
The bicyclic lactone (18a), prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanoneas described in WO2005/073195 can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (18b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature. For example the Mitsunobu conditions may be employed i.e. treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate, in combination with triphenylphosphine, followed by reaction with azide for example DPPA and finally reduction of the azido group effected for example by catalytic hydrogenation in the presence of a suitable catalyst, for example Lindlar's catalyst or by treatment with triphenylphosphine, provides amino derivative (18c). Mesylation of the afforded amine using for example methanesulphonyl chloride or any corresponding sulphonylating agent in the presence of pyridine and in a solvent like dichloromethane or the like followed, if desired, by alkylation of the nitrogen, effected by a displacement reaction with a desired alkylating agent Ra-X, whereinX is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (18d). Selective removal of the tert. butyl group by subjecting the diester to acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylene chloride then provides the acid (18e). Coupling of a desired amine (18f) followed by hydrolysis of the methyl ester as described above then yields the acid (18g).
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.
Example 1
Step a
Figure imgf000048_0001
3-Deoxy-6-O-(4-bromobenzyiyi.2-O-isopropylidene-D-glucofuranoside (Ia) The diol 3-deoxy-l,2-O-isopropylidene-D-glucofuranoside (1.91 g, 9.34 mmol) and dibutyltin oxide (3.07 g, 12.3 mmol, 1.32 eq.) were dissolved in toluene (100 mL). The reaction mixture was refluxed for 5 hours with a Dean-Starke trap. The temperature was then loweredto 90 0C and tetrabutylammonium bromide (3.99 g, 12.3 mmol, 1.32 eq.) and 4-bromo benzyl bromide (2.97 g, 11.9 mmol, 1.27 eq.) were added. The reaction mixture was stirred at 90 0C over night and then the solvent was removed under vacuum, the residue was purified by column chromatography (toluene/ ethyl acetate 10:1 ) to afford the title compound (3.04 g, 8.14 mmol, 87%).
1H-NMR (400 MHz, CDCl3): δ 7.49-7.44 (d, 2H), 7.22-7.17 (d, 2H), 5.81-5.78 (d, IH), 4.75- 4.71 (t, IH), 4.55-4.45 (m, 2H), 4.24-4.18 (m, IH), 4.01-3.95 (m, IH), 3.60-3.55 (m, IH), 3.49- 3.44 (m, IH), 2.09-2.03 (m, IH), 1.88-1.79 (m, IH), 1.49 (s, 3H), 1.31 (s, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 137.0, 131.7, 129.5, 121.8, 111.4, 105.5, 80.7, 78.4, 72.8, 71.5, 71.1, 34.0, 26.9, 26.3; MS m/z 395.05 [(M+Na)+ calcd for C16H2JBrNaO5 + 395.04]
Figure imgf000049_0001
5-Azido-3.5-dideoxy-6-Q-(4-bromobenzylV1.2-Q-isopropylidene-L-/vxo-hexofuranoside (Ib") The alcohol Ia (4.62 g, 12.39 mmol) and triphenyl phosphine (4.22 g, 16.1 mmol, 1.3 eq.) was dissolved in THF (60 niL). The mixture was cooled to -15 0C (ice/acetone). Diisopropyl azodicarboxylate (5.12 rnL, 5.26 g, 26.0 mmol, 2.1 eq.) was added drop wise to the solution. The temperature was then increased to 0 0C, and diphenylphosphoryl azide (3.74 mL, 4.77 g, 17.34 mmol, 1.4 eq.) was added. The temperature was kept at 0 0C for an additional 30 minutes and then in room temperature over night. The reaction mixture was concentrated and the residue was purified by column chromatography (toluene/ ethyl acetate 30:1) to yield the title compound (3.373 g, 8.47 mmol, 68%).
1H-NMR (CDCl3): δ 7.50-7.44 (d, 2H), 7.24-7.18 (d, 2H), 5.82-5.79 (d, IH), 4.75-4.71 (t, IH), 4.52 (s, 2H), 4.33-4.26 (m, IH), 3.74-3.69 (m, 2H), 3.54-3.50 (m, IH), 2.07-2.01 (m, IH), 1.92- 1.84 (m, IH), 1.49 (s, 3H), 1.31 (s, 3H); 13C-NMR (CDCl3): δ 136.9, 131.8, 129.5, 122.0, 111.7, 105.7, 80.4, 77.5, 73.0, 70.9, 62.7, 35.6, 27.0, 26.4; MS m/z 420.05 [(M+Na)+ calcd for C16H20BrN3NaO4 + 420.05]
Step c
Figure imgf000049_0002
Methyl 5-azido-3.5-dideoxy-6-Q-(4-bromobenzylVL-/vxo-hexofuranoside (Ic") Compound Ib (5.256 g, 13.20 mmol) was dissolved in IM HCl in MeOH (40 mL) and stirred at room temperature for two hours. The mixture was then neutralized with NaHCO3 (aq). The volatile solvents were removed under vacuum and the residue was dissolved in DCM and washed with water (2x 30 mL). The organic layer was dried over MgSO4 and concentrated, the residue was purified by column chromatography (toluene/ ethyl acetate 15:1) which gave the title compound (4.271 g, 11. 47 mmol, 87%).
1H-NMR (CDCl3): δ 7.50-7.45 (d, 2H), 7.23-7.18 (d, 2H), 4.70 (s, IH), 4.50 (s, 2H), 4.46-4.38 (m, IH), 4.26-4.22 (t, IH), 3.62-3.54 (m, 2H), 3.48-3.44 (m, IH), 3.37 (s, 3H), 2.06-1.98 (m, IH), 1.93-1.86 (m, IH), 1.82-1.78 (d, IH); 13C-NMR (CDCl3): δ 136.8, 131.8, 129.4, 121.9, 109.5, 79.3, 75.9, 72.9, 70.2, 66.0, 55.1, 35.3. tep d
Figure imgf000050_0001
Methyl 5-azido-3.5-dideoxy-6-Q-(4-bromobenzylV2-O-methyl-L-/vxo-hexofuranoside (Id") Compound Ic (4.271 g, 11.5 mmol) was dissolved in DMF (60 niL) and methyl iodide (5.7 mL, 13.0 g, 91.8 mmol, 8 eq.) and Ag2O (5.318 g, 23.0 mmol, 2 eq.) were added. The reaction was stirred in room temperature over night. The reaction was quenched with CHCl3 and the solids were filtered off. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (toluene/ ethyl acetate 15:1) to yield the title compound (4.24 g, 11.0 mmol, 96 %).
1H-NMR (CDCl3): δ 7.50-7.45 (d, 2H), 7.23-7.18 (d, 2H), 4.99-4.96 (d, IH), 4.50 (s, 2H), 3.79 (s, 3H), 3.60-3.56 (m, 2H), 3.50-3.44 (m, IH), 3.39 (s, 3H), 3.33 (s, IH), 2.20-2.12 (m, IH), 2.09-2.03 (m, IH); 13C-NMR (CDCl3): δ 136.7, 131.8, 129.4, 121.9, 106.8, 81.0, 79.5, 73.0, 70.1, 65.4, 55.3, 32.4.
Step e
Figure imgf000050_0002
5-Azido-3,5-dideoxy-6-O-(4-bromobenzyl)-2-O-methyl-L-/vxo-hexofuranoside (Ie) The methyl glycoside Id (3.824 g, 9.90 mmol) was dissolved in 1, 4-dioxane/ 0.5 M H2SO4 1 :1 (120 mL) and heated to reflux. After complete reaction (~1 hour according to TLC), the reaction was cooled to room temperature and then neutralized with Na2CO3 (aq). The volatile solvents were concentrated under vacuum. The residue was dissolved in DCM and washed with H2O (x 2). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (toluene/ ethyl acetate 10:1) which gave the title compound (2.55 g, 6.85 mmol, 69%).
1H-NMR (CDCl3): δ 7.48-7.46 (d, 2H), 7.22-7.19 (d, 2H), 5.32-5.27 (d, IH), 4.51 (s, 2H), 4.38- 4.28 (m, IH), 3.78-3.75 (m, IH), 3.72-3.68 (m, 2H), 3.61-3.54 (m, IH), 3.35 (s, 3H), 3.16-3.12 (d, IH), 2.14-1.96 (m, 2H); 13C-NMR (CDCl3): δ 136.7, 131.7, 129.4, 121.9, 100.3, 85.6, 78.9, 72.9, 71.3, 64.5, 57.1, 31.7.
Step f
Figure imgf000051_0001
5-Azido -3.5-dideoxy-6-Q-(4-bromobenzylV2-Q-methyl-L-/vxo- 1.4-lactone (If) Compound Ie (2.55 g, 6.85 mmol) was dissolved in DCM (50 niL) at 0 0C and pyridinium dichromate (3.87 g, 10.28 mmol, 1.5 eq.) and Al molecular sieves powder were added. The reaction was stirred over night in room temperature. The solids were filtered off and the filtrate was concentrated under vacuum, the residue was purified by column chromatography (toluene/ ethyl acetate 10:1) to yield the title compound (1.68 g, 4.55 mmol, 66%).
1H-NMR (CDCl3): δ 7.50-7.46 (d, 2H), 7.22-7.18 (d, 2H), 4.71-4.64 (m, IH), 4.52 (s, 2H), 4.18- 4.12 (dd, IH), 3.76-3.75 (d, IH), 3-74 (s, 2H), 3.70-3.64 (m, IH), 3.55 (s, 3H), 2.48-2.38 (m, IH), 2.32-2.21 (m, IH); 13C-NMR (CDCl3): δ 174.0, 131.8, 130.0, 129.4, 121.9, 76.1, 74.8, 73.0, 70.0, 63.4, 58.4, 32.4; m/z 392.02 [(M+Na)+ calcd for C14H16BrN3NaO4 + 392.02].
Figure imgf000051_0002
(5V2-amino-jV-benzyl-3 -methyl -butyramide (Ig)
Boc-Val-OH (500 mg, 2.30 mmol), benzylamine (321 mg, 2.99 mmol) and DIPEA (0.52 mL, 2.99 mmol) were dissolved in DMF (12 mL) and cooled (0 0C). HATU (137 mg, 2.99 mmol) was added and the mixture was allowed to attain room temperature and was stirred for 2 hours. The DMF was removed under reduced pressure and the crude residue was purified by flash column chromatography (toluene/ethyl acetate 6:1) to yield ((S)-l-benzylcarbamoyl-2-methyl- propyl)-carbamic acid tert-butyl ester (666 mg, 95 %).
1H-NMR (CDCl3): δ 0.94 (m, 6H), 1.42 (s, 9H), 2.18 (m, IH), 3.90 (m, IH), 4.42 (m, 2H), 5.10 (s, IH), 6.43 (s, IH), 7.30 (m, 5H); 13C NMR: δ 19.0, 28.1, 30.8, 42.9, 59.9, 79.2, 126.9, 127.3, 128.2, 138.1, 155.9, 172.0.
The Boc-derivative (666 mg, 2.17 mmol) was dissolved in CH2Cl2 (7.3 ml) and cooled to 0 0C in an ice bath. Et3SiH (0.52 mL, 3.27 mmol) and TFA (3.5 mL) was added and the mixture were allowed to attain room temperature. After 3 hours the solution was co-evaporated with toluene (3 x 20 mL), which gave the TFA salt of the title compound as a white powder (448 mg, quant.). 1H-NMR (CDCl3): δ 0.94 (m, 6H), 2.0-2.15 (m, IH), 3.90 (d, J= 6.32, IH), 4.15-4.40 (m, 2H), 7.05-7.15 (m, 5H), 8-8.15 (m, 3H); 13C-MNR (CDCl3): δ 17.7, 17.9, 30.3, 43.6, 59.1, 125.3, 127.4, 127.6, 128.2, 128.6, 129.0, 168.7. Step h
Figure imgf000052_0001
(2R AS,5S)-5 - Azido-6-(4-bromo-bensyloxy) -4-hydroxy-2-methoxy-hexanoic acid (YS)-I- benzylcarbamoyl-2-methyl-propyO-amide (Ih)
Compound If (106 mg, 0.286 mmol) and (S)-2-amino-iV-benzyl-3-methyl-butyramide (118 mg, 0.573 mmol, 2 eq.) were dissolved in diisopropyl ethyl amine (5 mL). 2-Hydroxy-pyridine was added and the mixture was heated to 70 0C over night, and a few drops of DMF was added for solubility. The reaction mixture was concentrated and the residue was purified by column chromatography (toluene/ ethyl acetate 6:1) which gave the title compound (140 mg, 0.243 mmol, 85%).
1H-NMR (400 MHz, CDCl3): δ 7.48-7.45 (d, 2H), 7.31-7.14 (m, 8H), 7.02-6.99 (d, IH), 4.46 (s, 2H), 4.38-4.34 (d, 2H), 4.34-4.28 (m, IH), 3.88-3.80 (m, 2H), 3.63-3.51 (m, 2H), 3.44-3.39 (m, IH), 3.41 (s, 3H), 2.72-2.68 (d, IH), 2.44-2.34 (m, IH), 2.10-2.02 (m, IH), 1.90-1.83 (m, IH), 0.98-0.90 (dd, 6H); 13C-NMR (100.5 MHz, CDCl3): δ 172.5, 170.9, 138.4, 136.7, 131.8, 129.4, 128.8, 127.9, 127.5, 121.9, 79.6, 72.9, 70.7, 67.8, 65.3, 58.5, 58.1, 43.6, 35.5, 29.9, 19.7, 17.6; MS m/z 576.18 [(M+H)+ calcd. for C26H35BrN5O5 + 576.18].
Sten i
Figure imgf000052_0002
N-r(16'.26'.4i?)-4-((y)-l-Benzylcarbamoyl-2-methyl-propylcarbamoyl)-l-(4-bromo- bensyloxymethyl) -2-hydroxy-4-methoxy-butyl1 -5 -(methanesulphonyl -methyl-aminoViV7 -((R)- 1 - phenyl -ethvD-isophthalamide (Ii)
The azide Ih (47 mg, 0.08 mmol) and triphenylphosphine (32 mg, 0.12 mmol) was dissolved in MeOH (5 mL) and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step. 5-Methanesulphonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalic acid, prepared as described in J. Med. Chem., 47, 2004, 6447-6450, (20 mg, 0.05 mmol, 1 eq), Py-BOP (28 mg, 0.05 mmol, leq) and DIPEA (10 μL, 0.05 mmol, leq) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~1.5 eq) from the previous reaction dissolved in DCM (2 mL) and DIPEA (10 uL, 0.05 mmol, leq) were added. After complete reaction the mixture were washed with NaHCθ3 (Ix 10 mL) and brine (Ix 1OmL). The water phase was washed with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (toluene/ ethyl acetate 1 : 1) to give the title compound (11 mg, 0.01 mmol, 47 %).
1H-NMR (CDCl3): δ 8.14 (s, IH), 7.96 (s, IH), 7.92 (s, IH), 7.44-7.02 (m, 18H), 5.32-5.25 (m, IH), 4.43 (s, 2H), 4.30-4.27 (t, 2H), 4.27-4.14 (m, 3H), 3.80-3.76 (t, IH), 3.65-3.57 (m, 3H), 3.42 (s, 3H), 3.31 (s, 3H), 2.82 (s, 3H), 2.34-2.26 (m, IH), 2.12-2.03 (m, IH), 1.92 (bs, IH), 1.60-1.57 (d, 3H), 0.96-0.89 (dd, 6H); 13C-NMR (CDCl3): δ 173.0, 171.0, 166.4, 164.8, 143.2, 142.3, 138.3, 136.6, 136.1, 135.8, 131.8, 129.6, 128.9, 128.7, 128.1, 127.8, 127.6, 127.5, 126.4, 124.2, 122.0, 79.4, 72.8, 70.5, 67.7, 58.4, 58.3, 53.6, 49.9, 43.5, 38.1, 35.7, 35.5, 30.2, 21.9, 19.7, 17.8; HRMS m/z 908.2898 [(M+H)+ calcd. for C44H55BrNSaS+ 908.2872].
Figure imgf000053_0001
S-Deoxy-ό-O-G.S-difluorobenzyiyi^-O-isopropylidene-D-glucofuranoside f2a") The diol 3-deoxy-l,2-O-isopropylidene-D-glucofuranoside (2.15 g, 10.52 mmol) and dibutyltin oxide (3.46 g, 13.9 mmol, 1.32 eq.) were dissolved in toluene (100 mL). The reaction mixture was refluxed for 5 hours with a Dean-Starke trap. The temperature was then loweredto 90 0C and tetrabutylammonium bromide (4.49 g, 13.9 mmol, 1.32 eq.) and 3,5-difluoro benzyl bromide (1.73 mL, 2.77 g, 13.4 mmol, 1.27 eq.) were added. The reaction mixture was stirred at 90 0C over night and then the solvent was removed under vacuum, the residue was purified by column chromatography (toluene/ ethyl acetate 10:1 ) which gave the title compound (2.73 g, 8.26 mmol, 78%).
1H-NMR (400 MHz, CDCl3): δ 6.88-6.81 (m, 2H), 6.74-6.67 (m, IH), 5.80-5.78 (d, IH), 4.75- 4.72 (t, IH), 4.54-4.50 (d, 2H), 4.25-4.19 (m, IH), 4.02-3.96 (m, IH), 3.62-3.57 (m, IH), 3.52- 3.46 (m, IH), 2.45-2.42 (d, IH), 2.10-2.04 (m, IH), 1.88-1.80 (m, IH), 1.49 (s, 3H), 1.31 (s, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 164.4 (d,JCF= 12.9 Hz), 162.0 (d, JcF = 12.9 Hz), 142.2 (t, JCF = 8.4 Hz), 111.5, 110.0 (dd, JCF = 12.3, 25.9 Hz), 105.4, 103.1 (t, JCF = 25.1 Hz), 80.7, 78.4, 72.3, 71.8, 71.1, 34.0, 26.9, 26.3; MS m/z 353.12 [(M+Na)+ calcd. for Ci6H20F2NaO5 + 353.12]
Figure imgf000054_0001
5-Azido-3.5-dideoxy-6-Q-^3.5-difluorobenzylV1.2-Q-isopropylidene-L-/vxo-hexofuranoside T2tΛ Compound 2b (2.58 g, 7.26 mmol, 88%) was synthesized from 2a (2.73 g, 8.25 mmol) according to the method described for the preparation of compound Ib.
1H-NMR (400 MHz, CDCl3): δ 6.90-6.82 (m, 2H), 6.77-6.68 (m, IH), 5.83-5.79 (d, IH), 4.77- 4.72 (m, IH), 4.55 (s, 2H), 4.36-4.27 (m, IH), 3.77-3.72 (m, 2H), 3.60-3.52 (m, IH), 2.11-2.03 (m, IH), 1.96-1.85 (m, IH). 1.49 (s, 3H), 1.32 (s, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 164.5 (d, JcF = 12.3 Hz), 162.0 (d,JCF = 12.3 Hz), 141.9 (t, JCF = 8.4 Hz), 111.7, 110.1 (dd,JCF = 12.3, 25.9 Hz), 105.6, 103.2 (t, JCF = 25.2 Hz), 80.4, 77.3, 72.4, 71.1, 62.6, 35.5, 26.9, 26.3; MS m/z 378.12 [(M+Na)+ calcd for Ci6Hi9F2N3NaO4 + 378.15].
Step c
Figure imgf000054_0002
Methyl 5 -azido-3r5-dideoxy-6-(9-r3r5-difluorobenzyπ-L-/vx(9-hexofuranoside (2oλ Compound 2c (1.816 g, 5.53 mmol, 76%) was synthesized from compound 2b (2.586 g, 7.28 mmol) according to the method described for the preparation of compound Ic. 1H-NMR (400 MHz, CDCl3): δ 6.90-6.83 (m, 2H), 6.76-6.68 (m, IH), 4.81 (s, IH), 4.53 (s, 2H), 4.47-4.40 (m, IH), 4.27-4.23 (t, IH), 3.65-3.56 (m, 2H), 3.52-3.46 (m, IH), 3.38 (s, 3H), 2.09- 2.01 (m, IH), 1.95-1.88 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ; 164.5 (d, JCF = 12.9 Hz), 162.0 (d, JCF = 12.9 Hz), 141.9 (t, JCF = 8.4 Hz), 110.0 (dd,JCF = 11.5, 25.9 Hz), 109.9, 103.2 (t, JCF = 25.1 Hz), 79.3, 75.9, 72.4, 70.5, 65.9, 55.1, 35.2.
Step d
Figure imgf000055_0001
Methyl 5 -azido-3.5-dideoxy-6-Q-(3.5-difluorobenzvπ-2-Q-methyl-L-/vxo-hexofuranoside (2d) Compound 2d (1.449 g, 4.25 mmol, 77%) was synthesized from 2c (1.816 g, 5.51 mmol) according to the method described for the preparation of compound Id.
1H-NMR (300 MHz, CDCl3): δ 6.90-6.83 (m, 2H), 6.77-6.68 (m, IH), 5.01-4.96 (d, IH), 4.94 (s, IH), 4.53 (s, 2H), 4.45-4.35 (m, IH), 3.79 (s, 3H), 3.64-3.59 (m, 2H), 3.54-3.46 (m, IH), 3.40 (s, 3H), 2.23-2.03 (m, 2H); 13C-NMR (75.5 MHz, CDCl3): δ; 164.9 (d, JCF = 12.6 Hz), 161.6 (d, JCF = 12.3 Hz), 141.8 (t, JCF = 8.4 Hz), 110.0 (dd,JCF = 9.1, 25.2 Hz), 106.8, 103.2 (t, JCF = 25.2 Hz), 81.0, 79.4, 72.4, 70.4, 65.3, 55.3, 32.4.
Ster
Figure imgf000055_0002
5-Azido-3,5-dideoxy-6-Q-(3,5-difluorobenzyl)-2-Q-methyl-L-/vxo-hexofuranoside (2e) Compound 2e (876 mg, 2.66 mmol, 63%) was synthesized from compound 2d (1.449 g, 4.22 mmol) according to the method described for the preparation compound of Ie. 1H-NMR (400 MHz, CDCl3): δ 6.90-6.84 (d, 2H), 6.76-6.70 (t, IH), 5.32-5.30 (m, IH), 4.55 (s, 2H), 4.40-4.31 (m, IH), 3.80-3.73 (m, 2H), 3.72-3.70 (m, IH), 3.50-3.43 (m, IH), 3.37 (s, 3H), 2.97-2.94 (d, IH), 2.16-2.01 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ; 168.1 (d, JCF = 12.57 Hz), 165.6 (d, JCF = 12.45 Hz), 145.4 (t, JCF = 8.4 Hz), 110.0 (dd,JCF = 12.1, 25.9 Hz), 103.2 (t, JCF = 25.2 Hz), 100.4, 85.6, 78.8, 72.4, 71.6, 64.4, 57.2, 31.6; MS m/z 352.11 [(M+Na)+ calcd for C14H17F2N3NaO4 + 352.11]
Figure imgf000055_0003
5-Azido-3.5-dideoxy-6-Q-r3.5-difluorobenzylV2-Q-methyl-L-/vxo-1.4-lactone f2f) Compound 2f (593 mg, 1.81 mmol, 68%) was synthesized from compound 2e (876 mg, 2.66 mmol) according to the method described for the preparation of compound 28. 1H-NMR (300 MHz, CDCl3): δ 6.90-6.80 (m, 2H), 6.80-6.69 (m, IH), 4.73-4.65 (m, IH), 4.55 (s, 2H), 4.19-4.13 (m, IH), 3.82-3.76 (m, 2H), 3.76-3.68 (m, IH), 3.77 (s, 3H), 2.51-2.41 (m, IH), 2.34-2.24 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ; 173.9, 164.8 (d, JCF = 12.6 Hz), 161.5 (d, JCF = 12.3 Hz), 141.7 (t, JCF = 8.4 Hz), 110.1 (dd, JCF = 9.2, 25.2 Hz), 103.4 (t, JCF = 25.2 Hz), 76.1, 74.9, 72.6, 70.4, 63.5, 58.5, 32.5; MS m/z 350.09 [(M+Na)+ calcd for Ci4Hi5F2N3NaO4 + 350.09].
Figure imgf000056_0001
(2i?.46'.5y)-5-Azido-6-(3.5-difluoro-bensyloxyV4-hydroxy-2-methoxy-hexanoic acid (YSVl- benzylcarbamoyl-2-methyl-propy0-amide (2%S
Compound (106 mg, 0.198 mmol, 82%) was synthesized by reaction of compound 2f (79 mg, 0.2419 mmol) with compound Ig according to the method described for the preparation of compound Ih.
1H-NMR (300 MHz, CDCl3): δ 7.32-7.21 (m, 5H), 7.00-6.96 (d, 2H), 6.87-6.83 (m, 2H), 6.76- 6.69 (m, IH), 4.49 (s, 2H), 4.41 -4.37 (d, 2H), 4.32-4.27 (m, IH), 3.90-3.83 (m, 2H), 3.65-3.54 (m, 2H), 3.47-3.42 (m, IH), 3.44 (s, 3H), 2.63-2.58 (d, IH), 2.46-2.37 (m, IH), 2.14-2.05 (m, IH), 1.92-1.85 (m, IH), 1.00-0.91 (dd, 6H); 13C-NMR (75.5 MHz, CDCl3): δ 172.5, 170.9, 164.9 (d, JCF = 12.6 Hz), 161.6 (d,JcF = 12.6 Hz), 141.9 (t, JCF = 8.9 Hz), 138.3, 128.8, 128.0, 127.6, 110.0 (dd, JCF = 9.1, 25.0 Hz), 103.2 (t, JCF = 25.2 Hz), 79.6, 72.4, 70.9, 67.7, 65.4, 58.5, 58.2, 43.7, 35.6, 29.9, 19.8, 17.6; MS m/z 556.23 [(M+Na)+ calcd for C26H33F2N5NaO5 + 556.23].
Figure imgf000056_0002
N-[(l Sr2Sr4R )-4-((S)- 1 -Benzylcarbamoyl^-methyl-propylcarbamoyD- 1 -(3 r5 -difluoro- bensyloxymethyP -2-hydroxy-4-methoxy-butyl] -5 -(methanesulphonyl -methyl-amino ViV -((R)- 1 - phenyl -ethyl Visophthalamide (2h)
The title compound (21 mg, 0.02 mmol, 51 %) was synthesized by reduction of compound 2g (32 mg, 0.06 mmol) followed by coupling to the acid 5-methanesulphonyl-methyl-amino)-N'-(l- phenyl -ethyl)-isophthalic acid (18mg, 0.05 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (500 MHz, CDCl3): δ 8.18 (s, IH), 7.99 (s, 2H), 7.40- 7.04 (m, 14H), 6.82-6.80 (m, 2H), 6.71-6.69 (m, IH), 5.32-5.28 (m, IH), 4.50-4.46 (m, 2H), 4.40- 4.34 (m, IH), 4.35- 4.20 (m, 4H), 3.90- 3.84 (m, IH), 3.68- 3.64 (d, 2H), 3.47 (s, 3H), 3.37 (s, 3H), 2.82 (s, 3H), 2.38- 2.30 (m, IH), 2.30- 1.96 (m, 3H), 1.62-1.60 (d, 3H), 0.98- 0.90 (dd, 6H); HRMS m/z 866.3646 [(M+H)+ calcd for C44H54F2N5O9S+SOOJOOS]
Example 3 Step a
Figure imgf000057_0001
S.ό-Anhvdro-S-deoxy-l^-Q-isopropylidene-D-glucofuranoside (3a")
The title compound was prepared from 3-deoxy-l,2-O-isopropyliden-D-glucofuranoside according to the procedure described by 5 Samuelsson et al. in J. Med. Chem., 2004, 47, 3353-
3366.
Figure imgf000057_0002
3-Deoxy-6-O-(4-bromophenvD- 1 ,2-O-isopropylidene-D-glucofuranoside (3b) The epoxide 3a (373 mg, 2.00 mmol) and 4-bromo phenol (693 mg, 4.01 mmol, 2 eq.) were dissolved in DMF (15 mL), K2CO3 (69 mg, 0.50 mmol, 0.25 eq.) was added and the reaction mixture was heated to 110 0C and stirred at that temperature over night. The solvent was removed by co -evaporation with toluene. The residue was purified by column chromatography (toluene/ ethyl acetate 20:1) which gave the title compound (580 mg, 1.62 mmol, 81%). 1H-NMR (CDCl3): δ 7.38-7.34 (d, 2H), 6.81-6.76 (d, 2H), 5.83-5.80 (d, IH), 4.78-4.74 (t, IH), 4.34-4.27 (m, IH), 4.16-4.11 (m, IH), 4.07-4.02 (m, IH), 3.96-3.91 (m, IH), 2.60-2.40 (bs, IH), 2.18-2.13 (m, IH), 1.94-1.85 (m, IH), 1.51 (s, 3H), 1.32 (s, 3H); 13C-NMR ( CDCl3): δ 157.7, 132.4, 116.5, 105.5, 80.7, 78.2, 70.8, 69.5, 34.2, 26.9, 26.3. MS m/z 381.03 [(M+Na)+ calcd for Ci5Hi9BrNaO5 + 381.03]
Figure imgf000058_0001
5-Azido-3.5-dideoxy-6-Q-r4-bromophenylV1.2-O-isopropylidene-L-/vxo-hexofuranoside Gc^) The title compound (849 mg, 2.21 mmol, 90%) was synthesized from compound 3b (880 mg, 2.45 mmol) according to the method described for the preparation of compound Ib. 1H-NMR (CDCl3): δ 7.40-7.33 (d, 2H), 6.82-6.76 (d, 2H), 5.83-5.80 (d, IH), 4.76-4.72 (t, IH), 4.42-4.34 (m, IH), 4.20-4.14 (m, 2H), 3.75-3.68 (m, IH), 2.14-2.06 (m, IH), 1.99-1.88 (m, IH), 1.50 (s, 3H), 1.31 (s, 3H); 13C-NMR (CDCl3): δ 157.3, 132.4, 116.5, 113.7, 111.6, 105.6, 80.2, 77.2, 68.9, 61.8, 35.3, 26.8, 26.2.
Step d
Figure imgf000058_0002
Methyl 5 -azido-3.5-dideoxy-6-Q-^4-bromophenyπ-L-/vxo-hexofuranoside (3d") The title compound (752 mg, 2.10 mmol, 95%) was synthesized from compound 3c (849 mg, 2.21 mmol) according to the method described for the preparation of compoundlc. 1H-NMR (CDCl3): δ; 7.42-7.36 (d, 2H), 6.83-6.77 (d, 2H), 4.84 (s, IH), 4.58-4.49 (m, IH), 4.32- 4.24 (t, IH), 4.08-4.02 (m, 2H), 3.73-3.64 (m, IH), 3.40 (s, 3H), 2.18-2.07 (m, IH), 2.03-1.93 (m, IH), 1.90-1.85 (d, IH); 13C-NMR (CDCl3): δ; 157.5, 132.6, 116.5, 113.9, 109.6, 79.2, 75.9, 68.4, 65.0, 55.2, 35.2; MS
Ster
Figure imgf000059_0001
Methyl 5 -azido-3.5-dideoxy-6-O-(4-bromophenviy2-O-methyl-L-/vxo-hexofuranoside (3e) The title compound (315 mg, 0.85 mmol, 90%) was synthesized from compound 3d (338 mg, 0.94 mmol) according to the method described for the preparation of compound 18. 1H-NMR (CDCl3): δ 7.40-7.36 (d, 2H), 6.82-6.77 (d, 2H), 4.92 (s, IH), 4.48-4.41 (m, IH), 4.09- 4.02 (m, 2H), 3.82-3.78 (t, IH), 3.71-3.65 (m, IH), 3.40 (s, 3H), 3.36 (s, 3H), 2.06-2.01 (m, 2H); 13C-NMR (CDCl3): δ 157.5, 132.5, 116.5, 113.8, 106.8, 84.8, 79.3, 68.5, 64.7, 57.1, 55.2, 32.3.
Figure imgf000059_0002
5-Azido-3.5-dideoxy-6-O-r4-bromophenyπ-2-Q-methyl-L-/vxo-hexofuranoside (3f)
The title compound (580 mg, 1.61 mmol, 81%) was synthesized from compound 3e (373 mg,
2.00 mmol) according to the method described for the preparation of compound 23.
1H-NMR (CDCl3): δ 7.40-7.35 (d, 2H), 6.82-6.77 (d, 2H), 5.34-5.31 (d, IH), 4.49-4.40 (m, IH),
4.20-4.15 (m, 2H), 3.81-3.75 (m, 2H), 3.37 (s, 3H), 3.14-3.11 (d, IH), 2.21-2.04 (m, 2H); 13C-
NMR (CDCl3): δ 157.3, 132.6, 116.5, 113.9, 100.4, 85.6, 78.7, 69.3, 63.7, 57.2, 31.6.
Step g
Figure imgf000059_0003
5-Azido-3.5-dideoxy-6-Q-(4-bromophenvπ-2-Q-methyl-L-/vxo-1.4-lactone (3g)
The title compound (264 mg, 0.744 mmol, 59%) was synthesized from compound 3f (454 mg,
1.27 mmol) according to the method described for the preparation of compound If.
1H-NMR (CDCl3): δ 7.42-7.37 (d, 2H), 6.82-6.77 (d, 2H), 4.80-4.74 (m, IH), 4.24-4.20 (d, 2H),
4.20-4.15 (m, IH), 3.93-3.86 (m, IH), 3.57 (s, 3H), 2.56-2.28 (m, 2H); 13C-NMR (CDCl3): δ
173.8, 157.0, 132.6, 116.5, 114.2, 75.9, 74.8, 68.3, 62.9, 58.5, 32.4; MS m/z 378.01 [(M+Na)+ calcd for C13H14BrN3NaO4 + 378.01]. tep h
Figure imgf000060_0001
^^^.S^VS-Azido-ό-^-bromo-phenoxy^-hydroxy^-methoxy-hexanoic acid ((S)-I- benzylcarbamoyl-2-methyl-propylVamide Gh)
The title compound (122 mg, 0.218 mmol, 96%) was synthesized by opening of the lactone 3g (80.5 mg, 0.227 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
1 H-NMR ^OO MHZ5 CDCI3): 57.41-7.36 (d, 2H), 7.31-7.21 (m, 5H), 7.03-6.99 (d, IH), 6.94- 6.90 (t, IH), 6.79-6.74 (d, 2H), 4.42-4.38 (d, 2H), 4.32-4.27 (m, IH), 4.10-4.05 (m, IH), 4.02- 3.98 (m, IH), 3.98-3.91 (m, IH), 3.90-3.86 (m, IH), 3.66-3.62 (m, IH), 3.46 (s, 3H), 2.70 (bs, IH), 2.43-2.34 (m, IH), 2.19-2.10 (m, IH), 1.97-1.90 (m, IH), 1.00-0.92 (dd, 6H); 13C-NMR (100.5 MHz, CDCl3): δ; 172.5, 170.9, 157.4, 138.3, 132.5, 128.8, 128.0, 127.6, 116.6, 113.9, 79.7, 68.6, 67.5, 64.9, 58.6, 58.2, 43.7, 35.6, 30.0, 19.8, 17.7; MS m/z 562.11 [(M+H)+ calcd for C25H33BrN5O5 + 562.16].
Step i
Figure imgf000060_0002
N-r(16'.26'.4i?)-4-((y)-l-Benzylcarbamoyl-2-methyl-propylcarbamovπ-l-(4-bromo- phenoxymethyO -2-hydroxy-4-methoxy-butyl] -5 -(methanesulphonyl -methyl-aminoViV7 -((R)- 1 - phenyl -ethyO-isophthalamide (3i)
The title compound (18 mg, 0.02 mmol, 50 %) was synthesized by reduction of compound 3h
(71 mg, 0.13 mmol) followed by coupling to the acid 5-methanesulphonyl-methyl-amino)-Λf'-(l- phenyl-ethyl)-isophthalic acid (15 mg, 0.04 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (CDCl3): δ 8.15 (s, IH), 7.92 (s, 2H), 7.36-7.08 (m, 16H), 6.80-6.77 (d, 2H), 5.28-5.20
(m, IH), 4.38-4.30 (m, 2H), 4.27-4.15 (m, 3H), 4.08-4.02 (m, 2H), 3.80-3.73 (m, 2H), 3.41 (s, 3H), 3.30 (s, 3H), 2.80 (s, 3H), 2.30-2.21 (m, IH), 2.06 (bs, IH), 1.96-1.88 (m, IH), 1.57-1.54 (d, 3H), 0.95-0.87 (dd, 6H); 13C-NMR (CDCl3): δ 173.0, 171.0, 166.5, 164.9, 157.6, 143.1, 142.3, 138.2, 136.0, 135.6, 132.5, 128.8, 128.7, 128.0, 127.9, 127.6, 127.5, 126.4, 124.5, 116.7, 113.6, 79.5, 67.1, 66.5, 58.4, 58.3, 53.7, 50.0, 43.6, 38.0, 35.7, 35.6, 30.4, 21.9, 19.7, 17.9; HRMS m/z 894.2742 [(M+H)+ calcd for C43H53BrN5O9S+ 894.2783].
Example 4 Sten a
Figure imgf000061_0001
S-Deoxy-ό-O-G.S-difluorophenyiyi^-O-isopropylidene-D-glucofuranoside ^a^) The epoxide 3a (75.5 mg, 0.41 mmol) and 3,5-difluorophenol (106 mg, 0.81 mmol, 2 eq.) were dissolved in DMF (5 mL), K2CO3 (14 mg, 0.10 mmol, 0.25 eq.) was added and the reaction mixture was heated to 110 0C and stirred at that temperature over night. The solvent was removed by co -evaporation with toluene. The residue was purified by column chromatography (toluene/ ethyl acetate 15:1) which gave the title compound (91 mg, 0.29 mmol, 71%). 1H-NMR (400 MHz, CDCl3): 56.47-6.39 (m, 3H), 5.83-5.81 (d, IH), 4.79-4.75 (t, IH), 4.33- 4.27 (m, IH), 4.17-4.11 (m, IH), 4.07-4.02 (m, IH), 3.97-3.91 (m, IH), 2.53-2.50 (d, IH), 2.19- 2.13 (m, IH), 1.94-1.85 (m, IH), 1.51 (s, 3H), 1.32 (s, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JcF = 15.9 Hz), 162.5 (d,JCF = 15.3 Hz), 160.5 (t, JCF = 13.7 Hz), 111.6, 105.5, 98.6 (dd, JCF = 12.2, 28.2 Hz), 97.0 (t, JCF = 25.9 Hz), 80.7, 78.1, 70.6, 69.9, 34.2, 26.9, 26.2. MS m/z 339.10 [(M+Na)+ calcd for Ci5Hi8F2NaO5 + 339.10].
Figure imgf000061_0002
5-Azido-3.5-dideoxy-6-Q-(3.5-difluorophenylV1.2-Q-isopropylidene-L-/vxo-hexofuranoside (4b).
The title compound (621 mg, 1.82 mmol, 58%) was synthesized from compound 4a (992 mg, 3.14 mmol) according to the method described for the preparation of compound Ib. 1H-NMR (400 MHz, CDCl3): δ 6.49-6.42 (m, 3H), 5.85-6.82 (d, IH), 4.79-4.76 (t, IH), 4.42- 4.36 (m, IH), 4.22-4.17 (m, 2H), 3.77-3.72 (m, IH), 2.16-2.10 (m, IH), 2.02-1.94 (m, IH), 1.51 (s, 3H), 1.33 (s, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF = 15.9 Hz), 162.6 (d,JCF = 16.1 Hz), 160.1 (t, JCF = 13.7 Hz), 111.9, 105.7, 98.7 (dd, JCF = 12.2, 28.9 Hz), 97.3 (t, JCF = 25.9 Hz), 80.4, 69.3, 61.7, 35.4, 27.0, 26.3.
Figure imgf000062_0001
Methyl 5 -azido-3.5-dideoxy-6-O-(3.5-difluorvphenylVL-/vxo-hexofuranoside (4c) The title compound (1.857 g, 5.86 mmol, 85%) was synthesized from compound 4b (2.355 g, 6.90 mmol) according to the method described for the preparation of compound Ic. 1H-NMR (400 MHz, CDCl3): δ 6.49-6.41 (m, 3H), 4.85 (s, IH), 4.56-4.50 (m, IH), 4.32-4.28 (t, IH), 4.10-4.01 (m, 2H), 3.73-3.67 (m, IH), 3.41 (s, 3H), 2.17-2.09 (m, IH), 2.02-1.95 (m, IH), 1.73-1.70 (d, IH); 13C-NMR (100.5 MHz, CDCl3): δ; 165.0 (d, JCF = 15.3 Hz), 162.5 (d, JCF = 16.1 Hz), 160.1 (t, JCF = 13.7 Hz), 109.6, 98.6 (dd, JCF = 12.2, 28.9 Hz), 97.2 (t, JCF = 25.9 Hz), 79.0, 75.8, 68.6, 64.7, 55.2, 35.0.
Step d
Figure imgf000062_0002
Methyl 5-azido-3.5-dideoxy-6-O-(3.5-difluorophenyπ-2-Q-methyl-L-/vxo-hexofuranoside (4d") The title compound (1.249 g, 3.77 mmol, 64%) was synthesized from compound 4c (1.857 g, 5.89 mmol) according to the method described for the preparation of compound Id. 1H-NMR (400 MHz, CDCl3): δ 6.49-6.41 (m, 3H), 4.92 (s, IH), 4.47-4.40 (m, IH), 4.10-4.02 (m, 2H), 3.83-3.78 (m, IH), 3.71-3.66 (m, IH), 3.41 (s, 3H), 3.37 (s, 3H), 2.06-2.02 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d,JCF = 15.9 Hz), 162.6 (d, JCF = 15.9 Hz), 160.2 (t, JCF = 13.7 Hz), 106.9, 98.5 (dd, JcF = 12.2, 28.2 Hz), 97.3 (t, JCF = 25.9 Hz), 84.7, 79.2, 68.8, 64.4, 57.2, 55.3.
Step e
Figure imgf000063_0001
5-Azido-3r5-dideoxy-6-O-Gr5-difluorophenylV2-O-methyl-L-/vxo-hexofuranoside (4e) The title compound (1.60 g, 3.68 mmol, 97%) was synthesized from compound 4d (1.249 g, 3.79 mmol) according to the method described for the preparation of compound Ie. 1H-NMR (300 MHz, CDCl3): δ 6.49-6.41 (m, 3H), 5.35-5.32 (d, IH), 4.49-4.41 (m, IH), 4.20- 4.14 (m, 2H), 3.84-3.76 (m, 2H), 3.38 (s, 3H), 3.11-3.07 (d, IH), 2.23-2.04 (m, 2H); 13C-NMR (75.5 MHz, CDCl3): δ 165.4 (d, JCF = 15.8 Hz), 162.1 (d, JCF = 15.8 Hz), 160.0 (t, JCF = 13.7 Hz), 100.4, 98.5 (dd, JCF = 9.4, 27.8 Hz), 97.4, 97.3 (t, JCF = 26.1 Hz), 85.5, 85.5, 78.6, 69.5, 63.5, 57.2, 31.6.
Figure imgf000063_0002
5-Azido-3,5-dideoxy-6-Q-(3,5-difluorophenyl)-2-Q-methyl-L-/vxo-l,4-lactone (4f) The title compound (222 mg, 0.707 mmol, 63%) was synthesized from compound 4e (354 mg, 1.12 mmol) according to the method described for the preparation of compound If. 1H-NMR (400 MHz, CDCl3): δ 6.50-6.41 (m, 3H), 4.80-4.75 (m, IH), 4.24-4.21 (d, 2H), 4.21- 4.16 (m, IH), 3.94-3.89 (m, IH), 2.56-2.48 (m, IH), 2.39-2.31 (m, IH); 13C-NMR (100.5 MHz, CDCl3): δ 173.7, 165.1 (d,JCF = 15.3 Hz), 162.6 (d, JCF = 15.3 Hz), 159.7 (t, JCF = 13.7 Hz), 98.7 (dd, JCF = 12.2, 28.9 Hz), 97.7 (t, JCF = 25.9 Hz), 75.8, 74.8, 68.6, 62.8, 58.6, 32.5; MS m/z 336.08 [(M+Na)+ calcd for C13H13F2N3NaO4 + 336.07].
Figure imgf000063_0003
(2i?r4£r5ΛV5-Azido-6-(3r5-difluoro-phenoxyV4-hydroxy-2-methoxy-hexanoic acid ((SV 1- benzylcarbamoyl-2-methyl-propylVamide (4g)
The title compound (180 mg, 0.348 mmol, 97%) was synthesized by opening of the lactone 4f (112.5 mg, 0.3591 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
1H-NMR (400 MHz, CDCl3): δ 7.33-7.22 (m, 5H), 7.04-6.99 (d, IH), 6.89-6.84 (t, IH), 6.49- 6.38 (m, 3H), 4.43-4.39 (d, 2H), 4.32-4.27 (m, IH), 4.07-4.03 (m, IH), 3.99-3.87 (m, 3H), 3.67- 3.62 (m, IH), 3.46 (s, 3H), 2.74-2.70 (d, IH), 2.44-2.35 (m, IH), 2.20-2.12 (m, IH), 1.98-1.90 (m, IH), 1.00-0.92 (dd, 6H); 13C-NMR (100.5 MHz, CDCl3): δ 172.5, 170.9, 165.0 (d, JCF = 15.3 Hz), 162.6 (d, JcF = 15.3 Hz), 160.1 (t, JCF = 13.7 Hz), 128.9, 128.0, 127.7, 98.6 (dd,JCF = 12.2, 28.2 Hz), 97.3 (t, JCF = 25.9 Hz), 79.7, 68.9, 67.4, 64.7, 58.6, 58.3, 43.7, 35.6, 30.0, 19.8, 17.7; MS m/z 520.24 [(M+H)+ calcd for C25H32F2N5O5 + 520.24].
Step h
Figure imgf000064_0001
N-\( 1 S 2SAR V 4-(CSV 1 -Benzylcarbamoyl-2-methyl-propylcarbamovn- 1 -(3.5 -difluoro- phenoxymethyl)-2-hvdroxy-4-methoxy-butyll -5 -(methanesulphonyl -methyl-amino ViV7 -((R)- 1 - phenyl -ethyl Visophthalamide (4h)
The title compound (33 mg, 0.04 mmol, 81 %) was synthesized by reduction of the azide of compound 4g (50 mg, 0.10 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (18 mg, 0.05 mmol), as described for the preparation of compound Ii.
HRMS m/z 852.3448 [(M+H)+ calcd for C43H52F2N5O9S+ 852.3448].
Example 5 Step a
Figure imgf000064_0002
3-Deoxy-6-Q-phenyl- 1.2-Q-isopropylidene-D-glucofuranoside (5a") The epoxide 3a (376 mg, 2.02 mmol) and phenol (380 mg, 4.04 mmol, 2 eq.) were dissolved in DMF (10 rnL), K2CO3 (70 mg, 0.50, 0.25 eq.) was added and the reaction mixture was heated to 110 0C and stirred at that temperature over night. The solvent was removed by co -evaporation with toluene. The residue was purified by column chromatography (toluene/ ethyl acetate 20:1) which gave the title compound (424 mg, 1.51 mmol, 75%).
1H-NMR (400 MHz, CDCl3): δ 7.31-7.25 (t, 2H), 6.99-6.93 (t, IH), 6.93-6.89 (d, 2H), 5.84-5.82 (d, IH), 4.79-4.75 (t, IH), 4.37-4.31 (m, IH), 4.20-4.13 (m, IH), 4.12-4.07 (m, IH), 4.01-3.95 (m, IH), 2.52-2.49 (d, IH), 2.21-2.14 (m, IH), 1.97-1.88 (m, IH), 1.52 (s, 3H), 1.33 (s, 3H); 13C- NMR (100.5 MHz, CDCl3): δ; 158.5, 129.6, 121.4, 114.7, 111.5, 105.5, 80.7, 78.4, 70.8, 69.2, 34.2, 26.9, 26.3. MS m/z 303.12 [(M+Na)+ calcd for Ci5H20NaO5 + 303.12].
Step b
Figure imgf000065_0001
5-Azido-3.5-dideoxy-6-Q-phenyl-1.2-Q-isopropylidene-L-/vxo-hexofuranoside (5b") The title compound (396 mg, 1.30 mmol, 68 %) was synthesized from compound 5a (534 mg,
1.90 mmol) according to the method described for the preparation of compound Ib. 1H-NMR (300 MHz, CDCl3): δ 7.43-7.34 (t, 2H), 7.02-6.91 (m, 3H), 5.86-5.82 (d, IH), 4.78- 4.74 (t, IH), 4.45-4.38 (m, IH), 4.26-4.20 (m, 2H), 3.79-3.72 (m, IH), 2.17-2.09 (m, IH), 2.02-
1.91 (m, IH), 1.52 (s, 3H), 1.33 (s, 3H); 13C-NMR (75.5 MHz, CDCl3): δ 158.2, 129.6, 121.5, 114.7, 111.7, 105.7, 80.3, 77.3, 68.6, 62.0, 35.4, 26.9, 26.2.
Step c
Figure imgf000065_0002
Methyl 5 -azido-3.5-dideoxy-6-Q-phenyl-L-/vxo-hexofuranoside f5c")
The title compound (356 mg, 1.27 mmol, 98%) was synthesized from compound 5b (396 mg, 1.30 mmol) according to the method described for the preparation of compound Ic. 1H-NMR (300 MHz, CDCl3): δ 7.33-7.27 (t, 2H), 7.02-6.95 (t, IH), 6.95-6.89 (d, 2H), 4.85 (s, IH), 4.60-4.51 (m, IH), 4.31-4.26 (t, IH), 4.12-4.04 (m, 2H), 3.73-3.65 (m, IH), 3.41 (s, 3H), 2.19-2.08 (m, IH), 2.03-1.95 (m, IH), 1.90-1.87 (d, IH); 13C-NMR (75.5 MHz, CDCl3): δ 158.3, 129.7, 121.6, 114.7, 109.5, 79.3, 75.9, 68.1, 65.2, 55.2, 35.2. tep d
Figure imgf000066_0001
Methyl 5-azido-3.5-dideoxy-6-O-phenyl-2-O-methyl-L-/vxo-hexofuranoside (5d) The title compound (186 mg, 0.64 mmol, 90%) was synthesized from compound 5c (198 mg, 0.71 mmol) according to the method described for the preparation of compound Id. 1H-NMR (400 MHz, CDCl3): δ 7.32-7.26 (t, 2H), 7.01-6.95 (t, IH), 6.94-6.90 (d, 2H), 4.93 (s, IH), 4.50-4.43 (m, IH), 4.14-4.06 (m, 2H), 3.82-3.78 (t, IH), 3.72-3.66 (m, IH), 3.41 (s, 3H), 3.37 (s, 3H), 2.07-2.03 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 158.4, 129.7, 121.6, 114.7, 106.8, 84.8, 79.5, 68.2, 64.9, 57.1, 55.2, 32.4.
Step e
Figure imgf000066_0002
5-Azido-3.5-dideoxy-6-O-phenyl-2-O-methyl-L-/vxo-hexofuranoside (5e)
The title compound (175 mg, 0.626 mmol, 59%) was synthesized from compound 5d (314 mg,
1.07 mmol) according to the method described for the preparation of compound Ie.
1H-NMR (300 MHz, CDCl3): δ; 7.32-7.26 (t, 2H), 7.01-6.95 (t, IH), 6.95-6.90 (d, 2H), 5.35-5.32
(d, IH), 4.51-4.43 (m, IH), 4.24-4.19 (m, 2H), 3.82-3.77 (m, 2H), 3.38 (s, 3H), 3.23-3.20 (d,
IH), 2.22-2.06 (m, 2H); 13C-NMR (75.5 MHz, CDCl3): δ; 158.2, 129.7, 121.6, 114.7, 100.4,
85.6, 78.8, 69.0, 63.9, 57.1, 31.7.
Figure imgf000066_0003
5-Azido-3.5-dideoxy-6-(9-phenyl-2-(9-methyl-L-/vx(9-1.4-lactone (5f)
The title compound (125 mg, 0.450 mmol, 72%) was synthesized from compound 5e (175 mg,
0.626 mmol) according to the method described for the preparation of compound If. 1H-NMR (300 MHz, CDCl3): δ 7.34-7.27 (t, 2H), 7.03-6.97 (t, IH), 6.94-6.89 (d, 2H), 4.83-4.76 (m, IH), 4.30-4.24 (d, 2H), 4.24-4.16 (m, IH), 3.94-3.87 (m, IH), 3.57 (s, 3H), 2.57-2.47 (m, IH), 2.38-2.29 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ 173.9, 157.9, 129.8, 121.9, 114.6, 76.1, 74.8, 67.9, 63.0, 58.5, 32.4; [(M+Na)+ calcd for Ci3Hi5N3NaO4 + 300.10].
Figure imgf000067_0001
(2i?,4£,55V5-Azido-6-phenoxy-4-hydroxy-2-methoxy-hexanoic acid ((S)-l-benzylcarbamoyl-2- methyl-propyD-amide (5g)
The title compound (22 mg, 0.045 mmol, 30%) was synthesized by opening of the lactone 5f (43 mg, 0.155 mmol) with the amine Ig according to the method described for the preparation of compound Ih.
1H-NMR (300 MHz, CDCl3): δ 7.33-7.20 (m, 7H), 7.06-6.96 (m, 3H), 6.91-6.86 (d, 2H), 4.42-
4.37 (d, 2H), 4.34-4.28 (m, IH), 4.15-4.09 (m, IH), 4.07-3.99 (m, IH), 4.00-3.91 (m, IH), 3.90-
3.85 (m, IH), 3.67-3.61 (m, IH), 3.45 (s, 3H), 2.68-2.63 (d, 2H), 2.48-2.34 (m, IH), 2.22-2.10
(m, IH), 1.98-1.89 (m, IH), 1.00-0.91 (dd, 6H); 13C-NMR (75.5 MHz, CDCl3): δ; 172.5, 170.9,
158.2, 138.3, 129.7, 128.8, 128.0, 127.6, 121.6, 114.8, 79.6, 68.3, 67.5, 65.0, 58.5, 58.2, 43.7,
35.6, 29.9, 19.8, 17.6; MS m/z 484.26 [(M+H)+ calcd for C25H34N5O5 + 484.26].
Figure imgf000067_0002
N ~ -\i\S{lS,AR )-4-((ιS)-l -Benzylcarbamoyl-2 -methyl -propylcarbamoyD- 1 -phenoxymethyl-2- hydroxy-4-methoxy-butyl] -5 -f methanesulphonyl-methyl-amino )-N' -((R )- 1 -phenyl-ethyD- isophthalamide (5K)
The title compound (19 mg, 0.02 mmol, 58 %) was synthesized by reduction of the azide of compound 5g (123 mg, 0.25 mmol) followed by coupling to 5 -methanesulphonyl -methyl - amino)-7V'-(l-phenyl-ethyl)-isophthalic acid (15 mg, 0.04 mmol), according to the method described for the preparation of compound Ii. 1H-NMR (CDCl3): δ 8.21 (s, IH), 7.98 (s, IH), 7.96 (s, IH), 7.64-7.56 (m, 2H), 7.38-7.10 (m, 4H), 6.98-6.89 (m, 3H), 5.28-5.22 (m, IH), 4.44-4.37 (m, 2H), 4.35-4.24 (m, 2H), 4.20-4.09 (m, 3H), 3.89-3.85 (m, IH), 3.45 (s, 3H), 3.30 (s, 3H), 2.81 (s, 3H), 2.29-2.14 (m, 2H), 2.05 (s, IH), 1.62-1.57 (d, 3H), 0.96-0.88 (dd, 6H); 13C-NMR (CDCl3): δ 173.1, 171.0, 166.6, 165.0, 158.4, 143.2, 142.3, 138.3, 136.0, 135.7, 129.7, 128.8, 128.7, 128.0, 127.9, 127.6, 127.5, 126.4, 124.4, 121.5, 114.8, 79.5, 67.1, 67.0, 58.4, 58.3, 53.8, 50.0, 43.6, 38.0, 35.7, 35.5, 30.4, 21.9, 19.7, 17.8; HRMS m/z 816.3637 [(M+H)+ calcd for C43H54NSaS+ 816.3650].
Example 6 Sten a
Figure imgf000068_0001
r2i?.46'.5y)-5-Azido-6-r3.5-difluoro-phenoxyV4-hydroxy-2-methoxy-hexanoic acid cyclopropylamide f6a)
The title compound (16.3 mg, 0.046 mmol, 82%) was synthesized by opening of the lactone 4f
(17.4 mg, 0.056 mmol) according to the method described for the preparation of compound Ih but using cyclopropylamine instead of the amine Ig.
1H-NMR (400 MHz, CDCl3): δ 6.63-6.60 (bs, IH), 6.47-6.40 (m, 3H), 4.24-4.13 (m, 2H), 4.06-
4.00 (m, IH), 3.90-3.86 (t, IH), 3.70-3.65 (m, IH), 3.41 (s, 3H), 3.29 (bs, IH), 2.78-2.71 (m,
IH), 2.18-2.09 (m, IH), 1.94-1.87 (m, IH), 0.84-0.78 (m, 2H), 0.58-0.49 (m, 2H); 13C-NMR
(100.5 MHz, CDCl3): δ 173.6, 165.1 (d, JCF = 15.3 Hz), 162.7 (d, JCF = 15.9 Hz), 160.3 (t, JCF =
13.7 Hz), 98.7 (dd, JcF = 12.2, 28.2 Hz), 97.2 (t, JCF = 25.9 Hz), 80.7, 68.9, 68.8, 64.5, 58.6,
36.3, 22.4, 6.77, 6.71; MS m/z 393.14 [(M+Na)+ calcd for Ci6H20F2N4NaO4 + 393.14].
Figure imgf000068_0002
N-\( 1 S, 2SAR V 4-Cyclopropylcarbamoyl- 1 -(3.5 -difluoro-phenoxymethyO-2-hydroxy- 4-methoxy- butyl]-5-(methanesulphonyl-methyl-amino)-Λr-((i?)-l-phenyl-ethvπ-isophthalamide (6b) The title compound (26 mg, 0.04 mmol, 76 %) was synthesized by reduction of the azide of compound 6a (18 mg, 0.05 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (19 mg, 0.05 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (300 MHz, CDCl3): δ 8.16 (s, IH), 7.97 (s, IH), 7.94 (s, IH), 7.40-7.20 (m, 6H), 7.06- 7.01 (d, IH), 6.72-6.69 (d, IH), 6.50-6.35 (m, 3H), 5.34-5.24 (m, IH), 4.46-4.35 (m, IH), 4.26- 4.19 (m, IH), 4.19-4.04 (m, 2H), 3.80-3.74 (t, IH), 3.37 (s, 3H), 3.33 (s, 3H), 2.85 (s, 3H), 2.73- 2.62 (m, IH), 2.09-1.97 (m, 2H), 1.94-1.81 (m, IH), 1.63-1.55 (d, 3H), 0.78-0.71 (m, 2H), 0.54- 0.47 (m, 2H); HRMS m/z 703.2608 [(M+H)+ calcd for C34H4iF2N4O8S+703.2584].
Example 7 Step a
Figure imgf000069_0001
(2i?.46'.5y)-5-Azido-6-(3.5-difluoro-phenoxy)-4-hvdroxy-2-methoxy-hexanoic acid 2-methyl- propylamide (7a)
The title compound (30.6 mg, 0.079 mmol, 80%) was synthesized by opening of the lactone 4f (31.1 mg, 0.099 mmol) according to the method described for the preparation of compound Ih but using isobutylamine instead of the amine Ig.
1H-NMR (300 MHz, CDCl3): δ; 6.67-6.60 (m, IH), 6.48-6.39 (m, 3H), 4.24-4.11 (m, 2H), 4.08- 4.00 (m, IH), 3.94-3.88 (t, IH), 3.72-3.64 (m, IH), 3.45 (s, 3H), 3.33 (s, IH) 3.17-3.09 (m, 2H), 2.20-2.08 (m, IH), 1.97-1.86 (m, IH), 1.86-1.74 (m, IH), 0.94 (s, 3H), 0.92 (s, 3H); 13C-NMR (75.5 MHz, CDCl3): δ; 172.0, 165.4 (d, JCF = 15.8 Hz), 162.1 (d, JCF = 15.8 Hz), 160.2 (t, JCF = 13.7 Hz), 98.6 (dd, 9.4, 28.9 Hz), 97.1 (t, JCF = 25.8 Hz), 80.9, 68.9, 68.8, 64.4, 58.6, 46.4, 36.6, 28.7, 20.2, 20.1; MS m/z 409.17 [(M+Na)+ calcd for C17H24F2N4NaO4 + 409.17].
Figure imgf000069_0002
N-[rLS'r2tS'r4i?Vl-r3r5-Difluoro-phenoxymethyπ-2-hydroxy-4-isobutylcarbamoyl-4-methoxy- butyl]-5-rmethanesulphonyl-methyl-aminoVΛr-rri?Vl-phenyl-ethylVisophthalamide (7b") The title compound (32 mg, 0.04 mmol, 64 %) was synthesized by reduction of the azide of compound 7a (31 mg, 0.08 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (25 mg, 0.07 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (400 MHz, CDCl3): δ 8.16 (s, IH), 7.97 (s, IH), 7.93 (s, IH), 7.40-7.21 (m, 6H), 7.09- 7.02 (d, IH), 6.73-6.66 (m, IH), 6.52-6.35 (m, 3H), 5.35-5.23 (m, IH), 4.45-4.35 (m, IH), 4.28- 4.20 (m, IH), 4.17-4.04 (m, 2H), 3.93-3.88 (d, IH), 3.84-3.77 (t, IH), 3.41 (s, 3H), 3.32 (s, 3H), 3.17-2.96 (m, 2H), 2.84 (s, 3H), 2.04 (bs, IH), 1.91-1.70 (m, 2H), 1.63-1.56 (d, 3H), 0.94-0.86 (d, 6H); 13C-NMR (100.5 MHz, CDCl3): δ 172.4, 166.3, 165.0 (d, JCF = 15.9 Hz), 164.7, 162.5 (d, JCF = 15.9 Hz), 160.4 (t, JCF = 13.7 Hz), 143.0, 142.4, 136.2, 135.6, 128.9, 127.9, 127.8, 127.7, 126.4, 124.3, 98.7 (dd, JcF = 12.2, 28.9 Hz), 96.9 (t, JCF = 25.9 Hz), 80.7, 67.1, 67.0, 58.6, 53.0, 49.9, 46.5, 38.1, 36.7, 35.7, 28.6, 21.8, 20.2, 20.2.
Example 8 Sten a
Figure imgf000070_0001
(2i?.46'.5y)-5-Azido-6-(3.5-difluoro-phenoxy)-4-hvdroxy-2-methoxy-hexanoic acid benzylamide
(M
The title compound (45.5 mg, 0.108 mmol, 79%) was synthesized by opening of the lactone 4f
(43 mg, 0.137 mmol) according to the method described for the preparation of compound Ih but using benzylamine instead of the amine Ig..
1H-NMR (300 MHz, CDCl3): δ 7.38-7.24 (m, 5H), 6.96-6.88 (m, IH), 6.50-6.40 (m, 3H), 4.52-
4.45 (m, 2H), 4.23-4.14 (m, 2H), 4.10-4.02 (m, IH), 4.00-3.94 (t, IH), 3.73-3.66 (m, IH), 3.43
(s, 3H), 3.38-3.33 (d, IH), 2.24-2.12 (m, IH), 2.02-1.92 (m, IH); 13C-NMR (75,5 MHz, CDCl3): δ; 172.0, 165.4 (d, JCF = 15.8 Hz), 162.2 (d,JCF = 15.8 Hz), 160.2 (t, JCF = 13.4 Hz), 137.8,
129.0, 127.9, 127.8, 198.6 (dd, JCF = 9.4, 28.9 Hz), 97.2 (t, JCF = 25.8 Hz), 80.7, 68.8, 68.8, 64.4,
58.6, 43.2, 36.4; MS m/z 443.15 [(M+Na)+ calcd for C20H22F2N4NaO4 + 443.15].
Figure imgf000071_0001
N-[ri6'.26'.4i?V4-Benzylcarbamoyl-l-r3.5-difluoro-phenoxymethylV2-hydroxy-4-methoxy- butyl]-5-rmethanesulphonyl-methyl-aminoVΛr-rri?Vl-phenyl-ethylVisophthalamide (Sb) The title compound (49 mg, 0.07 mmol, 61%) was synthesized by reduction of the azide of compound 8a (46 mg, 0.11 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (41 mg, 0.11 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (400 MHz, CDCl3): δ 8.17 (s, IH), 7.98 (s, IH), 7.94 (s, IH), 7.39-7.21 (m, HH), 7.08- 7.04 (d, IH), 7.02-6.96 (t, IH), 6.49-6.36 (m, 3H), 5.34-5.25 (m, IH), 4.51-4.33 (m, 3H), 4.29- 4.24 (d, IH), 4.15-4.04 (m, 2H), 3.89-3.84 (t, IH), 3.38 (s, 3H), 3.32 (s, 3H), 2.83 (s, 3H), 2.12- 2.03 (m, 2H), 1.95-1.87 (m, IH), 1.61-1.56 (d, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 172.5,
166.3, 165.0 (d, JcF = 16.1 Hz), 164.8, 162.5 (d,JCF = 16.0 Hz), 160.4 (t, JCF = 13.7 Hz), 143.0,
142.4, 137.7, 136.2, 135.6, 129.0, 128.9, 128.0, 127.9, 127.8, 127.7, 126.4, 124.3, 98.7 (dd, JCF = 12.2, 28.2 Hz), 96.9 (t, JCF = 25.9 Hz), 80.4, 67.2, 67.0, 58.6, 53.1, 49.9, 43.3, 38.1, 36.4, 35.7, 21.8.
Example 9 Step a
Figure imgf000071_0002
(2i?.46'.5y)-5-Azido-6-(3.5-difluoro-phenoxy)-4-hvdroxy-2-methoxy-hexanoic acid anilineamide
(M
The title compound (21.3 mg, 0.052 mmol, 39%) was synthesized by opening of the lactone 4f
(42 mg, 0.134 mmol) according to the method described for the preparation of compound Ih but using aniline instead of the amine Ig.
1H-NMR (300 MHz, CDCl3): δ 8.32 (s, IH), 7.60-7.54 (d, 2H), 7.39-7.31 (t, 2H), 7.19-7.12 (t,
IH), 6.50-6.40 (m, 3H), 4.25-4.15 (m, 2H), 4.15-4.07 (m, IH), 4.07-4.00 (t, IH), 3.55 (s, 3H),
3.15-3.05 (bs, IH), 2.32-2.21 (m, IH), 2.07-1.97 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ
170.2, 165.4 (d, JCF = 15.8 Hz), 162.1 (d,JCF = 15.8 Hz), 160.1 (t, JCF = 13.4 Hz), 137.0, 129.3, 125.1, 120.0, 98.6 (dd, JcF = 9.4, 28.9 Hz), 97.2 (t, JCF = 25.8 Hz), 80.8, 68.9, 68.7, 64.5, 58.8, 36.4; MS m/z 429.14 [(M+Na)+ calcd for Ci9H20F2N4NaO4 + 429.14].
Figure imgf000072_0001
N-[ri6'.26'.4i?Vl-r3.5-difluoro-phenoxymethylV2-hydroxy-4-methoxy-4-phenylcarbamoyl- butyl]-5-rmethanesulphonyl-methyl-aminoVΛr-rri?Vl-phenyl-ethylVisophthalamide T9tΛ The title compound (31 mg, 0.04 mmol, 81%) was synthesized by reduction of the azide of compound 9a (21 mg, 0.05 mmol) followed by coupling to 5-methanesulphonyl-methyl-amino)- jV'-(l-phenyl-ethyl)-isophthalic acid (20 mg, 0.05 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (400 MHz, CDCl3): δ 8.43 (s, IH), 8.15 (s, IH), 7.92 (s, IH), 7.63-7.40 (m, 5H), 7.36- 7.22 (m, 5H), 7.19-7.07 (m, 3H), 6.45-6.35 (m, 3H), 5.28-5.20 (m, IH), 4.45-4.38 (m, IH), 4.34- 4.28 (m, IH), 4.13-4.03 (m, 2H), 3.95-3.90 (t, IH), 3.46 (s, 3H), 3.24 (s, 3H), 2.79 (s, 3H), 2.34 (s, IH), 2.16-2.07 (m, IH), 2.02-1.95 (m, IH), 1.56-1.51 (d, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 170.7, 166.5, 164.9 (d,JCF = 16.2 Hz), 164.9, 162.5 (d,JCF = 15.3 Hz), 160.3 (t, JCF = 13.7 Hz), 143.0, 142.3, 137.0, 136.1, 135.5, 132.2, 132.1, 129.2, 128.8, 128.7, 128.6, 128.0, 127.6, 126.4, 125.0, 124.4, 120.2, 98.6 (dd, JcF = 12.2, 28.2 Hz), 96.9 (t, JCF = 25.9 Hz), 80.7, 67.3, 67.2, 58.7, 53.1, 50.0, 38.0, 36.2, 35.7, 21.7; MS m/z 520.24 [(M+H)+ calcd for C25H32F2N5O5 + 520.24]
Example 10 Step a
Figure imgf000072_0002
(2i?,4ιS,561-5-Azido-6-(3,5-difluoro-phenoxy)-4-hvdroxy-2-methoxy-hexanoic acid 4-fluoro- anilineamide (IQa) The title compound (26 mg, 0.062 mmol, 43%) was synthesized by opening of the lactone 4f (45 mg, 0.144 mmol) according to the method described for the preparation of compound Ih but using 4-fluoroanilineinstead of the amine Ig.
1H-NMR (300 MHz, CDCl3): δ 8.31 (s, IH), 7.56-7.49 (m, 2H), 7.08-6.99 (m, 2H), 6.49-6.40 (m, 3H), 4.25-4.13 (m, 2H), 4.13-4.06 (m, IH), 4.06-4.01 (t, IH), 3.75-3.69 (m, IH), 2.32-2.21 (m, IH), 2.06-1.97 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ 170.2, 165.4 (d, JCF = 15.8 Hz), 162.1 (d, JCF = 15.8 Hz), 161.4, 160.1 (t, JCF = 13.7 Hz), 158.2, 133.0, 121.8 (d,JCF = 7.7 Hz), 115.9 (d, JCF = 22.7 Hz), 98.6 (dd,JCF = 9.4, 28.9 Hz), 97.2 (t, JCF = 25.8 Hz), 80.6, 68.9, 68.6, 64.5, 58.8, 36.2; MS m/z 447.13 [(M+Na)+ calcd for Ci9Hi9F3N4NaO4 + 447.13].
Step b
Figure imgf000073_0001
N-[(lSr2Sr4R V 1 -r3r5-difluoro-phenoxymethyπ-4-r4-fluoro-phenylcarbamoylV2 -hydroxy-4 - methoxy-butyl]-5-rmethanesulphonyl-methyl-aminoVΛr-rri?Vl -phenyl-ethylVisophthalamide am
The title compound (20 mg, 0.03 mmol, 43%) was synthesized by reduction of the azide of compound 10a (26 mg, 0.06 mmol) followed by coupling to 5 -methanesulphonyl-methyl- amino)-iV'-(l-phenyl-ethyl)-isophthalic acid (23 mg, 0.06 mmol), according to the method described for the preparation of compound Ii.
1H-NMR (400 MHz, CDCl3): δ 8.40 (s, IH), 8.14 (s, IH), 7.93 (s, IH), 7.64-7.41 (m, 4H), 7.37- 7.16 (m, 5H), 7.03-6.94 (m, 3H), 6.47-6.36 (m, 3H), 5.30-5.22 (m, IH), 4.45-4.38 (m, IH), 4.35- 4.29 (m, IH), 4.14-4.04 (m, 2H), 3.96-3.91 (t, IH), 3.48 (s, 3H), 3.27 (s, 3H), 2.18 (s, 3H), 2.35 (s, IH), 2.17-2.07 (m, IH), 2.02-1.95 (m, IH), 1.57-1.53 (d, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 170.7, 166.5, 165.1 (d,JCF = 15.9 Hz), 165.0, 162.6 (d,JCF = 15.9 Hz), 161.1, 160.4 (t, JCF = 13.7 Hz), 158.7, 143.0, 142.4, 136.2, 135.6, 133.1, 132.3 (d, JCF = 10.8 Hz), 129.0, 128.1, 128.0, 127.8, 126.5, 124.4, 122.1 (d, JcF = 9.2 Hz), 115.9 (d,JCF = 24.3 Hz), 98.7 (dd, JcF = 12.3, 28.9 Hz), 97.1 (t, JCF = 25.9 Hz), 80.8, 67.4, 58.8, 53.2, 50.1, 38.1, 36.3, 35.8, 29.9, 21.8; HRMS m/z 757.2514 [(M+H)+ calcd for C37H40F3N4O8S+ 757.2519].
Example 1
Figure imgf000074_0001
N-\( 1 S.2SAR V 4-f CSV 1 -Benzylcarbamoyl^-methyl-propylcarbamoyl)- 1 -(3.5 -difluoro- benzyloxymethyl) -2-hvdroxy-4-methoxy-butyl]-,/V' JV -dipropyl-isophthalamide (11) The title compound (17 mg, 0.02 mmol, 72 %) was synthesized by reduction of the azide of compound 2g (32 mg, 0.06 mmol) followed by coupling to N,N-dipropyl-isophthalamic acid (8 mg, 0.03 mmol), according to the method described for the preparation of compound Ii. 1H-NMR (500 MHz, CDCl3): δ 7.86-7.76 (m, 2H), 7.51-7. 31 (m , 3H), 7.31-7.09 (m, 7H), 6.88- 6.69 (m, 3H), 4.64-4.40 (m, 3H), 4.36-4.19 (m, 3H), 3.91-3.82 (m, 2H), 3.68-3.62 (m, 2H), 3.50- 3.38 (m, 4H), 3.20-2.90 (m, 4H), 2.38-2.30 (m, IH), 2.17-1.97 (m, 2H), 1.72-1.62 (m, 2H), 1.59- 1.45 (m, 2H), 1.00-0.80 (m, 9H), 0.80-0.70 (m, 3H); HRMS m/z 739.3900 [(M+H)+ calcd for C40H53F2N4O7 + 739.3877]
Example 12
Figure imgf000074_0002
N-r(16'.2tS'.4i?)-4-((SVl-Benzylcarbamoyl-2-methyl-propylcarbamovn -l-(3.5-difluoro- phenoxymethyl) -2-hydroxy-4-methoxy-butyll -TV JV -dipropyl-isophthalamide (12) The title compound (11 mg, 0.02 mmol, 30 %) was synthesized by reduction of the azide of compound 4g (50 mg, 0.10 mmol) followed by coupling to N,N-dipropyl-isophthalamic acid (13 mg, 0.05 mmol), according to the method described for the preparation of compound Ii. 1H-NMR (500 MHz, CDCl3): δ 7.91-7.80 (m, 2H), 7.67-7.60 (m, IH), 7.49-7.41 (m, IH), 7.39- 7.37 (m, IH), 7.30-7.15 (m, 6H), 7.08-7.04 (d, IH), 6.48-6.40 (m, 3H), 5.17-5.14 (m, IH), 4.90- 4.75 (m, 3H), 4.53-4.43 (m, 2H), 4.37-4.33 (m, IH), 4.28-4.00 (m, 4H), 3.95-3.81 (m, IH), 3.45 (s, 3H), 3.39-3.31 (m, 2H), 3.18-3.10 (m, 2H), 2.40-2.29 (m, IH), 2.17-1.99 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.48 (m, 2H), 0.96-0.84 (m, 9H), 0.77-0.70 (m, 3H); δ; HRMS m/z 725.3752 [(M+H)+ calcd for C39H51F2N4O7 + 725.3752]
Example 13 Step a
Figure imgf000075_0001
3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butγi ester (13a) 3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid (0.75 g, 4.8 mmol) was dissolved in dichloromethane (DCM) (48 rnL). Tert-butyi 2,2,2 -trichloroacetimidate (3.2 g, 14.5 mmol) was added and the reaction mixture was stirred for 23 h. The solution was concentrated and purified using flash column chromatography (toluene/ethyl acetate 9:1). The title compound was collected as white crystals (0.73 g, 71 %).
1H-NMR (SOO MHz, CDCl3): δ 1.41 (s, 9H), 1.87 (d, J = 10.5 Hz, IH), 2.08-2.14 (m, 3H), 2.74- 2.79 (m, IH), 3.05 (s, IH), 4.91 (bs, IH); 13C-NMR (75.5 MHz, CDCl3): δ 28.1, 33.3, 38.0, 40.8, 46.2, 80.7, 81.9, 171.8, 176.8.
Figure imgf000075_0002
(lR2RAS)-l-Tert-butγ\ 2-methyl 4-hydroxycyclopentane-1.2-dicarboxylate (13b) 3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butyi ester (72 mg, 0.34 mmol) was dissolved in methanol (3 mL) and cooled to 0 0C. Potassium carbonate (70 mg, 0.50 mmol) was added and the reaction mixture was stirred for 30 min. Then the solution was neutralized with 1 M HCl and concentrated. Purificationusing flash column chromatography (toluene/ethyl acetate 3:1) gave the title compound as an oil (82 mg, 99%).
1H-NMR (300 MHz, CDCl3): δ 1.42 (s, 9H), 1.86-1.99 (m, 2H), 2.02-2.11 (m, IH), 2.17-2.27 (m, IH), 2.29 (s, IH), 3.10-3.17 (m, IH), 3.23-3.32 (m, IH), 3.70 (s, 3H), 4.32-4.38 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ 28.1, 38.8, 39.9, 45.4, 46.8, 52.3, 73.1, 80.9, 173.9, 176.5.
Step c
N3
\ O O
(lR*2RAR)-l-tert-buty\ 2-methyl 4-azidocyclopentane-1.2-dicarboxylate (13c) (lR,2R,4S)-l-Tert-buty{ 2-methyl 4-hydroxycyclopentane-l,2-dicarboxylate (648 mg, 2.65 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to 0 0C. PPh3 (1.04 g, 3.96 mmol) and DIAD (1.3 mL, 6.6 mmol) were added and the mixture was stirred for 10 min. Then, DPPA (0.86 niL, 4.0 mmol) was added drop wise and the reaction mixture was stirred for 2 h and 20 min. The solution was concentrated and purified by flash column chromatography (toluene/ethyl acetate 39:l)which gave the title compound as an oil (663 mg, 93 %). 1H-NMR (300 MHz, CDCl3): δ 1.45 (s, 9H), 1.99-2.08 (m, 3H), 2.24-2.35 (m, IH), 3.05-3.13 (m, IH), 3.31 (q, J = 8.4 Hz, IH), 3.70 (s, 3H), 4.07 (quintet, J= 5.1 Hz, IH); 13C-NMR (75.5 MHz, CDCl3): δ 28.1, 35.3, 36.3, 44.9, 46.8, 52.3, 61.7, 81.3, 172.6, 174.9.
Figure imgf000076_0001
(lR2RAR)-l-Tert-buUl 2-methyl 4-aminocvclopentane-1.2-dicarboxylate (13d) (lR,2R,4R)-l-Tert-buty{ 2-methyl 4-azidocyclopentane-l,2-dicarboxylate (80 mg, 0.30 mmol) was dissolved in methanol (4 mL). PPh3 (128 mg, 0.49 mmol) and H2O (3 drops) were added and the reaction mixture was stirred for 23 h. The solution was concentrated and purified by flash column chromatography (methanol/ethyl acetate 1 :9 + 1 % TEA) to give the title compound as an oil, which crystallized upon cooling (69 mg, 96 %).
1 H-NMR (SOO MHZ5 CDCI3): δ 1.43 (s, 9H), 1.54-1.64 (m, IH), 1.71-1.80 (m, IH), 2.02-2.11 (m, IH), 2.21-2.31 (m, IH), 3.04 (q, J = 8.4 Hz, IH), 3.29 (q, J= 8.2 Hz, IH), 3.47 (quintet, J= 6.3 Hz, IH), 3.68 (s, 3H); 13C-NMR (75.5 MHz, CDCl3): δ 28.1, 39.8, 40.0, 45.2, 47.3, 52.1, 52.5, 80.8, 174.0, 175.7.
Step e
/ NH
Figure imgf000076_0002
rii?.2i?.4i?V4-Methanesulphonylamino-cyclopentane-1.2-dicarboxylic acid 1-ferf-butyl ester 2- methyl ester H3e)
(lR,2R,4R)-l-tert-buty{ 2-methyl 4-aminocyclopentane-l,2-dicarboxylate (155 mg, 0.64 mmol) was dissolved in DCM/pyridine (2.1 :0.7 mL) and cooled to 0 0C. Methanesulphonyl chloride (50 μL, 0.64 mmol) was added and the reaction mixture was allowed to reach room temperature. The mixture was stirred over night, concentrated and purified using flash column chromatography (toluene/ethyl acetate 3:1). The title compound was collected as white crystals (154 mg, 75 %). Step f
/ N
Figure imgf000077_0001
(IR .2i?.4i?V 4-f Methanesulphonyl -methyl-aminoV cyclopentane- 1.2-dicarboxylic acid 1 -tert- butyl ester 2 -methyl ester fl3f)
Compound 13e (145 mg, 0.45 mmol) was dissolved in DMF (1.5 mL). Sodium hydride (18 mg, 60 % solution) and methyl iodide (56 μL, 0.9 mmol) were added and the reaction mixture was stirred for 1 h and 20 min. The reaction was quenched with H2O (6 mL) and extracted twice with ethyl acetate (6 mL). The organic layers were pooled, dried with MgSO4 and concentrated. Purificationby flash column chromatography (toluene/ethyl acetate 3:1) gave the title compound as white crystals (143 mg, 95%).
Step g
O
O
7^
Figure imgf000077_0002
(Ii? .2i?.45V4-(Methanesulphonyl-methyl -amino)-2-(Yi?V 1 -phenyl-ethylcarbamoyO- cyclopentanecarboxylic acid methyl ester (13g)
(Ii? ,2i?,4i?)-4-(Methanesulphonyl -methyl-amino)-cyclopentane- 1 ,2-dicarboxylic acid 1 -tert- butyl ester 2-methyl ester (38 mg, 0.11 mmol) was dissolved in DCM (1.5 mL). Triethylsilane (36 μL, 0.22 mmol) and TFA (0.7 mL) were added. The reaction mixture was stirred for 1 h, concentrated and re-dissolved in DMF (0.9 mL). (R)-(+)-l-phenylethylamine (17 μL, 0.13 mmol), TEA (50 μL, 0.36 mmol) and HOBt (23 μL, 0.18 mmol) were added and the solution was cooled to 0 0C. EDC (35 mg, 0.18 mmol) was added and the reaction mixture was stirred for 2.5 h. Brine (3 mL) was added and the solution was extracted twice with ethyl acetate. The organic phases were combined, dried with MgSO4, filtered and concentrated. Purificationby flash column chromatography (toluene/ethyl acetate 1 :2) gave the title compound as an oil (40.6 mg, 93 %).
Figure imgf000078_0001
(Ii? .2i?.45V4-(Methanesulphonyl-methyl -aminoVcyclopentane- 1 ,2-dicarboxylic acid 1 - ( IY 1 S2S AR)A-(JS)- 1 -benzylcarbamoyl^-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-amide| 2-r((i?)-l-phenyl-ethyl)-amidel (13h) Compound 13g (13 mg, 0.03 mmol) was dissolved in dioxane/MeOH (1.0:0.2 niL), LiOH (40 μL, 40 mg/niL) was added and the reaction mixture was stirred over night. The solution was concentrated and re-dissolved in DMF (1.2 mL). The azide of compound 4g was reduced as described in example 1, step h, whereafter the afforded amine, DIPEA (17 μL, 0.09 mmol) and HATU (16 mg, 0.04 mmol) were added to the DMF -solution. The reaction mixture was stirred for 2.5 h and the solution was co -evaporated with toluene and concentrated. The crude was purified using prep. LC-MS which gave the title compound as white crystals (20 mg, 73 %). 1H-NMR (300 MHz, DMSO-d6): δ 0.81 (t, J= 6 Hz, 6H), 1.31 (d, J= 6.6 Hz, 3H), 1.66-2.11 (m, 7H), 2.71 (s, 3H), 2.84 (s, 3H), 2.89-3-15 (m, 3H), 3.18 (s, 3H), 3.73 (t,J = 6.6 Hz, 2H), 3.85- 4.31 (m, 6H), 4.88-4.92 (m, 2H), 6.63 (d, J = 7.5 Hz, 2H), 6.76 (d, J= 9.3 Hz, IH), 7.07-7.30 (m, 10 H), 7.62 (d, J = 9.6 Hz, IH), 7.71 (d, J= 8.4 Hz, IH), 8.25 (d, J= 7.2 Hz, IH), 8.49 (d, J = 5.4 Hz, IH); 13C-NMR (75.5 MHz, CDC13): δ 18.2, 19.3, 22.4, 28.3, 30.6, 32.3, 32.9. 36.6, 42.0, 45.3, 45.6, 47.8, 50.8, 56.2, 57.1, 57.5, 64.7, 66.8, 78.8, 96.2 (t, JCF = 24.9 Hz), 98.7 (d, JCF = 28.1 Hz, 2C), 125.8, 126.4, 126.8, 127.2, 128.0, 128.2, 139.2, 144.5, 160.4 (t, JCF = 14.3 Hz) 162.9 (d, JCF = 245.0 Hz), 163.1 (d,JCF = 244.4 Hz), 170.7, 171.2, 171.9, 174.0.
Example 14 Step a
Figure imgf000078_0002
(Ii? .2i?.45V4-f Methanesulphonyl-methyl -amino )-2-((S)- 1 -phenyl-ethylcarbamoyD - cyclopentanecarboxylic acid methyl ester H4a^)
Compound 13f (24 mg, 0.07 mmol) was dissolved in DCM (1 mL). Triethylsilane (23 DL, 0.14 mmol) and TFA (0.4 mL) was added and the reaction mixture was stirred for 45 min. The solution was concentrated and the crude was re-dissolved in DMF (0.6 mL). (S)-(-)-l- Phenylethylamine (11 μL, 0.08 mmol), TEA (30 μL, 0.22 mmol) and HOBt (14 μL, 0.11 mmol) were added and the mixture was cooled to 0 0C. EDC (20 mg, 0.10 mmol) was added and the reaction mixture was stirred for 3 h. The solution was co -evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound as syrup (25 mg, 92 %).
Figure imgf000079_0001
(li?.2i?Λ5V4-(Methanesulphonyl-methyl -amino Vcvclopentane-1 ,2-dicarboxylic acid 1- ( PC 1 S.2SAR)4-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethvO -2-hydroxy-4-methoxy-butyl1 -amidel 2- \((S)- 1 -phenyl-ethvO-amidel ( 14b) Compound 14a (11 mg, 0.03 mmol) was dissolved in dioxane (0.9 mL) and LiOH (35 μL, 0.06 mmol) was added. The reaction mixture was stirred over night, concentrated, and re-dissolved in DMF (1.2 mL). The azide of compound 4g was reduced as described in Example 1, step h, whereafter the afforded amine, (11 mg, 0.02 mmol), DIPEA (15 μL, 0.08 mmol) and HATU (13 mg, 0.03 mmol) were added to the DMF solution. The reaction mixture was stirred for 2.5 h and then co-evaporated with toluene, concentrated and purified using prep. LC-MS which gave the title compound as a white powder (10 mg, 55%).
1H-NMR (300 MHz, DMSO-d6): δ 0.81 (bt, J= 6.2 Hz, 6H), 1.27 (d, J= 7.2 Hz, 3H), 1.60-1.71 (m, 3H), 1.90-2.10 (m, 4H), 2.65 (s, 3H), 2.82 (s, 3H), 2.84-3.12 (m, 2H), 3.19 (s, 3H), 3.37-3.40 (m, IH), 3.76 (t, J= 6.6 Hz, IH), 3.82-3.93 (m, 2H), 4.02-4.10 (m, 2H), 4.11-4.20 (m, IH), 4.25- 4.26 (m, 2H), 4.86 (t, J= 7.5 Hz, IH), 4.91-4.95 (m, IH), 6.68-6.80 (m, 3H), 7.14-7.30 (m, 10H), 7.61 (d, J= 9.3 Hz, IH), 7.66-7.68 (m, IH), 8.27 (d, J= 7.8 Hz, IH), 8.49 (t, J= 6 Hz, 1H);13C-NMR (75.5 MHz, DMSO-d6): δ 18.2, 19.3, 22.5, 28.2, 30.6, 31.7, 33.1, 36.6, 42.0, 45.1, 45.9, 47.9, 51.0, 56.3, 57.2, 57.5, 65.0, 67.2, 78.8, 96.2, 98.8 (d, JCF = 28.1 Hz, 2C), 125.8, 126.5, 126.8, 127.2, 128.2, 139.2, 144.7, 160.5 (t, JCF = 14.0 Hz), 162.9 (d, JCF = 244.1 Hz), 163.2 (d, JCF = 244.4 Hz), 170.7, 171.2, 171.7, 174.0.
Example 15 Step a
Figure imgf000079_0002
(Ii? r2i?r4i?V4-f Methanesulphonyl -methyl-amino )-2-((i?)- 1 -phenyl-ethylcarbamoyD- cyclopentanecarboxylic acid tert-butyl ester Tl 5 a")
Compound 13f (19.8 mg, 0.06 mmol) was dissolved in MeOH (1.5 rnL) and 4 drops H2O. A solution of LiOH (71 μL, 40 mg/mL) was added and the reaction mixture was stirred for 6.5 h. The mixture was concentrated and re-dissolved in DMF (0.6 mL). (R)-(+)-l-phenylethylamine (9.1 μL, 0.07 mmol), TEA (25 μL, 0.18 mmol) and HOBt (12 μL, 0.09 mmol) were added and the mixture was cooled to 0 0C. EDC (18 mg, 0.09 mmol) was added and the reaction mixture was stirred for 1 h. Then the mixture was allowed to reach rt and was stirred over night. The solution was co -evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as a syrup (14 mg, 56 %).
Step h
Figure imgf000080_0001
(Ii? r2i?r4i?V4-f Methanesulphonyl -methyl-amino Vcyclopentane- 1 r2-dicarboxylic acid 1 - {[(] S.2SΛR^-((S)-] -benzyl carbamoy1-2-methy1-propy1carbamoy1V1 -f3.5-difluoro- phenoxymethyD -2-hydroxy-4-methoxy-butyl] -amide} 2-[((R)- 1 -phenyl-ethyD-amide] ( 15V) Compound 15a (14 mg, 0.03 mmol) was dissolved in DCM (0.5 mL), triethylsilane (10 μL, 0.06 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2 h. The solution was concentrated and re-dissolved in DMF (1.2 mL). The azide of compound 4g was reduced as described in Example 1, step h whereafter the formed amine (23 mg, 0.05 mmol) together with DIPEA (17 μL, 0.1 mmol) and HATU (16 mg, 0.04 mmol) were added and to the DMF solution and the reaction mixture was stirred for 2 h. The solution was co -evaporated with toluene, concentrated and purified using prep. LC-MS which gave the title compound as a white powder (19 mg, 71 %).
1H-NMR (300 MHz, DMSO-d6): δ 0.83 (t, J= 6.0 Hz, 6H), 1.32 (d, J= 6.9 Hz, 3H), 1.69-2.12 (m, 7H), 2.72 (s, 3H), 2.86 (s, 3H), 2.91 -3.14 (m, 2H), 3.20 (s, 3H), 3.25 (m, IH), 3.73-4.15 (m, 4H), 4.19-4.32 (m, 4H), 4.88-4.94 (m, 2H), 6.65 (d, J= 8.1 Hz, 2H), 6.78 (t, J= 9.2 Hz, IH), 7.11-7.28 (m, 10H), 7.61 (d, J = 9.0 Hz, IH), 7.70 (d, J= 7.8 Hz, IH), 8.28 (d, J= 7.8 Hz, IH), 8.52 (m, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.2, 19.3, 22.4, 28.2, 30.6, 31.9, 33.4, 36.6, 42.0, 45.2, 45.7, 47.8, 50.8, 56.3, 57.2, 57.5, 64.8, 66.9, 78.9, 96.2 (t, JCF = 26.7 Hz), 98.7 (d, JCF = 28.4 Hz, 2C), 125.8, 126.4, 126.8, 127.2, 128.1, 128.2, 139.2, 144.5, 160.4 (t, JCF = 14.2 Hz), 162.9 (d, JCF = 244.4 Hz), 163.1 (d,JCF = 244.1 Hz), 170.7, 171.2,.172.5, 173.5. Example 16
Step a
Figure imgf000081_0001
(Ii? .2i?.,4i?y 4-(Methanesulphonyl -methyl-amino V2-(CSV 1 -phenyl-ethylcarbamovO- cvclopentanecarboxylic acid tert-butyl ester (16a)
Compound 13f (21 mg, 0.06 mmol) was dissolved in MeOH (1.2 mL). A solution of LiOH (75 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The mixture was concentrated and re-dissolved in DMF (0.6 mL). (S)-(-)-l-phenylethylamine (9.7 μL, 0.07 mmol), TEA (26 μL, 0.18 mmol) and HOBt (12 μL, 0.09 mmol) were added and the mixture was cooled to 0 0C. EDC (18 mg, 0.09 mmol) was added and the reaction mixture was stirred for 0.5 h. Then the mixture was allowed to reach rt and was stirred over night. The solution was co- evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as a syrup (15 mg, 55%).
Step b
Figure imgf000081_0002
(Ii? .2i?.4i?V 4-(Methanesulphonyl -methyl-amino Vcyclopentane- 1.2-dicarboxylic acid 1 - ( [( 1 S.2SAR)A-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyO -2-hydroxy-4-methoxy-butyl] -amide! 2- [((S)- 1 -phenyl-ethyO-amide] ( 16b) Compound 16a (15 mg, 0.03 mmol) was dissolved in DCM (0.5 mL). Triethylsilane (11 μL, 0.07 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 3 h. The solution was concentrated and re-dissolved in DMF (1.2 mL). The azide of compound 4g was reduced as described in Example 1, step h whereafter the formed amine (23 mg, 0.05 mmol) together with DIPEA (18 μL, 0.1 mmol) and HATU (17 mg, 0.04 mmol) were added to the DMF solution and the reaction mixture was stirred for 2 h. The solution was co -evaporated with toluene, concentrated and purified using prep. LC-MS which gave the title compound as a white powder (18 mg, 63 %). 1H-NMR (300 MHz, DMSO-d6): δ 0.83 (t, J= 6.0 Hz, 6H), 1.23 (s, IH), 1.29 (d, J= 7.2 Hz, 3H), 1.69-1.87 (m, 3H), 1.93-2.13 (m, 3H), 2.71 (s, 3H), 2.82 (s, 3H), 2.94-3.08 (m, 2H), 3.21 (s, 3H), 3.42 (m, IH), 3.78 (t, J = 6.5 Hz, IH), 3.86-3.96 (m, 2H), 4.06-4.30 (m, 5H), 4.86 (quintet, J = 7.2 Hz, IH), 4.95 (d, J= 5.4 Hz, IH), 6.70-6.84 (m, 3H), 7.17-7.33 (m, 10H), 7.66 (d, J= 9.3 Hz, IH), 7.70-7.74 (m, IH), 8.33 (d, J= 8.1 Hz, IH), 8.56 (t, J= 6.0 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.3, 19.4, 22.6, 28.3, 30.7, 32.1, 32.9, 36.6, 42.1, 45.4, 47.9, 51.0, 56.2, 57.2, 57.5, 65.1, 65.2, 78.9, 96.3 (t, JCF = 26.4 Hz), 98.8 (d, JCF = 28.1 Hz, 2C), 125.8, 126.6, 126.8, 127.2, 128.3, 139.3, 144.8, 160.5 (t, JCF = 14.2 Hz), 163.0 (d, JCF = 244.1 Hz), 163.2 (d, JCF = 244.1 Hz), 170.8, 171.3, 172.4, 173.5.
Example 17 Step a
O O
/S N
Figure imgf000082_0001
(Ii? .2i?.45V4-(Methanesulphonyl-methyl -amino V2-(CSV 1 -phenyl-propylcarbamovO- cvclopentanecarboxylic acid methyl ester (17a)
Compound 13f (11 mg, 0.03 mmol) was dissolved in DCM (0.5 mL). Triethylsilane (10 μL, 0.06 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2 h. The solution was concentrated and re-dissolved in DMF (1 mL). (5)-(-)-α-Ethylbenzylamine (5.6 μL, 0.04 mmol), TEA (14 μL, 0.09 mmol) and HoBt (6.2 μL, 0.05 mmol) were added and the mixture was cooled to 0 0C. EDC (10 mg, 0.05 mmol) was added and the reaction mixture was stirred for 30 min and additionaB h at rt. The solution was co -evaporate with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound as a syrup (12 mg, 89%).
Figure imgf000082_0002
(Ii? .2i?.45V4-(Methanesulphonyl-methyl -amino Vcyclopentane- 1.2-dicarboxylic acid 1 - ( [( 1 S2SAR\4-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethvD -2-hvdroxy-4-methoxy-butyl1 -amidel 2- K(S)- 1 -phenyl-propyD -amidel ( 17b) Compound 17a (12 mg, 0.03 mmol) was dissolved in dioxane (1.2 niL). A solution of LiOH (35 μL, 40 mg/niL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was re-dissolved in DMF (1.2 mL). The azide of compound 4g was reduced as described in Example 1, step h whereafter the formed amine (17 mg, 0.03 mmol) together with DIPEA (15 μL, 0.09 mmol) and HATU (15 mg, 0.04 mmol) were added and the reaction mixture was stirred for 2 h. The solution was co -evaporated, concentrated and purified using prep. LC-MS which gave the title compound as white crystalls (14 mg, 58 %). 1 H-NMR (300 MHz, CD3OD): δ 0.82 (t, J = 7.4 Hz, 3H), 0.94 (d, J= 2.7 Hz, 3H), 0.96 (d, J= 2.7 Hz, 3H), 1.72 (quintet, J = 7.5 Hz, 2H), 1.82-1.92 (m, 2H), 2.06-2.18 (m, 4H), 2.77 (s, 3H), 2.82 (s, 3H), 2.99-3.09 (m, IH), 3.13-3.22 (m, IH), 3.30-3.32 (overlap, IH), 3.39 (s, 3H), 3.90 (t, J = 6.0 Hz, IH), 3.95-4.00 (m, IH), 4.06-4.15 (m, 2H), 4.22-4.30 (m, 2H), 4.40 (s, 2H), 4.41- 4.53 (m, IH), 4.70 (t, J= 7.5 Hz, IH), 6.49-6.63 (m, 3H), 7.18-7.32 (m, 10H);13C-NMR (75.5 MHz, CD3OD): δ 11.4, 18.7, 19.8, 28.9, 30.5, 32.1, 33.1, 34.7, 37.3, 37.8, 44.1, 47.5, 53.1, 56.8, 58.1, 58.6, 59.9, 67.3, 68.9, 80.6,.97.2 (t, JCF = 26.8 Hz), 99.6 (d, JCF = 28.1 Hz, 2C), 127.6, 128.1, 128.3, 128.6, 129.5, 129.6, 139.7, 144.1, 162.3, 165.1 (d, JCF = 247.1 Hz), 165.3 (d,JCF = 245.6 Hz), 173.3, 174.9, 176.7.
Example 18 Sten a
Figure imgf000083_0001
(1R.2R)- & ri6*.2y)-Cyclopentane-1.2-dicarboxylic acid monobenzyl ester H8a^) 7>α/?5-DL-l,2-cyclopentanedicarboxylic acid (38 mg, 0.24 mmol) was dissolved in DCM (2.4 mL). 4-dimethylaminopyridine (15 mg, 0.12 mmol) and benzyl alcohol (25 μL, 0.24 mmol) were added and the mixture was cooled to 0 0C. EDC (45 mg, 0.24 mmol) was added and the reaction mixture was stirred for 2 h and then additional 1.5 h at rt. The solution was concentrated and purified using flash column chromatography (toluene/ethyl acetate 3:1 + 1 % AcOH) which gave a diastereomericmixture of the title compound as s powder (34 mg, 59 %).
Step b
Figure imgf000083_0002
(IR.2R)- & fl£.25V2-ff5Vl-Phenyl-ethylcarbamoyr)-cyclopentanecarboxylic acid benzyl ester
ClSbJ
Compound 18a (13 mg, 0.05 mmol) was dissolved in DMF (0.5 mL). (S)-(-)-l-phenylethylamine
(9 μL, 0.07 mmol), DIPEA (26 μL, 0.15 mmol) and HATU (27 mg, 0.07 mmol) were added and the reaction mixture was stirred for 2 h. The solution was co -evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 6:1) which gave a diastereomericmixture of the title compound as white crystals (17 mg, 96 %).
Step c
Figure imgf000084_0001
(1R.2RV & (lS.2S)-Cvclopentane-1.2-dicarboxylic acid l-U(lS2SAR)-4-(( S)-I- benzylcarbamoyl-2-methyl-propylcarbamoyl)- 1 -(3 ,5 -difluoro -phenoxymethyD-2 -hydroxy-4 - methoxy-butyll -amide) 2-r((£)-l-phenyl-ethvO-amide1 (18c)
Compound 18b (17 mg, 0.05 mmol) was dissolved in ethanol (3 mL, 95%) and Pd-C (-30 mg) was added. The reaction mixture was placed under H2-atmosphere over night. The solution was filtered trough a pad of celite and concentrated. The crude was re-dissolved in DMF (1 mL). The azide of compound 4g was reduced as described in Example 1 , step h whereafter the formed amine (29 mg, 6 mmol) together with DIPEA (26 μL, 0.15 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction mixture was stirred for 3 h, concentrated and purified using prep. LC-MS which gave a diastereomericmixture of the title compound as crystals (28 mg, 76%).
1H-NMR (300 MHz, DMSO-d6): δ 0.80-0.85 (m, 6H), 1.30-1.33 (m, 3H), 1.57-1.73 (m, 6H), 1.88-2.07 (m, 3H), 2.93-3.00 (m, 2H), [(3.18 & 3.22) (s, 3H)], 3.76-3.81 (m, IH), 3.85-3.92 (m, 2H), 4.04-4.10 (m, 2H), 4.18-4.29 (m, 3H), 4.81-4.93 (m, 2H), 6.68-6.79 (m, 3H), 7.15-7.32 (m, 10H), 7.57-7.62 (m, 2H), 811-8.23 (dd, J= 2.0, 7.1 Hz, IH)., 8.52 (m, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.1, 19.3, 22.4, 22.6, 25.3, 25.6, 30.6, 31.0, 31.2, 31.5, 36.6, 42.0, 47.3, 47.5, 47.8, 50.9, 51.2, 57.1, 57.4, 57.5, 65.0, 65.1, 67.3, 78.8, 96.1, 96.2, 98.7 (d, JCF = 28.2 Hz, 2C), 125.7, 125.9, 126.3, 126.4, 126.8, 127.2, 128.2, 139.1, 139.2, 144.5, 144.9, 160.6 (t, JCF = 14.5 Hz), 162.9 (d, JCF = 244.5 Hz), 163.1 (d,JCF = 243.6 Hz), 170.6, 170.7, 171.2, 171.3, 173.1, 173.4, 174.7, 175.1.
Example 19 Step a
Figure imgf000084_0002
(1R.2R)- & (l£.25V2-((iO-l-Phenyl-ethylcarbamovO-cvclopentanecarboxylic acid benzyl ester (\9Ά) Compound 18a (17 mg, 0.06 mmol) was dissolved in DMF (0.7 niL). (R)-(+)-l- phenylethylamine (12 μL, 0.09 mmol), DIPEA (34 μL, 0.19 mmol) and HATU (32 mg, 0.08 mmol) were added and the reaction mixture was stirred for 3.5 h. The solution was co- evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 6:1) which gave a diastereomericmixture of the title compound as white crystals (19 mg, 82 %).
Figure imgf000085_0001
(1R2RY & πS.2^-Cvclopentane-1.2-dicarboxylic acid \-U(\S.2SAR)-4-(( S)-I- benzylcarbamoyl-2-methyl-propylcarbamovO- 1 -(3.5 -difluoro -phenoxymethv0-2 -hvdroxy-4 - methoxy-butyl"|-amidel 2-[((7?Vl-phenyl-ethvP)-amide] (19b")
Compound 19a (19 mg, 0.05 mmol) was dissolved in ethanol (3 mL, 95 %) and Pd-C (-30 mg) was added. The reaction mixture was placed under H2-atmosphere over night. The solution was filtered trough a pad of celite and concentrated. The crude was re-dissolved in DMF (1 mL). The azide of compound 4g was reduced as described in Example 1 , step h whereafter the formed amine 30 mg, 0.06 mmol together with DPEA 28 μL, 0.16 mmol) and HATU (246 mg, 0.07 mmol) were added. The reaction mixture was stirred for 3 h, co -concentrated and purified using prep. LC-MS which gave a diastereomericmixture of the title compound as crystals (36 mg, 91 %).
1H-NMR (300 MHz, DMSO-d6): δ 0.81-0.86 (m, 6H), 1.30 (t, J= 6.8 Hz, 3H), 1.57-2.06 (m, 9H), 2.89-2.98 (m, 2H), [(3.20 & 3.24) (s, 3H)], 3.74-4.09 (m, 5H), 4.17-4.32 (m, 3H), 4.84-4.92 (m, 2H), 6.63-6.80 (m, 3H), 7.11-7.30 (m, 10H), 7.59-7.69 (m, 2H), 8.20 (t, J= 8.1 Hz, IH), 8.50-8.54 (m, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.1, 19.3, 22.4, 22.5, 25.3, 25.5, 30.6, 31.1, 31.4, 31.5, 36.6, 42.0, 47.3, 47.6, 47.9, 48.2, 50.8, 51.1, 57.1, 57.2, 57.5, 65.0, 66.9, 67.3, 78.8, 78.9, 96.1, 98.8 (d, JCF = 27.8 Hz, 2C), 125.7, 125.8, 126.3, 126.8, 127.1, 128.0, 128.2, 139.1, 139.2, 144.7, 145.1, 160.6, 162.9 (d, JCF = 243.6 Hz), 163.1 (d,JCF = 244.2 Hz), 170.6, 170.7, 171.1, 171.4, 173.1, 173.2, 174.7, 174.9.
Example 20 Step a
Figure imgf000086_0001
(li?,2i?,4tSl-2-Benzylcarbamoyl-4-(methanesutohonyl-methyl-amino)-cvclopentanecarboxylic acid methyl ester (20a)
The diester 13f (10 mg, 0.03 mmol) was dissolved in DCM (0.5 rnL). Triethylsilane (9.5 μL, 0.06 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2.5 h. The solution was concentrated and re-dissolved in DMF (1 mL). Benzylamine (4 μL, 0.04 mmol), TEA (12 μL, 0.09 mmol) and HOBt (5.5 μL, 0.04 mmol) were added and the mixture was cooled to 0 0C. EDC (8.5 mg, 0.04 mmol) was added and the reaction mixture was stirred for 30 min and additional h at rt. The solution was co -evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as an oil (7 mg, 62 %).
1H-NMR (300 MHz, CDCl3): 52.05-2.2 (m, 4H), 2.81 (s, 3H), 2.84 (s, 3H), 2.85-2.2.92 (m, IH), 3.13-3.21 (m, IH), 3.68 (s, 3H), 4.37-4.47 (m, 3H), 6.23 (m, IH), 7.25-7.36 (m, 5H); 13C-NMR (75.5 MHz, CDCl3): 528.6, 31.0, 32.5, 37.7, 43.9, 45.4, 46.3, 52.6, 56.3, 127.8, 128.4, 128.9, 138.2, 172.6, 174.9.
Figure imgf000086_0002
(li?.2i?.4y)-4-(Methanesulphonyl-methyl-amino)-cyclopentane-1.2-dicarboxylic acid 1- benzylamide 2 - { [( lS.2SAR)-4-((S)- 1 -benzylcarbamoyl-2-methyl-propylcarbamoyl)- 1 -(3.5 - difluoro-phenoxymethyl)-2-hydroxy-4-methoxy-butyl]-amide} (20b)
Compound 20a (10 mg, 0.03 mmol) was dissolved in dioxane (1 mL). A solution of LiOH (33 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was re-dissolved in DMF (1 mL). The azide 4g was reduced as described in Example 1, step i. The afforded amine (16 mg, 0.03 mmol), DIPEA (14 μL, 0.08 mmol) and HATU (15 mg, 0.04 mmol) were added to the DMF-solution and the reaction mixture was stirred for 2 h. The solution was co -evaporated, concentrated and purified using prep. LC- MS which gave the title compound as white crystals (10 mg, 46 %). 1H-NMR (300 MHz, CD3OD): δ 0.93 (d, J= 2.7 Hz, 3H), 0.95 (d, J= 3.0 Hz, 3H), 1.84-1.90 (m, 2H), 1.93-2.23 (m, 4H), 2.83 (s, 3H), 2.84 (s, 3H), 2.94-3.07 (m, 2H), 3.13-3.22 (m, IH), 3.37 (s, 3H), 3.84-3.90 (m, 2H), 3.98-4.04 (m, IH), 4.07-4.13 (m, IH), 4.19-4.24 (m, 2H), 4.32 (s, 2H), 4.35-4.37 (m, 2H), 4.42-4.54 (m, IH), 6.48-6.53 (m, 3H), 7.15-7.31 (m, 10 H); 13C-NMR (75.5 MHz, CD3OD): δ 18.1, 19.3, 28.3, 30.6, 32.0, 32.9, 36.6, 41.9, 42.0, 45.4, 45.8, 50.8, 56.3, 57.2, 57.4, 64.9, 67.0, 78.8, 96.2 (t, JCF = 27.4 Hz), 98.7 (d, JCF = 28.4 Hz, 2C), 126.6, 126.8, 127.0, 127.1, 128.1, 128.2, 139.2, 139.4, 160.4 (t, JCF = 14.0 Hz), 162.9 (d, JCF = 244.5 Hz), 163.1 (d, JCF = 234.4 Hz), 170.6, 171.1, 172.7, 173.8.
Example 21 Step a
R
\^=y \ ° ° rii?.2i?.4y)-2-[ry)-l-r4-Fluoro-phenylVethylcarbamoyl]-4-rmethanesulphonyl-methyl-aminoV cyclopentanecarboxylic acid methyl ester (2Ia^)
The diester 13f (14 mg, 0.04 mmol) was dissolved in DCM (0.7 mL). Triethylsilane (13 μL, 0.08 mmol) and TFA (0.2 mL) were added and the reaction mixture was stirred for 2 h. The solution was concentrated and re-dissolved in DMF (1 mL). (S)-(-)-l-(4-fluorophenyl)ethylamine (6.7 μL, 0.05 mmol), TEA (17 μL, 0.12 mmol) and HoBt (7.8 μL, 0.06 mmol) were added and the mixture was cooled to 0 0C. EDC (7.8 mg, 0.06 mmol) was added and the reaction mixture was stirred for 30 min and additionaB h at rt. The solution was co-evaporated with toluene, concentrated and purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as an oil (13 mg, 78 %).
Step b
Figure imgf000087_0001
(Ii? .2i?.45V4-(Methanesulphonyl-methyl -amino Vcyclopentane- 1.2-dicarboxylic acid 1 - ( |Y 1 S.2SAR)A-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyiy2-hydroxy-4-methoxy-butyll -amidel 2- ( \(S)- 1 -(4-fluoro -phenyO-ethyl] -amidel (2iω Compound 21a (13 mg, 0.03 mmol) was dissolved in dioxane (0.5 niL). A solution of LiOH (40 μL, 40 mg/niL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was re-dissolved in DMF (1 mL). The azide 4g was reduced as described in Example 1, step i. The afforded amine (14 mg, 0.03 mmol), DIPEA (17 μL, 0.09 mmol) and HATU (19 mg, 0.05 mmol) were added to the DMF solution and the reaction mixture was stirred for 3 h. The solution was co -evaporated, concentrated and purified using prep. LC- MS, which gave the title compound as white crystals (14 mg, 56 %).
1H-NMR (300 MHz, DMSO-d6): δ 0.80-0.86 (m, 3H), 1.26 (d, J= 6.9 Hz, 3H), 1.61-1.71 (m, 2H), 1.89-2.10 (m, 4H), 2.65 (s, 3H), 2.82 (s, 3H), 2.85-3.17 (m, 3H), 3.20 (s, 3H), 3.76 (t, J = 6.3 Hz, IH), 3.89-3.93 (m, 2H), 4.03-4.26 (m, 5H), 4.84-4.89 (m, IH), 4.94-4.96 (m, IH), 6.68- 6.79 (m, 3H), 7.07-7.12 (m, 2H), 7.19-7.31 (m, 7H), 7.61-7.71 (m, 2H), 8.28 (d, J = 7.8 Hz, IH), 8.50 (t, J= 5.7 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.1, 19.3, 22.5, 28.2, 30.6, 31.7, 33.1, 36.6, 42.0, 45.1, 45.8, 47.3, 51.0, 56.3, 57.1, 57.5, 65.0, 67.2, 78.8, 96.2 (t, JCF = 26.3 Hz), 98.8 (d, JCF = 28.4 Hz, 2C), 114.9 (d, JcF = 21.2 Hz, 2C), 126.8, 127.2, 127.7 (d, JCF = 8.1 Hz, 2C), 128.2, 139.2, 140.9, 160.5 (t, JCF = 14.0 Hz), 160.9 (d, JCF = 242.2 Hz), 162.9 (d,JCF = 243.9 Hz), 163.2 (d, JCF = 244.2 Hz), 170.7, 171.2, 171.8, 173.9.
Example 22 Sten a
Figure imgf000088_0001
3 -(I -Hy droxy-3 -phenyl -propylV 5 -f methanesulphonyl-methyl-aminoVbenzoic acid methyl ester (22a")
Phenylethylmagnesium chloride (1.0 M in THF, 0.32 mL, 0.32 mmol) was added dropwise to a cooled solution (-78 0C) of the aldehyde 3-formyl-5-[methanesulphonyl(methyl)amino]benzoic acid methyl ester (0.26 mmol as 3.0 mL solution in 2/1 THF-Et2O), prepared as described in Bioorg. Med. Chem. letters, (2006), 641 -644, and the mixture was stirred for 6 h. Saturated aqueous NH4Cl solution (5 mL) was added, the mixture was warmed to RT, and then more NH4Cl solution (5 mL) was added. The mixture was extracted with EtOAc (3 x 10 mL). The organic phase was washed with saturated aqueous NaCl (10 mL), dried over Na2SO4 and evaporated to give a colourless oil. A second batch of aldehyde (1.09 mmol) suspended in 10 mL THF was treated similarly, using 1.65 ml of the Grignard reagent (1.65 mmol) with stirring for
4 h. The crude products were combined and subjected to flash chromatography (silica, 97/3 CH2Cl2 - MeOH) to give the title alcohol (321.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (m, IH), 7.89 (m, IH), 7.63 (m, IH), 7.32 - 7.18 (m, 5H), 4.77 (m, IH, CHOH), 3.93 (s, 3H), 3.35 (s, 3H), 2.86 (s, 3H), 2.75 (m, 2H. PhCH2), 2.14 - 2.0 (m, 3H, CHOH and PhCH2CH2). LCMS [M+18]+ =395
Step b
Figure imgf000089_0001
3-(Methanesulphonyl-methyl-amino)-5-ri-(2-methoxy-ethoxy)-3-phenyl -propyl] -benzoic acid (22^
NaH (35.4 mg 60% dispersion in mineral oil, 2 eq) in DMF (4 rnL) was added to a solution of alcohol 22a (167 mg, 0.442 mmol, 1 eq) in 2 mL DMF with cooling at -10 to -15 0C. After 30 min, 2-bromoethyl methyl ether ( 41.5 μL, 1 eq) was added. The mixture was stirred in the cold bath for 3 h, then quenched with IN HCl and MeOH, concentrated under vacuum, and partitioned between saturated aqueous NaCl and EtOAc. The organic phase was dried (Na2SO4) and evaporated. Flash column chromatography (silica, 95/5/0.5 CH2Cl2-MeOH-HOAc) gave the carboxylic acid from hydrolysis (135.5 mg, 84%) but not the ether.
NaH (49 mg, 60 wt% dispersion, 6.8 eq) was added to the hydrolysis product above (65.1 mg, 0.18 mmol, 1 eq) followed by DMF (2 mL). The suspension was stirred for 20 min at RT, and then 2-bromoethyl methyl ether (115 μL, 6.8eq) was added. After 4 h, the mixture was quenched with water - ice and acidified with IN HCl. The mixture was extracted with EtOAc ( 4 x 10 mL). The organic phase was washed with saturated aqueous NaCl (10 mL), dried (Na2SO4), and evaporated. Flash chromatography ( silica, 95/5/0.5 CH2Cl2-MeOH-HOAc) gave the title compound (70.4 mg, 93% yield).
1H NMR (400 MHz, CDCl3) δ 7.98 - 7.94 (m, 2H), 7.66 (m, IH), 7.3 - 7.14 (m, 5H), 4.32 (dd, IH, J = 8.6, 4.6 Hz, CHOCH2), 3.62 - 3.46 (m, 4H, OCH2CH2O), 3.39 (s, 3H), 3.36 (s, 3H), 2.87 (s, 3H), 2.84 - 2.66 (m, 2H, PhCH2), 2.15 (m, IH, PhCH2CH2), 1.95 (m, IH, PhCH2CH2). LCMS [M+ 18]+ = 439
Step c
Figure imgf000090_0001
f2i?r4£r5ΛV5-Amino-6-Gr5-difluoro-phenoxyV4-hydroxy-2-methoxy-hexanoic acid ((S)-I - benzylcarbamoyl-2-methyl-propyD-amide f22c^)
The azide 4g was dissolved in MeOH (5 niL) triphenylphosphine and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step.
Step d
Figure imgf000090_0002
N-[4-(l-Benzylcarbamoyl-2-methylpropylcarbamoyπ-l-(3.5-difluorophenoxymethylV2- hydroxy-4-methoxy-butyl] -3 -methanesulphonylamino-5 - [ 1 -(2 -methoxy-ethoxy V3 -phenyl- propyl] -benzamide (22d)
HATU (74 mg, 0.195 mmol) was added at O 0C to a solution of the acid 22b (41 mg, 0.097 mmol), the amine 22c (72 mg, 0.146 mmol), and DIEA (68 μL, 0.389 mmol) in DMF (7 mL) . The solution was stirred at 0 0C for Ih and then at room temperature overnight. The solvent was evaporated and the remainder was extracted with ethyl acetate and washed twice with brine. The organic phase was dried, filtered, and concentrated. The crude material was purified by flash column chromatography (ethyl acetate) which gave the title compound (87 mg, 100%) as a colourless solid. (M+H)+ calcd: 897.4; found: 897.7; LC-MS purity: >98%.
Example 23 Step a
\
Figure imgf000090_0003
2'-Trifluoromethyl-biphenyl-3.5-dicarboxylic acid dimethyl ester (23a") An oven-dried vial containinga magnetic stir bar was charged with dimethyl-5-bromo isophthalate (500 mg, 1.83 mmol), Pd(OAc)2 (4 mg, 1.0 mol%), S-Phos (15.0 mg, 2.0 mol%), 2- (trifluoromethyl) -phenyl boronic acid (695 mg, 3.66 mmol, 2 equiv.) and powdered, anhydrous KsPO4(1.16 g, 5.49 mmol, 3 equiv.). The vial was capped with a Teflon septum and then evacuated and backfilled with azote (this sequence was repeated three times). Dry toluene (4.0 mL) was added through the septum via syringe and the resulting mixture was stirred at 100 0C for 24 h. The reaction mixture was then allowed to cool to room temperature, diluted with diethyl ether (20 mL), filtered through a thin pad of silica gel (eluting with EtOAc) and concentrated under reduced pressure. The golden oil obtained which solidified upon standing was used as such. LCMS m/z 356 (M+Na)+, Rf = 0.32 (EtOAc/n-Heptane, 1/1).
Step b
Figure imgf000091_0001
5 -(I -Phenyl -ethylcarbamoylV2'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (23b) LiOH was added to a solution of compound 23a in MeOH-THF. When TLC indicated complete conversion to the mono acid, the solution was concentrated, the residue was dissolved in DMF whereafter HATU and DIEA was added. When TLC indicated complete conversion to the amide, the reaction mixture was concentrated and the residue purified by flash chromatography (EtOAc/n-Heptane, 3/7) which gave the title compound (65%) as colourless oil. LCMS m/z 428 (MH)+, Rf = 0.18 (EtOAc/n-Heptane, 3/7).
Step c
Figure imgf000091_0002
5 -(I -Phenyl -ethylcarbamoyπ-2'-trifluoromethyl-biphenyl-3-carboxylic acid (23 c) LiOH was added to a solution of compound 23b in MeOH-THF. When TLC indicated complete conversion to the acid, the solution was concentrated and the afforded white solid was used in the next step without further purification. LCMS m/z 414 (MH)
Step d
Figure imgf000092_0001
2'-Trifluoromethyl-biphenyl-3.5-dicarboxylic acid 5-{[7-benzylcarbamoyl-l-f3.5-difluoro- phenoxymethylV2-hydroxy-4-methoxy-8-methyl-5-oxo-nonyl] -amide} 3-[(l -phenyl-ethyl)- amide] (23d)
The acid 23c was coupled to the amine of compound 2g according to the procedure described in
Example 2h which, after chromatography (EtOAc/n-Heptane, 6/4), gave the title compound
(60%) as a white solid.
LCMS m/z 889 (MH)+. Rf = 0.25 (EtOAc/n-Heptane, 6/4)
Example 24
Figure imgf000092_0002
5-Pyridin-3-yl-isophthalic acid dimethyl ester (24a)
A oven-dried vial containinga magnetic stir bar was charged with 3 -pyridine boronic acid (500 mg, 1.83 mmol), Pd2(dba)3 (10 mg, 1.0 mol%), S-Phos (15.0 mg, 2.0 mol%), 2-(trifluoromethyl)- phenyl boronic acid (695 mg, 3.66 mmol, 2 equiv.) and powdered, anhydrous KsPO4(LIo g, 5.49 mmol, 3 equiv.). The vial was capped with a Teflon septum and then evacuated and backfilled with azote (this sequencewas repeated three times). Butanol (4.0 mL) was added through the septum via syringe and the resulting mixture was stirred at 100 0C for 16 h. The reaction mixture was then allowed to cool to room temperature, diluted with EtOAc (20 mL), filtered through a thin pad of silica gel (eluting with EtOAc) and concentrated under reduced pressure. The brown oil obtained was purified by flash chromatography (EtOAc/n-Heptane, 1/1) to yield the title compound. Rf = 0.28 (EtOAc/n-Heptane, 1/1). Step h
Figure imgf000093_0001
N-[7-Benzylcarbamoyl-l-r3.5-difluoro-phenoxymethylV2-hydroxy-4-methoxy-8-methyl-5-oxo- nonyl]-N'-(l -phenyl-ethylVS-pyridin-S-yl-isophthalamide (24b)
The title compound will be obtained by taking compound 24a through the steps b, c and d of example 23.
Example 25 Step a
Figure imgf000093_0002
5-Bromo-isophthalic acid monomethyl ester (25 a)
LiOH was added to a solution of compound dimethyl-5-bromo isophthalate in MeOH-THF. When TLC indicated complete conversion to the mono acid, the solution was concentrated and the residue was purified by flash chromatography (EtOAc/n-Heptane/AcOH, 6/4/0.5%) which gave the title compound (75%) as a white solid. LCMS m/z 257-259 (M)". Rf = 0.1 (EtOAc/n-Heptane, 6/4).
Figure imgf000093_0003
5-Bromo-N-(l-phenyl-ethyπ-isophthalamic acid methyl ester (25b)
Compound 25a was reacted as described in Example 23 step b, which gave the title compound (70%) as a white solid. LCMS m/z 362-364 (MH)+. Rf = 0.25 (EtOAc/n-Heptane, 3/7).
Step c
Figure imgf000094_0001
5-Bromo-N-(l-phenyl-ethv0-isophthalamic acid (25c")
The methyl ester of compound 25b was hydro lyzed as described in Example 23 step c, which gave the title compound (98%) as a white solid. The acid was used in the next step without further purification. LCMS m/z 348-350 (MH)+. Rf = 0.1 (EtOAc/n-Heptane, 6/4).
Figure imgf000094_0002
N-[7-Benzylcarbamoyl-l-r3.5-difluoro-phenoxymethylV2-hydroxy-4-methoxy-8-methyl-5-oxo- nonyl] -5-bromo-N'-(l -phenyl-ethylVisophthalamide (25 d)
The acid 24c was coupled to the amine of compound 2g according to the procedure described in Example 2h which, after chromatography (EtOAc/n-Heptane, 7/3), gave the title compound (55%) as a white solid. LCMS m/z 823-825 (MH)+. Rf = 0.25 (EtOAc/n-Heptane, 7/3).
Step e
Figure imgf000094_0003
N-[7-Benzylcarbamoyl-l-(3.5-difluoro-phenoxymethyπ-2-hydroxy-4-methoxy-8-methyl-5-oxo- nonyl] -5 -(2-oxo-pyrrolidin- 1 -yl)-N'-( 1 -phenyl- ethylVisophthalamide (25 e) An oven-dried vial containinga magnetic stir bar was charged with the bromo derivative 25 d (75.5 mg, 0.12 mmol), CuI (I mg, 5.0 mol%), (R,R)-N,N' -dimethyl- 1, 2 -cyclohexanediamine (1.7 mg, 10.0 mol%), and K2CO3 (33.2 mg, 0.24 mmol, 2 equiv.).The vial was capped with a Teflon septum and then evacuated and backfilled with azote (this sequencewas repeated three times). 2- Pyrrolidinone (12.8 mg, 0,15 mmol, 1.2 equiv.) followed by dry toluene (0.12 mL) were added through the septum via syringe and the resulting mixture was stirred at 100 0C for 20 h. The reaction mixture was then allowed to cool to room temperature, diluted with EtOAc (5 mL), filtered through a thin pad of silica gel (eluting with EtOAc) and concentrated under reduced pressure. The brown oil obtained was purified by flash chromatography. LCMS m/z 828 (MH)+.
Example 26 Step a
Figure imgf000095_0001
Methyl 5-azido-2-O-benzyl-3.5-dideoxy-6-O-(3.5-difluorophenviyL-/vxo-hexofuranoside (26a") Compound 2c (226 mg, 0.717 mmol) was dissolved in DMF (5 mL), benzyl bromide (0.68 mL, 5.76 mmol, 8 eq.) and Ag2O (332 mg, 1.43 mmol, 2 eq.) were added. The reaction was stirred at room temperature over night. The reaction was quenched with CHCl3 and the solids were filtered off. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (isohexane→ isohexane: ethyl acetate 10:1) which gave the title compound (136 mg, 0.337 mmol, 47%).
1H-NMR (400 MHz, CDCl3): δ 7.40-7.27 (m, 5H), 6.50-6.41 (m, 3H), 4.98 (s, IH), 4.59-4.55 (d, 2H), 4.55-4.48 (m, IH), 4.10-4.01 (bm, 2H+1H), 3.73-3.67 (m, IH), 3.41 (s, 3H), 2.11 -2.06 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.6 (d, JCF= 15.48 Hz), 160.2 (t, JCF= 13.27 Hz), 137.7, 128.7, 128.0, 127.8, 107.3, 98.6 (dd, JCF= 11.76, 28.74 Hz), 97.2 (t, JCF= 25.83 Hz), 82.8, 79.4, 71.6, 68.7, 64.4, 55.2, 32.8;
Step b
Figure imgf000095_0002
5-Azido-2-Q-benzyl-3.5-dideoxy-6-Q-(3.5-difluorophenylVL-/vxo-hexofuranoside (26b") Compound 26a (136 mg, 0.336 mmol) was dissolved in l,4-dioxane/0.5 M H2SO4 1 :1 (14 mL) and heated to reflux. After complete reaction (~1 hour according to TLC), the reaction was cooled to room temperature and then neutralized with Na2CO3 (aq). The volatile solvents were concentrated under vacuum. The residue was dissolved in DCM and washed with H2O (x2). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (isohexane — » isohexane: ethyl acetate 10:1) which gave the title compound (61 mg, 0.157 mmol, 47 %).
1H-NMR (400 MHz, CDCl3): δ 7.39-7.27 (m, 5H), 6.50-6.41 (m, 3H), 5.40-5.38 (d, IH), 4.60- 4.56 (d, 2H), 4.55-4.49 (m, IH), 4.20-4.16 (m, 2H), 4.04-4.01 (d, IH), 3.83-3.78 (m, IH), 3.03- 3.00 (d, IH), 2.25-2.09 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.6 (d, JCF= 15.48 Hz), 160.0 (t,JCF= 13.27 Hz), 137.7, 128.7, 128.1, 127.8, 100.9, 98.6 (dd, JCF= 11.76, 28.74 Hz), 97.3 (t, JCF= 25.73 Hz), 83.6, 78.8, 71.6, 69.6, 63.4, 32.1; MS calcd. for Ci9Hi9F2N3O4 (M + Na+) xxx, found 414.01
Step c
Figure imgf000096_0001
5-Azido-2-Q-benzyl-3.5-dideoxy-6-Q-(3.5-difluorophenylVL-/vxo-1.4-lactone (10) Compound 26b (61 mg, 0.157 mmol) was dissolved in DCM (5 mL). At 0 0C pyridinium dichromate (88 mg, 0.235 mmol, 1.5 eq.) and 4A molecular sieves powder were added. The reaction was stirred over night in room temperature. The solids were filtered off and the filtrate was concentrated under vacuum, the residue was purified by column chromatography (isohexane — » isohexane: ethyl acetate 15:1) which gave the title compound (59 mg, 0.150 mmol, 96 %).
1H-NMR (400 MHz, CDCl3): δ 7.41-7.30 (m, 5H), 6.52-6.40 (m, 3H), 4.96 (d, IH, J= 12 Hz), 4.82-4-76 (m, IH), 4.70 (d, IH, J= 12 Hz), 4.36 (dd, IH), 4.22 (d, 2H), 3.92- 3.87 (m, IH), 2.53- 2.35 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 173.8, 164.9 (d, JCF= 15.48 Hz) 162.4 (d, JCF= 16.28 Hz), 159.5 (t, JCF= 13.27 Hz), 136.8, 128.7, 128.2, 98.5 (dd, JCF= 12.56, 28.74 Hz), 97.5 (t, JCF= 25.73 Hz), 75.9, 72.6, 72.4, 68.5, 62.7, 32.7;
Figure imgf000096_0002
5-Azido-2-benzyloxy-6-(3.5-difluoro-phenoxy)-4-hydroxy-hexanoid acid (1 -benzylcarbamoyl-2- methyl-propyQ-amide (26d) Compound 26c (43 mg, 0.111 mmol) and (S)-2-Amino-iV-benzyl-3-methyl-butyramide (69 mg, 0.333 mmol, 3 eq.) were dissolved in diisopropyl ethyl amine (5 mL). 2 -Hydroxy -pyridine (21 mg, 0.222, 2 eq.) was added and the mixture was heated to 70 0C over night. The reaction mixture was concentrated and the residue was purified by column chromatography (isohexane: ethyl acetate 10:1) which gave the title compound (46 mg, 0.078 mmol, 70%). 1H-NMR (400 MHz, CDCl3): 57.41-7.20 (m, 10H), 7.14-7.07 (d, IH), 6.90-6.82 (t, IH), 6.50- 6.35 (m, 3H), 4.67-4.55 (q, 2H), 4.43-4.38 (d, 2H), 4.34-4.27 (dd, IH), 4.14-4.08 (m, IH), 4.03- 3.98 (dd, IH), 3.97-3.90 (m, 2H), 3.64-3.55 (m, IH), 2.59-2.50 (d, IH), 2.47-2.35 (m, IH), 2.25- 2.13 (m, IH), 1.94-1.85 (m, IH), 1.00-0.87 (dd, 6H);
Step e
Figure imgf000097_0001
A/-[fh9r2Sr4i?V4-ff£Vl-Benzylcarbamoyl-2 -methyl -propylcarbamoyπ-4-benzyl-l-r3r5-difluoro- phenoxymethyD -2-hydroxy-butyl] -5 -f methanesulfonyl-methyl-amino )-7V -((R)- 1 -phenyl-ethyl)- isophthalamide f26e")
The azide 26d (46 mg, 0.078 mmol) and triphenyl phosphine (31 mg, 0.012 mmol, 1.5 eq.) were dissolved in MeOH (5 mL) and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step.
5-Methanesulfonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalacid (29 mg, 0.078 mmol, 1 eq), Py-BOP (40 mg, 0.078 mmol, leq) and DIPEA (14 μL, 0.078 mmol, 1 eq) were dissolved in DCM (2.5 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~1 eq) from the previous reaction dissolved in DCM (4 mL) and DIPEA (14 μL, 0.078 mmol, 1 eq) were added. After complete reaction the mixture was washed with NaHCO3 (Ix 10 mL) and brine (Ix 1OmL). The water phase was extracted with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (isohexan: ethyl acetate 1 :1) which gave the title compound (46 mg, 0.050 mmol, 64%).
Example 27 Step a
Figure imgf000098_0001
OEt
Methyl 5 -azido-3.5-dideoxy-6-O-G.5-difluorophenylV2-O-ethyl-L-/vxo-hexofuranoside f27a^) Compound 2c (248 mg, 0.787 mmol) was dissolved in DMF (5 niL), ethyl iodide (0.50 niL, 6.29 mmol, 8 eq.) and Ag2O (365 mg, 1.57 mmol, 2 eq.) were added. The reaction was stirred at room temperature over night. The reaction mixture was quenched with CHCb and the solids were filtered off. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (isohexane→ isohexane: ethyl acetate 20:1) which gave the title compound (92 mg, 0.267 mmol, 34%).
1H-NMR (400 MHz, CDCl3): δ 6.49-6.40 (m, 3H), 4.91 (s, IH), 4.50-4.43 (q, IH), 4.10-4.01 (m, 2H), 3.91-3.88 (t, IH), 3.72-3.66 (m, IH), 3.58-3.49 (m, 2H), 3.40 (s, 3H), 2.06-2.01 (m, 2H), 1.23-1.18 (t, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.6 (d, JCF= 15.48 Hz), 160.2 (t, JCF= 13.27 Hz), 107.3, 98.4 (dd, JcF= 11.76, 28.74 Hz), 97.2 (t, JCF= 25.83 Hz), 83.0, 79.3, 68.8, 65.1, 64.5, 55.3, 32.8, 15.5.
Step b
Figure imgf000098_0002
5-Azido-3.5-dideoxy-6-O-r3.5-difluorophenylV2-Q-ethyl-L-/vxo-hexofuranoside f27b^) Compound 27a (92 mg, 0.267 mmol) was treated according to the method described in Example 26 step b, which gave the title compound (72 mg, 0.219 mmol, 82%).
1H-NMR (400 MHz, CDCl3): δ 6.50-6.39 (m, 3H), 5.35-5.29 (d, IH), 4.51-4.44 (m, IH), 4.19- 4.14 (d, 2H), 3.92-3.88 (d, IH), 3.82-3.77 (m, IH), 3.57-3.52 (m, 2H), 3.10-3.04 (d, IH), 2.22- 2.05 (m, 2H), 1.23-1.17 (t, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 16.18 Hz), 162.6 (d, JCF= 16.28 Hz), 160.0 (t,JCF= 13.27 Hz), 100.9, 98.6 (dd, JCF= 12.46, 28.74 Hz), 97.3 (t, JCF= 25.73 Hz), 83.8, 78.7, 69.5, 65.1, 63.5, 32.1, 15.5.
Step c
Figure imgf000099_0001
5-Azido-3.5-dideoxy-6-Q-(3.5-difluorophenylV2-Q-ethyl-L-/vxo-1.4-lactone (27c) Compound 27b (72 mg, 0.219 mmol) was treated according to the method described in Example 26 step c, which gave the title compound (49 mg, 0.150 mmol, 68%).
1H-NMR (400 MHz, CDCl3): δ 6.50-6.41 (m, 3H), 4.81-4.73 (m, IH), 4.29-4.25 (dd, IH), 4.23- 4.20 (d, 2H), 3.98-3.88 (m, 2H), 3.68-3.59 (m, IH), 2.55-2.47 (m, IH), 2.40-2.30 (m, IH), 1.26- 1.19 (t, 3H); 13C-NMR (100.5 MHz, CDCl3): δ 174.0, 165.0 (d, JCF= 15.48 Hz), 162.5 (d, JCF= 15.48 Hz), 159.7 (t, JCF= 13.27 Hz), 98.6 (dd, JCF= 12.46, 28.74 Hz), 97.6 (t, JCF= 25.73 Hz), 75.9, 73.3, 68.6, 66.6, 62.8, 32.7, 15.2.
Figure imgf000099_0002
5-Azido-6-(3.5-difluoro-phenoxyV2-etoxy-4-hydroxy-hexanoid acid d-benzylcarbamoyl-2- methyl-propyD-amide (27d)
Compound 27c (49 mg, 0.150 mmol) was treated according to the method described in Example 26 step d, which gave the title compound (67 mg, 0.126 mmol, 84%).
Ster
Figure imgf000099_0003
N-\(\ S.2SΛR )-4-((S)- 1 -Benzylcarbamoyl^-methyl-propylcarbamoylV 1 -G .5 -difluoro- phenoxymethyD -4-ethyl-2-hydroxy-butyl] -5 -f methanesulfonyl-methyl-amino )-N' -((R)- 1 -phenyl - ethylVisophthalamide f27e)
The azide 27d (67 mg, 0.126 mmol) and triphenyl phosphine (50 mg, 0.189 mmol, 1.5 eq.) were dissolved in MeOH (5 mL) and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step.
5-methanesulfonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalacid (24 mg, 0.063 mmol, 1 eq), Py-BOP (33 mg, 0.063 mmol, leq) and DIPEA (11 uL, 0.063 mmol, leq) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~2 eq) from the previous reaction dissolved in DCM (2.5 mL) and DIPEA (22 μL, 0.126 mmol, 2 eq.) were added. After complete reaction the mixture were washed with NaHCO 3 (1x 10 mL) and brine (Ix 1OmL). The water phase was extracted with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (isohexan: ethyl acetate 1 :1) which gave the title compound (36 mg, 0.042 mmol, 67%)
Example 28 Step a
Figure imgf000100_0001
Methyl 5-azido-3r5-dideoxy-6-(9-r3r5-difluorophenyπ-2-(9-r2-methoxy-ethoxyVL-/vx(9- hexofuranoside f28a^)
Compound 2c (161 mg, 0.511 mmol) dissolved in DMF (ImL) was added to 60% sodium hydride (31 mg, 0.766 mmol, 1.5 eq.) dissolved in DMF (1 mL) at 0 0C. The reaction mixture was stirred for 30 minutes before 2-bromoethyl methyl ether (0.38 mL, 4.09 mmol, 8 eq.) was added at 0 0C. The reaction was then stirred at room temperature for 3 hours and then quenched with methanol, concentrated and purified by column chromatography (isohexane→ isohexane: ethyl acetate 20:1) which gave the title compound (37 mg, 0.099 mmol, 19%). 1H-NMR (400 MHz, CDCl3): δ 6.50- 6.39 (m, 3H), 4.94 (s, IH), 4.52- 4.42 (m, IH), 4.08- 4.01 (m, 2H), 3.97- 3.94 (d, IH), 3.71- 3.66 (m, IH), 3.66- 3.62 (m, 2H), 3.40 (s, 3H), 3.38 (s, 3H), 2.13- 2.00 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.5 (d, JCF= 15.48 Hz), 160.2 (t, JCF= 13.27 Hz), 107.2, 98.6 (dd, JCF= 12.56, 28.74 Hz), 97.2 (t, JCF= 25.83 Hz), 83.6, 79.3, 72.0, 69.0, 68.7, 64.4, 59.3, 55.3.
Step b
Figure imgf000101_0001
5-Azido-3r5-dideoxy-6-(9-r3r5-difluorophenylV2-(9-r2-methoxy-ethoxyVL-/vx(9-hexofuranoside
QShX
Compound 28a (64 mg, 0.170 mmol) was treated according to the method described in Example 26 step b, which gave the title compound (49 mg, 0.136 mmol, 80%).
1H-NMR (400 MHz, CDCl3): 56.49- 6.39 (m, 3H), 5.37- 5.31 (d, IH), 4.52- 4.43 (m, IH), 4.17- 4.13 (d, 2H), 3.96- 3.93 (m, IH), 3.82- 3.75 (m, IH), 3.67- 3.62 (m, 2H), 3.54- 3.50 (m, 2H), 3.39 (s, IH), 3.37 (s, 3H), 3.27- 3.24 (d, IH) 2.22- 2.08 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.5 (d, JCF= 15.48 Hz), 160.0 (t, JCF= 13.27 Hz), 100.8, 98.6 (dd, JCF= 12.56, 28.64 Hz), 97.3 (t, JCF= 25.73 Hz), 84.5, 78.7, 72.0, 69.5, 69.0, 63.5, 59.2, 32.0.
Figure imgf000101_0002
5-Azido-3,5-dideoxy-6-Q-(3,5-difluorophenyl)-2-Q-(2-methoxy-ethoxy)-L-/vxo-l,4-lactone
(28c).
Compound 28b (49 mg, 0.136 mmol) was treated according to the method described in Example
26 step c, which gave the title compound (40 mg, 0.111 mmol, 81%).
1H-NMR (400 MHz, CDCl3): 56.51-6.40 (m, 3H), 4.81-4.74 (m, IH), 4.38-4.33 (dd, IH), 4.23-
4.20 (d, 2H), 4.12-4.06 (m, IH), 3.94-3.88 (dt, IH), 3.81-3.74 (m, IH), 3.59-3.54 (m, IH), 3.38
(s, 3H), 2.58-2.39 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 173.9, 165.0 (d, JCF= 15.48 Hz),
162.6 (d, JCF= 15.48 Hz), 159.7 (t, JCF= 14.07 Hz), 98.6 (dd, JCF= 11.86, 29.45 Hz), 97.6 (t,
JCF= 25.73 Hz), 75.8, 73.8, 71.8, 70.1, 68.6, 62.8, 59.2, 32.6.
Figure imgf000102_0001
5-Azido-6-(3.5-difluoro-phenoxyy4-hydroxy-2-(2-methoxy-etoxyVhexanoid acid (1- benzylcarbamoyl-2-methyl-propylVamide (28d^)
Compound 28c (40 mg, 0.110 mmol) was treated according to the method described in Example 26 step d, which gave the title compound (54 mg, 0.096 mmol, 87%).
Step e
Figure imgf000102_0002
N-F(I S.2SAR V 4-(CSV 1 -Benzylcarbamoyl^-methyl-propylcarbamovO- 1 -(3.5 -difluoro- phenoxymethyl)-2-hydroxy-4-(2-methoxy-ethoxy)-butyl1-5-(methanesulfonyl-methyl-amino)- N -((R)- 1 -phenyl-ethvD-isophthalamide (28e)
Azide 28d (54 mg, 0.096 mmol) and triphenyl phosphine (38 mg, 0.144 mmol, 1.5 eq.) were dissolved in MeOH (5 mL) and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step. 5-methanesulfonyl-methyl-amino)-N'-(l-phenyl-ethyl)- isophthalacid (18 mg, 0.048 mmol, 1 eq), Py-BOP (25 mg, 0.048 mmol, leq) and DIPEA (9 μL, 0.048 mmol, leq) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~2 eq) from the previous reaction dissolved in DCM (2.5 mL) and DIPEA (17 μL, 0.96 mmol, 2 eq.) were added. After complete reaction the mixture were washed with NaHCO3 (Ix 10 mL) and brine (Ix 1OmL). The water phase was extracted with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (isohexan: ethyl acetate 1 :1) which gave the title compound (42 mg, 0.047 mmol, 97%).
Example 29 Step a
Figure imgf000103_0001
Methyl 2-Q-allyl-5-azido-3.5-dideoxy-6-Q-(3.5-difluorophenvπ-L-/vxo-hexofuranoside (29a) Compound 2c (279 mg, 0.884 mmol) dissolved in DMF (2mL) was added to 60% sodium hydride (31 mg, 0.766 mmol, 1.5 eq.) dissolved in DMF (4 mL) at 00C. The reaction mixture was stirred for 20 minutes before allyl bromide (0.61 mL, 7.07 mmol, 8 eq.) was added drop wise at 0 0C. The reaction was then stirred in room temperature over night and then quenched with methanol, concentrated and purified by column chromatography (isohexane→ isohexane: ethyl acetate 20:1) which gave the title compound (155 mg, 0.435 mmol, 49%). 1H-NMR (400 MHz, CDCl3): δ 6.49-6.40 (m, 3H), 5.95-5.82 (m, IH), 5.33-5,24 (m, IH), 5.23- 5.17 (m, IH), 4.93 (s, IH), 4.51 -4.43 (m, IH), 4.08-4.04 (m, 2H), 4.04-4.01 (m, 2H), 3.97-3.94 (t, IH), 3.72-3.66 (m, IH), 3.40 (s, 3H), 2.07-2.03 (dd, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 164.9 (d, JCF= 15.48 Hz), 162.4 (d, JCF= 15.48 Hz), 160.0 (t, JCF=13.27 Hz), 134.1, 117.4, 107.2, 98.4 (dd, JCF= 12.56, 28.74 Hz), 97.1 (t,JCF= 25.73 Hz), 82.5, 79.2, 70.4, 68.6, 64.3, 55.1, 32.6.
Figure imgf000103_0002
2-Q-Allyl-5-azido-3.5-dideoxy-6-O-r3.5-difluorophenylVL-/vxo-hexofuranoside f29b) Compound 29a (155 mg, 0.435 mmol) was treated as described in Example 26 step b, which gave the title compound (82 mg, 0.241 mmol, 55%).
1H-NMR (400 MHz, CDCl3): δ 6.51-6.39 (m, 3H), 5.97-5.81 (m, IH), 5.36-5.32 (m, IH), 5.32- 5.25 (m, IH), 5.22-5.17 (m, IH), 4.53-4.45 (m, IH), 4.18-4.15 (d, 2H), 4.06-4.02 (m, 2H), 3.97- 3.94 (d, IH), 3.17-3.12 (d, IH), 2.24-2.04 (m, 2H); 13C-NMR (100.5 MHz, CDCl3): δ 165.0 (d, JCF= 15.48 Hz), 162.5 (d, JCF= 15.48), 160.0 (t, JCF= 13.27 Hz), 134.2, 117.6, 100.9, 98.6 (dd, JCF= 11.86, 28.74 Hz), 97.3 (t, JCF= 25.73 Hz), 83.4, 78.7, 70.5, 69.6, 63.5, 32.0.
Step c
Figure imgf000104_0001
2-Q-Allyl-5-azido-3.5-dideoxy-6-Q-(3.5-difluorophenylVL-/vxo-1.4-lactone (29d
Compound 29b (82 mg, 0.241 mmol)was treated according to the method in Example 26 step c, which gave the title compound (31 mg, 0.092 mmol, 38%).
Figure imgf000104_0002
2-Allyloxy-5-azido-6-(3.5-difluoro-phenoxyV4-hvdroxy-hexanoid acid (l-benzylcarbamoyl-2- methyl-propyO-amide (29d)
Compound 29c (31 mg, 0.092 mmol) was treated according to the method in Example 26 step d, which gave the title compound (39 mg, 0.071 mmol, 77%).
Step e
Figure imgf000104_0003
N-[(LSl.2S.4igV4-((^-l-Benzylcarbamoyl-2-methyl-propylcarbamoyπ-4-allyloxy-l-(3.5- difluoro-phenoxymethylV2-hydroxy-butyl]-5-rmethanesulfonyl-methyl-aminoVΛr-rri?Vl- phenyl -ethylV isophthalamide f 29e^)
Azide 29d (19 mg, 0.036 mmol) and triphenyl phosphine (14 mg, 0.053 mmol, 1.5 eq.) were dissolved in MeOH (3 mL) and four drops of water were added. The reaction was stirred at room temperature over night and then concentrated under vacuum. Without further purification the formed amine was used in the next step. 5-methanesulfonyl-methyl-amino)-Λf'-(l-phenyl-ethyl)- isophthalacid (13 mg, 0.036 mmol, 1 eq), Py-BOP (19 mg, 0.036 mmol, leq) and DIPEA (6.5 μL, 0.036 mmol, leq) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~1 eq) from the previous reaction dissolved in DCM (2 mL) and DIPEA (6.5 μL, 0.036 mmol, leq) were added. After complete reaction the mixture were washed with NaHCCb (Ix 10 mL) and brine (Ix 1OmL). The water phase was extracted with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (toluen: ethyl acetate 1 :1) which gave the title compound (18 mg, 0.021 mmol, 58 %)
Example 30
Figure imgf000105_0001
N-FfI S.2SAR )-4-((S)- 1 -Benzylcarbamoyl^-methyl-propylcarbamoylV 1 -f 3.5 -difluoro- phenoxymeth ylV2-hvdroxy-4-propyloxy-butyll -5 -f methanesulfonyl-methyl-amino VN' -((R Vl- phenyl -ethyl Visophthalamide f 30)
Azide 29d (18 mg, 0.034 mmol) was dissolved in MeOH (4 mL) and a catalytical amount of Pd on carbonwas added, the mixture was then treated with hydrogen gas (1 atm) for 2 hours. Then the solids were filtered off and the filtrate was concentrated under vacuum. Without further purification the formed amine was used in the next step.
5-methanesulfonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalacid (13 mg, 0.034 mmol, 1 eq), Py-BOP (18 mg, 0.034 mmol, leq) and DIPEA (6 uL, 0.034 mmol, leq) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 30 minutes before the amine (~1 eq) from the previous reaction dissolved in DCM (2 mL) and DIPEA (6 uL, 0.034 mmol, leq) were added. After complete reaction the mixture were washed with NaHCO3 (1x 10 mL) and brine (Ix 1OmL). The water phase was extracted with DCM (2x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography (toluen: ethyl acetate 1 : 1) which gave the title compound (26 mg, 0.030 mmol, 88%).
Example 31 Step a
Figure imgf000105_0002
fli?.2i?.4y)-2-Hydroxymethyl-4-fmethanesulfonyl-methyl-aminoVcyclopentanecarboxylic acid methyl ester f31a") Compound 13f was dissolved in methylencloride, triethylsilane and THF were added and the reaction was stirred for Ih and then concentrated. The afforded residue (23 mg, 0.08 mmol) was dissolved in dry THF (1 mL) and cooled to 0 0C. Under an N2-atmosphare, borane in THF (110 D L, 1 M) was added dropwise and the reaction mixture was stirred for 4 h. The reaction was quenched with 5 drops of water.10 % Na2CCb (aq) was added and the solution was extracted three times with methylene chloride. The organic phases was pooled, dried with MgSO4, filtered and concentrated. The mixture was purified using flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound (20 mg, 90 %) as an oil.
1 H-NMR (SOO MHZ5 CDCI3): δ 1.59 (dd, J= 11.7, 23.1 Hz, IH), 1.92-2.06 (m, 2H), 2.17-2.27 (m, IH), 2.30-2.42 (m, IH), 2.70-2.77 (m, IH), 2.80 (s, 3H), 2.81 (s, 3H), 3.69 (ddd, J= 5.4, 6.0, 11.1 Hz, 2H), 3.71 (s, overlap, 3H), 4.35-4.47 (m, IH); 13C-NMR (75.5 MHz, CDCl3): δ 28.8, 31.3, 32.1, 37.6, 43.7, 44.3, 52.3, 56.5, 64.8, 175.7.
Step h
Figure imgf000106_0001
(li?.2i?.4y)-2-Benzyloxymethyl-4-(methanesulfonyl-methyl-aminoVcvclopentanecarboxylic acid methyl ester (3Ib")
Compound 31a (29 mg, 0.11 mmol) was dissolved in toluene (2 ml). 2-Benzyloxy-l- methylpyridinium (76 mg, 0.22 mmol) and magnesium oxide (9 mg, 0.22 mmol) were added and the reaction mixture was refluxed for 6 h. Additional 2-benzyloxy-l-methylpyridinium (38 mg, 0.11 mmol) was added. The solution reached room temperature and was stirred over night. The reaction mixture was concentrated and purified using flash column chromatography (toluene/ethyl acetate 3:1). which gave the title compound (34 mg, 87 %) as an oil. 1 H-NMR (SOO MHZ5 CDCI3): δ 1.63 (dd, J= 11.1, 23.1 Hz, IH), 1.90-2.08 (m, 2H), 2.10-2.20 (m, IH), 2.41-2.54 (m, IH), 2.71-2.76 (m, IH), 2.77 (s, 3H), 2.79 (s, 3H), 3.50 (d, J= 5.1 Hz, 2H), 3.65 (s, 3H), 4.36-4.47 (m, IH), 4.51 (s, 2H), 7.23-7.37 (m, 5H); 13C-NMR (75.5 MHz , CDCl3): δ 28.8, 31.7, 32.5, 37.6, 41.9, 44.5, 52.2, 56.8, 72.0, 73.4, 127.8, 127.9, 128.6, 138.5, 175.6.
Ster
Figure imgf000107_0001
(li?.2i?.4tS)-2-Benzyloxymethyl-4-(methanesulfonyl-methyl-amino)-cyclopentanecarboxylic acid [ri6'.26'.4i?V4-rry)-l-benzylcarbamoyl-2-methyl-propylcarbamoyπ-l-r3.5-difluoro- phenoxymethylV2-hydroxy-4-methoxy-butyl] -amide (3Ic^)
Compound 31a (20 mg, 0.06 mmol) was dissolved in dioxane (1 mL). A solution of LiOH (67 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was re-dissolved in DMF (1 mL). (2i?,45',55)-5-Amino-6-(3,5- difluoro -phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((S)- 1 -benzylcarbamoyl-2-methyl - propyl)-amide (22 mg, 0.04 mmol), DIPEA (29 μL, 0.17 mmol) and HATU (32 mg, 0.08 mmol) were added and the reaction mixture was stirred for 4 h. The solution was concentrated and purified using prep. HPLC, which gave the title compound (16 mg, 49 %) as white crystals. 1 H-NMR POO MHZ, DMSO-d6): δ 0.81 (dd, J= 4.8, 6.6 Hz, 6H), 1.45 (dd, J = 11.1, 22.8 Hz, IH), 1.68 (t, J = 6.6 Hz, 2H), 1.83-2.02 (m, 4H), 2.28-2.36 (m, IH), 2.58-2.63 (m, IH), 2.65 (s, 3H), 2.83 (s, 3H), 3.19 (s, 3H), 3.30-3.42 (overlap, 2H), 3.75-3.86 (m, 3H), 3.99-4.09 (m, 2H), 4.15-4.21 (m, 2H), 4.26 (d, J = 6.3 Hz, 2H), 4.42 (s, 2H), 4.95 (bs, IH), 6.62-6.67 (m, 2H), 6.73- 6.81 (m, IH), 7.17-7.32 (m, 10H), 7.63 (d, J = 8.7 Hz, IH), 7.72 (d, J= 8.1 Hz, IH), 8.53 (t, J= 6.0 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.2, 19.4, 28.3, 30.6, 32.0, 32.1, 36.5, 36.8, 41.2, 42.0, 45.1, 50.9, 56.3, 57.2, 57.6, 65.1, 67.4, 72.0, 72.3, 78.9, 96.2 (t, JCF = 26.3 Hz), 98.7 (d, JCF = 28.1 Hz), 126.8, 127.2, 127.4, 128.2, 128.3, 138.5, 139.3, 160.5 (t, JCF = 14.0 Hz), 163.0 (d, JCF = 243.9 Hz), 163.2 (d,JCF = 244.2 Hz), 170.8, 171.3, 174.7.
Example 32 Step a
Figure imgf000107_0002
(lR.2R.4S)-4-(Methanesulfonyl-methyl-amino)-2-r(SVl-(4-methoxy-phenvπ-ethylcarbamoyl1- cvclopentanecarboxylic acid methyl ester (32a)
Compound 13f (24 mg, 0.07 mmol) was dissolved in DCM (1.2 mL). Triethylsilane (23 μL, 0.14 mmol) and TFA (0.6 mL) were added and the reaction mixture was stirred for 3 h. The solution was concentrated and re-dissolved in DMF (1 rnL). (5)-(-)-4-Methoxy-methyl benzylamine (16 μL, 0.1 mmol), DIPEA (37 μL, 0.2 mmol) and HATU (38 mg, 0.1 mmol) were added and the reaction mixture was stirred for 4 h. The solution was co -evaporated with toluene and concentrated. The residue was purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound (31 mg, quant.) as a syrup.
1H-NMR (300 MHz, CDCl3): δ 1.45 (d, J= 6.9 Hz, 3H), 2.02-2.17 (m, 4H), 2.79 (s, 3H), 2.80- 2.85 (m, IH), 2.81 (s, overlap, 3H), 3.12-3.21 (m, IH), 3.72 (s, 3H), 3.79 (s, 3H), 4.38 (m, IH), 5.03 (app. quintet, J= 6.9 Hz, IH), 6.14 (d, J= 8.1 Hz, IH), 6.84-6.89 (m, 2H), 7.16-7.27 (m, 2H); 13C-NMR (75.5 MHz, CDCl3): 521.9, 28.6, 31.0, 32.4, 37.6, 45.3, 46.4, 48.7, 52.5, 55.4, 56.3, 114.2, 127.4, 135.3, 159.0, 171.6, 174.9.
Step h
Figure imgf000108_0001
(li?.2i?.4y)-4-(Methanesulfonyl-methyl-amino)-cvclopentane-1.2-dicarboxylic acid 1- ( IY 1 S2S AR)A-(JS)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-amide| 2-{r(5Vl-(4-methoxy-phenyl)-ethyl"|- amidel (32b)
Compound 32a (29 mg, 0.07 mmol) was dissolved in dioxane (1 mL). A solution of LiOH (84 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The solution was neutralized with 1 M HCl. The solution was concentrated and the crude was dissolved in DMF (1 mL). (2i?,45',55)-5-Amino-6-(3,5-difluoro-phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((S)-I- benzylcarbamoyl-2-methyl-propyl)-amide (22 mg, 0.04 mmol), DIPEA (36 μL, 0.2 mmol) and HATU (39 mg, 0.1 mmol) were added and the reaction mixture was stirred for 4 h. The solution was concentrated and the residue purified using prep. HPLC which gave the title compound (27 mg, 76 %) as white crystals.
1H-NMR (300 MHz, DMSO-d6): δ 0.84 (app. t, J = 6.0 Hz, 6H), 1.27 (d, J= 6.6 Hz, 3H), 1.67- 1.74 (m, 2H), 1.92-2.11 (m, 4H), 2.68 (s, 3H), 2.84 (s, 3H), 2.87-2.93 (m, IH), 3.07-3.15 (m, 2H), 3.22 (s, 3H), 3.71 (s, 3H), 3.78 (t, J= 6.3 Hz, IH), 3.88-3.95 (m, 2H), 4.05-4.14 (m, 2H), 4.17-4.24 (m, IH), 4.29 (d, J = 6.9 Hz, 2H), 4.85 (app. quintet, J= 7.2 Hz, IH), 4.93 (d, J = 5.7 Hz, IH), 6.71-6.81 (m, 3H), 6.85 (d, J= 7.8 Hz, 2H), 7.18-7.33 (m, 7H), 7.62 (d, J= 9.0 Hz, IH), 7.67 (d, J= 7.5 Hz, IH), 8.20 (d, J= 8.1 Hz, IH), 8.51 (t, J= 5.9 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.1, 19.3, 22.5, 28.2, 30.6, 31.7, 33.1, 36.6, 42.0. 45.1, 45.9, 47.3, 51.0, 55.0, 56.3, 57.2, 57.5, 65.0, 67.2, 78.9, 96.2 (t, JCF = 26.4 Hz), 98.8 (d, JCF = 28.1 Hz), 113.6, 126.8, 126.9, 127.2, 128.2, 136.6, 139.2, 157.9, 160.5 (t, JCF = 14.0 Hz), 162.9 (d, JCF = 244.5 Hz), 163.2 (d, JCF = 244.2 Hz), 170.7, 171.2, 171.6, 174.0.
Example 33 Step a
Figure imgf000109_0001
(li?.2i?.4y)-2-r(y)-l-(4-Chloro-phenvπ-ethylcarbamoyl1-4-(methanesulfonyl-methyl-amino)- cyclopentanecarboxylicacid methyl ester (33a)
Compound 13f (24 mg, 0.07 mmol) was dissolved in DCM (1 mL). Triethylsilane (23 μL, 0.14 mmol) and TFA (0.5 mL) were added and the reaction mixture was stirred for 3.5 h. The solution was concentrated and the afforded residue dissolved in DMF (1 mL). (5)-4-Chloro- D -methyl benzylamine (15 μL, 0.1 mmol), DIPEA (37 μL, 0.2 mmol) and HATU (40 mg, 0.1 mmol) were added and the reaction mixture was stirred for 4 h. The solution was co -evaporate with toluene and concentrated. The residue was purified using flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound (30 mg, 100 %) as an oil.
1H-NMR (300 MHz, CDCl3): δ 1.44 (d, J= 7.2 Hz, 3H), 2.00-2.22 (m, 4H), 2.80 (s, 3H), 2.81 (s, 3H), 2.82-2.89 (m, IH), 3.11-3.19 (m, IH), 3.73 (s, 3H), 4.32-4.44 (m, IH), 5.03 (app. quintet, J = 7.1 Hz, IH), 6.26 (d, J= 7.5 Hz, IH), 7.16-7.33 (m, 4H); 13C-NMR (75.5 MHz, CDCl3): δ 22.0, 28.5, 30.8, 32.3, 37.6, 45.2, 46.2, 48.7, 52.6, 56.2, 127.6, 129.0, 133.2, 141.8, 171.8, 175.0.
Figure imgf000109_0002
(lR.2R.4SV4-(Methanesulfonyl-methyl -amino Vcyclopentane-1.2-dicarboxylic acid 1- (r(lS.2S.4RV4-((SVl-benzylcarbamoyl-2-methyl-r)ror)ylcarbamovn-l-(3.5-difluoro- phenoxymethyl)-2-hydroxy-4-methoxy-butyl]-amide} 2-{[(S)-l-(4-chloro-phenyl)-ethyl]- amidel (33b)
Compound 33a (20 mg, 0.05 mmol) was dissolved in dioxane (1 niL). A solution of LiOH (55 μL, 40 mg/niL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was dissolved in DMF (1 mL). (2i?,45',55)-5-Amino-6-(3,5-difluoro- phenoxy) -4-hydroxy-2-methoxy-hexanoic acid ((S)- 1 -benzylcarbamoyl-2-methyl-propyl)-amide (22 mg, 0.04 mmol), DIPEA (24 μL, 0.14 mmol) and HATU (28 mg, 0.07 mmol) were added and the reaction mixture was stirred for 4 h and then concentrated. The residue was purified using prep. HPLC which gave the title compound (20 mg, 57 %) as white crystals. 1H-NMR (300 MHz, DMSO-d6): δ 0.81 (d, J= 6.6 Hz, 3H), 0.83 (d, J = 5.4 Hz, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.64-1.71 (m, 2H), 1.88-2.10 (m, 4H), 2.65 (s, 3H), 2.83 (s, 3H), 2.87-2.93 (m, IH), 3.04-3.15 (m, 2H), 3.19 (s, 3H), 3.76 (t, J= 6.3 Hz, IH), 3.84-3.93 (m, 2H), 4.02-4.07 (m, 2H), 4.15-4.23 (m, 2H), 4.26 (d, J= 5.7 Hz, 2H), 4.84 (app. quintet, J = 7.1 Hz, IH), 6.69-6.81 (m, 3H), 7.17-7.36 (m, 9H), 7.65 (d, J = 9.0 Hz, IH), 7.73 (d, J= 7.2 Hz, IH), 8.35 (d, J= 8.1 Hz, IH), 8.53 (t, J = 6.0 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 18.2, 19.4, 22.4, 28.3, 30.6, 31.8, 33.1, 36.6, 42.1, 45.0, 45.8, 47.5, 51.0, 56.3, 57.2, 57.6, 65.0, 67.2, 78.9, 96.3 (t, JCF = 26.3 Hz), 98.8 (d, JCF = 28.1 Hz), 126.8, 127.2, 127.8, 128.2, 128.3, 131.1, 139.2, 143.9, 160.5 (d, JCF = 14.0 Hz), 163.0 (d,JcF = 244.2 Hz), 163.2 (d, JcF = 244.2 Hz), 170.8, 171.3, 171.9, 174.0.
Example 34 Step a
Figure imgf000110_0001
(li?.2i?.4y)-4-(Methanesulfonyl-methyl-aminoV2-((y)-l-p-tolyl-ethylcarbamoylV cyclopentanecarboxylic acid methyl ester (34a)
Compound 13f (21 mg, 0.06 mmol) was dissolved in DCM (0.8 mL). Triethylsilane (20 μL, 0.12 mmol) and TFA (0.4 mL) were added and the reaction mixture was stirred for 2.5 h. The solution was concentrated and then dissolved in DMF (1 mL). (5)-(-)-α-4-dimethyl benzylamine (11 μL, 0.07 mmol), TEA (26 μL, 0.18 mmol) and HOBt (12 μL, 0.09 mmol) were added and cooled to 0 0C. EDC (16 mg, 0.08 mmol) was added and the reaction mixture was stirred for 4.5 h. The solution was co -evaporate with toluene and then concentrated. The residue was purified using flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound (24 mg, 96 %) as an oil. 1H-NMR (300 MHz, CDCl3): δ 1.45 (d, J= 7.2 Hz, 3H), 2.01 -2.19 (m, 4H), 2.33 (s, 3H), 2.78- 2.87 (m, IH), 2.79 (overlap, s, 3H), 2.82 (overlap, s, 3H), 3.13-3.21 (m, IH), 3.72 (s, 3H), 4.83 (m, IH), 5.04 (app. quintet, J= 7.2 Hz, IH), 6.17 (d, J= 7.5 Hz, IH), 7.13-7.20 (m, 4H); 13C- NMR (75.5 MHz, CDCl3): 521.2, 22.0, 28.5, 31.0, 32.4, 37.6, 45.3, 46.4, 49.0, 52.5, 56.3, 126.1, 129.5, 137.3, 140.2, 171.7, 174.9.
Step b
Figure imgf000111_0001
(li?,2i?,4tSl-4-(Methanesulfonyl-methyl-amino)-cvclopentane-l,2-dicarboxylic acid 1- ( IY 1 S2SAR)4-((S)- 1 -benzylcarbamoyl^-methyl- propylcarbamovQ- 1 -(3.5 -difluoro- phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-amide| 2-r((5Vl-p-tolyl-ethyl)-amide1 (34b) Compound 34a (0.019g, 0.048 mmol) was dissolved in MeOH (1 niL) and LiOH (63 μL, 0.096 mmol) was added and the reaction mixture was stirred overnight. The solution was concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 1 :2 + 2 % AcOH). The afforded acid was dissolved in DMF (0.7 mL), (2R, AS, 55)-5-amino-6-(3,5- difluoro -phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((S)- 1 -benzylcarbamoyl-2-methyl - propyl)-amide (0.028g, 0.058 mmol), DIPEA (21 μL, 0.123 mmol) and HATU (0.02Og, 0.053 mmol) were added and the reaction mixture was stirred for 4 h. The solution was concentrated and re-dissolved in DMSO (1 mL) and then purified with HPLC (85 % MeOH, 15 % H2O + 0.1 % TFA). BEA-1052 which gave the title compound (22 % yield).
1H-NMR (DMSO-d6, 300 MHz): δ 0.80 (t, J= 6.3 Hz, 9H), 1.24 (d, J= 6.9 Hz, 3H), 1.58-1.80 (m, 4H), 1.83-2.15 (m, 6H), 2.23 (s, 3H), 2.65 (s, 3H), 2.83 (s, 3H), 3.20 (s, 3H), 3.70-4.35 (m, 8H), 4.83 (t, J = 7.2 Hz, IH), 6.60-6.85 (m, 3H), 7.00-7.40 (m, 7H), 7.65 (d, J= 9 Hz, IH), 7.70 (d, J = 7.2 Hz, IH), 8.25 (d, J= 8.1 Hz, IH), 8.53 (t, J= 5.7 Hz, IH). 13C-NMR (DMSO-d6, 75.5 MHz): δ 18.9, 20, 21.3, 23.3, 28.9, 31.3, 32.4, 33.8, 37.3, 42.7, 45.7, 46.6, 48.4, 51.7, 57, 57.9, 58.2, 65.6, 67.8, 79.5, 96.9 (t, JCF = 27 Hz), 99.6 (d, JCF = 28 Hz), 126.4, 127.5, 127.9, 128.9, 129.5, 136, 139.9, 142.4, 161.2 (t, JCF = 14 Hz), 163.7 (d, JCF = 244.5 Hz), 163.9 (d,JCF = 244.1 Hz), 171.4, 171.9, 172.3, 174.7.
Example 35 Step a
Figure imgf000112_0001
(Ii? .2i?.4y)-2-Cyclopropylcarbamoyl-4-(methanesulfonyl-methyl-amino V cyclopentanecarboxylic acid methyl ester (35 a")
Compound 13f (20 mg, 0.060 mmol) was dissolved in DCM (0.790 mL), Triethylsilane (19 μL, 0.120 mmol) and TFA (0.368 mL) were added and the reaction mixture was stirred for approximately 1 h. The solution was concentrated and the residue dissolved in DMF (0.5 mL). Cyclopropylamine (5 μL, 0.072 mmol), DIPEA (18 μL, 0.101 mmol) and HATU (0.030g, 0.078 mmol) were added and the reaction mixture was stirred for 2.5 h. The solution was concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 1 :3) which gave the title compound in 85 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.80-1.90 (m, 2H), 2.00-2.18 (m, 2H), 3.20-3.80 (m, 2H), 3.95- 4.10 (m, IH), 4.22 (s, 3H), 4.48-4.62 (q, J= 6 Hz, IH), 4.67 (s, 3H), 5.04 (s, 3H), 5. 45 (q, J= 6.1 Hz, IH), 5.65-5.80 (m, IH), 6.34 (s, 3H). 13C-NMR (CDCl3, 75.5 MHz): δ 6.4, 6.5, 14.4, 20.9, 23.4, 28.8, 30.1, 31.4, 34.5, 37.2, 45.9, 52.6, 57.9, 61.6, 176, 177.1.
Step b
Figure imgf000112_0002
(li?.2i?.4y)-4-(Methanesulfonyl-methyl-aminoVcyclopentane-1.2-dicarboxylic acid 1- ( [( 1 S.2SΛR)A-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethylV2-hydroxy-4-methoxy-butyl]-amide} 2-cyclopropylamide (35V) Compound 35a (0.016g, 0.050 mmol) was dissolved in MeOH (1 mL), LiOH (61 μL, 0.101 mmol) was added and the reaction was stirred overnight, concentrated and the crude was used directly for coupling. The afforded acid was dissolved in DMF (1 mL) and (2R, AS, 55)-5-amino- 6-(3,5-difluoro-phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((5)-l-benzylcarbamoyl-2- methyl-propyl)-amide (0.02Og, 0.041 mmol), DIPEA (26 μL, 0.151 mmol) and HATU (0.025g, 0.066 mmol) were added and the reaction mixture was stirred for 4 h. The mixture was concentrated and the residue dissolved in DMSO (1 mL) and purified by HPLC (MeOH 80 %, H2O 20 % + 0.2 % TFA) and then purified again by flash column chromatography (MeOH/EtOAcl :34) which gave the title compound in 57 % yield.
1H-NMR (DMSO-d6, 300 MHz): δ 0.30-0.40 (m, 9H), 0.5-0.6 (m, 2H), 0.80 (t, J= 6 Hz, 3H), 1.60-1.80 (m, 2H), 1.82-2.06 (m, 3H), 2.28 (s, IH), 2.48 (s, 3H), 2.56 (m, IH), 2.70 (s, 3H), 2.84 (s, 3H), 3.05 (q, J= 8.7 Hz, IH), 3.19 (s, 3H), 3.33 (s, 3H), 3.75 (t, J = 6.6 Hz, IH), 3.80-3.96 (m, 2H), 3.98-4.10 (m, 2H), 4.18 (t, J= 6.9 Hz, IH), 4.26 (d, J =5.7 Hz, 2H), 6.64-6.82 (m, 2H), 7.08-7.32 (m, 3H), 7.58-7.74 (m, IH). 13C-NMR (DMSO-d6, 75.5 MHz): δ 5.7, 18.3, 19.4, 22.4, 22.4, 30.6, 31.8, 32.9, 36.6, 42.1, 45.4, 46, 51, 56.3, 57.2, 57.6, 65.0, 67.1, 78.9, 96.3 (t, JCF = 26.3 Hz), 98.7 (d, JCF = 27.8 Hz), 126.8, 127.2, 128.3, 139.3, 160.5 (t, JCF = 14 Hz), 163.0 (d,JCF = 244.2 Hz), 163.2 (d, JCF = 244.2 Hz), 170.8, 171.3, 173.8.
Example 36 Step a
Figure imgf000113_0001
13f 38a
(li?.2i?.4y)-2-(Cvclopropylmethyl-carbamovπ-4-(methanesulfonyl-methyl-amino)- cvclopentanecarboxylic acid methyl ester (36a)
Compound 13f (20 mg, 0.060 mmol) was dissolved in DCM (0.790 mL). Triethylsilane (19 μL, 0.120 mmol) and TFA (0.368 mL) were added and the reaction mixture was stirred for 1 h. The solution was concentrated and the residue dissolved in DMF (0.5 mL). Cyclopropylmethanamine (7.2 μL, 0.084 mmol), DIPEA (18 μL, 0.102 mmol) and HATU (0.029g, 0.078 mmol) were added and the solution was stirred for 2.5 hours. The solution was concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 1 :9) which gave the title compound in approximately 100 % yield.
1H-NMR (CDCl3, 300 MHz): δ 0.19 (m, 2H), 0.40 (m, 2H), 0.84-1.02 (m, IH), 1.86-2.20 (m, 3H), 2.82 (s, 3H), 2.84 (s, 3H), 2.87-3.01 (m, IH), 3.02 (s, 3H), 3.04-3.26 (m, 3H), 3.64 (s, 2H), 4.30-4.42 (m, IH). 13C-NMR (CDCl3, 75.5 MHz): δ 2.9, 10.9, 30.8, 33.3, 36.4, 43.7, 44.7, 46.6, 51.5, 56.8, 172.7, 174.7.
Figure imgf000114_0001
(li?.2i?.4y)-4-(Methanesulfonyl-methyl-amino)-cvclopentane-1.2-dicarboxylic acid 1-
( IY 1 S2SAR)A-((S)- 1 -benzylcarbamoyl^-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethylV2-hvdroxy-4-methoxy-butvH-amidel 2-cvclopropylmethyl-amide (36b) Compound 36a (0.02Og, 0.060 mmol) was dissolved in MeOH (1 niL). LiOH (73 μL, 0.120 mmol) was added and the reaction mixture was stirred overnight and then concentrated. The afforded acid was dissolved in DMF (1 mL) and (IR, AS, 5S)-5-amino-6-(3,5-difluoro-phenoxy)- 4-hydroxy-2-methoxy-hexanoic acid ((5)-l-benzylcarbamoyl-2-methyl-propyl)-amide (0.02Og, 0.041 mmol), DIPEA (32 μL, 0.180 mmol) and HATU (0.03Og, 0.079 mmol) were added and the solution was stirred for 4 h and then concentrated. The residue was dissolved in DMSO (1 mL) and purified by HPLC (85 % MeOH, 15 % H2O + 0.1 % TFA) which gave the title compound as a white powder in 50 % yield.
1H-NMR (DMSO-d6, 300 MHz): δ 0.06-0.12 (d, J= 4.8 Hz, 9H), 0.30-0.35 (d, J = 8.1 Hz, 3H), 0.81 (t, J= 5.1 Hz, 4H), 1.64-2.10 (m, 4H), 2.50 (s, 3H), 2.69 (s, 2H), 2.84 (s, 2H), 2.87-2.95 (m, IH), 3.06 (q, J= 8.7 Hz, IH), 3.19 (s, 2H), 3.39 (s, 3H), 3.75 (t, J= 6.3 Hz, IH), 3.80-3.94 (m, 2H), 3.96-4.10 (m, 2H), 4.17 (t, J = 7.2 Hz, IH), 4.26 (d, J= 5.4 Hz, 2H), 6.60-6.82 (m, 2H), 7.10-7.31 (m, 5H), 7.30 (d, J = 9 Hz, IH), 7.70 (d, J= 7.2 Hz, IH), 7.89 (t, J= 6 Hz, IH), 8.51 (t, J= 5.7 Hz, IH). 13C-NMR (DMSO-d6, 75.5 MHz): δ 3.2, 10.7, 18.2, 19.4, 27.6, 28.3, 30.6, 30.7, 31.9, 33.0, 33.6, 33.9, 36.6, 42.0, 42.8, 44.7, 45.3, 46.0, 47.1, 49.3, 51.0, 52.0, 56.3, 57.2, 57.6, 64.9, 67.1, 78.9, 80.6, 96.3 (t, JCF = 26.7 Hz), 98.8 (d, JCF = 27.8 Hz), 126.8, 127.2, 128.2, 139.3, 160.5 (t, JCF = 14 Hz), 163.0 (d, JCF = 244.5 Hz), 163.2 (d,JCF = 244.2 Hz), 170.8, 171.3, 171.7, 172.5, 173.5, 174.0.
Example 37 Step a
Figure imgf000114_0002
rii?r2i?r4^-2-rr^-l-Cyclohexyl-ethylcarbamoyπ-4-rmethanesulfonyl-methyl-aminoV cyclopentanecarboxylic acid methyl ester G 7a")
Compound 13f (47 mg, 0.14 mmol) was dissolved in DCM (2.1 mL). Triethylsilane (45 μL, 0.28 mmol) and TFA (0.7 mL) were added and the reaction mixture was stirred for 2.5 h. The solution was concentrated and one third of the residue was dissolved in DMF (1 mL). (5)-(+)-l- Cyclohexylethylamine (9 μL, 0.06 mmol), DIPEA (24 μL, 0.14 mmol) and HATU (26 mg, 0.07 mmol) were added and the reaction mixture was stirred for 4 h. The solution was co-evaporate with xylene, concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 1 :2) which gave the title compound (17 mg, 91 %) as an oil. 1 H-NMR (SOO MHZ5 CDCI3): δ 0.86-1.00 (m, 2H), 1.05 (d, J= 6.9 HZ, 3H), 1.12-1.35 (m, 3H), 1.64-1.77 (m, 6H), 2.01-2.21 (m, 4H), 2.75-2.79 (m, IH), 2.81 (s, 3H), 2.83 (s, 3H), 3.08-3.17 (m, IH), 3.70 (s, 3H), 3.78-3.85 (m, IH), 4.34-4.46 (m, IH), 5.73 (d, J= 9.0 Hz, IH); 13C-NMR (75.5 MHz, CDCl3): δ 18.0, 26.3, 26.5, 28.5, 29.1, 29.2, 30.9, 32.6, 37.6, 43.1, 45.3, 46.6, 49.8, 52.5, 56.3, 171.9, 175.0.
Step b
Figure imgf000115_0001
(li?.2i?.4y)-4-(Methanesulfonyl-methyl-amino)-cvclopentane-1.2-dicarboxylic acid 1- ( PC 1 S2SAR)4-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyl) -2-hydroxy-4-methoxy-butyll -amide) 2- \((S)- 1 -cyclohexyl-ethvD-amidel ( 37b) Compound 37a (16 mg, 0.04 mmol) was dissolved in dioxane (1 mL). A solution of LiOH (49 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude was dissolved in DMF (1 mL). (2i?,45',55)-5-Amino-6-(3,5-difluoro- phenoxy) -4-hydroxy-2-methoxy-hexanoic acid ((S)- 1 -benzylcarbamoyl-2-methyl-propyl)-amide (22 mg, 0.04 mmol), DIPEA (22 μL, 0.12 mmol) and HATU (23 mg, 0.06 mmol) were added and the reaction mixture was stirred over night. The solution was concentrated and the residue purified by prep. HPLC which gave the title compound (24 mg, 69 %) as white crystals. 1H-NMR (300 MHz, DMSO-d6): δ 0.79-0.83 (m, 6H), 0.83-0.88 (m, IH), 0.90 (d, J= 6.9 Hz, 3H), 1.01-1.26 (m, 4H), 1.40-1.78 (m, 8H), 1.90-2.08 (m, 4H), 2.69 (s, 3H), 2.76-2.82 (m, IH), 2.84 (s, 3H), 3.02-3.11 (m, IH), 3.19 (s, 3H), 3.52-3.59 (m, IH), 3.75 (t, J = 6.6 Hz, IH), 3.70- 3.89 (m, 2H), 3.99-4.05 (m, 2H), 4.14-4.22 (m, 2H), 4.26 (d, J = 6.6 Hz, 2H), 4.93 (d, J= 6.0 Hz, IH), 6.67-6.81 (m, 3H), 7.20-7.31 (m, 5H), 7.57 (d, J= 8.7 Hz, IH), 7.64 (d, J= 9.0 Hz, IH), 8.53 (t, J = 5.9 Hz, IH); 13C-NMR (75.5 MHz, DMSO-d6): δ 17.7, 18.3, 19.4, 25.8, 26.1, 28.3, 28.8, 28.9, 30.6, 31.6, 33.4, 36.6, 42.1, 42.3, 45.2, 46.2, 48.6, 51.0, 56.3, 57.2, 57.6, 65.0, 67.2, 78.9, 96.3 (t, JCF = 26.0 Hz), 98.8 (d, JCF = 28.4 Hz), 126.8, 127.2, 128.3, 139.3, 160.5 (t, JCF = 14.2 Hz), 163.0 (d, JCF = 244.2 Hz), 163.2 (d, JCF = 243.9 Hz), 170.8, 171.3, 171.8, 174.1.
Example 38 Step a
,0
7V N '
Figure imgf000116_0001
13f 38a
(li?.2i?.4y)-2-(Allyl-benzyl-carbamovπ-4-(methanesulfonyl-methyl-amino)- cvclopentanecarboxylic acid methyl ester (38a)
Compound 13f (76 mg, 0.22 mmol) was dissolved in DCM (3 mL). Triethylsilane (72 μL, 0.45 mmol) and TFA (1.5 mL) were added and the reaction mixture was stirred for 1 h and 15 min. The solution was concentrated and the residue dissolved in DMF (2 mL). Allylbenzylamine (46 μL, 0.31 mmol), DIPEA (120 μL, 0.69 mmol) and HATU (113 mg, 0.30 mmol) were added and the reaction mixture was stirred for 3 h. The solution was co -evaporate with xylene, concentrated and the residue purified using flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound (85 mg, 91 %) was collected as oil.
1H-NMR (300 MHz, CDCl3, rotamer ratio 1 :0.7): δ 1.88-2.03 (m, 2H), 2.08-2.18 (m, 2H), [2.74 (s, minor rotamer) and 2.80 (s, major rotamer), 3H], [2.81 (s, minor rotamer) and 2.84 (s, major rotamer), 3H], 3.20-3.30 (m, IH), 3.49 (quintet, J= 8.4 Hz, IH), [3.63 (s, minor rotamer) and 3.64 (s, major rotamer), 3H], 3.78-4.03 (m, 2H), 4.50-4.69 (m, 2H), 5.06-5.24 (m, 2H), 5.69- 5.82 (m, IH), 7.14-7.22 (m, 2H), 7.23-7.38 (m, 3H); 13C-NMR (75.5 MHz, CDCl3) : δ 28.5, [30.3 & 30.4], [34.0 & 34.1], [37.4 & 37.5], [42.3 & 42.4], [45.4 & 45.6], 48.7, 48.9, 49.2, 50.2, 52.2, [56.5 & 56.6], [117.0 & 117.5], 126.4, 127.5, [127.8 & 127.9], [128.7 & 129.0], [132.6 & 132.8], [136.7 & 137.3], [173.7 & 173.8], [174.4 & 174.5].
Figure imgf000117_0001
(li?.2i?.4i?)-4-(Methanesulfonyl-methyl-amino)-cvclopentane-1.2-dicarboxylic acid l-(allyl- benzyl-amide) 2 - ( IY lS,2SAR)-4-((S)- 1 -benzylcarbamoyl-2 -methyl -propylcarbamovD- 1-0.5- difluoro-phenoxymethyl)-2-hvdroxy-4-methoxy-butyl]-amide| (38b)
Compound 38a (24 mg, 0.06 mmol) was dissolved in dioxane (1 mL). A solution of LiOH (71 μL, 40 mg/mL) was added and the reaction mixture was stirred over night. The solution was concentrated and the crude dissolved in DMF (1 mL). (2i?,45',55)-5-Amino-6-(3,5-difluoro- phenoxy) -4-hydroxy-2-methoxy-hexanoic acid ((S)- 1 -benzylcarbamoyl-2-methyl-propyl)-amide (22 mg, 0.04 mmol), DIPEA (31 μL, 0.18 mmol) and HATU (28 mg, 0.07 mmol) were added and the reaction mixture was stirred for 5 h. The solution was concentrated and the residue purified by prep. HPLC which gave the title compound (35 mg, 91 %) as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.92-0.98 (dd, J= 6.9, 9.6 Hz, 6H), 1.86-2.09 (m, 4H), 2.16-2.35 (m, 2H), 2.69-2.82 (m, 7H), 3.17-3.34 (m, 2H), 3.43 (s, 3H), 3.69-3.74 (m, IH), 3.78-3.87 (m, 3H), 3.92-4.02 (m, IH), 4.06-4.17 (m, 2H), 4.25-4.30 (m, IH), 4.39 (d, J= 5.4 Hz, 2H), 4.42- 4.48 (m, IH), 4.53-4.66 (m, IH), 5.00-5.29 (m, 2H), 5.60-5.76 (m, 2H), 6.29-6.45 (m, 3H), 6.68 (bs, IH), 7.10-7.35 (m, 10H); 13C-NMR (75.5 MHz, CDCl3, both rotamers): δ 17.9, 19.6, 28.6, [30.4 & 30.9], [34.3 & 34.6], 35.9, [37.4 & 37.5], [43.8 & 44.2], 47.4, [48.6 & 48.8], 49.3, 50.4, [53.0 & 53.1], [56.5 & 56.6], [58.4 & 58.5], [66.0 & 66.1], [67.2 & 67.3], 79.8, 96.9 (t, JCF = 25.8 Hz), 98.6 (d, JCF = 28.1 Hz), [117.6 & 117.9], 126.6, [127.7 & 127.8], 128.0, [128.8 & 128.9], 129.1, [132.2 & 132.5], [136.2 & 136.9], 137.8, 160.3, [161.9 & 162.2], [165.2 & 165.4], 171.4, 173.1, [173.7 & 173.8], [174.1 & 174.2].
Example 39
Figure imgf000117_0002
2-Oxo-tetrahydro-pyran-4-carboxylic acid (0.21g, 1.36 mmol) was dissolved in DCM (13.6 mL), TBTA (0.73 mL, 4.10 mmol) was added and the reaction mixture was stirred overnight. The solution was concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 6:1) which gave the title compound as white crystals in 64 % yield. 1H-NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.90 (d, J = 10.4 Hz, IH), 2.10-2.22 (m, 3H), 2.76-
22..8855 ((mm,, IIHH)),, 33..1100 ((ss,, IIHH)),, 44..992 (s, IH). 13C-NMR (CDCl3, 75.5 MHz): 528.1, 33.3, 38.0, 40.8, 46.1, 80.6, 82.0, 171.7, 176.8.
Step b
Figure imgf000118_0001
(IS. 2S. 4i?V4-Hydroxy-cyclopentane-1.2-dicarboxyric acid 1-tert-butyl ester 2-methyl ester
Q2hX
Compound 39a (0.18g, 0.85 mmol) was dissolved in MeOH (7.5mL) and cooled to 0 °C. K2CO3 (0.18 g, 1.27 mmol) was added and the reaction mixture was stirred for 30 minutes. The solution was neutralised with 1 M HCl and concentrated and the residue purified by flash column chromatography (toluene/ethyl acetate 3:1) which gave the title compound as a yellowish oil in 92 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.87-2.01 (m, 2H), 2.04-2.14 (m, IH), 2.17-2.29 (m, 2H), 3.11-3.20 (2q, J = 5.2 Hz, IH), 3.24-3.34 (q, J= 7.4 Hz, IH), 3.72 (s, 3H), 4.39 (m, IH). 13C-NMR (CDCl3, 75.5 MHz): δ 28.2, 38.8, 40.0, 45.4, 46.9, 52.4, 73.2, 80.9, 173.9, 176.6.
Step c
N3
Figure imgf000118_0002
(\St IS. 4ff)-4-Azido-cyclopentane-lr2-dicarboxyric acid 1-tert-butyl ester 2-methyl ester T39c^> Compound 39b (0.19g, 0.77 mmol) was dissolved in THF (5.8 mL) and cooled to 0 °C. PPh3 (0.30g, 1.16 mmol) and DIAD (0.39g, 1.94 mmol, 0.38 mL) were added and the reaction mixture was stirred for 10 minutes. DPPA (0.32g, 1.16 mmol, 0.25mL) was added drop wise and the reaction mixture was stirred overnight. The solution was concentrated and the residue purified by flash column chromatography (toluene/ ethyl acetate 39:1) which gave the title compound as a colourless oil in 89 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.97-2.10 (m, 3H), 2.22-2.35 (m, IH), 3.08 (q, J = 8 Hz, IH), 3.30 (q, J= 8.5 Hz, IH), 3.69 (s, 3H), 4.06 (quintet, J = 5 Hz, IH). 13C-NMR (CDCl3, 75.5 MHz): δ 28.1, 35.3, 36.2, 45.0, 46.8, 52.2, 61.6, 81.3, 172.5, 174.9.
Step d
Figure imgf000119_0001
(IS. 2S. 4Λ)-4-Amino-cyclopentane-1.2-dicarboxyric acid 1-tert-butyl ester 2-methyl ester (39d) Compound 39c (0.18g, 0.66 mmol) was dissolved in MeOH (8.8 niL), PPh3 (0.28g, 1.08 mmol) and 7 drops of water were added and the reaction mixture was stirred overnight. The solution was concentrated and the residue purified by flash column chromatography (methanol/ethyl acetate 1 :9 + 1 % triethylamine) which gave the title compound as a pale yellowish oil in 71 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.41 (s, 9H), 1.52-1.64 (m, IH), 1.69-1.81 (m, IH), 2.0-2.11 (m, IH), 2.19-2.30 (m, IH), 3.03 (q, J= 8.5 Hz, IH), 3.28 (q, J= 9 Hz, IH), 3.46 (quintet, J= 6 Hz, IH), 3.66 (s, 3H). 13C-NMR (CDCl3, 75.5 MHz): δ 28.1, 39.7, 39.9, 45.1, 47.3, 52.0, 52.5, 80.8, 173.9, 175.7.
Step e
/S ^NH
/
O O
(IS, IS, 45V4-Methanesulfonylamino-cvclopentane-l.,2-dicarboxylic acid 1-tert-butyl ester 2- methyl ester (39e)
Compound 39d (0.1 Ig, 0.47 mmol) was dissolved in DCM/pyridine 2.1 :0.7 mL, and the solution was cooled to 0 °C. Methanesulfonyl chloride (0.036 mL, 0.47 mmol) was added and the reaction mixture was allowed to reach rt. The solution was stirred overnight, concentrated and the residue was purified by flash column chromatography (toluene/ethyl acetate 3:1) which gave the title compound as a yellow-brown oil in 85 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.42 (s, 9H), 1.79-1.90 (m, IH), 2.00-2.11 (m, IH), 2.14-2.26
(m, IH), 2.28-2.40 (m, IH), 2.95 (s, 3H), 3.04-3.12 (m, IH), 3.20 (q, J= 8 Hz, IH), 3.68 (s, 3H),
3.98 (m, IH), 5.10 (d, J = 7.7 Hz, IH). 13C-NMR (CDCl3, 75.5 MHz): 528.1, 37.1, 37.8, 41.5,
45.5, 46.7, 52.3, 54.6, 81.8, 174.4, 174.6.
Step f
Figure imgf000120_0001
(IS, 2S. 45V4-(Methanesulfonyl-methyl-amino)-cyclopentane-l.,2-dicarboxylic acid 1-tert-butyl ester 2 -methyl ester (39f)
Compound 39e (0.12g, 0.38 mmol) was dissolved in DMF (1.3 mL). NaH (15 mg, 0.625 mmol,
60% solution) and MeI (0.047 mL, 0.759mmol) were added and the reaction mixture was stirred for 2.5 hours. The reaction was quenched with H2O (5.1 mL) and extracted twice with ethyl acetate (6 mL). The organic phases were pooled, dried, filtered and concentrated. Purificationof the afforded residue by flash column chromatography (toluene/ethyl acetate 3:1) gave the title compound in 78 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.41 (s, 9H), 1.80-2.28 (m, 4H), 2.79 (s, 6H), 2.93-3.05 (m, IH),
3.07-3.18 (m, IH), 3.69 (s, 3H), 4.41 (quintet, J= 8.5 Hz, IH). 13C-NMR (CDCl3, 75.5 MHz): δ
28.1, 28.6, 31.1, 32.5, 37.6, 44.9, 46.3, 52.3, 56.4, 81.4, 172.8, 174.3.
Figure imgf000120_0002
(IS. 2S. 4y)-4-(Methanesulfonyl-methyl-aminoV2-((i?)-l-phenyl-ethylcarbamovπ- cvclopentanecarboxylic acid tert-butyl ester (39g")
Compound 39f (0.02Og, 0.060 mmol) was dissolved in MeOH (1.5 mL). Four drops OfH2O and LiOH (71 μL, 0.119 mmol, 40 mg/mL) were added and the reaction mixture was stirred overnight. The crude solution was concentrated and dissolved in DMF (0.6 mL). R-(+)-l -phenyl ethyl amine (9.1 μL, 0.074 mmol), TEA (25 μL, 0.204 mmol) and HOBt (0.102 mmol, 90 μL, IM) were added and the reaction mixture was cooled to 0 0C. EDC (0.02Og, 0.102 mmol) was added and the reaction mixture was stirred for one hour. The mixture was allowed to reach rt and was stirred overnight. The solution was co -evaporated with toluene and the residue was purified by flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as a yellowish oil in 73 % yield.
1H-NMR (CDCl3, 300 MHz): δ 1.58 (s, 9H), 1.88-2.02 (m, 2H), 2.30-2.50 (m, 2H), 2.90 (s, 6H), 3.95-3.12 (m, 2H), 4.50 (quintet, J= 8.5 Hz, IH,), 5.18 (quintet, J= 6.9 Hz, IH), 6.40 (d, J = 7.4 Hz, IH), 7.30-7.50 (m, 5H). 13C-NMR (CDCl3, 75.5 MHz): 522.0, 28.2, 28.9, 29.8, 34.0, 37.6, 45.5, 47.5, 49.1, 56.7, 82.0, 126.2, 127.6, 128.9, 143.3, 172.1, 173.8.
O
Figure imgf000121_0001
(16'.26'.4y)-4-(Methanesulfonyl-methyl-amino)-cyclopentane-1.2-dicarboxylic acid 1-
( IY 1 S2SAR)4-((S)- 1 -benzylcarbamoyl^-methyl- propylcarbamoylV 1 -(3.5 -difluoro- phenoxymethyO -2-hydroxy-4-methoxy-butyl] -amidel 2-\((R)- 1 -phenyl-ethyO-amide] (39h) Compound 39g (0.019 g, 0.045 mmol) was dissolved in DCM (0.69 niL). Triethylsilane (0.015 niL, 0.090 mmol) and TFA (0.28 mL) were added and the reaction mixture was stirred for two hours. The solution was concentrated and the residue dissolved in DMF. (2 R, 4S, 55)-5-Amino- 6-(3,5-difluoro-phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((5)-l-benzylcarbamoyl-2- methyl-propyl)-amide (0.025 g, 0.054 mmol), DIPEA (24 μL, 0.141 mmol) and HATU (0.021g, 0.053 mmol) were added and the reaction mixture was stirred overnight. The solution was co- evaporated with toluene and the residue purified by LC -MS which gave the title compound as a yellowish -white powder (10 mg, 26 %).
1H-NMR (CDCl3, 300 MHz): δ 0.90-1.07 (m, 6H), 1.28-1.40 (m, 5H), 1.50 (d, J= 7.2 Hz, 4H), 1.62 (bs, 3H), 1.90-2.25 (m, 4H), 2.77 (s, 2H), 2.81 (s, 2H), 2.90-3.05 (m, IH), 3.03-3.19 (m, IH), 3.50 (s, 3H), 3.90-4.10 (m, 3H), 4.19-4.38 (m, 3H), 4.42 (d, J = 6.3 Hz, 2H), 5.18 (quintet, J = 6.6 Hz, IH), 6.45 (d, J= 9.1 Hz, 3H), 6.55 (d, J = 9.1 Hz, IH), 6.95 (d, J = 9.1 Hz, IH), 7.11 (d, J = 8.2 Hz, IH), 7.20-7.40 (m, 9H). 13C-NMR (DMSO-d6, 75.5 MHz): δ 11.5, 14.6, 18.8, 20.0, 23.1, 23.9, 28.3, 28.9, 29.1, 30.5, 31.4, 33.1, 37.3, 41.1, 42.0, 42.6, 45.9, 46.2, 48.6, 51.8, 57.0, 57.9, 65.7, 68.0, 79.6, 90.6, 99.3, 99.7, 126.4, 127.2, 127.5, 127.9, 128.9, 139.8, 145.6, 161.3, 165.3, 171.2, 172.0, 173.1, 174.2.
Example 40 Step a
Figure imgf000121_0002
ΓLS* Γ 2S. 4ΛV4-fMethanesulfonyl-methyl-aminoV2-(YS)- 1 -phenyl-ethylcarbamoylV cyclopentanecarboxylic acid tert-butyl ester f 40a")
Compound 39f (0.02Og, 0.060 mmol) was dissolved in MeOH (1.5 rnL). Four drops OfH2O and LiOH (71 μL, 0.119 mmol, 40 mg/mL) were added and the reaction mixture was stirred overnight. The solution was concentrated, the residue dissolved in DMF (0.6 mL) and i_>-(+)-l- phenyl ethyl amine (9.1 μL, 0.074 mmol), TEA (25 μL, 0.204 mmol) and HOBt (90 μL, 0.102 mmol, IM) were added and the reaction mixture was cooled to 0 °C. EDC (20 mg, 0.102 mmol) was added and the reaction mixture was stirred for one hour. The mixture was allowed to reach rt and was stirred overnight. The solution was co-evaporated with toluene and the residue purified by flash column chromatography (toluene/ethyl acetate 1 :1) which gave the title compound as a yellowish oil in 73 % yield.
1H-NMR (DMSO-d6, 300 MHz): δ 1.40 (s, 9H), 1.50 (d, 3H), 1.75-2.00 (m, 2H), 2.20-2.50 (m, 2H), 2.81 (s, 3H), 2.82 (s, 3H), 2.95-3.10 (m, 2H), 4.30-4.50 (m, IH), 5.10 (quintett, J = 7.1 Hz, IH), 6.40 (d, J= 7.7 Hz, IH), 7.10-7.40 (m, 5H). 13C-NMR (DMSO-d6, 75.5 MHz): δ 22.4, 28.4, 29.0, 29.7, 34.0, 37.6, 45.1, 47.4, 49.1, 56.8, 82.0, 126.0, 127.4, 128.4, 128.8, 129.2, 143.5, 172.1, 173.8.
Step b
Figure imgf000122_0001
(16'.26'.4y)-4-(Methanesulfonyl-methyl-aminoVcyclopentane-1.2-dicarboxylic acid 1- ( |Y 1 S2SAR)A-((S)- 1 -benzylcarbamoyl-2-methyl- propylcarbamoylV 1 -G .5 -difluoro- phenoxymethyl)-2-hydroxy-4-methoxy-butyl]-amide} 2-[((5Vl-phenyl-ethyP)-amide] (4Ob") Compound 40a (22.8 mg, 0.054 mmol) was dissolved in DCM (0.830 mL). Triethylsilane (17 μL, 0.108 mmol) and TFA (0.335 mL) were added and the reaction mixture was stirred for 2 h. The solution was concentrated and the residue dissolved in DMF (2 mL). (2 R, 4S, 55)-5-Amino- 6-(3,5-difluoro-phenoxy)-4-hydroxy-2-methoxy-hexanoic acid ((5)-l-benzylcarbamoyl-2- methyl-propyl)-amide (20 mg, 0.041 mmol), DIPEA (28 μL, 0.162 mmol) and HATU (0.027g, 0.071 mmol) were added and the reaction mixture was stirred for 4 h. The solution was concentrated, the residue dissolved in DMSO (1 mL) and then purified by HPLC (85 % MeOH, 15 % H2O + 0.1 % TFA) which gave the title compound as a white powder in 46 % yield. 1H-NMR (DMSO-d6, 300 MHz): δ 0.76-0.86 (t, J= 6.9 Hz, 9H), 1.28-1.34 (d, J= 6.9 Hz, 3H), 1.60-2.10 (m, 6H), 2.68 (s, 2H), 2.84 (s, 3H), 2.90-3.10 (m, 2H), 3.16 (s, 2H), 3.33 (s, 3H), 3.70- 3.80 (t, J= 6.3 Hz, IH), 3.81-3.90 (m, 2H), 4.01-4.05 (d, J = 6 Hz, 2H), 4.15-4.35 (m, 3H), 4.85- 4.95 (d, J = 6.6 Hz, 2H), 6.65-6.80 (m, 3H), 7.10-7.30 (m, 8H), 7.63-7.67 (d, J= 9 Hz, IH), 7.70-7.74 (d, J = 7.8 Hz, IH), 8.20-8.25 (d, J= 7.8 Hz, IH), 8.53-8.58 (t, J = 5.7 Hz, IH). 13C- NMR (DMSO-d6, 75.5 MHz): δ 18.2, 19.4, 22.5, 28.2, 30.7, 32.4, 32.8, 36.6, 42.1, 45, 45.1, 47.9, 51.4, 56.4, 57.2, 57.5, 64.9, 67.3, 78.9, 96.9 (t, JCF = 26.3 Hz), 98.8 (d, JCF = 28.1 Hz), 126, 126.5, 126.8, 127.3, 128.2, 128.3, 139.2, 144.3, 160.6 (t, JCF = 14.3 Hz), 163.0 (d, JCF = 243.9 Hz), 163.2 (d, JCF = 244.2 Hz), 170.7, 171.4, 172.9, 173.9.
Biological Examples
To evaluate the enzymatic inhibition of BACEl exhibitedby 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, lanthanidefluorescence 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 exhibitedby the cleavage product. The compounds were tested at a range of concentrationswhereas the enzyme and substrate concentrationswere 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 concentrationof 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:
x 100 = % inhibition '
Figure imgf000123_0001
For example, Table 1 shows the enzymatic inhibition exhibitedby a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above. Category A indicates an IC 50 value of < 1 μM, category B indicates 1 - 5 μM and category C indicates > 5 μM.
TABLE 1
Figure imgf000124_0001

Claims

Claims
1. A compound of formula (I) :
Figure imgf000125_0001
wherein
R2 is H or Ci-Cealkyl;
R is Ci-Cβalkoxy, Ci-CβalkoxyCi-Cβalkoxy, -O-Co-C^lkanediylaryl, -0-Co-
C3 alkanediylheterocyclyl, azide, amine, S(=0)rCi-C6alkyl;
R is Ci-Cβalkyl and R is H; or R and R together with the carbonatom to which they are attached define C3-C6cycloalkyl;
R6 is hydrogen, Ci-C6alkyl,
Figure imgf000125_0002
-C6alkyl, N(Ra)S(=O)rNRaRb, S(O)1Ci-
Cβalkyl, halo or cyano;
Figure imgf000125_0003
R7 is Ci-Cealkyl, Ci-C6 alkoxyCi-C3alkyl, hydroxyCi-C3alkyl, Ci-C3alkanediylNRaRb, aryl, heterocyclyl, C3-C6cycloalkyl, Ci-C3 alkanediylC3-C6cycloalkyl, Ci-C3 alkanediylaryl, Ci -C3 alkanediylheterocyclyl, Ci-C3alkanediyl-0-Co-C3alkanediyl aryl or Ci-C3alkanediyl- 0-Co-C3alkanediyl heterocyclyl; wherein the Ci-C3alkanediylmoietyis optionally substituted with Ci-Cβalkyl; R8 is H, Ci-Cealkyl; or
R and R together with the N atom to which they are attached define a heterocyclyl group; R9 is H, Ci-Cioalkyl, C2-Ci0alkenyl, C2-Cioalkynyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C3alkyl, Ci
Figure imgf000125_0004
Ci-CioalkanediylC3-C6cycloalkyl, Ci- Cio alkanediylaryl or Ci- Cioalkanediylheterocyclyl;
E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)-, -CH(Rd)-NRd-, -NRd-NRd-, -CH(Rd)-O-, -O- CH(Rd)- -CH(Rc)-, -NRe-, or -O-; Q is aryl or heterocyclyl;
W is H, Ci-Cβalkyl, C3-C6 cycloalkyl, aryl or heterocyclyl; X' is H, F, OH, or NRaRb; X" is H or when X' is F, X" can also be F; Y is H, Ci-Cβalkyl, Co-C3alkanediylaryl, Co-C3 alkankediylC3-C6cycloalkyl or Co-
C3 alkankediylheterocyclyl;
Z is O, S(=O)r or NRa; ring A is a saturated, partially unsaturated or aromatic ring; m is 0 or 1 , wherebyring A defines a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or a phenyl ring; n is 0, 1, 2 or 3; p is 0 or 1 ; q is 0, 1 or 2; thereby defining a bond, methylene or ethylene, or when q is 1, the methylenemay alternatively be a 1,1 -cyclopropyl group; r is 0, 1 or 2;
Ra is independently H or Ci -Cβalkyl;
Rb is H or Ci-Cβalkyl; or Ra and Rb together with the nitrogen atom to which they are attached define a heterocyclyl group;
Rc is H, Ci -Cyalkyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C3alkyl, Ci-C6alkoxyCi -C6alkoxy, hydroxyCo-Csalkyl or C0-C3 alkanediy INRaRb, O-Ci-C5alkanediylC3-C6cycloalkyl;
Rd is H, Ci-Cyalkyl, Ci-C6alkoxyCi-C3alkyl, Ci-C6alkoxyCi-C6alkoxyCi-C3alkyl, hydroxyCi-C3alkyl or Ci-C3alkandiylNRaRa;
Re is H, Ci -Cioalkyl, C2-Cioalkenyl, C2-Cioalkylnyl, Ci-Cioalkoxy or Ci-CioalkanediylC3-
Cβcycloalkyl; or Re and R9 together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted with Ci-Cioalkyl, C2-Cioalkenyl, C2-Cioalkylnyl, C3-C6cycloalkyl, Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl; where aryl is independently phenyl, naphthyl or phenyl fused to Cs-Cβcycloalkyl or C5-
Cβcycloalkenyl; aryl is phenyl, naphthyl, or phenyl fused to Cs-Cβcycloalkyl or Cs-Cβcycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; and whereineach occurrence of Ci-Cβalkyl, C2-C6alkenyl, C2-Cβalkynyl, C3-C6cycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as alkoxy or alkanediy laryl) is optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl , amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-C6alkenyl, C2-Cβalkynyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-
C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C6alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, Ci-C4alkylcarbonyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co-CsalkanediylCs-Cβcycloalkyl, Co-
C3 alkanediylaryl , Co-C3alkanediylheterocyclyl , C2-C3alkenediylC3-C6cycloalkyl, C2-
C3 alkenediylaryl , C2-C3alkenediylheterocyclyl , C2-C3alkynediylC3-C6cycloalkyl, C2-
C3 alkynediylaryl , C2-C3alkynediylheterocyclyl ; and whereineach occurrence of the Ci-Cioalkyl, C2-Cioalkenyl, C2-Cioalkynyl, Ci-
Cioalkoxy or Ci-CioalkanediylC3-C6cycloalkyl moieties are optionally substituted with 1, 2 or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, aryl, heterocyclyl, C3-C6cycloalkyl, Ci-Cioalkoxy, haloCi-C4alkyl, halo, hydroxy, cyano, amino, and a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; and whereineach occurrence of aryl and heterocyclyl above (including those in composite expressions such as alkanediylaryl and alkanediylheterocyclyl ) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, halo and haloCi-C4alkyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
2. A compound according to claim 1, wherein ring A is phenyl.
3. A compound according to claim 1, wherein ring A is cyclopentyl.
4. A compound according to any preceding claim, whereinR6 is N(Co-C2alkyl)S(=0)2Ci- C4alkyl, preferably -NHS(=O)2CH3.
5. A compound according to any preceding claim, whereinR is H.
6. A compound according to any preceding claim, whereinn is 0.
7. A compound according to any of the preceding claims, whereinQ 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.
8. A compound according to claim 7, wherein Q is optionally substituted phenyl.
9. A compound according to claim 8, wherein Q is mono-, di- or trifluorophenyl.
10. A compound according to any preceding claim, whereinX' is OH.
11. A compound according to any preceding claim, whereinR is Ci-C4alkoxy, preferably methoxy.
12. A compound according to any preceding claim, whereinp is 0;
13. A compound according to any preceding claim, where p is 1 and R 4' i •s Ci-Cβalkyl, preferably isopropyl.
14. A compound according to any preceding claim, whereinW is optionally substituted phenyl.
15. A compound according to claim 14, wherein the optional substituents to W are selected from fluoro, chloro, methyl and cyclopropyl.
16. A compound according to any preceding claim, whereinq is 0 or 1.
17. A compound according to any preceding claim, wherein D is
Figure imgf000128_0001
18. A compound according to claim 17, wherein R7 is CrC3alkanediylaryl such as benzyl or 1- phenylethyl.
19. A compound according to any preceding claim, wherein D is
Figure imgf000128_0002
20. A compound according to claim 19, wherein R8 is H or methyl.
21. A pharmaceutical composition comprising 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.
22. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 20, for use in therapy.
23. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 20, in the manufacture of a medicament for use in the treatment or prevention of Alzheimer's disease.
PCT/EP2008/053767 2007-03-30 2008-03-28 Amide derivatives as inhibitors of aspartyl proteases WO2008119773A1 (en)

Applications Claiming Priority (4)

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

Publications (1)

Publication Number Publication Date
WO2008119773A1 true WO2008119773A1 (en) 2008-10-09

Family

ID=39591593

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/053767 WO2008119773A1 (en) 2007-03-30 2008-03-28 Amide derivatives as inhibitors of aspartyl proteases

Country Status (1)

Country Link
WO (1) WO2008119773A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009110985A2 (en) 2008-02-29 2009-09-11 Renovis, Inc. Amide compounds, compositions and uses thereof
WO2010042030A1 (en) * 2008-10-07 2010-04-15 Medivir Ab Aspartyl protease inhibitors
US20140336208A1 (en) * 2010-08-09 2014-11-13 Hoffmann-La Roche Inc. 1,4,5,6-tetrahydro-pyrimidin-2-ylamine compounds
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof

Citations (1)

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

Patent Citations (1)

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

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009110985A2 (en) 2008-02-29 2009-09-11 Renovis, Inc. Amide compounds, compositions and uses thereof
US8946439B2 (en) 2008-02-29 2015-02-03 Evotec Ag Amide compounds, compositions and uses thereof
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof
WO2010042030A1 (en) * 2008-10-07 2010-04-15 Medivir Ab Aspartyl protease inhibitors
US20140336208A1 (en) * 2010-08-09 2014-11-13 Hoffmann-La Roche Inc. 1,4,5,6-tetrahydro-pyrimidin-2-ylamine compounds

Similar Documents

Publication Publication Date Title
CA2634005C (en) N-hydroxyamide derivatives possessing antibacterial activity
US7714021B2 (en) Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of Alzheimer&#39;s disease
MX2007008238A (en) Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme.
TW202227433A (en) Medium- or macro-cyclic benzyl-substituted heterocycle derivatives and related uses
EA029672B1 (en) METHOD OF TREATMENT OF CONTRAST-INDUCED NEPHROPATHIA
US20230271973A1 (en) Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists
AU5903100A (en) Vla-4 inhibitor compounds
IL317949A (en) Kcnt1 inhibitors and methods of use
EP1689713A1 (en) Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer s disease
KR20080039946A (en) Derivatives Having PAPR Activity
CN100509782C (en) NK* antagonists
WO2008119773A1 (en) Amide derivatives as inhibitors of aspartyl proteases
EA001341B1 (en) Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists
US20030078249A1 (en) VLA-4 inhibitor compounds
WO2008119772A1 (en) Amide derivatives as inhibitors of aspartyl proteases
WO2010042030A1 (en) Aspartyl protease inhibitors
WO2008107365A1 (en) New compounds
CA3037406A1 (en) 6-membered cyclic amines or lactames substituted with urea and phenyl
CA2558249A1 (en) Substituted urea and carbamate, phenacyl-2-hydroxy-3-diaminoalkane, and benzamide-2-hydroxy-3-diaminoalkane aspartyl-protease inhibitors
WO2005044810A1 (en) Glyt2 modulators
WO2008135488A1 (en) Aspartyl protease inhibitors
KR101771698B1 (en) 5-amino-4-hydroxypentoyl amides
EP1740558A1 (en) Benzoxazocines and their therapeutic use as monoamine reuptake inhibitors
JP2023510947A (en) HDAC decomposer
WO2009053277A1 (en) Aspartyl protease inhibitors

Legal Events

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

Ref document number: 08735587

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08735587

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载