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WO2010042030A1 - Aspartyl protease inhibitors - Google Patents

Aspartyl protease inhibitors Download PDF

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Publication number
WO2010042030A1
WO2010042030A1 PCT/SE2009/051105 SE2009051105W WO2010042030A1 WO 2010042030 A1 WO2010042030 A1 WO 2010042030A1 SE 2009051105 W SE2009051105 W SE 2009051105W WO 2010042030 A1 WO2010042030 A1 WO 2010042030A1
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alkyl
mmol
acid
compound
heterocyclyl
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French (fr)
Inventor
Stina Lundberg
Susana Ayesa
Oscar Belda
Ismet Dorange
Karolina Ersmark
Kristin Hammer
Per-Ola Johansson
Stefan LINDSTRÖM
Åsa ROSENQUIST
Bertil Samuelsson
Marcus BÄCK
Ingemar KVARNSTRÖM
Fredrik WÅNGSELL
Katarina BJÖRKLUND
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Medivir AB
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Medivir AB
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
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    • 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
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    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • 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
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE). It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their in the preparation of a medicament or their use in therapy.
  • aspartyl proteases such as ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE).
  • AD Alzheimer's disease
  • Fibrillary tangles consists mainly of hyperphosphorylated tau protein and are also found in other neurodegenerative disorders. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioural decline. A ⁇ is a peptide comprised of 40-42 amino acid residues, which is formed by proteolytic cleavage of the large transmembrane amyloid precursor protein (APP). APP is processed along two pathways, the major ⁇ - and the minor ⁇ -secretase pathway.
  • APP large transmembrane amyloid precursor protein
  • the ⁇ - secretase pathway results in non-pathogenic products known as soluble APP, whereas the ⁇ - secretase pathway produces pathogenic A ⁇ peptides by cleavage by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , followed by cleavage by ⁇ -secretase at the C-terminus.
  • the sequential proteolytic cleavage of APP by ⁇ - and ⁇ -secretase is a key step in the production of A ⁇ .
  • the amyloid cascade hypothesis supported by genetic and pathological evidence, claims that the formation of A ⁇ plays an early and vital role in all cases of AD.
  • a ⁇ forms aggregates that are thought to initiate a pathogenic cascade that leads to neuronal loss and dementia.
  • BACE was identified a few years ago as a type 1 glycosylated transmembrane homodimer with two aspartic acids at the active catalytic site.
  • BACE and BACE-2 (64 % amino acid sequence similarity to BACE) constitute a novel class of aspartic proteases closely related to the pepsin family.
  • the function of BACE-2 is relatively unknown and several studies indicate that this enzyme is not involved in the A ⁇ generation.
  • BACE knockout homozygote mice show complete absence of producing A ⁇ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that ⁇ -secretase is expressed in all tissues but at highest levels in the neurons in the brain. Therefore, in vivo inhibition of BACE is likely to reduce the production of A ⁇ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
  • the compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved potency in inhibiting BACE.
  • A is CR 1 or N
  • D is H, Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl or
  • R 1 is H, Ci-Cealkyl, Ci-Cealkoxy, N 3 or halo;
  • R 2 is H or Ci-C ⁇ alkyl
  • R 3 is Ci-C 6 alkyl, C 2 -C6alkenyl, C 2 -C 3 alkynyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 6 alkoxy, arylCi- C 6 alkoxy, heterocyclylCi-C 6 alkoxy, NRaRb or N 3 ;
  • R 7 is Ci-C 6 alkyl, C 3 -C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-CealkoxyCi-Qsalkyl, arylC 0 -C 3 alkoxyCi-
  • Ci-C 3 alkyl C 3 alkyl, heterocyclylC 0 -C 3 alkoxyCi-C 3 alkyl, N(Ra)(Rb)Ci -C 3 alkyl; wherein, when present, the Ci-C 3 alkyl moiety of R 7 is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-C 6 alkyl
  • R 7 and R 8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with or fluoro;
  • R 9 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C 6 alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or phenyl;
  • Q is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heterocyclyl;
  • W is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, haloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, C 3 -C 6 Cy cloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH 3 , the other is Ci-C 3 alkyl, F, OH, NRaRb, CF 3 or N 3 ; or X' and X" are both F;
  • Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached may form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro; Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocyclic ring; Rd is H or Ci-C 3 alkyl; and wherein aryl is independently phenyl, naphthyl or phenyl fused to C 4 -Cecycloalkyl or Q-Qcycloalkenyl; heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and
  • R 1 is H, Ci-Csalkyl, N 3 or halo;
  • R 2 is H or Ci-C 6 alkyl;
  • R 3 is Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 6 alkoxy, arylCi-C 6 alkoxy, heterocyclylCi-
  • R 7 is Ci-C 6 alkyl, C 3 -C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-Qsalkyl, hydroxyCi-C 3 alkyl, Ci-CealkoxyCi-Gsalkyl, Ci-C 3 alkanediyl-O-C 0 -
  • Ci -C 3 alkanediylaryl Ci -C 3 alkanediyl-0-Co-C 3 alkanediylheterocyclyl, Ci -C 3 alkanediylNRaRb; wherein the Ci-C 3 alkanediyl moiety is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-Cealkyl; or R 7 and R 8 together with the N atom to which they are attached define a heterocyclyl group;
  • R 9 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 CyC loalkyl, C 3 -C 6 CyC loalkylCi-C 3 alkyl, aryl, arylCi-C 3 alkyl, heterocyclyl, heterocyclylCi-C 3 alkyl;
  • R 10 is H or Ci-C 6 alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 6 membered heterocyclic ring;
  • Q is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heterocyclyl;
  • W is H, Ci-C 6 alkyl, Ci-C 6 alkenyl, haloCi-C 3 alkyl, polyhaloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, C 3 -
  • X' and X" are both F;
  • Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl group;
  • Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached form a heterocyclic ring; and wherein aryl is independently phenyl, naphthyl or phenyl fused to Q-Qcycloalkyl or Q-Qcycloalkenyl;
  • heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N; and wherein each occurrence of Q-Qalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Q-Qcycloalkyl, ary
  • R 1 is H or F
  • R 2 is H
  • R 7 is Ci-C ⁇ alkyl, Cs-C 6 Cy cloalkyl, C 3 -C 6 Cy cloalkylCi-Csalkyl, aryl, arylCi-Csalkyl, heterocyclyl, heterocyclylCi-Csalkyl; wherein, when present, the Ci-Csalkyl moiety of R 7 is optionally substituted with Ci-C 6 alkyl;
  • R 8 is H, Ci-Cealkyl
  • Q is optionally substituted aryl or optionally substituted heterocyclyl
  • W is C 3 -C 6 Cy cloalkyl, C 2 -C 6 alkenyl, aryl or heterocyclyl, any of which is optionally substituted; one of X' and X" is OH;
  • Y is O or NH
  • D is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or
  • A is CR 1 .
  • R 7 is as recited above. Typical values for R 7 include Ci-C 6 alkyl, arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein each Ci-C 6 alkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, C 1 - C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • a further configuration for R 7 include arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein the Ci-C3alkyl moiety is optionally substituted with Ci-C6alkyl.
  • Ci-C 4 alkyl such as methyl or ethyl
  • haloCi- C 4 alkyl such as trifluoromethyl
  • C 3 -C 4 cycloalkyl such as cyclopropyl
  • the optional substituents to the aryl, heterocyclyl and alkyl moieties of R 7 are as defined above. Representative values include one or two substituents independently selected from Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • favoured values for R 7 include phenylmethyl, 1-phenylethyl and 1-phenylpropyl, especially phenylmethyl and 1-phenylethyl, wherein the phenyl ring is optionally substituted. Accordingly, favoured embodiments of the invention include compounds having the partial structure shown below:
  • A is CR 1 .
  • the substituent(s) is preferably the in the para and/or ortho position of the phenyl ring.
  • R 7 is Cs-Coheteroarylmethyl, I-C 5 - C ⁇ heterarylethyl or l-Cs-C ⁇ heterarylpropyl, especially Cs-C ⁇ heterarylmethyl, wherein the heteroaryl ring is optionally substituted.
  • Suitable heteroaryl rings according to this embodiment include, but are not limited to thiazolyl, pyrazolyl, imidazolyl.
  • favoured compounds of the invention according to this embodiment include those having the partial structure shown below:
  • A is CR .
  • R 8 is as recited above, preferably hydrogen or methyl.
  • a further embodiment of the invention include compounds of formula (I) wherein R >7 and R together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6 membered cyclic amine, for example optionally substituted pyrrole, piperidine, piperazine or morpholine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro.
  • R 7 and R 8 are both Ci-C ⁇ alkyl, such as ethyl, propyl or butyl.
  • Typical values for R include Ci-C ⁇ alkyl, C 2 -Cealkenyl and C 2 -C 6 alkylnyl wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted.
  • Typical substituents according to this embodiment include Cs-C ⁇ cycloalkyl for example cyclopropyl, Ci-C4alkyl for example isopropyl or t.butyl, haloalkyl for example CH 2 F, CHF 2 or CF 3 , hydroxy and phenyl.
  • R 9 is optionally substituted C 2 -C 6 alkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF 3 . and C 3 -C 6 Cy cloalkylCi-Csalkyl, any of which is optionally substituted as defined above.
  • Typical substituents include Ci-C 3 alkyl, halo, polyhaloalkyl, hydroxy, phenyl.
  • R 9 Preferred values for R 9 include C 3 -C 6 cycloalkylCi-C 3 alkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C 3 alkyl. Specially preferred are cyclopropylmethyl and 2- methylcyclopropylmethyl. For these values of R 9 , R 10 is preferably H or methyl.
  • R 10 is typically H or Ci-C 3 alkyl, preferably H or methyl.
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6 membered cyclic amine, which cyclic amine is optionally substituted, thus giving the partial structures:
  • A is CR 1 .
  • Optional substituent to the R 9 -R 10 ring is selected from Ci-C 6 alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl and phenyl.
  • D is Ci-C 6 alkyl, C 2 -Cealkenyl or C 2 - C 6 alkynyl, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted.
  • Typical substituents according to this embodiment include Cs-C 6 CyC loalkyl for example cyclopropyl, C 1 - C 4 alkyl for example isopropyl or t.butyl, and haloalkyl for example CH 2 F, CHF 2 or CF 3 .
  • D is optionally substituted C 2 -C 6 alkynyl, such as ethynyl which is unsubstituted or, preferably, substituted with cyclopropyl or CF 3 .
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R 2 is attached has the stereochemistry shown in the partial structure: ⁇ ,Q
  • Z is O.
  • Z is NRa, wherein Ra is hydrogen or Ci-C 3 alkyl, preferably hydrogen or methyl.
  • the group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively.
  • Q is bonded to Z via a methylene moiety, i.e. n is 1.
  • Q is bonded directly to Z, i.e. n is 0.
  • Q is typically aryl or heterocyclyl, which is optionally substituted with one, two or three substituents as defined above.
  • Q is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • the heterocyclyl moiety contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • Representative bicyclic rings according to this embodiment include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl, each of which is optionally substituted.
  • Q is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-C ⁇ cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclic rings include phenyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • Typical values for Q according to this embodiment include 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
  • Representative values for the optional substituents to Q include one or two substituents independently selected from Ci-C 4 alkyl, C 3 -C 4 cycloalkyl, Ci-C 4 alkoxy, Ci-CsalkoxyCi- C ⁇ alkoxy, cyano, halo, haloCi-C 4 alkyl and arylCi-Csalkyl, heterocyclylCi-Csalkyl, C 2 - Csalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 alkynylC 3 -C 6 Cycloalkyl.
  • favoured values include halo such as mono- di or trifluoro, chloro, bromo and haloCi-C4alkyl for example trifluoromethyl.
  • Q is a monosubstituted phenyl or a 6- membered heterocyclyl
  • the substituent is preferably in the meta or para position.
  • Preferred configurations for Q according to these embodiments include meta and para substituted phenyl.
  • substituents are preferably in the two meta positions or one substituent is in the meta position and the other in the para position.
  • Preferred substituents to Q according to these embodiments are independently chloro, fluoro, bromo, methyl, optionally substituted phenyl, 5- or 6 membered heteroaryl.
  • favoured configurations for Q include optionally substituted phenyl, such as bromo substituted phenyl and mono- or difluorophenyl, especially difluorophenyl.
  • Q include phenyl which is substituted with heteroaryl, C 2 - C ⁇ alkenyl, C 2 -C 6 alkynyl, cyano or cyclopropylethynyl.
  • Q is optionally substituted phenyl, n is 0 and Z is O.
  • Q is optionally substituted pyridyl
  • n is 0 and Z is O.
  • Specially preferred compounds according to this embodiment are those wherein Q is pyrid-3-yl.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • Y is O or NH.
  • X' and X" are as defined above, preferably one of X' and X" is H and the other is F, or more preferably one of X' and X" is H and the other is OH.
  • X' and X" are both fluoro.
  • Y is NH
  • Typical values for R in compounds of formula (Ic) include optionally substituted Ci-C ⁇ alkoxy such as optionally substituted methoxy, ethoxy and propoxy, preferably R 3 is Ci-C4alkoxy, especially methoxy.
  • R 3 include optionally substituted Ci-Cealkoxy-Ci-C ⁇ alkoxy such as optionally substituted methoxypropoxy and methoxyethoxy.
  • Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di- and trifluoro.
  • Preferred compounds of formula (I) wherein p is 1 and one of X' and X" is H and the other is OH, are those having the stereochemistry indicated in formula (Id):
  • Preferred compounds of formula (I) wherein p is 0, one of X' and X" is H and the other is OH, and Y is NH are those having the stereochemistry indicated in formula (Ie):
  • R 1 is H.
  • R 1 is halo, such as fluoro.
  • R 6 includes cyclic sulphonamides, i.e. Ra and Rc together with the atoms to which they are attached form a heterocyclic ring.
  • the heterocyclic ring is a 5 or 6-membered ring, thus providing compounds of the general formula (If).
  • A is CR 1 .
  • R 6 is a cyclic sulphonamide
  • A is CH and R 1 is halo, preferably fluoro.
  • R 1 is in the ortho position of the phenyl ring.
  • R 6 examples include hydrogen and Ci-C ⁇ alkyl, especially hydrogen or methyl.
  • the group W is bonded either directly to Y, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively. In favoured embodiments of the invention W is bonded directly to Y or via a methylene moiety, i.e. q is 0 or 1 respectively.
  • the moiety linking W to Y may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
  • W is hydrogen, Ci-C ⁇ alkyl, C 2 -Cealkenyl, haloCi-Csalkyl, hydroxyCi-Csalkyl, Cs-C ⁇ cycloalkyl, aryl or heterocyclyl wherein the alkyl, alkenyl, cycloalkyl, aryl or heterocyclyl moiety is optionally substituted with one, two or three substituents.
  • One embodiment of the invention includes compounds wherein W is optionally substituted Ci- C ⁇ alkyl such as methyl, ethyl or isopropyl.
  • Preferred substituents to W according to these embodiments include halo such as mono-, di- or trifluoro.
  • a further embodiment of the invention includes compounds wherein W is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, chromanyl, dihydrobenzofuran, dihydroisobenzofuran.
  • Representative substituents to the bicyclic ring include Ci-C 4 alkyl, e.g. t.butyl and haloalkyl, e.g. trifluoromethyl.
  • a further embodiment of the invention includes compounds wherein W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-C ⁇ cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclic heterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • a preferred embodiment of the invention includes compounds wherein W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl.
  • a further preferred embodiment of the invention includes compounds wherein W is optionally substituted Cs-C ⁇ cycloalkyl such as optionally substituted cyclopropyl.
  • a typical configuration for W according to this embodiment is cyclopropyl which is substituted with Ci-C 4 alkyl e.g. methyl or with C 2 -C 4 alkenyl e.g. ethenyl or propenyl.
  • W is a substituted 6-membered ring
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • Preferred configurations according to this embodiment include meta or para substituted phenyl, for example p- ⁇ uoro phenyl.
  • the substituents are preferably selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl and tert. butyl.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C3-C4CVC loalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C3-C4CVC loalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the TV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, /V-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or an prodrug, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as BACE. Accordingly, one embodiment of the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
  • the compounds of the present invention have utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • the compounds of the present invention may be used in combination with one or more additional compounds useful in the treatment and/or prophylaxis of Alzheimer's disease, or the symptoms thereof.
  • additional compounds include NSAIDs including ibuprofen; vitamin E; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin, cognition-enhancing drugs such as acetylcholinesterase inhibitors, e.g. donepezil, rivastigmine, tacrine and galanthamine; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. memantine; or PDE4 inhibitors, e.g. ArifloTM.
  • NSAIDs including ibuprofen; vitamin E; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin, cognition-enhancing drugs such as acetylcholinesterase inhibitors
  • Such additional compounds also include cholesterol-lowering drugs such as HMG-CoA reductase inhibitors, e.g. lovastatin and simvastatin.
  • Such additional compounds also include compounds known to modify the production or processing of A ⁇ in the brain ("amyloid modifier"), such as compounds which inhibit the secretion of A ⁇ , compounds which inhibit the aggregation of A ⁇ , and antibodies which selectively bind to A ⁇ .
  • additional compounds also include growth hormone secretagogues, e.g. such as ibutamoren, ibutamoren mesylate and capromorelin.
  • the amyloid modifiers according to this embodiment of the invention may be a ⁇ -secretase inhibitor other than any of those included in the present invention, such as any of the compounds disclosed in Recent Patents on CNS Drug Discovery, 2 (2007), 188-199; an inhibitor/modulator of ⁇ -secretase, or any other compound which inhibits the formation or release of A ⁇ .
  • the amyloid modifier may also be a GSK-3 inhibitor, particularly a GSK-3 ⁇ inhibitor, such as lithium, as disclosed by Phiel et al in Nature, 423 (2003), 435-439.
  • the amyloid modifier may also be a compound which inhibits the aggregation of A ⁇ or otherwise attenuates its neurotoxicity.
  • Suitable examples include chelating agents such as clioquinol (Gouras and Beal, Neuron, 30 (2001), 641-642) and the compounds disclosed in
  • WO99/ 16741 particularly the one known as DP- 109 (Kalendarev et al, J. Pharm. Biomed. Anal, 24 (2001), 967-975).
  • Other inhibitors of A ⁇ aggregation suitable for use in the present invention include for example ApanTM (Praecis) and in particular 3-aminopropane-l-sulphonic acid, also known as tramiprosate or AlzhemedTM.
  • the amyloid modifier may also be an anti-amyloid antibody which binds selectively to A ⁇ .
  • Said antibody may be polyclonal or, preferably, monoclonal, and is preferably human or humanized.
  • the compounds of the present invention may also be used in combination with one or more P- glycoprotein inhibitor(s).
  • Non- limiting examples of Pgp inhibitors include ketoconazole, cyclosporine A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX710, LY335979 and PSC-833.
  • the compounds of the present invention may also contain, or be co- administered (simultaneously or sequentially) with one or more additional drugs that either increase the efficacy, safety and/or convenience, or treat, prevent, control or reduce the risk for side effects or toxicity of the compounds of the present invention.
  • additional drugs that either increase the efficacy, safety and/or convenience, or treat, prevent, control or reduce the risk for side effects or toxicity of the compounds of the present invention.
  • the species may be combined in a single dosage form for simultaneous administration to the subject, or be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close or remote in time, e.g. one species is administrated in the morning and the other in the evening.
  • the separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
  • the separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of the species is preferred, where possible.
  • the additional compound is an antibody, it will typically be administered parenterally and separately from the compound of Formula I.
  • the combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol wherein one or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
  • the invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • 'prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman The Pharmacological Basis of
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 -CsCyC loalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci -C ⁇ alkoxycarbonyloxy ethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylamino acetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic, />toluenesulphonic, cyclamic, salicylic, />amino salicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, /V-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
  • the TV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre. The presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • the terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally.
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral centre within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation.
  • the present invention also includes isotope- labelled compounds of formula I or any subgroup of formula I, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature.
  • isotopes examples include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 Cl, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 I, 124 I, 125 I and 131 I.
  • isotopes of hydrogen such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • phosphorus such as 31 P and 32 P
  • sulphur such
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 O will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
  • Isotope-labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotope-labelled reagent or starting material instead of the corresponding non- isotope-labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • the scientific and technological terms and nomenclature have the same meaning as commonly understand by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted.
  • Ci-C ⁇ alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • Preferred alkyl groups for use in the invention are Ci-C ⁇ alkyl groups, i.e. alkyl groups having from 1 to 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.butyl, pentyl, hexyl and the like.
  • the alkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • alkenyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkenyl means an alkenyl group having from 2 to 6 carbon atoms).
  • Preferred alkenyl groups for use in the invention are C 2 - C ⁇ alkenyl groups, i.e. alkenyl groups having from 2 to 6 carbon atoms.
  • alkenyl groups include ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like. Unless otherwise indicated the alkenyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 2 -C n alkynyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkynyl means an alkynyl group having from 2 to 6 carbon atoms).
  • Preferred alkynyl groups for use in the invention are C 2 -C 6 alkynyl, i.e. alkynyl groups having from 2 to 6 carbon atoms.
  • alkynyl groups include ethynyl, propynyl, propynyl, butynyl, and the like, especially propynyl. Unless otherwise indicated the alkynyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 3 -C n cycloalkyl as a group or part of a group defines a saturated cyclic hydrocarbon radical having the number of carbon atoms designated, e.g. Cs-C ⁇ cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl and the like, especially cyclopropyl.
  • the cycloalkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • 'C 3 -C n 'CycloalkylC m -C n alkyr represents a C m -C n alkyl radical which is substituted with a C 3 - C n 'Cycloalkyl moiety, wherein C 3 -C n 'Cycloalkyl and C m -C n alkyl are as defined for C 3 -
  • Preferred C 3 -C n 'CycloalkylC m -C n alkyl groups for use in the invention are C 3 -CycycloalkylCo-C 3 alkyl, i.e. the cycloalkyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • 'C 3 -C n 'CycloalkylC 2 -C n alkenyl' and 'C 3 -C n 'CycloalkylC 2 -C n alkynyl' have the corresponding meanings as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively, adjusted just for the link to the C 3 -C n 'Cycloalkyl moiety, as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively.
  • C 3 -C n 'CycloalkylC 2 -C n alkenyl and C 3 -C n 'CycloalkylC 2 -C n alkynyl groups for use in the invention are C 3 -C n 'CycloalkylC 2 -C 3 alkenyl and C 3 -C n 'CycloalkylC 2 -C 3 alkynyl, i.e. the C 3 - C n 'Cycloalkyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • C 3 -C n cycloalkenyl as a group or part of a group defines a cyclic hydrocarbon radical having one double bond and having the number of carbon atoms designated, e.g. C 3 - C ⁇ cycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkenyl groups include cyclobutenyl cyclopentenyl, cyclohexenyl and the like. Unless otherwise indicated the cycloalkenyl moiety is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • Ci-C n alkoxy' defines oxygen (Co) or a radical O-Ci-C n alkyl wherein Ci-C n alkyl is as defined for C m -C n alkyl above.
  • Preferred alkoxy groups for use in the invention are Ci-C ⁇ alkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like.
  • C 2 -C n alkenoxy defines a radical O-C 2 -C n alkenyl wherein C 2 -C n alkenyl is as defined above.
  • Preferred alkenoxy groups for use in the invention are C2-Cealkenoxy, i.e. alkenoxy groups having from 2 to 6 carbon atoms. Exemplary alkenoxy groups include but are not limited to ethenoxy, 1-propenoxy, 2-propenoxy, and the like.
  • C 2 -C 6 alkynoxy defines a radical O-C 2 -C n alkynyl wherein C 2 -C n alkynyl is as defined above.
  • Preferred alkynoxy groups for use in the invention are C2-C6alkynoxy, i.e. alkynoxy groups having from 2 to 6 carbon atoms. Exemplary alkynoxy groups include but are not limited to ethynoxy, 1-propynoxy, 2-propynoxy, and the like.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloC m -C n alkyr as a group or part of a group, represents a C m -C n alkyl radical which is substituted with one or more halogen atoms, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • 'Amino' as a group or part of a group, unless the context suggests otherwise, includes NH2, NHC m _C n alkyl or N(C m _C n alkyl)2, wherein m and n in the (C m -C n alkyl)2 are selected independentlly of each other, and wherein in the amino definition C m -C n alkyl is especially Ci-C 6 or Ci-C4alkyl variants.
  • 'C2-C n alkenylamino' and 'C2-C n alkynylamino' define NHC2-C n alkenyl and NHC2- C n alkynyl respectively, wherein the C 2 -C n alkenyl and C 2 -C n alkynyl are as defined above.
  • special interest for the invention are the C 2 -C 6 variants, and especially the C2-C4 variants.
  • 'Aryl' as a group or part of a group as applied herein represents an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C 6 CyC loalkyl (for example indanyl), or a C 5 -
  • Suitable aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with 1 or 2, or where valence allows up to 3 substituents.
  • 'ArylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with an aryl moiety, wherein aryl and C m -C n alkyl are as defined above.
  • Preferred arylC m -C n alkyl groups for use in the invention are arylCo-Csalkyl, i.e. the aryl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • arylC 2 -C n alkenyl and arylC 2 -C n alkynyl groups for use in the invention are arylC 2 - Csalkenyl and arylC 2 -C 3 alkynyl, i.e. the aryl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • ⁇ eterocyclyl', 'heterocyclic' or heterocycle as applied herein is meant to include a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring, which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • ⁇ eterocylylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with a heterocyclyl moiety, wherein heterocyclyl and C m -C n alkyl are as defined above.
  • Preferred heterocyclylC m - C n alkyl groups for use in the invention are heterocyclylCo-Csalkyl, i.e. the heterocyclyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • heterocyclylC 2 -C n alkenyl' and 'heterocyclylC 2 -C n alkynyl' have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively.
  • Preferred heterocyclylC 2 -C n alkenyl and heterocyclylC 2 -C n alkynyl groups for use in the invention are heterocyclylC 2 -C 3 alkenyl and heterocyclylC 2 -C 3 alkynyl, i.e. the heterocyclyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • ⁇ eteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • the compounds of the invention are prepared by reacting an acid of formula II
  • the coupling reaction is performed according to standard procedure used for amide bond formation in peptide synthesis.
  • General descriptions of such coupling reactions and reagents used therein can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993).
  • the starting materials are reacted in the presence of a coupling agent such as a carbodiimide like dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as N- ethyl-iV'- [(3 -dimethylamino)propyl] carbodiimide and a suitable catalyst, e.g. 1- hydroxybenzotriazole (HOBT), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 4- dimethylaminopyridine (4-DMAP).
  • a coupling agent such as a carbodiimide like dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as N- ethyl-iV'- [(3 -dimethylamino)propyl] carbodiimide and a suitable catalyst,
  • Further useful coupling agents are (benzotriazol-1-yloxy)- tris-(dimethylamino) phosphonium hexafluorophosphate (BOP), either by itself or in the presence of HOBT or 4-DMAP; or 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-7y,7V,N',N'-tetramethyluronium hexafluorophosphate (HATU) and similar.
  • BOP 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • TBTU 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium te
  • the coupling reactions are performed in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine, 7V-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like.
  • a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine, 7V-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like.
  • a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine,
  • the reaction temperature may range between 0 0 C and 50 0 C and the reaction time may range between 15 min and 24 h.
  • Acids of general formula (II) to be used in the coupling with an amine of general formula (III) are described in the literature, for example in WO06/057945, WO05/051914 and WO04/050619.
  • Amines of general formula (III) can be prepared as described in the schemes below and the in the experimental part that follows.
  • An intermediate to compounds of formula III wherein p is 1, Z is O, and the group Q is bonded via a methylene group to the oxygen, i.e. n is 1, can be prepared as outlined in scheme 1.
  • R 3' is C
  • Lg is a leaving group
  • the primary hydroxy group of the diol (Ia), achieved for example as described in Tetrahedron lett, 1987, 28, 1143, can be selectively alkylated by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-CH 2 -Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide, in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (Ib).
  • a suitable leaving group such as a halide like bromide or iodide
  • the substituent Q-CH 2n can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193- 6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the primary hydroxy group of the diol (Ia) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the secondary hydroxy group of the alcohol (Ib) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate sulphonic anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the formed leaving group with azide for example sodium azide, thus giving the azide derivative (Ic).
  • the azide moiety can be introduced using the Mitsunobu conditions, i.e.
  • compounds wherein R 3 is an O-linked substituent can be prepared by alkylation of the hydroxy group, effected for example by treatment with a suitable alkylating agent such as an alkyl halide like, methyl iodide, in the presence of a base like silver oxide thus giving the ether derivative (Ie).
  • a suitable alkylating agent such as an alkyl halide like, methyl iodide
  • Hydrolysis of the methyl glycoside by acidic treatment, followed by reduction effected for instance by LiBH 4 or the like then yields the linear compound (If).
  • Opening of the epoxide 2a achieved, for example, according to the procedure described by B. Samuelsson et al. in J. Med. Chem., 2004, 47, 3353-3356, with a desired nucleophile Q-OH in the presence of a base, such as potassium carbonate or the like, provides the ether derivative (2b).
  • a base such as potassium carbonate or the like
  • Inversion of the stereochemistry of the alcohol (3a), obtained as described above, can be effected for example by subjecting the alcohol to Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence of Ph 3 P and for instance p- nitrobenzoic acid, followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence of Ph 3 P and for instance p- nitrobenzoic acid
  • hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • the afforded primary amine can then be alkylated, conveniently by a reductive amination with a suitable aldehyde or keton using conditions known to the skilled person, or by reaction with an alkylating agent Ra-Lg, wherein Lg is a leaving group, optionally in the presence of a base.
  • the primary hydroxy group of the diol (Ia) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-CH 2 -S or Q-CH 2 -NRa.
  • a convenient method to effect this transformation is by using a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (4a) or the amine derivative (4b) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (Ia)
  • a further alternative method to obtain the amino derivative (4b) is to selectively oxidize the primary hydroxy group of the alcohol (Ia) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-CH 2 -NHRa in the presence of a reducing agent like NaCNBH 3 .
  • a reducing agent like NaCNBH 3
  • Intermediates for the preparations of compounds of formula (I) wherein the group Q is linked directly to a sulphur or nitrogen atom, i.e. Z is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (Ia) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or
  • An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (Ia) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (Ia) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like.
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate. Many suitable methods for this oxidation are described in the literature for example, a peroxyacid such as AcOOH, mCPBA can be used.
  • Alkylation of the primary hydroxy group of any of the previously described alcohols can be effected for example by reaction with a desired alkylating agent W-(CH 2 ) J1 -Lg, wherein Lg is a leaving group, such as a halide like bromo or iodo, or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as NaH or equivalent, to provide the ether derivative (5 a).
  • a desired alkylating agent W-(CH 2 ) J1 -Lg wherein Lg is a leaving group, such as a halide like bromo or iodo, or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as NaH or equivalent, to provide the ether derivative (5 a).
  • the Mitsunobu conditions with the alcohol of the desired group (W-(CH 2
  • 6d 6e Y' is O, S or NH
  • Selective protection of the secondary hydroxy group of any of the previously described alcohols can be effected by a using a suitable protection group strategy.
  • a benzylidene acetal of the two hydroxy groups may be formed, effected by treatment of the diol with anisaldehyde dimethylacetal in the presence of an acid like pTsOH or similar, followed by reductive opening of the acetal effected by treatment with Me 3 SiCl and NaCNBH 3 or equivalent, thus providing the p-MeO-protected compound (6b).
  • Amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is CH 2 NH, can be prepared according to the route illustrated in scheme 9.
  • Conversion of the ester function of compounds 7c or 8a to the corresponding aldehyde 9b can be performed by first protecting the free secondary alcohol with a suitable protecting group, for example a silyl group, followed by reduction of the ester to the alcohol (9a), using for instance sodium borohydride, and, finally, oxidation of the alcohol using for example Dess-Martin periodinate or any other suitable oxidation reagent.
  • a suitable protecting group for example a silyl group
  • the formed aldehyde is then reacted with a desired amine H 2 N-(CH 2 ) q -W in a reductive amination reaction, using reagents like NaCNBH 4 or the like to form the amine (9c).
  • the hydroxy group of compound 9d can be replaced by azide, thus affording amines of formula III wherein one of X' and X" is H and the other is N 3 , and Y is CH 2 NH.
  • the amino group of compound 9d is conveniently protected, for example with a Boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA.
  • the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH 2 .
  • Alkylation of the primary hydroxy group of the isopropylidene derivative (10a), prepared e.g. according to the method described by Mori, K. and Kinsho, T. in Liebigs. Ann. Chem 1991, 1309-1315, with a suitable derivative of the group Q-(CH 2 )J 1 can be performed using any suitable alkylation method such as any of those described above, for instance the Mitsunobu conditions can be used, or the alkylation may be effected by treatment with a alkylating agent Q-(CH 2 )-Lg in the presence of a base, may be used
  • Amines of formula III wherein Z is S or NH can be prepared, for example, by the Mitsunobu conditions using a thiol, (Q-(CH 2 ) n -SH) or an amine (Q-(CH 2 ) n -NH 2 ) respectively , as described above.
  • a suitable catalyst for instance Lindlar catalyst, or the like
  • the linear compound achieved after opening of the epoxide may be subjected to Mitsunobu conditions as illustrated in scheme 11.
  • the hydroxy group of compound 1Oi or 1 Ib can be replaced by azide, thus affording the corresponding amines of formula III wherein one of X' and X" is H and the other is N 3 .
  • the amino group of compound 1Oi is first protected, for example with a boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA.
  • the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH 2 .
  • Compound 12a can be prepared by alkylation of N-trityl-L-serine methyl ester with a desired group Q-(CH 2 ) J1 ZH or Q-CH 2 -Lg according to any of the methods described herein, followed by replacing the N-protecting group to a Boc group using standard conditions.
  • the Weinreb amide (12b) can then be achieved by hydrolysis of the methyl ester effected for example by treatment with LiOH, followed by reaction with N,O-dimethylhydroxylamine in the presence of NMM.
  • the group W-(CH 2 ) a - can then replace the hydroxylamine moiety by reaction with a suitable organometallic nucleophile, such as an organolithium reagent or a Grignard reagent, to afford the keton (12b).
  • a suitable organometallic nucleophile such as an organolithium reagent or a Grignard reagent
  • Benzyl derivatives Q-CH 2 - wherein Q is substituted with aryl, heterocyclyl, alkenyl or alkynyl can be prepared for example by using palladium promoted reactions, whereof many are described in the literature. A general is illustrated in scheme 14.
  • Q' is optionally substituted aryl or heterocyclyl, alkenediylcycloalkyl, alkynediylcycloalkyl, alkenediylaryl, alkynediylaryl, alkenediylheteocyclyl or alkynediylheterocyclyl
  • the desired substituent Q' can be introduced using for instance a Pd-catalyzed cross coupling reaction.
  • a Pd-catalyzed cross coupling reaction For example the Suzuki conditions may be used, i.e. reaction of the bromo derivative (14a) with the boronic acid of a desired substituent Q' in the presence of a palladium catalyst such as Pd(PPli3)4 or Pd(OAc) 2 or the like and a suitable base such as potassium carbonate or potassium fluoride or the like, thus providing the Q '-substituted compound (14b).
  • a palladium catalyst such as Pd(PPli3)4 or Pd(OAc) 2 or the like
  • a suitable base such as potassium carbonate or potassium fluoride or the like
  • Suitable reactions that can be used for the introduction of the substituent Q are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative (14a) in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative (14a) is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPlIs) 4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • a Pd catalyst such as Pd(PPlIs) 4 PdCl 2 or Pd(OAc) 2
  • a base such as triethylamine, potassium carbonate or the like.
  • the afforded alcohol can then either be used directly in the couplings to the primary hydroxy group of any of the intermediates described above, employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromomethane in the presence of triphenylphosphine, and subsequently coupled to the primary hydroxy group as described above.
  • a substituent Q' of Q as phenyl may alternatively be introduced at a later stage of the synthesis, for example as the last step, using similar conditions.
  • the free hydroxy group of compound (15a), prepared as described above, can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (15b).
  • the monofluoro compound (15c) will be achieved by treatment of the alcohol to fluorinating conditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g.
  • the monofluoro compound (15e) having the reversed stereochemistry at the carbon atom to which the fluoro atom is attached can be achieved by reverting the stereochemistry of hydroxy compoundl5a to the hydroxy compound 15d, for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph 3 P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like, and thereafter replace the hydroxy group with fluorine, as previously described.
  • X is a leaving group, e.g. Br or I Rc' is C r C 6 alkyl
  • Useful sulphamoyl chlorides can be prepared for example as described by W. L. Matier et al. in J. Med. Chem. 1972, 15, 4, 538-541.
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • Step b) 2.2-Dioxo-21ambda*6*-[1.3.21dioxathiolane-4.5-dicarboxylic acid diethyl ester
  • E-Ib Compound E-Ia (6.3 g, 25 mmol), NaIO 4 (8 g, 37.5 mmol) was suspended in acetonitrile (375 mL) and water (50 mL). RuCl3 (50 mg) was added and the mixture was stirred at ambient temperature for 30 min. Ether (400 mL) was added and the precipitated solid was removed by decantation and washed with ether. The ether fractions was combined, the volume reduced to half and filtrated through a pad of silica. Evaporation gave the title compound as yellow to reddish crystals (4 g, 60 %)
  • Triphenylphosphine (3.38 mg, 12.9 mmol) was dissolved in THF (40 mL) and the solution was cooled on an ice-bath. Diisopropyl azidocarboxylate (2.9 g, 94%, 14.2 mmol) was added slowly. After stirring for 15 min, a solution of 3, 5-difluorophenol (1.7 g, 13.1 mmol) in THF (10 ml) was added and the mixture was left stirring for another 15 min.
  • Step h) Acetic acid 2-azido-l-bromomethyl-3-(3,5-difluoro-phenoxy)-propyl ester (E-Ih)
  • the diol E-Ig was reacted according to the procedure described by T. Suzuki et al. in Tetrahedron Letters 46, (2005), 5811-5814. Purification by chromatography on silica gel (iso- hexane - diethyl ether, 5:1) gave pure title compound (90 %).
  • Step b) 2-Amino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester ( E-16b)
  • Compound E-16a 14.02 g, 29.61 mmol was dissolved in dichloromethane (72 mL) and the solution was cooled to 0 0 C.
  • TFA 58 mL was added dropwise during 5 minutes and the solution was stirred for 30 minutes at 0 0 C and for an additional 3.5 hours at room temperature.
  • the solvents were evaporated and co-evaporated three times with toluene.
  • the residue was dissolved in methanol (75 niL) and solid sodium hydrogen carbonate (7 g) was added and the slurry was stirred for 40 minutes.
  • Tetrabutylammoniumfluoride (0.664 mL, 1 M in THF) was added to a solution of compound E- 18a (240 mg, 0.53 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the afforded residue purified by column chromatography (SiO 2 , iso-hexane to isohexane-ether, 3:1) which gave the title compound (78 mg, 60 %).
  • the Epoxide (1 eq, prepared as described above) was dissolved in isopropanol/H 2 O 1 :1 (0.5 mL), the amine (2 eq) was added and the mixture was stirred at a temperature between room temperature and 83 0 C for 1 to 2Oh.
  • the reaction mixture was partitioned between DCM and H 2 O, the organic phase was dried (Na 2 SO 4 ), filtered and concentrated.
  • the afforded residue was purified by column chromatography, dissolved in MeOH (11 mL) and triphenylphosphine (1.5 eq) and two drops OfH 2 O were added to the solution.
  • the reaction mixture was stirred for 18h, and then concentrated.
  • the afforded crude product was then either purified by column chromatography, or used directly in the next step.
  • Step b) (2R3S)-3-amino-4-(3.5-difluorophenoxy)-l- ⁇ henoxybutan-2-ol (A-24)
  • the azide derivative A-24a was reduced according to the method described in Example 37 step b, which gave the title compound in quantitative yield.
  • the product was purified by column chromatography using toluene/ethyl acetate 1 :3 containing 1% MeOH saturated with NH 3 as mobile phase.
  • the title compound was prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO06/057945.
  • Acid-2 2-(((lS.2S)-2-methylcyclopropy ⁇ methylamino)-6-(N-methylmethylsulfonamido)isonicotinic acid (Acid-2) &
  • the title compound were prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO05/051914.
  • the title compound was prepared from 2,6-dichloroisonicotinic acid methyl ester using a procedure similar to the one described in WO06/057945.
  • Step b) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid methyl ester (Acid-5b) Triethylamine (one drop) was added to 5-bromo-isophthalic acid monomethyl ester (230 mg, 0.888 mmol) in SOCl 2 (3 ml). The mixture was stirred at 90 0 C for 1 h whereafter the solvent was evaporated and the residue dissolved in DCM (3 ml). Compound Acid-5a (200 mg, 1.40 mmol) in DCM (3 ml) was added and the mixture was stirred at rt. After 30 min the solvent was evaporated and the residue purified by flash chromatography using 1-2% MeOH in DCM as eluent, which gave the title compound (188 mg, 55%). MS: 383/385.
  • Step a) 2'-Trifluoromethyl-biphenyl-3.5-dicarboxylic acid dimethyl ester (Acid-6a) An oven-dried vial containing a magnetic stir bar was charged with dimethyl-5-bromo isophthalate (500 mg, 1.83 mmol), Pd(OAc> (4 mg, 1.0 mol%), S-Phos (15.0 mg, 2.0 mol%), 2- (trifluoromethyl)-phenyl boronic acid (695 mg, 3.66 mmol, 2 equiv.) and powdered, anhydrous KsPO 4 (LIo g, 5.49 mmol, 3 equiv.).
  • Step c) 5-Dimethylsulfamoyl-isophthalic acid monomethyl ester (Acid IQc) 1 M NaOH (0.60 ml, 0.60 mmol) was added to Acid-lOb (181 mg, 0.600 mmol) in THF (5 ml) and MeOH (5 ml). The mixture was stirred at rt overnight whereafter the solvents were evaporated and 1 M HCl (2 ml) was added. The mixture was extracted with EtOAc, the organic layers were dried (MgSO 4 ) and evaporated. Yield: 167 mg (97%); white solid.
  • Acid-lOa (1.00 g, 3.38 mmol) was added to a solution of sodium sulphite (0.85 g, 6.8 mmol) and sodium bicarbonate (0.60 g, 7.1 mmol) in water. The mixture was heated at 50 0 C for 2 h whereafter the solvent was evaporated and the residue dried at high vacuum overnight. The material was suspended in DMF (10 ml) and MeI (1.00 ml, 16.0 mmol) was added. The mixture was stirred at rt for 3 h, EtOAc (50 ml) was added and the organic layer was washed with sat. NaHCO 3 ,water and dried (MgSO4)which gave the title compound (764 mg, 83%).
  • N-Methylethylene diamine (1.02 ml, 11.6 mmol) in dioxane (4 ml) was added dropwise to sulphamide (1.12 g, 11.6 mmol) in dioxane (10 ml) over 2 h.
  • the mixture was refluxed for 18 h, solvent evaporated and residue purified by flash chromatography using 3% MeOH in DCM as eluent which gave the title compound (259 mg, 16%) as a semisolid.
  • Step c) 5-(5-Methyl- 1.1 -dioxo- 1 lambda*6*-[ 1 ,2.51thiadiazolidin-2-ylVN-(l -phenyl-ethvO- sophthalamic acid methyl ester (Acid-12)
  • Acid-12b 83 mg, 0.243 mmol
  • Acid- 10 The compound Acid-12b (83 mg, 0.243 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (34 mg, 88%) as a pale yellow solid.
  • Step a) 5-(2-Oxo-oxazolidin-3-yl)-isophthalic acid dimethyl ester (Acid-14a) Tris(dibenzylideneacetone)palladium (58 mg, 0.063 mmol) was added to a degassed mixture of 5-bromo-isophthalic acid dimethyl ester (345 mg, 1.26 mmol), 2-oxazolidinone (220 mg, 2.52 mmol), CS2CO3 (1.03 g, 3.16 mmol) and Xantphos (109 mg, 0.189 mmol) in dioxane (10 ml). The mixture was stirred at 105 0 C under N 2 for 4 h. The solvent was evaporated and the residue taken up in DCM/water. The organic phase was separated and concentrated. The residue was purified by flash chromatography using 2% MeOH in DCM which gave the title compound (264 mg, 75%) as a beige solid.
  • Step a) 5-Methyl-N- ⁇ -phenyl-ethvD-isophthalamic acid methyl ester (Acid-15a) Triphenylphosphine (7 mg) was added to a mixture of 5-bromo-N-(l-phenyl-ethyl)- isophthalamic acid methyl ester (Acid- 7b) (164 mg, 0.452 mmol), trimethylboroxine (64 ⁇ l, 0.452 mmol) and K 2 CO 3 (191 mg, 1.36 mmol) in DMF (5 ml). The mixture was heated at 150 0 C for 15 min in microwave reactor. The solvent was evaporated and residue purified by flash chromatography using 1% MeOH in DCM which gave the title compound (87 mg, 71%).
  • Step b) 5-Methyl-N-(l-phenyl-ethyl)-isophthalamic acid (Acid-15) The compound Acid- 15a (97 mg, 0.326 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (91 mg, 99%) as a white solid.
  • Step N [I-O -Bromo-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- F(2-methyl-cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide
  • 2-Thiazole tributylstannane (0.050 ml, 0.16 mmol), CuI (0.003, 0.016 mmol), LiCl (0.013 g, 0.32 mmol), and (CySP) 2 PdCl 2 (0.009 g, 0.012 mmol) were added.
  • the reaction was degassed and stirred under N 2 at 125 0 C for 15 min.
  • the reaction mixture was diluted with CH3CN, the major Sn-residues were washed away by ⁇ o-hexane.
  • Step a) 6-(3.5-Difluorophenoxy)-3-deoxy-1.2-O-isopropylidene- ⁇ -D-glucose (9a) To a solution of the epoxide 5,6-anhydro-3-deoxy-l,2-O-isopropylidene-D-glucofuranoside (0.893 g, 4.80 mmol), prepared from 3-deoxy-l,2-O-isopropyliden-D-glucofuranoside according to the procedure described by B. Samuelsson et al. in J. Med.
  • Step b) 5-Azido-6-(3,5-difluorophenoxy)-3,5 dideoxy-l,2-O-isopropylidene- ⁇ -L-iodose 9b) The alcohol 9a (1.16 g, 3.65 mmol) and triphenylphosphine (1.44 g, 5.64 mmol) were dissolved in dry THF (19 rnL). The mixture was cooled to -15 0 C and diisopropyl azodicarboxylate (DIAD) (1.80 mL, 9.13 mmol) was added.
  • DIAD diisopropyl azodicarboxylate
  • Step d) (3£,45V4-Azido-5-(3,5-difluorophenoxy)-3-hvdroxy-pentanoic methyl ester (9d)
  • the carboxylic acid 9c was dissolved in methanol (100 mL) at 0 0 C and acetyl chloride (9 mL) was added slowly. The solution was stirred for 20 minutes at 0 0 C and for an additional 48 hours at room temperature. The solvent was evaporated and the residue co-evaporated with toluene and then purified by flash column chromatography, which gave the title compound.
  • Dibutyltin oxide (170 mg, 0.68 mmol) was added to a solution of the diol 9e (145 mg, 0.53 mmol) in toluene (40 mL), whereafter the solution was refluxed at 125 °C with a Dean-Stark adapter for 4h. The solution was allowed to cool to 90 °C followed by addition of methyl iodide (23.6 ⁇ L, 0,53 mmol) and tetrabutylammonium bromide (195 mg, 0.85 mmol). The reaction mixture was stirred at 90 °C for 16h. The solution was carefully concentrated, dissolved in DCM (3 mL) and applied to a silica column (10 g).
  • Step g) 2-Amino-l-(3,5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (9g) Polymer supported triphenylphosphine (270 mg, 1.48 mmol/g) was added to a solution of the azide 9f (23 mg, 0.08 mmol) in THF:MeOH (10:1.5, 11.5 ml) and the mixture was shaken for 16 h. The solution was filtered from the resin and concentrated which gave the title compound (15.6 mg, 0.06 mmol, 75%). MS m/z 262.2 (M+H) + .
  • Alcohol 10b (313 mg, 0.8 mmol) was dissolved in dry DMF (5 mL), cooled to 0 °C and hexane washed sodium hydride (60% oil suspension, 25.5 mg, 1.04 mmol) was added, followed by addition of methyl iodide (500 ⁇ L, 8 mmol). The reaction mixture was stirred for 1.5h, quenched with methanol, diluted with DCM and washed with water. The organic phase was collected, dried over sodium sulphate and the residue was purified by flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (226 mg, 70%).
  • the alcohol l ib (52.4 mg, 0.145 mmol), triphenylphosphine (42 mg, 0.16 mmol), DIAD (35 ⁇ L, 0.174 mmol) and p-nitrobenzoic acid (29 mg, 0.17 mmol) were dissolved in dry THF (30 mL) and cooled to 0 0 C. The reaction was allowed to reach RT during 16h. The solution was concentrated and the residues was purified by silica flash chromatography.
  • Alcohol 1 Ic (20 mg, 0.055 mmol) was dissolved in dry THF (1 mL) together with triphenylphosphine (21 mg, 0.082 mmol) and then cooled to 0 0 C. DIAD (16 ⁇ L, 0.82 mmol) was added drop wise, and the mixture was stirred at 0 0 C for 5 min, followed by drop wise addition of DPPA (36 ⁇ L, 0.165 mmol). The reaction was stirred at 0 0 C and allowed to reach RT overnight. The solution was concentrated, and purified by silica flash chromatography (hexane: ethyl acetate (100:0-75:25) which gave the title compound (9.8 mg, 46%).
  • Azide compound 10a (210 mg, 0.505 mmol) was dissolved in ethyl acetate (25 mL) together with Boc-anhydride (551 mg, 2.52 mmol) and then subjected to catalytic hydrogenation using an H-Cube equipment and a 10% Pd/C cartridge at 25 0 C. The solution was concentrated and the residue purified by silica flash chromatography (Hexane 100:0-80:20) which gave the title compound (146 mg, 59%). MS m/z 489 (M+H) + , 389 (M-Boc) +
  • Methyl ester 12a (146 mg, 0.298 mmol) was dissolved in hexane (30 mL) followed by addition of lithium borohydride (2M in THF, 600 ⁇ L, 1.2 mmol). The reaction mixture was stirred at RT for 2h, quenched with methanol, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (140 mg, 100%). MS m/z 462.5 (M+H) + .
  • DIBAL 3.74 mL, 3.74 mmol, IM in hexane
  • the reaction mixture was agitated at RT for 4h, and then quenched by addition of water.
  • the solution was diluted with DCM and washed with water.
  • the organic phase was separated, concentrated and purified by flash chromatography (hexane:ethyl acetate 100:0-75:25) which gave the title compound (136.5 mg, 25%), MS m/z 362.8 (M+H) + .
  • Step b) N- r2-(tert-Butyl-dimethyl-silanyloxy)- 1 -(3 ,5 -difluoro-phenoxymethvO-4-hvdroxy- butyll -2- r(2-methyl-cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (14b)
  • Step c) N-r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-oxo-butyll-2- [(2-methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (14c)
  • the alcohol 14b (69.2 mg, 0.1 mmol) was dissolved in dry dichloroethane (3 mL), followed by the addition of Dess- Martin reagent (59 mg, 0.14 mmol). The reaction mixture was stirred at RT for Ih, quenched with a saturated solution of sodium bicarbonate and Na 2 S 2 O 3 10% aq, diluted with DCM and washed with water. The organic phase was separated, concentrated and used in next step without further purification.
  • Boc anhydride (251mg, 1.14 mmol) and DMAP (0.57 mmol) were added to a solution of compound 12a (282 mg, 0.57 mmol) in acetonitrile (15 mL).
  • the reaction mixture was stirred at RT for 16h, concentrated and the residue was purified by silica flash chromatography which gave the title compound (86 mg, 25%). MS m/z 590.2 (M+H) + .
  • Step b) 4-(Bis-tert-butoxycarbonylamino)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro- phenoxy)-pentan-l-ol (17b)
  • Compound 17e (26.5 mg, 0.058 mmol) was dissolved in dioxanexonc. HCl (3:1, 4 mL) after Ih stirring, the solution was concentrated and co-evaporated with toluene.
  • Step l N-r3-Cvclopropylamino-l-(3,5-difluoro-phenoxymethyl)-2-hvdroxy-propyll-2-rmethyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (19)
  • the title compound was prepared from compound 30a and Acid-3, in 67% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer, according to the method described in Example 28 step b.
  • Step b) (2-Hydroxy-3-methoxy-l-phenoxymethyl-propy ⁇ -carbamic acid tert-butyl ester (33 a)
  • Epoxide E-17 was reacted according to the procedure described in Example 28 step a, which gave the title compound in 80% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
  • Step c) N-(2-Hvdroxy-3-methoxy-l-phenoxymethyl-propyl)-2-r(2-methyl-cvclopropylmethyl)- aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (33b)
  • Compound 34a and Acid-3 were reacted according to the method described in Example 28 step b, which gave the title compound in 96% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer.
  • Compound 36a 50 mg, 0.159 mmol was dissolved in THF/H 2 O/MeOH 4:2:1 (7 mL) and LiOH (23 mg, 0.960 mmol) and cesium carbonate (112 mg, 0.318 mmol) were added.
  • the epoxide E-Ii was opened with sodium hydride according to the conditions described in Example 28 step , but using ⁇ o-butanol instead of methanol.
  • the title compound was achieved in 84% yield after column chromatography using toluene/ ethyl acetate 15:1 as mobile phase.
  • Step a) 3-Azido-4-(3,5-difluoro-phenoxy)-l-fluoro-butan-2-ol (40a) Epoxide E-Ii (105.5 mg, 0.437 mmol) was dissolved in chlorobenzene (3 mL) and potassiumhydrogen fluoride (68 mg, 0.875 mmol) and TBAF (IM in THF) (0.875 mL, 0.875 mmol) were added and the mixture was stirred at 120 0 C for 90 minutes. The mixture was diluted with ethyl acetate and washed twice with brine whereafter the organic phase was dried, filtered, and concentrated.
  • the title compound was prepared from compound 4Od and Acid-1, in 88% yield according to the method described for the synthesis of compound 28b.
  • compound 42a (269 mg, 0.746 mmol) dissolved in dry ether (6 mL) at 0 0 C was added butylmagnesium chloride (2M in THF) (149 ⁇ L, 2.99 mmol) dropwise during 5 minutes.
  • the solution was stirred at 0 0 C for 1.5 hours and the reaction was subsequently quenched by the addition of saturated NH 4 Cl (aq) (15 rnL).
  • sodium borohydride (14.5 mg, 0.383 mmol) and the mixture was stirred at 0 0 C for 1 hour.
  • Saturated NH 4 Cl (aq) was added and the methanol was evaporated.
  • the mixture was extracted with ethyl acetate and washed twice with saturated NH4CI (aq) and the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ ethyl acetate 7:1) provided the title compound (106 mg, 92%) as a diastereomeric mixture; 3:1 in favor of the R isomer.
  • Compound 42d was prepared from compound 42c and Acid-1 in 90% yield as a diastereomeric mixture; 3:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • Compound 43b was prepared from compound 43a in 95% yield as a diastereomeric mixture; 5:1 in favor of the R isomer according to the method described for the synthesis of compound 42c.
  • Compound 43c was prepared from compound 43b and Acid-3 in 93% yield as a diastereomeric mixture; 5:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • the title compound was prepared from compound 44a in 90% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 42c.
  • Step c) N- [ 1 -(3.5 -Difluoro-phenoxymethylV 2-hydroxy-4-phenyl-butyr
  • the title compound was prepared from compound 44b and Acid-3 in 82% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 28b.
  • Diastereomer mixture 45a (218 mg, 0.480 mmol) was dissolved in a solution of 4M HCl in dioxane (8 ml). The reaction mixture was stirred at room temperature for 1 1/2 h and then concentrated under reduced pressure. The residue was dried by evaporation of added toluene (2x10 ml) and CH 3 CN (10 ml), to afford crude title compound.
  • Step c) N- [2-Hydroxy- 1 -phenoxymethyl-3 -(3 -trifluoromethyl-benzylaminoVpropyH -2- [methyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (45c)
  • the crude amine 45b and Acid-1 (171 mg, 0.480 mmol) were dissolved in dry DMF (8 ml) and diisopropylethylamine (416 ⁇ l, 2.40 mmol) was added. The solution was cooled on an ice-water bath and HATU (237 mg, 0.623 mmol) was then added.
  • pTSA 86.8 mg, 0.46 mmol, 3 equiv.
  • the mixture was stirred at rt for 15 h and then filtered which gave the title compound as a white solid.
  • LCMS m/z 341 (MH) + .
  • Step c) 2'-Trifluoromethyl-biphenyl-3.,5-dicarboxylic acid 5-([2-hydroxy-l-phenoxymethyl-3-(3- trifluoromethyl-phenylamino)-propyl "
  • HATU 68 mg, 0.18 mmol, 1.2 equiv.
  • Step a (2,3-Dihvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47a)
  • (l-phenoxymethyl-allyl)-carbamic acid tert-butyl ester 200 mg, 0.76 mmol
  • acetone:water 10:1 mL
  • a catalytic amount OfOsO 4 and NMO 0.16 mL, 1.52 mmol, 2 equiv., wt 50% in water.
  • Step c (3-Chloro-2-hvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47c)
  • acetone 11 rnL
  • LiCl 1.24 g, 29.3 mmol, 24 equiv.
  • EtOH aqueous ethanol
  • 3- (trifluoromethyl)benzyl amine 31 ⁇ L, 0.21 mmol, 3 eq.
  • the mixture was refluxed overnight, cooled down to rt and concentrated.
  • EtOAc was added and the solution was washed with a sat aq. solution of NaHCOs.
  • the organic phase was dried and evaporated and the afforded residue was used in the next step without any further purification.
  • HATU 25 mg, 0.07 mmol, 1.2 equiv.
  • PPI13 103.2 mg, 0.39 mmol, 1.5 equiv.
  • the mixture was stirred at rt overnight and concentrated. Purification by flash chromatography (toluene/npropanol/N ⁇ OH, 8/2/0.1) afforded pure title compound (73%).
  • Step b) (26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-5-methoxy-6-phenoxy-hexan-3-ol
  • DDQ (11.5 mg, 0.051 mmol, 1.3 equiv) was added at 0 0 C to a stirred solution of I- Ia (20 mg, 0.039 mmol) in DCM:H 2 0 (19:1, 10 mL). The reaction was allowed to reach room temperature then stirred for an additional 3 h.
  • Nosylchloride (177 mg, 0.8 mmol) and pyridine (194 ⁇ L, 2.4 mmol, 3 equiv) were added to a solution of 4-flouranilin (154 ⁇ L, 1.6 mmol, 2 equiv) in freshly distilled DCM (2mL).
  • the reaction was stirred at room temperature for two hours then quenched with 10% HCl (aq), the pH was set to ⁇ 1 before extracting with DCM (2x).
  • DIAD 32 ⁇ L, 0.164 mmol, 1.4 equiv
  • Ph 3 P 43 mg, 0.164 mmol, 1.4 equiv
  • reaction mixture was allowed to reach room temperature, then left stirring over night.
  • the solvent was evaporated and the crude product was used dissolved in MeCN and thiophenol (36 ⁇ L, 0.351 mmol, 3 equiv) was added followed by potassium carbonate (48 mg, 0.351 mmol, 3 equiv).
  • the reaction was heated to 50 0 C and followed by TLC. After 3h all starting material was consumed.
  • the methyl glycoside I-3b (1.449 g, 4.22 mmol) was dissolved in 1, 4-dioxane/ 0.5 M H 2 SO 4 1 :1 and heated to reflux. After complete reaction ( ⁇ 1 hour according to TLC), the reaction was cooled to room temperature and then neutralized with Na 2 CO 3 (aq). The volatile solvents were evaporated under vacuum and the afforded residue dissolved in DCM and washed with H 2 O (x 2). The organic phase was dried over Na 2 SO 4 and concentrated.
  • Step d) (2i?.46'.55)-5-Azido-6-(3.5-difluoro-phenoxyV2-methoxy-hexane-1.4-diol (I-3cD LiBH 4 (200 mg, 9.22 mmol, 2 equiv) was added under an argon atmosphere at 0 0 C to a stirred solution of compound I-3c (1.45 g, 4.61 mmol) in dry THF (20 mL). After 1 h the reaction was quenched with water, extracted with EtOAc, dried over Na 2 SO 4 and concentrated.
  • I-3cD LiBH 4 200 mg, 9.22 mmol, 2 equiv
  • Triphenyl phosphine (1.5 equiv) was added together with a drop of water to a solution of the azide (1 equiv) in MeOH. The reaction mixture was stirred for 16 h, concentrated to yield the crude compound which was used in the next step without further purification. Acid A (I equiv) was dissolved in dry DCM and pyBOP (1 equiv) was added followed by DIPEA (1 equiv). After 30 minutes the crude amine (1 equiv, dissolved in DCM) was added to the mixture, followed by DIPEA (1 equiv). After 2 h, the reaction mixture was diluted with DCM, washed with Na 2 CO 3 (sat.) and NH 4 Cl (aq).
  • TruPointTM Beta-Secretase Assay Kit was used to evaluate the enzymatic inhibition of BACEl exhibited by the compounds of the invention.
  • the assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanide fluorescence can be measured by time-resolved fluorometry (TRF).
  • TRF time-resolved fluorometry
  • the enzyme used in the assay is recombinant BACEl (produced in house) and the substrate is a 10 amino acids long peptide with a fluorescent europium chelate coupled to one end and a quencher of europium fluorescence (QSY 7) coupled via lysine to the other end; EU- CEVNLDAEFK-QSY 7.
  • the cleavage site by BACEl is the peptide bond between L and D.
  • a spectroscopic response is generated by peptidase cleavage, and the activity was measured by a continuous detection of increased fluorescence intensity exhibited by the cleavage product.
  • the compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed.
  • the substrate was prepared at a 120 ⁇ M stock solution in distilled water. The stock solution was diluted to 400 nM in an amount which was needed for the day.
  • To each well of a 96-well half area polystyrene plate was added the enzyme containing reaction buffer (15 ⁇ l) and inhibitor of different concentrations in DMSO (1 ⁇ l). To control wells were added reaction buffer (15 ⁇ l) and DMSO (1 ⁇ l).
  • the enzyme with inhibitor in DMSO was preincubated at room temperature (20-25 0 C) for 30 min whereafter the reactions were started by addition of substrate, 15 ⁇ l/well, thus giving a total volume of 31 ⁇ l/well and a substrate concentration of 200 nM.
  • Product TR- fluorescence was monitored during 90 min with a 1420 VICTOR and presented as Relative Fluorescence units (RFu).
  • the IC50 value was calculated with GraFit software.
  • Activity of the inhibitors was determined by measuring the TR-fluorescence at ⁇ g X 330 nm and ⁇ gm 615 nm. The inhibition is calculated as follows:
  • Example 68 which is a representative compound of the invention, exhibited an enzymatic inhibition of 6.5 nm, when tested in a BACE enzyme assay such as the one described above.
  • Table 1 shows the enzymatic inhibition represented as intervals exhibited by the compounds according to the invention.
  • Category A indicates an IC50 value of ⁇ 1 ⁇ M
  • category B indicates 1 - 5 ⁇ M
  • category C indicates > 5 ⁇ M.

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Abstract

A compound of formula (I): N-oxides, addition salts, quaternary amines metal complexes stereochemically isomeric forms and metabolites thereof, wherein A is CR1 or N; D is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or Q is C2-C6alkenyl, C2-Cealkynyl, aryl or heterocyclyl; W is H, Ci-Cealkyl, C2-C6alkenyl, haloC1-C3alkyl, hydroxyC1-C3alkyl, C3-C6Cy cloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH3, the other is C1-C3alkyl, F, OH, NRaRb, CF3 or N3; or X' and X" are both F; Y is a bond, CH2, NRa, O, CH2CH2, CH2NRa, CH2O or S(=O)r; Z is O, S(=O)r or NRa; the other variables are as defined in the specification. The compounds of the invention are inhibitors of BACE and are among other things useful for the treatment and/or prevention of conditions associated with BACE activity such as Alzheimer's disease.

Description

Aspartyl protease inhibitors
Technical field
This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as β-secretase (β-site amyloid precursor protein-cleaving enzyme, BACE). It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their in the preparation of a medicament or their use in therapy.
Background to the invention
A number of aspartic proteases are known to date, including pepsin A and C, Renin, BACE, BACE2, Napsin and Cathepsin D, which have been implicated in pathological conditions. For example the aspartyl protease BACE causes the production of the protein β amyloid (Aβ) in the brain, which is characteristic of Alzheimer's disease (AD). AD is a progressive neurogdegenerative disease of the brain characterized by gradual loss of cognitive function related to memory, reasoning, orientation and judgement and eventually death. Pathological features of AD 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 non-pathogenic products known as soluble APP, whereas the β- secretase pathway produces pathogenic Aβ peptides by cleavage by β-secretase at the position corresponding to the N-terminus of Aβ, followed by cleavage by γ-secretase at the C-terminus. The sequential proteolytic cleavage of APP by β- and γ-secretase is a key step in the production of Aβ. The amyloid cascade hypothesis, supported by genetic and pathological evidence, claims that the formation of Aβ plays an early and vital role in all cases of AD. Aβ forms aggregates that are thought to initiate a pathogenic cascade that leads to neuronal loss and dementia. BACE was identified a few years ago as a type 1 glycosylated transmembrane homodimer with two aspartic acids at the active catalytic site. BACE and BACE-2 (64 % amino acid sequence similarity to BACE) constitute a novel class of aspartic proteases closely related to the pepsin family. The function of BACE-2 is relatively unknown and several studies indicate that this enzyme is not involved in the Aβ generation. BACE knockout homozygote mice show complete absence of producing Aβ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that β-secretase is expressed in all tissues but at highest levels in the neurons in the brain. Therefore, in vivo inhibition of BACE is likely to reduce the production of Aβ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
Presently there are no known effective treatments for preventing, delaying or reversing the progression of AD. Current available therapies for mild to moderate AD are safe but of limited benefit to most of the patients since they treat the symptoms and do not affect the progression of aggregated protein breakdown products underlying the pathology of the disease. In view of the fact that amyloid β peptides are formed as a result of BACE activity, inhibition of BACE is an attractive therapeutic approach to the treatment and prevention of AD and other cognitive and degenerative diseases caused by Aβ plaque deposition. Desirable characteristics for inhibitors of BACE include low molecular weight and features that would allow them to cross the blood-brain barrier.
The compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved potency in inhibiting BACE.
Brief description of the Invention
In accordance with the present invention, there is provided novel compounds which are aspartyl protease inhibitors. Accordingly, in one aspect of the invention, there is provided compounds represented by general formula (I):
Figure imgf000004_0001
wherein
A is CR1 or N;
D is H, Ci-Cβalkyl, C2-Cealkenyl, C2-Cealkynyl or
Figure imgf000005_0001
R1 is H, Ci-Cealkyl, Ci-Cealkoxy, N3 or halo;
R2 is H or Ci-Cβalkyl;
R3 is Ci-C6alkyl, C2-C6alkenyl, C2-C3alkynyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C6alkoxy, arylCi- C6alkoxy, heterocyclylCi-C6alkoxy, NRaRb or N3;
R6 is hydrogen, Ci-C6alkyl, aryl, NRaRb, N(Ra)S(=O)rRc, N(Ra)S(=O)rNRaRc, S(O)1Ci-
C6alkyl, N(Ra)C(=O)Rc, N(Ra)C(=O)ORc, N(Ra)C(=O)NRaRc, OS(=O)2CiC6alkyl, halo or cyano;
R7 is Ci-C6alkyl, C3-C6Cy cloalkyl, C3-C6Cy cloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl, hydroxyCi-C3alkyl, Ci-CealkoxyCi-Qsalkyl, arylC0-C3alkoxyCi-
C3alkyl, heterocyclylC0-C3alkoxyCi-C3alkyl, N(Ra)(Rb)Ci -C3alkyl; wherein, when present, the Ci-C3alkyl moiety of R7 is optionally substituted with Ci-C6alkyl;
R8 is H, Ci-C6alkyl; or
R7 and R8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with
Figure imgf000005_0002
or fluoro;
R9 is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl;
R10 is H or Ci-C6alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci- C6alkyl, C2-C6alkenyl, C2-C6alkynyl or phenyl;
Q is C2-C6alkenyl, C2-C6alkynyl, aryl or heterocyclyl;
W is H, Ci-C6alkyl, C2-C6alkenyl, haloCi-C3alkyl, hydroxyCi-C3alkyl, C3-C6Cy cloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH3, the other is Ci-C3alkyl, F, OH, NRaRb, CF3 or N3; or X' and X" are both F;
Y is a bond, CH2, NRa, O, CH2CH2, CH2NRa, CH2O or S(=O)r;
Z is O, S(=O)r or NRa; 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 methylene may alternatively be a 1,1-cyclopropyl group; r is 0, 1 or 2; Ra is independently H or Q -Qalkyl;
Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached may form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro; Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocyclic ring; Rd is H or Ci-C3alkyl; and wherein aryl is independently phenyl, naphthyl or phenyl fused to C4-Cecycloalkyl or Q-Qcycloalkenyl; heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N; and wherein each occurrence of Q-Qalkyl, C2-C6alkenyl, C2-C6alkynyl, Q-Qcycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as arylalkyl or heterocyclylalkyl) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from C1-QaIkVl, C2-Cealkenyl, Q-Qalkynyl, C3- Cecyclolkyl, Ci-Qalkoxy, Ci-C4alkoxyCi-C3alkyl, Ci-QalkoxyQ-QalkoxyQ-Qalkyl, halo, haloCi-Qalkyl, hydroxy, hydroxyCi-Qalkyl, NRaRb, NRaRbCi -Qalkyl, C(=O)NRaRb, NRaC(=O)Rb, cyano, azido, Ci-Qalkylcarbonyl, Q-Qcyc loalkyl1 Q-Qalkyl, ary^Q-Qalkyl, heterocyclyl1 Co-C3alkyl, C3-C4CyC loalkyl1C2-C3alkenyl, aryl1C2-C3alkenyl, heterocyclyl1 Q-
C3alkenyl, C3-C4CyC loalkyl1C2-C3alkynyl, aryl1C2-C3alkynyl or heterocyclyl1 C2-C3alkynyl, or a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci -Qalkyl or fluoro); where aryl1 is independently phenyl, naphthyl, or phenyl fused to Q-Qcycloalkyl or Q- Qcycloalkenyl; heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence of C3-C4CyC loalkyl1, aryl1 and heterocyclyl1 above (including those in composite expressions such as C3-C4CyC loalkyl1 Q-Qalkyl, ary^Q-Qalkyl and heterocyclyl1 Q-Qalkyl), the cycloalkyl1, aryl1 and heterocyclyl1 is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Q -Qalkyl, C3- Qcycloalkyl, halo, haloQ-Qalkyl and polyhaloQ -Qalkyl; or a pharmaceutically acceptable salt, hydrate, quaternary amine, metal complex or N-oxide thereof. In one embodiment of the invention compounds of formula (I) are included wherein A is CH or N;
Figure imgf000007_0001
R1 is H, Ci-Csalkyl, N3 or halo; R2 is H or Ci-C6alkyl;
R3 is Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkoxyCi-C6alkoxy, arylCi-C6alkoxy, heterocyclylCi-
C6alkoxy, NRaRb or N3;
R6 is hydrogen, Ci-C6alkyl, aryl, N(Ra)S(=O)rRc, N(Ra)S(=O)rNRaRb, S(=O)rCi-C6alkyl,
N(Ra)C(=O)Rc, N(Ra)C(=O)ORc, N(Ra)C(=O)NRaRc, halo or cyano; R7 is Ci-C6alkyl, C3-C6Cy cloalkyl, C3-C6Cy cloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-Qsalkyl, hydroxyCi-C3alkyl, Ci-CealkoxyCi-Gsalkyl, Ci-C3alkanediyl-O-C0-
C3alkanediylaryl, Ci -C3alkanediyl-0-Co-C3alkanediylheterocyclyl, Ci -C3alkanediylNRaRb; wherein the Ci-C3alkanediyl moiety is optionally substituted with Ci-C6alkyl;
R8 is H, Ci-Cealkyl; or R7 and R8 together with the N atom to which they are attached define a heterocyclyl group;
R9 is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6CyC loalkyl, C3-C6CyC loalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl;
R10 is H or Ci-C6alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered heterocyclic ring; Q is C2-C6alkenyl, C2-C6alkynyl, aryl or heterocyclyl;
W is H, Ci-C6alkyl, Ci-C6alkenyl, haloCi-C3alkyl, polyhaloCi-C3alkyl, hydroxyCi-C3alkyl, C3-
C6cycloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH3, the other is Ci-C3alkyl, F, OH, NRaRb, CF3 or N3; or
X' and X" are both F; Y is a bond, CH2, NRa, O, CH2CH2, CH2NRa, CH2O or S(=O)r;
Z is O, S(=O)r or NRa; n is 0, 1, 2 or 3; p is 0 or 1 ; q is 0, 1 or 2; thereby defining a methylene or ethylene or when q is 1, the methylene may alternatively be a 1,1-cyclopropyl group; r is 0, 1 or 2; Ra is independently H or Q -Qalkyl;
Rb is independently H or Q -Qalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl group; Rc is independently Q -Qalkyl; or Rc and Ra together with the atoms to which they are attached form a heterocyclic ring; and wherein aryl is independently phenyl, naphthyl or phenyl fused to Q-Qcycloalkyl or Q-Qcycloalkenyl; heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N; and wherein each occurrence of Q-Qalkyl, C2-C6alkenyl, C2-C6alkynyl, Q-Qcycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as arylalkyl or heterocyclylalkyl) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from C1-QaIkVl, Ci-Qalkoxy, Q-QalkoxyQ- Qalkyl, Ci-QalkoxyCi-C3alkoxyCo-C3alkyl, halo, haloCi-Qalkyl, polyhaloCi-Qalkyl, hydroxy, hydroxyCi-Qalkyl, NRaRb, NRaRbCi -Qalkyl, C(=O)NRaRb, NRaC(=O)Rb, cyano, azido, Ci-Qalkylcarbonyl, Q-Qcycloalkyl1 Q-Qalkyl, ary^Q-Qalkyl, heterocyclyl1 Q- Qalkyl, C3-C4Cy cloalky^Q-Qalkenyl, ary^Q-Qalkenyl, heterocyclyl1 Q-Qalkenyl, Q- C4cyc loalky^Q-Qalkynyl, ary^Q-Qalkynyl or heterocyclyl1 Q-Qalkynyl, or a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Q -Qalkyl or fluoro); where aryl1 is independently phenyl, naphthyl, or phenyl fused to Q-Qcycloalkyl or Q- Qcycloalkenyl; heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence of C3-C4CyC loalkyl1, aryl1 and heterocyclyl1 above (including those in composite expressions such as C3-C4CyC loalky^Q-Qalkyl, ary^Q-Qalkyl and heterocyclyl1 Q-Qalkyl), the cycloalkyl1, aryl1 and heterocyclyl1 is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Q -Qalkyl, Q- Qcycloalkyl, halo, haloQ-Qalkyl and polyhaloQ -Qalkyl; or a pharmaceutically acceptable salt, hydrate, quaternary amine, metal complex or N-oxide thereof.
In a typical embodiment of the invention, compounds are included wherein R1 is H or F;
R2 is H;
R6 is N(Ra)S(=O)2Rc, N(Ra)S(=O)2NRaRc, OS(=O)2CiC6alkyl or halo;
R7 is Ci-Cβalkyl, Cs-C6Cy cloalkyl, C3-C6Cy cloalkylCi-Csalkyl, aryl, arylCi-Csalkyl, heterocyclyl, heterocyclylCi-Csalkyl; wherein, when present, the Ci-Csalkyl moiety of R7 is optionally substituted with Ci-C6alkyl;
R8 is H, Ci-Cealkyl;
Q is optionally substituted aryl or optionally substituted heterocyclyl;
W is C3-C6Cy cloalkyl, C2-C6alkenyl, aryl or heterocyclyl, any of which is optionally substituted; one of X' and X" is OH;
Y is O or NH;
Z is O or NH; n is 0 or 1 ; r is 2.
As indicated above, D is H, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or
Figure imgf000009_0001
Consequently, according to one embodiment of the invention, compounds are included wherein D represents an amide moiety, thus giving compounds according to formula Ia.
Figure imgf000009_0002
Typically, according to this embodiment, A is CR1.
R7 is as recited above. Typical values for R7 include Ci-C6alkyl, arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein each Ci-C6alkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, C1- C4alkyl, Ci-C4alkoxy, hydroxy and cyano. A further configuration for R7 include arylCi-Csalkyl and heterocyclylCi-Csalkyl, wherein the Ci-C3alkyl moiety is optionally substituted with Ci-C6alkyl. Preferred configurations for the C1- Cβalkyl according to this embodiment include Ci-C4alkyl such as methyl or ethyl; haloCi- C4alkyl, such as trifluoromethyl and C3-C4cycloalkyl such as cyclopropyl.
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.
Currently favoured values for R7 include phenylmethyl, 1-phenylethyl and 1-phenylpropyl, especially phenylmethyl and 1-phenylethyl, wherein the phenyl ring is optionally substituted. Accordingly, favoured embodiments of the invention include compounds having the partial structure shown below:
Figure imgf000010_0001
Typically in compounds having this partial structure, A is CR1.
If present, the substituent(s) is preferably the in the para and/or ortho position of the phenyl ring.
In a further favoured embodiment of the invention, R7 is Cs-Coheteroarylmethyl, I-C5- Cβheterarylethyl or l-Cs-Cβheterarylpropyl, especially Cs-Cβheterarylmethyl, wherein the heteroaryl ring is optionally substituted. Suitable heteroaryl rings according to this embodiment include, but are not limited to thiazolyl, pyrazolyl, imidazolyl.
Accordingly, favoured compounds of the invention according to this embodiment include those having the partial structure shown below:
Figure imgf000010_0002
Typically in compounds having this partial structure, A is CR .
R8 is as recited above, preferably hydrogen or methyl.
A further embodiment of the invention include compounds of formula (I) wherein R >7 and R together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6 membered cyclic amine, for example optionally substituted pyrrole, piperidine, piperazine or morpholine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro.
According to a further embodiment of the invention, R7 and R8 are both Ci-Cβalkyl, such as ethyl, propyl or butyl.
According to a further embodiment of the invention, compounds are included wherein D represents an amine moiety, thus giving compounds according to formula Ia'.
Figure imgf000011_0001
Typically, according to this embodiment, A is N, thus affording compounds according to formula Ia":
Figure imgf000011_0002
Typical values for R include Ci-Cβalkyl, C2-Cealkenyl and C2-C6alkylnyl wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted. Typical substituents according to this embodiment include Cs-Cβcycloalkyl for example cyclopropyl, Ci-C4alkyl for example isopropyl or t.butyl, haloalkyl for example CH2F, CHF2 or CF3, hydroxy and phenyl. A typical value for R9 according to this embodiment is optionally substituted C2-C6alkynyl, such as ethynyl, which is unsubstituted or substituted with cyclopropyl or CF3. and C3-C6Cy cloalkylCi-Csalkyl, any of which is optionally substituted as defined above. Typical substituents include Ci-C3alkyl, halo, polyhaloalkyl, hydroxy, phenyl.
Preferred values for R9 include C3-C6cycloalkylCi-C3alkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C3alkyl. Specially preferred are cyclopropylmethyl and 2- methylcyclopropylmethyl. For these values of R9, R10 is preferably H or methyl.
R10 is typically H or Ci-C3alkyl, preferably H or methyl.
In a further configuration according to this embodiment of D, R9 and R10 together with the nitrogen atom to which they are attached form a 4-6 membered cyclic amine, which cyclic amine is optionally substituted, thus giving the partial structures:
Figure imgf000012_0001
Typically in compounds having this partial structure, A is CR1.
Optional substituent to the R9-R10 ring is selected from Ci-C6alkyl, C2-Cealkenyl, C2-Cealkynyl and phenyl.
According to a further embodiment of the invention, D is Ci-C6alkyl, C2-Cealkenyl or C2- C6alkynyl, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted. Typical substituents according to this embodiment include Cs-C6CyC loalkyl for example cyclopropyl, C1- C4alkyl for example isopropyl or t.butyl, and haloalkyl for example CH2F, CHF2 or CF3. Typically according to this embodiment, D is optionally substituted C2-C6alkynyl, such as ethynyl which is unsubstituted or, preferably, substituted with cyclopropyl or CF3.
The compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres. In typical embodiments of the invention, the chiral centre whereto the group R2 is attached has the stereochemistry shown in the partial structure: ψ ,Q
According to preferred embodiments of the invention, Z is O.
According to other embodiments Z is NRa, wherein Ra 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 typically aryl or heterocyclyl, which is optionally substituted with one, two or three substituents as defined above.
In some embodiments of the invention Q is an optionally substituted bicyclic aryl or heterocyclyl moiety. Typically, the heterocyclyl moiety contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulphur. Representative bicyclic rings according to this embodiment include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl, each of which is optionally substituted.
According to a further embodiment of the invention, Q is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-Cβcycloalkyl or monocyclic heterocyclyl. The heterocyclic ring according to this embodiment typically contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Representative values for monocyclic rings include phenyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted. Typical values for Q according to this embodiment include 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents. Representative values for the optional substituents to Q include one or two substituents independently selected from Ci-C4alkyl, C3-C4cycloalkyl, Ci-C4alkoxy, Ci-CsalkoxyCi- Cβalkoxy, cyano, halo, haloCi-C4alkyl and arylCi-Csalkyl, heterocyclylCi-Csalkyl, C2- Csalkenyl, C2-C3alkynyl, C2-C3alkynylC3-C6Cycloalkyl. Currently favoured values include halo such as mono- di or trifluoro, chloro, bromo and haloCi-C4alkyl for example trifluoromethyl.
According to embodiments of the invention wherein Q is a monosubstituted phenyl or a 6- membered heterocyclyl, the substituent is preferably in the meta or para position. Preferred configurations for Q according to these embodiments include meta and para substituted phenyl.
According to embodiments of the invention wherein Q is a disubstituted phenyl or a 6-membered heterocyclyl, the substituents are preferably in the two meta positions or one substituent is in the meta position and the other in the para position. Preferred substituents to Q according to these embodiments are independently chloro, fluoro, bromo, methyl, optionally substituted phenyl, 5- or 6 membered heteroaryl.
Currently favoured configurations for Q include optionally substituted phenyl, such as bromo substituted phenyl and mono- or difluorophenyl, especially difluorophenyl.
Further favoured configurations for Q include phenyl which is substituted with heteroaryl, C2- Cβalkenyl, C2-C6alkynyl, cyano or cyclopropylethynyl.
In preferred embodiments of the invention, Q is optionally substituted phenyl, n is 0 and Z is O.
In further preferred embodiments of the invention, Q is optionally substituted pyridyl, n is 0 and Z is O. Specially preferred compounds according to this embodiment are those wherein Q is pyrid-3-yl.
R2 is Ci-Cβalkyl such as methyl or ethyl, or preferably R2 is hydrogen.
In typical embodiments of the invention Y is O or NH. X' and X" are as defined above, preferably one of X' and X" is H and the other is F, or more preferably one of X' and X" is H and the other is OH.
In an alternative embodiment of the invention X' and X" are both fluoro.
In compounds of formula (I) wherein p is 0, Y is NH, one of X' and X" is OH and the other is H, the chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
HO H H In compounds of formula (I) wherein p is 1 and one of X' and X" is OH and the other is H, the chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
Figure imgf000015_0001
In one embodiment of the invention, compounds of general formula (I) are included wherein p is 0, thus giving compounds of general formula (Ib):
Figure imgf000015_0002
Typically according to this embodiment, Y is NH.
In an alternative embodiment of the invention, compounds of general formula (I) are included wherein p is 1, thus giving compounds of general formula (Ic):
Figure imgf000016_0001
In compounds of formula (Ic), i.e. wherein p is 1, the chiral centre whereto R3 is attached typically has the configuration shown in the partial structure below.
Figure imgf000016_0002
Typical values for R in compounds of formula (Ic) include optionally substituted Ci-Cβalkoxy such as optionally substituted methoxy, ethoxy and propoxy, preferably R3 is Ci-C4alkoxy, especially methoxy.
Further typical values for R3 include optionally substituted Ci-Cealkoxy-Ci-Cβalkoxy such as optionally substituted methoxypropoxy and methoxyethoxy. Preferred substituents to the alkoxy moieties include halo such as chloro and mono- di- and trifluoro.
Preferred compounds of formula (I) wherein p is 1 and one of X' and X" is H and the other is OH, are those having the stereochemistry indicated in formula (Id):
Figure imgf000016_0003
Preferred compounds of formula (I) wherein p is 0, one of X' and X" is H and the other is OH, and Y is NH are those having the stereochemistry indicated in formula (Ie):
Figure imgf000017_0001
In typical embodiments of the invention, R1 is H.
In alternative embodiments of the invention, R1 is halo, such as fluoro.
According to one embodiment of the invention R6 is N(Ra)S(=O)2Rc. Typical configurations for R6 according to this embodiment include N(Co-C2alkyl)S(=0)2Rc, wherein Rc is typically is C1- C4alkyl, preferably methyl or isopropyl.
Further typical values for R6 according to this embodiment include cyclic sulphonamides, i.e. Ra and Rc together with the atoms to which they are attached form a heterocyclic ring. Preferably according to this configuration of R6, the heterocyclic ring is a 5 or 6-membered ring, thus providing compounds of the general formula (If).
Figure imgf000017_0002
Typically in compounds of formula (If), A is CR1.
Typically, in embodiments of the invention wherein R6 is a cyclic sulphonamide, A is CH and R1 is halo, preferably fluoro. Preferably, according to these embodiments, R1 is in the ortho position of the phenyl ring.
Further typical values for R6 include hydrogen and Ci-Cβalkyl, especially hydrogen or methyl. The group W is bonded either directly to Y, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively. In favoured embodiments of the invention W is bonded directly to Y or via a methylene moiety, i.e. q is 0 or 1 respectively.
Alternatively, when q is 1, the moiety linking W to Y may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
Figure imgf000018_0001
As stated above, W is hydrogen, Ci-Cβalkyl, C2-Cealkenyl, haloCi-Csalkyl, hydroxyCi-Csalkyl, Cs-Cβcycloalkyl, aryl or heterocyclyl wherein the alkyl, alkenyl, cycloalkyl, aryl or heterocyclyl moiety is optionally substituted with one, two or three substituents.
One embodiment of the invention includes compounds wherein W is optionally substituted Ci- Cβalkyl such as methyl, ethyl or isopropyl. Preferred substituents to W according to these embodiments include halo such as mono-, di- or trifluoro.
A further embodiment of the invention includes compounds wherein W is an optionally substituted bicyclic aryl or heterocyclyl moiety. Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, chromanyl, dihydrobenzofuran, dihydroisobenzofuran. Representative substituents to the bicyclic ring include Ci-C4alkyl, e.g. t.butyl and haloalkyl, e.g. trifluoromethyl.
A further embodiment of the invention includes compounds wherein W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-Cβcycloalkyl or monocyclic heterocyclyl. The heterocyclic ring according to this embodiment, typically contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Representative values for monocyclic heterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
A preferred embodiment of the invention includes compounds wherein W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl. A further preferred embodiment of the invention includes compounds wherein W is optionally substituted Cs-Cβcycloalkyl such as optionally substituted cyclopropyl. A typical configuration for W according to this embodiment is cyclopropyl which is substituted with Ci-C4alkyl e.g. methyl or with C2-C4alkenyl e.g. ethenyl or propenyl.
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 embodiment include meta or para substituted phenyl, for example p-ϋuoro phenyl.
In embodiments wherein W is substituted phenyl, the substituents are preferably selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl and tert. butyl.
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-C4CVC loalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C4alkyl such as methyl, ethyl and isopropyl.
It is to be understood that whenever used above and hereinafter, the term 'compounds of formula (I)', or 'the present compounds' or similar terms, it is meant to include the compounds of formula (I) and any subgroups of the compounds of formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
The invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the TV-oxides, salts, as the possible stereoisomeric forms thereof. The invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, /V-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
The invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament. 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, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
The compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as BACE. Accordingly, one embodiment of the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
The compounds of the present invention have utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease. 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, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis. 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.
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.
In a further embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
The compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or 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 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 pharmaceutical compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. The oral delivery route, particularly capsules or tablets is favoured.
The compounds of the present invention may be used in combination with one or more additional compounds useful in the treatment and/or prophylaxis of Alzheimer's disease, or the symptoms thereof. Examples of such additional compounds include NSAIDs including ibuprofen; vitamin E; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin, cognition-enhancing drugs such as acetylcholinesterase inhibitors, e.g. donepezil, rivastigmine, tacrine and galanthamine; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. memantine; or PDE4 inhibitors, e.g. Ariflo™. Such additional compounds also include cholesterol-lowering drugs such as HMG-CoA reductase inhibitors, e.g. lovastatin and simvastatin. Such additional compounds also include compounds known to modify the production or processing of Aβ in the brain ("amyloid modifier"), such as compounds which inhibit the secretion of Aβ, compounds which inhibit the aggregation of Aβ, and antibodies which selectively bind to Aβ. Such additional compounds also include growth hormone secretagogues, e.g. such as ibutamoren, ibutamoren mesylate and capromorelin. The amyloid modifiers according to this embodiment of the invention may be a β-secretase inhibitor other than any of those included in the present invention, such as any of the compounds disclosed in Recent Patents on CNS Drug Discovery, 2 (2007), 188-199; an inhibitor/modulator of γ-secretase, or any other compound which inhibits the formation or release of Aβ. The amyloid modifier may also be a GSK-3 inhibitor, particularly a GSK-3α inhibitor, such as lithium, as disclosed by Phiel et al in Nature, 423 (2003), 435-439.
The amyloid modifier may also be a compound which inhibits the aggregation of Aβ or otherwise attenuates its neurotoxicity. Suitable examples include chelating agents such as clioquinol (Gouras and Beal, Neuron, 30 (2001), 641-642) and the compounds disclosed in
WO99/ 16741, particularly the one known as DP- 109 (Kalendarev et al, J. Pharm. Biomed. Anal, 24 (2001), 967-975). Other inhibitors of Aβ aggregation suitable for use in the present invention include for example Apan™ (Praecis) and in particular 3-aminopropane-l-sulphonic acid, also known as tramiprosate or Alzhemed™.
The amyloid modifier may also be an anti-amyloid antibody which binds selectively to Aβ. Said antibody may be polyclonal or, preferably, monoclonal, and is preferably human or humanized.
The compounds of the present invention may also be used in combination with one or more P- glycoprotein inhibitor(s).
Non- limiting examples of Pgp inhibitors include ketoconazole, cyclosporine A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX710, LY335979 and PSC-833.
Additionally, the compounds of the present invention may also contain, or be co- administered (simultaneously or sequentially) with one or more additional drugs that either increase the efficacy, safety and/or convenience, or treat, prevent, control or reduce the risk for side effects or toxicity of the compounds of the present invention. The foregoing list of anti- Alzheimer's agents suitable for combinations is illustrative only and not intended to be limiting in any way.
The species may be combined in a single dosage form for simultaneous administration to the subject, or be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close or remote in time, e.g. one species is administrated in the morning and the other in the evening. The separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
The separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of the species is preferred, where possible. When the additional compound is an antibody, it will typically be administered parenterally and separately from the compound of Formula I.
The combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol wherein one or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
The invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
The term 'prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of
Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci-Cβalkoxymethyl esters for example methoxymethyl, Ci-Cβalkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-CsCyC loalkoxycarbonyloxyCi-Cβalkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci -Cβalkoxycarbonyloxy ethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and 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 hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylamino acetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
For therapeutic use, salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic, />toluenesulphonic, cyclamic, salicylic, />amino salicylic, pamoic acids and the like.
Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
The compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, /V-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice can be introduced using ion exchange resins.
The TV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide. The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre. The presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term
'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107). For instance, enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species. Examples of optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by 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.
The present invention also includes isotope- labelled compounds of formula I or any subgroup of formula I, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature. Examples of isotopes that may be incorporated into the compounds of formula I or any subgroup of formula I, include but are not limited to isotopes of hydrogen, such as 2H and 3H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11C, 13C and 14C, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 31P and 32P, sulphur, such as 35S, fluorine, such as 18F, chlorine, such as 36Cl, bromine such as 75Br, 76Br, 77Br and 82Br, and iodine, such as 123I, 124I, 125I and 131I.
The choice of isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3H or 14C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11C, 18F, 13N or 15O will be useful. The incorporation of a heavier isotope, such as deuterium, i.e. 2H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
Isotope-labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotope-labelled reagent or starting material instead of the corresponding non- isotope-labelled reagent or starting material, or by conventional techniques known to those skilled in the art. As used in the foregoing and hereinafter, the scientific and technological terms and nomenclature have the same meaning as commonly understand by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted.
As used herein 'Cm-Cnalkyl' as a group or part of a group defines a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g. Ci-Cβalkyl means an alkyl group having from 1 to 6 carbon atoms). Preferred alkyl groups for use in the invention are Ci-Cβalkyl groups, i.e. alkyl groups having from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.butyl, pentyl, hexyl and the like. Unless otherwise indicated the alkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
The term 'C2-Cnalkenyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms designated, (e.g. C2-Cealkenyl means an alkenyl group having from 2 to 6 carbon atoms). Preferred alkenyl groups for use in the invention are C2- Cβalkenyl groups, i.e. alkenyl groups having from 2 to 6 carbon atoms. Exemplary alkenyl groups include ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like. Unless otherwise indicated the alkenyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
The term 'C2-Cnalkynyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms designated, (e.g. C2-Cealkynyl means an alkynyl group having from 2 to 6 carbon atoms). Preferred alkynyl groups for use in the invention are C2-C6alkynyl, i.e. alkynyl groups having from 2 to 6 carbon atoms. Exemplary alkynyl groups include ethynyl, propynyl, propynyl, butynyl, and the like, especially propynyl. Unless otherwise indicated the alkynyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
The term C3-Cncycloalkyl as a group or part of a group defines a saturated cyclic hydrocarbon radical having the number of carbon atoms designated, e.g. Cs-Cβcycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl and the like, especially cyclopropyl. Unless otherwise indicated the cycloalkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
'C3-Cn'CycloalkylCm-Cnalkyr represents a Cm-Cnalkyl radical which is substituted with a C3- Cn'Cycloalkyl moiety, wherein C3-Cn'Cycloalkyl and Cm-Cnalkyl are as defined for C3-
CnCycloalkyl and Cm-Cnalkyl respectively above. Preferred C3-Cn'CycloalkylCm-Cnalkyl groups for use in the invention are C3-CycycloalkylCo-C3alkyl, i.e. the cycloalkyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
'C3-Cn'CycloalkylC2-Cnalkenyl' and 'C3-Cn'CycloalkylC2-Cnalkynyl' have the corresponding meanings as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively, adjusted just for the link to the C3-Cn'Cycloalkyl moiety, as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively. Preferred C3-Cn'CycloalkylC2-Cnalkenyl and C3-Cn'CycloalkylC2-Cnalkynyl groups for use in the invention are C3-Cn'CycloalkylC2-C3alkenyl and C3-Cn'CycloalkylC2-C3alkynyl, i.e. the C3- Cn'Cycloalkyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
The term C3-Cncycloalkenyl as a group or part of a group defines a cyclic hydrocarbon radical having one double bond and having the number of carbon atoms designated, e.g. C3- Cβcycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl cyclopentenyl, cyclohexenyl and the like. Unless otherwise indicated the cycloalkenyl moiety is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
'Co-Cnalkoxy' defines oxygen (Co) or a radical O-Ci-Cnalkyl wherein Ci-Cnalkyl is as defined for Cm-Cnalkyl above. Preferred alkoxy groups for use in the invention are Ci-Cβalkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like.
C2-Cnalkenoxy, defines a radical O-C2-Cnalkenyl wherein C2-Cnalkenyl is as defined above. Preferred alkenoxy groups for use in the invention are C2-Cealkenoxy, i.e. alkenoxy groups having from 2 to 6 carbon atoms. Exemplary alkenoxy groups include but are not limited to ethenoxy, 1-propenoxy, 2-propenoxy, and the like. C2-C6alkynoxy, defines a radical O-C2-Cnalkynyl wherein C2-Cnalkynyl is as defined above. Preferred alkynoxy groups for use in the invention are C2-C6alkynoxy, i.e. alkynoxy groups having from 2 to 6 carbon atoms. Exemplary alkynoxy groups include but are not limited to ethynoxy, 1-propynoxy, 2-propynoxy, and the like.
The term 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
The term 'haloCm-Cnalkyr as a group or part of a group, represents a Cm-Cnalkyl radical which is substituted with one or more halogen atoms, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of haloCm-Cnalkyl, the halogen atoms may be the same or different.
As used herein, the term '(=O)' or 'oxo' forms a carbonyl moiety when attached to a carbon atom, a sulphoxide moiety when attached to a sulphur atom and a sulphonyl moiety when two of said terms are attached to a sulphur atom. It should be noted that an atom can only be substituted with an oxo group when the valency of that atom so permits.
'Amino' as a group or part of a group, unless the context suggests otherwise, includes NH2, NHCm_Cnalkyl or N(Cm_Cnalkyl)2, wherein m and n in the (Cm-Cnalkyl)2 are selected independentlly of each other, and wherein in the amino definition Cm-Cnalkyl is especially Ci-C6 or Ci-C4alkyl variants. Included are also radicals wherein the two Cm-Cnalkyl groups of the N(Cm-Cnalkyl)2 together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro.
The terms 'Cm-Cnalkylamino' and '(Cm-Cnalkyl)2amino' as used herein has the same meaning as NHCm_Cnalkyl and N(Cm-Cn-alkyl)2 respectively as defined above.
The terms 'C2-Cnalkenylamino' and 'C2-Cnalkynylamino' define NHC2-Cnalkenyl and NHC2- Cnalkynyl respectively, wherein the C2-Cnalkenyl and C2-Cnalkynyl are as defined above. Among special interest for the invention are the C2-C6 variants, and especially the C2-C4 variants.
'Amido' as a group or part of a group represents a radical -Q=O)NH2, -C(=O)NHCm-Cnalkyl and -C(=O)N(Cm-Cnalkyl)2, especially C(=O)NHCi-C4alkyl and C(=O)N(Ci-C4alkyl)2. Included are also radicals wherein the two Cm-Cnalkyl groups together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which cyclic amine is optionally substituted with C1- C4alkyl or fluoro. Also included are radicals -NHC(=O)H, -NH(C=O)Cm-Cnalkyl, -N(C1n- CnalkylXC=O)H, -N(Cm-Cnalkyl)(C=O)Cm-Cnalkyl, especially NH(C=O)Ci -C4alkyl and -N(Ci- C4alkyl)(C=O)Ci-C4alkyl. The term 'alkoxyamido' is meant to include -NHC(=O)Ci-C6alkoxy, such as tert.butoxycarbonylamino
'Aryl' as a group or part of a group as applied herein represents an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C6CyC loalkyl (for example indanyl), or a C5-
CoCycloalkenyL Examples of suitable aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with 1 or 2, or where valence allows up to 3 substituents.
'ArylCm-Cnalkyl' represents a Cm-Cnalkyl radical which is substituted with an aryl moiety, wherein aryl and Cm-Cnalkyl are as defined above. Preferred arylCm-Cnalkyl groups for use in the invention are arylCo-Csalkyl, i.e. the aryl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
'ArylC2-Cnalkenyl' and 'arylC2-Cnalkynyl' have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively. Preferred arylC2-Cnalkenyl and arylC2-Cnalkynyl groups for use in the invention are arylC2- Csalkenyl and arylC2-C3alkynyl, i.e. the aryl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
Ηeterocyclyl', 'heterocyclic' or heterocycle as applied herein is meant to include a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring, which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, 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, thiomoφholinyl, triazinyl, 1 ,4-dioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo- 1,2,3-triazolyl, benzo- 1,2,4-triazolyl, benzotetrazolyl, benzo furanyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl indanyl, pyrrolopyridyl, naphtyridyl etc. Unless otherwise indicated the heterocyclyl group is optionally substituted with one, two or where valence allows three substituents.
ΗeterocylylCm-Cnalkyl' represents a Cm-Cnalkyl radical which is substituted with a heterocyclyl moiety, wherein heterocyclyl and Cm-Cnalkyl are as defined above. Preferred heterocyclylCm- Cnalkyl groups for use in the invention are heterocyclylCo-Csalkyl, i.e. the heterocyclyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
ΗeterocyclylC2-Cnalkenyl' and 'heterocyclylC2-Cnalkynyl' have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C2-Cnalkenyl' and 'C2-Cnalkynyl respectively. Preferred heterocyclylC2-Cnalkenyl and heterocyclylC2-Cnalkynyl groups for use in the invention are heterocyclylC2-C3alkenyl and heterocyclylC2-C3alkynyl, i.e. the heterocyclyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
Ηeteroaryl' as applied herein means an aromatic heterocyclyl moiety.
Typically aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
Unless otherwise indicated, the alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, aryl and heterocyclyl (including those in composite expressions such as arylalkyl or heterocyclylalkyl) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from: d-C4alkyl, C2-Cealkenyl, C2- Cβalkynyl, Cs-Cβcyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, NRaRb, N(RaRb)Ci -C4alkyl, NRaRbC(=O), RbC(=O)NRa, cyano, azido, nitro, Ci-Cβalkylcarbonyl, a 3 to 6 membered cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), oxo, mercapto, Cs-CycarbocyclylCo-Csalkyl, aryl'Co- Csalkyl, heterocyclyl'Co-Csalkyl, C3-CycarbocyclylC2-C3alkenyl, aryl^-Csalkenyl, heterocyclyl1C2-C3alkenyl, C3-CycarbocyclylC2-C3alkynyl, aryl^-Csalkynyl, heterocyclyl1C2- Csalkynyl, wherein the aryl1 or heterocyclyl1 moieties is optionally substituted with Ci-C4alkyl, halo, hydroxy or NRaRb.
It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
When any variable occurs more than one time in any constituent, each definition is independent.
General synthetic methodology
The compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art. The general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof. Alternative routes, which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
Generally, the compounds of the invention are prepared by reacting an acid of formula II
Figure imgf000034_0001
or an activated and optionally protected derivative thereof, wherein A, D, R1 and R6 are as defined above, with an amine of formula III
Figure imgf000035_0001
wherein Q, X', X", Y, Z, W, R3, n, p and q are as defined above. Typically, the coupling reaction is performed according to standard procedure used for amide bond formation in peptide synthesis. General descriptions of such coupling reactions and reagents used therein can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993). Typically, the starting materials are reacted in the presence of a coupling agent such as a carbodiimide like dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as N- ethyl-iV'- [(3 -dimethylamino)propyl] carbodiimide and a suitable catalyst, e.g. 1- hydroxybenzotriazole (HOBT), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 4- dimethylaminopyridine (4-DMAP). Further useful coupling agents are (benzotriazol-1-yloxy)- tris-(dimethylamino) phosphonium hexafluorophosphate (BOP), either by itself or in the presence of HOBT or 4-DMAP; or 2-(lH-benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-7y,7V,N',N'-tetramethyluronium hexafluorophosphate (HATU) and similar. Normally, the coupling reactions are performed in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), iV-methyl-morpholine, 7V-methylpyrrolidine, 4-DMAP or 1,8- diazabicycle[5.4.0]undec-7-ene (DBU) or the like. Coupling reactions are preferably conducted in an inert solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide (DMF), dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF). The reaction temperature may range between 0 0C and 50 0C and the reaction time may range between 15 min and 24 h.
Acids of general formula (II) to be used in the coupling with an amine of general formula (III) are described in the literature, for example in WO06/057945, WO05/051914 and WO04/050619. Amines of general formula (III) can be prepared as described in the schemes below and the in the experimental part that follows. An intermediate to compounds of formula III wherein p is 1, Z is O, and the group Q is bonded via a methylene group to the oxygen, i.e. n is 1, can be prepared as outlined in scheme 1.
Figure imgf000036_0001
R3' is C|-C6alkyl, C1-C6alkoxy-C1-C6alkyl, arylC1-C3alkyl or heterocyclylC1-C3alkyl; Lg is a leaving group
Scheme 1
The primary hydroxy group of the diol (Ia), achieved for example as described in Tetrahedron lett, 1987, 28, 1143, can be selectively alkylated by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-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 (Ib). 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 (Ia) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol. Replacement of the secondary hydroxy group of the alcohol (Ib) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate sulphonic anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the formed leaving group with azide for example sodium azide, thus giving the azide derivative (Ic). Alternatively, the azide moiety can be introduced using the Mitsunobu conditions, i.e. treatment of alcohol (Ia) with triphenylphosphine and a suitable azodicarboxylate, such as diisopropyl azodicarboxylate or the like, followed by displacement with azide for example in the form of diphenylphosphoryl azide (DPPA). Hydrolysis of the isopropylidene group, effected by treatment with a suitable acid, for example hydrochloric acid, in the presence of methanol provides the methyl glycoside (Id). 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 (Ie). Hydrolysis of the methyl glycoside by acidic treatment, followed by reduction effected for instance by LiBH4 or the like then yields the linear compound (If).
An intermediate to compounds of formula III wherein p is 1 , Z is O and the group Q is bonded directly to the oxygen atom, i.e. n is 0. can be prepared as outlined in scheme 2.
Figure imgf000037_0001
Scheme 2
Opening of the epoxide 2a, achieved, for example, according to the procedure described by B. Samuelsson et al. in J. Med. Chem., 2004, 47, 3353-3356, with a desired nucleophile Q-OH in the presence of a base, such as potassium carbonate or the like, provides the ether derivative (2b). Subsequent replacement of the secondary hydroxy group with azide, cleavage of the acetal, introduction of the group R3', hydrolysis of the glycosidic bond and finally reduction, provides the linear azide (2c).
Intermediates useful for the preparation of amines of formula III wherein R3 is azide, amine, alkylthio or alkoxy can be prepared by first inverting the stereochemistry of the steric centre whereto the hydroxy group is attached, and then replace the hydroxy group with the desired group as shown in scheme 3.
Figure imgf000038_0001
3d
Scheme 3
Inversion of the stereochemistry of the alcohol (3a), obtained as described above, can be effected for example by subjecting the alcohol to Mitsunobu conditions i.e. reaction with an azodicarboxylate such as DIAD or the like in the presence of 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 (3b) with the reversed stereochemistry can then be reacted in a Mitsunobu reaction with azide like sodium azide or DPPA or the like, to give compounds (3c) wherein R is azide, or the alcohol can be reacted with a thiol or alcohol to give alkylthio and alkoxy derivatives respectively. Hydrolysis of the glycosidic linkage followed by reduction as described above, then affords the linear compound (3d). Intermediates (3c) wherein R3 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 (3ba) 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 keton using conditions known to the skilled person, or by reaction with an alkylating agent Ra-Lg, wherein Lg is a leaving group, optionally in the presence of a base.
Intermediates to amines of formula III wherein Z is S or NH and n is 1 , can be prepared from the diol Ia for example by way of a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 4.
Figure imgf000039_0001
Scheme 4
The primary hydroxy group of the diol (Ia) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-CH2-S or Q-CH2-NRa. A convenient method to effect this transformation is by using a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (4a) or the amine derivative (4b) respectively. The amine (4b) may Alternatively be achieved by using an azide derivative, such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (Ia), 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). A further alternative method to obtain the amino derivative (4b) is to selectively oxidize the primary hydroxy group of the alcohol (Ia) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-CH2-NHRa in the presence of a reducing agent like NaCNBH3. Replacement of the secondary hydroxy group with azide, hydrolysis of the acetal, cleavage of the glycosidic linkage and finally reduction provides the linear compounds (4c and 4d).
Intermediates for the preparations of compounds of formula (I) wherein the group Q is linked directly to a sulphur or nitrogen atom, i.e. Z is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (Ia) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base. An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (Ia) with a desired diphenyl disulphide derivative in the presence of nBusP. Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (Ia) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH4 or the like.
Compounds of formula (I) wherein Z is a sulphone i.e. S(=O)2 may be obtained by oxidation of the sulphur of the corresponding thioether derivative. The oxidation can be performed either at the last step of the synthesis or on any suitable intermediate. Many suitable methods for this oxidation are described in the literature for example, a peroxyacid such as AcOOH, mCPBA can be used.
The above described intermediates, Ig, 2c, 3g, 4c and 4d, are then further transformed in order to obtain compounds of formula III. For example, alkylation of the primary hydroxy group with an alkylating agent such as the halide of a desired group W-(CH2)q- in the presence of a base like NaH or the like, as illustrated in scheme 5, provides amines of formula III wherein Y is O.
Figure imgf000040_0001
or I
Scheme 5
Alkylation of the primary hydroxy group of any of the previously described alcohols (Ig, 2c, 3d, 4c or 4d) can be effected for example by reaction with a desired alkylating agent W-(CH2)J1-Lg, wherein Lg is a leaving group, such as a halide like bromo or iodo, or a derivative of sulphonic acid such as a tosylate or a triflate or the like, in the presence of a base such as NaH or equivalent, to provide the ether derivative (5 a). Alternatively, the Mitsunobu conditions with the alcohol of the desired group (W-(CH2)n-0H) may be employed. Subsequent reduction of the azide using for example Ph3P, or by catalytic hydrogenation using for a catalyst like the Lindlar catalyst or the like, provides the amine (5b).
A route to amines of formula III wherein p isl and Y is O, S or NH is illustrated in scheme 6.
Figure imgf000041_0001
6d 6e Y' is O, S or NH
Scheme 6
Selective protection of the secondary hydroxy group of any of the previously described alcohols (Ig, 2c, 3d, 4c or 4d) can be effected by a using a suitable protection group strategy. For example, a benzylidene acetal of the two hydroxy groups may be formed, effected by treatment of the diol with anisaldehyde dimethylacetal in the presence of an acid like pTsOH or similar, followed by reductive opening of the acetal effected by treatment with Me3SiCl and NaCNBH3 or equivalent, thus providing the p-MeO-protected compound (6b). Subjection of the primary alcohol (6b) to Mitsunobu conditions using the appropriate alcohol (W-(CH2)n-0H), thiol (W- (CH2)n-SH) or amine (W-(CH2)n-NH2) then yields the ether, thioether or amine, respectively, i.e. compounds of formula (III) wherein Y is O, S or NH. Removal of the pMeO-benzyl group using any convenient method, for example by oxidation with DDQ, followed by reduction of the azide as described above yields the primary amine (6e).
The achieved amines 5b, and 6d are then reacted with a desired acid of general formula (II) using standard conditions for amide bond formation as generally described above. Amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is CH2O, can be prepared according to the route illustrated in schemes 7 and 8.
Figure imgf000042_0001
7d
Scheme 7
Hydrolysis of the acetal of compound 7a, conveniently effected by treatment with aqueous acid such as diluted acetic acid, followed by oxidative cleavage of the formed diol using conditions like sodium periodate in the presence of potassium carbonate or the like, provides the linear acid (7b). Conversion of the formed acid (7b) to the ether (7d) can then be effected for instance by first forming the methyl ester, effected by treatment with acetyl chloride in methanol followed by reduction using a reducing agent like sodium borohydride. Reduction, finally, of the azide as previously described yields the amine (7e).
In order to get the corresponding compounds having the reversed stereochemistry at the carbon atom the to which the hydroxy group is attached, the procedure shown in scheme 8 may be employed.
Figure imgf000042_0002
Scheme 8 Reaction of alcohol (7d) a with Ph3P, and an azodicarboxylate such as DIAD and for example p- nitrobenzylic acid followed by removal of the afforded ester by treatment with methanolic methanolate or the like, provides the alcohol (8a) with the reversed stereochemistry. Reduction, finally of the azide function then provides the corresponding amine (8b).
Amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is CH2NH, can be prepared according to the route illustrated in scheme 9.
Figure imgf000043_0001
Scheme 9
Conversion of the ester function of compounds 7c or 8a to the corresponding aldehyde 9b can be performed by first protecting the free secondary alcohol with a suitable protecting group, for example a silyl group, followed by reduction of the ester to the alcohol (9a), using for instance sodium borohydride, and, finally, oxidation of the alcohol using for example Dess-Martin periodinate or any other suitable oxidation reagent. The formed aldehyde is then reacted with a desired amine H2N-(CH2)q-W in a reductive amination reaction, using reagents like NaCNBH4 or the like to form the amine (9c). Reduction, finally, of the azide as described above, then yields the corresponding amine (9d).
If desired, the hydroxy group of compound 9d can be replaced by azide, thus affording amines of formula III wherein one of X' and X" is H and the other is N3, and Y is CH2NH. To effect this replacement, the amino group of compound 9d is conveniently protected, for example with a Boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA. Once coupled to the acid of formula I, the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH2.
A route to amines of formula III wherein p is 0, one of X' and X" is H, the other is OH, and Y is NH, is illustrated in scheme 10.
Figure imgf000044_0001
10a 10b 10c
N W
Figure imgf000044_0002
10d 10e
Scheme 10
Alkylation of the primary hydroxy group of the isopropylidene derivative (10a), prepared e.g. according to the method described by Mori, K. and Kinsho, T. in Liebigs. Ann. Chem 1991, 1309-1315, with a suitable derivative of the group Q-(CH2)J1 can be performed using any suitable alkylation method such as any of those described above, for instance the Mitsunobu conditions can be used, or the alkylation may be effected by treatment with a alkylating agent Q-(CH2)-Lg in the presence of a base, may be used Amines of formula III wherein Z is S or NH, can be prepared, for example, by the Mitsunobu conditions using a thiol, (Q-(CH2)n-SH) or an amine (Q-(CH2)n-NH2) respectively , as described above. Removal of the acetal group by subjecting the compound to acidic conditions provides the diol (10c). The epoxide (1Od) can then be achieved by the reaction sequence described by T. Suzuki et al. in Tet. Lett. 46, 2005, 5811-5814, i.e. reaction with trimethyl orthoacetate in the presence of trifluoroacetic acid and subsequent treatment with acetyl bromide to yield the acetoxybromide, followed by epoxidation effected by treatment with potassium carbonate or the like. Opening of the epoxide with a desired amino derivative and, finally, reduction of the azide function using for instance triphenyl phosphine or catalytic hydrogenation in the presence of a suitable catalyst, for instance Lindlar catalyst, or the like, provides the amine (1Oe).
In order to get the corresponding compounds having the reversed stereochemistry at the carbon atom the to which the hydroxy group is attached, the linear compound achieved after opening of the epoxide, may be subjected to Mitsunobu conditions as illustrated in scheme 11.
Figure imgf000045_0001
11a
11b
Scheme 11
Reaction of alcohol 11a with Ph3P, and an azodicarboxylate such as DIAD and for example p- nitrobenzylic acid followed by removal of the afforded ester by treatment with methanolic methanolate or the like, provides the alcohol with the reversed stereochemistry. Reduction, finally of the azide function then provides the corresponding amine (1 Ib).
If desired, the hydroxy group of compound 1Oi or 1 Ib can be replaced by azide, thus affording the corresponding amines of formula III wherein one of X' and X" is H and the other is N3. To effect this replacement, the amino group of compound 1Oi is first protected, for example with a boc group, whereafter the alcohol is subjected to Mitsunobu conditions, i.e. treatment with triphenylphosphine in the presence of a diazocarboxylat, such as DIAD, followed by reaction with a source of azide, for example DPPA. Once coupled to the acid of formula I, the azide moiety may, if desired, be reduced to the amine, thus affording compounds of general formula I wherein one of X' and X" is NH2.
A route to amines of formula III wherein p is 0, one of X' and X" is OH and the other is H, and Y is a bond, CH2 or CH2CH2, is illustrated in scheme 12
Figure imgf000046_0001
12d
Compound 12a can be prepared by alkylation of N-trityl-L-serine methyl ester with a desired group Q-(CH2)J1ZH or Q-CH2-Lg according to any of the methods described herein, followed by replacing the N-protecting group to a Boc group using standard conditions. The Weinreb amide (12b) can then be achieved by hydrolysis of the methyl ester effected for example by treatment with LiOH, followed by reaction with N,O-dimethylhydroxylamine in the presence of NMM. The group W-(CH2)a- can then replace the hydroxylamine moiety by reaction with a suitable organometallic nucleophile, such as an organolithium reagent or a Grignard reagent, to afford the keton (12b). Reduction of the keto group to a hydroxy using for instance NaBH4, followed by removal of the Boc group by acidic treatment, provides the amine (12d).
A method to prepare a substituted phenyl derivative useful for the preparation of amines of formula (III) wherein Q is phenyl substituted an alkoxy-alkoxy group is illustrated in scheme 13.
DIBAL
Figure imgf000046_0002
Scheme 13
Alkylation of the phenolic hydroxy group of ester (13a) using for example the Mitsunobu, such as in the presence OfPh3P, an azodicarboxylate like DIAD and the suitable alcohol followed by reduction of the ester function using any convenient reduction method known in the art provides benzylic alcohol (13b). The afforded alcohol (13b) can then either be used directly in the coupling to the primary hydroxyl group employing the Mitsunobu conditions, or the a hydroxy group can be transferred to a leaving group, such as a halide like bromide, and subsequently coupled to the primary hydroxyl group as described above.
Even though the strategy in scheme 13 is illustrates the introduction of a methoxy-ethoxy substituent to the phenyl ring, the skilled person will easily realise that the same methodology can be applied for the introduction of other O-linked substituents, such as substituents with other chain lengths. Furthermore, despite the fact that scheme 13 is illustrated with a 1,3 substituted phenyl derivative as starting compound, the skilled person will realise that the same methodology is also applicable to other phenyl derivatives, for example the corresponding 1,2- or 1 ,4-disubstituted derivatives.
Benzyl derivatives Q-CH2- wherein Q is substituted with aryl, heterocyclyl, alkenyl or alkynyl, can be prepared for example by using palladium promoted reactions, whereof many are described in the literature. A general is illustrated in scheme 14.
Figure imgf000047_0001
Figure imgf000047_0002
14c, R = OH 14d, R = Br
Q' is optionally substituted aryl or heterocyclyl, alkenediylcycloalkyl, alkynediylcycloalkyl, alkenediylaryl, alkynediylaryl, alkenediylheteocyclyl or alkynediylheterocyclyl
Scheme 14
The desired substituent Q' can be introduced using for instance a Pd-catalyzed cross coupling reaction. For example the Suzuki conditions may be used, i.e. reaction of the bromo derivative (14a) with the boronic acid of a desired substituent Q' in the presence of a palladium catalyst such as Pd(PPli3)4 or Pd(OAc)2 or the like and a suitable base such as potassium carbonate or potassium fluoride or the like, thus providing the Q '-substituted compound (14b). Other suitable reactions that can be used for the introduction of the substituent Q are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative (14a) in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative (14a) is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPlIs)4 PdCl2 or Pd(OAc)2 and a base such as triethylamine, potassium carbonate or the like. Reduction of the ester function of compound 12b using any convenient reduction method known in the art, such as treatment with DIBAL-H, provides benzylic alcohol (14c). The afforded alcohol can then either be used directly in the couplings to the primary hydroxy group of any of the intermediates described above, employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromomethane in the presence of triphenylphosphine, and subsequently coupled to the primary hydroxy group as described above. A substituent Q' of Q as phenyl may alternatively be introduced at a later stage of the synthesis, for example as the last step, using similar conditions.
An intermediate towards amines of formula (III) wherein X' is F and X" is H or X' and X" are both F can be prepared by replacement of the hydroxy with fluoro or difluoro as exemplified in scheme 15.
Figure imgf000048_0001
Scheme 15
The free hydroxy group of compound (15a), prepared as described above, can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (15b). The monofluoro compound (15c) will be achieved by treatment of the alcohol to fluorinating conditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions. The monofluoro compound (15e) having the reversed stereochemistry at the carbon atom to which the fluoro atom is attached, can be achieved by reverting the stereochemistry of hydroxy compoundl5a to the hydroxy compound 15d, for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph3P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like, and thereafter replace the hydroxy group with fluorine, as previously described.
A route to acids of general formula (II) wherein A is CH, R6 is NRaS(=O)2Ci-C6alkyl and D is C(=O)NR7R8 can be prepared according to the procedure described by Stachel et al. in J. Med. Chem., 47, 2004, 6447-6450 as depicted in scheme 16.
Figure imgf000049_0001
X is a leaving group, e.g. Br or I Rc' is CrC6alkyl
Figure imgf000049_0002
Scheme 16
Sulphonylation of the amino group of commercially available 5 -amino isophthalic ester (16a) with a desired sulphonylating agent such as a sulphonyl chloride, for example methane sulphonyl chloride, in the presence of pyridine in a solvent like dichloromethane or the like followed optionally by alkylation of the nitrogen effected by a displacement reaction with a desired alkylating agent Ra-X, wherein X is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (16b). Monohydrolysis of the bis-ester (16b) to the mono acid, for example by treatment with sodium hydroxide, followed by a peptide coupling of the amino derivative R7R8NH using any convenient method for amide bond formation such as using a reagent like BOP or the like provides the amide (16c). Subsequent hydrolysis of the methyl ester then affords the acid (16d).
Acids of formula (II) wherein the A is CH and the phenyl ring is substituted with a sulphamoyl amide group, i.e. R6 is NRaS(=O)2NRaRb, can be prepared according to the above scheme but using sulphamoyl chloride instead of a sulphonyl chloride in the reaction of the amino group of aniline (16c). Useful sulphamoyl chlorides can be prepared for example as described by W. L. Matier et al. in J. Med. Chem. 1972, 15, 4, 538-541.
Any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary. For example functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups depend upon the reaction conditions. Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
Detailed Description
Various embodiments of the compounds of the invention and key intermediates towards such compounds will now be described by way of illustration only with reference to the following non-limiting examples.
Epoxide E-I
Figure imgf000051_0001
E-1a E-1b E-1c
Figure imgf000051_0002
E-1f E-1g
OAc
N O
3\/ .Br N 3\
Figure imgf000051_0003
I-Eh E-1i
Step a) 2-Oxo-21ambda*4*-[1.3.2ldioxathiolane-4.5-dicarboxylic acid diethyl ester (E-Ia) Diethyl (D)-tartrate (25 g,121 mmol) and pyridine (29 g, 367 mmol) was dissolved in dichloromethane (1200 ml). Thionyl chloride (12.4 ml) was added slowly at O 0C. The reaction mixture was stirred for 2 h and the solvent was then removed by reduced pressure. The crude product was taken up in ether and purified by filtration through a pad of silica gel. Yield ~90 %. GC-MS: 253 (M+)
Step b) 2.2-Dioxo-21ambda*6*-[1.3.21dioxathiolane-4.5-dicarboxylic acid diethyl ester (E-Ib) Compound E-Ia (6.3 g, 25 mmol), NaIO4 (8 g, 37.5 mmol) was suspended in acetonitrile (375 mL) and water (50 mL). RuCl3 (50 mg) was added and the mixture was stirred at ambient temperature for 30 min. Ether (400 mL) was added and the precipitated solid was removed by decantation and washed with ether. The ether fractions was combined, the volume reduced to half and filtrated through a pad of silica. Evaporation gave the title compound as yellow to reddish crystals (4 g, 60 %)
Step c) 2-Azido-3-hydroxy-succinic acid diethyl ester (E-Ic)
Compound E-Ib (9.4 g, 35 mmol) was dissolved in acetone (125 mL) and water (25 mL). Sodium azide (4.6 g, 70 mmol) was added. The mixture was left with stirring at ambient temperature for 1.5 h or until complete reaction. The solvent was removed by reduced pressure. Ether (200 mL) was added followed by 200 mL 20 % aqueous sulphuric acid and the mixture was left with stirring at ambient temperature over night. The ether phase was collected and the aqueous phase extracted with ether. The combined organic phases were washed with water and dried over sodium sulphate. Purification by Flash chromatography (ώo-hexane-ethyl acetate, 5:1) gave the pure title compound (5.8 g, 70%)
Step d) 3-Azido-butane-1.2.4-triol (E-Id)
Compound E-Ic (3.3 g, 14.2 mmol) and sodium borohydride (1.1 g, 29 mmol) was stirred at 0 0C in ethanol (25 mL) for 3 hours. The solution was acidified to pH~7 by addition of aqueous hydrochloric acid whereafter the solvent was removed under reduced pressure. The residue was purified by flash chromatography (4% EtOH in EtOAc to 25% EtOH in EtOAc) which gave the crude title compound 4 (1.44 g, 68%) of sufficient purity.
Step e) 2-Azido-2-(2.2-dimethyl-π.31dioxolan-4-ylVethanol (E-Ie^)
The triol E-Id (4g, 27.2 mmol), dimethoxypropane (20 mL) and camphorsulphonic acid (5 mol %) were stirred at room temperature for 20 h. The solvent was then removed and the mixture of camphorsulphonic acid and 1,2- and 1,4- protected triol was dissolved in acetone and refluxed for 24 h. Neutralization using solid sodium hydrogen carbonate followed by filtration and chromatography on silica gel (Toluene - EtOAc, 10:1) gave pure title compound (3.9 g, 76%). GC-MS: 172 (M+ - Me).
4-ri-Azido-2-(3.5-difluoro-phenoxyVethyl1-2.2-dimethyl-ri.31dioxolane (E-If) Triphenylphosphine (3.38 mg, 12.9 mmol) was dissolved in THF (40 mL) and the solution was cooled on an ice-bath. Diisopropyl azidocarboxylate (2.9 g, 94%, 14.2 mmol) was added slowly. After stirring for 15 min, a solution of 3, 5-difluorophenol (1.7 g, 13.1 mmol) in THF (10 ml) was added and the mixture was left stirring for another 15 min. The alcohol E-Ie (2.3 g, 12.3 mmol) in THF was added drop wise. The ice-bath was removed and the reaction mixture was left at room temperature for 3 h, or until the reaction was complete (TLC, toluene-ethyl acetate, 15:1 or GC). After complete reaction the mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The solvent was removed, the crude product was purified by flash chromatography on silica gel (toluene) which gave the pure title compound (2.65 g, 72 %). GC- MS (m/z) 284 (M+- 15). 3-Azido-4-(3.5-difluoro-phenoxy)-butane- 1 ,2-diol (E- 1 g)
Compound E-If (2.65 g, 21, 7 mmol) was dissolved in acetic acid (30 ml) and water (20 ml). The mixture was then heated to 60 0C for 3-4 h. The solvent was the evaporated which gave crude title compound (98 %), which was used without further purification. HPLC-MS: 318.1 (M + OAc)"
Step h) Acetic acid 2-azido-l-bromomethyl-3-(3,5-difluoro-phenoxy)-propyl ester (E-Ih) The diol E-Ig was reacted according to the procedure described by T. Suzuki et al. in Tetrahedron Letters 46, (2005), 5811-5814. Purification by chromatography on silica gel (iso- hexane - diethyl ether, 5:1) gave pure title compound (90 %).
Step i) 2-ri-Azido-2-(3,5-difluoro-phenoxy)-ethvH-oxirane (E-Ii)
The title compound was prepared in 86 % yield from compound E-Ih according to the procedure described by T. Suzuki et al. in Tetrahedron Letters 46, (2005), 5811-5814.
1H NMR (400 MHz CDCl3): δ 6.46 (m, 3H), 4.11 (m, 2H), 3.66 (m, IH), 3.22 (m, IH), 2.89 (m,
IH), 2.81 (m, IH).
The following epoxides were prepared by reaction of the acetal E-Ie with the appropriate phenol derivative according to the procedure described for the preparation of Epoxide 1 :
Figure imgf000053_0001
Figure imgf000054_0002
Epoxide E- 16
Figure imgf000054_0001
r E-16a, R = Ph3C E-16d
E-16 7Ε-16b, R = H
-E-16c, R = Boc
Step a) 3-(3.5-Difluoro-phenoxy)-2-(tritylamino)-propionic acid methyl ester ( E-16a) To a solution of 7V-trityl-L-serine methyl ester (5.33 g, 14.8 mmol), 3,5-difluorophenol (2.111 g, 16.225 mmol), and triphenylphosphine (4.26 g, 16.22 mmol) in toluene (55 mL) under nitrogen atmosphere was added DIAD (3.20 mL, 16.22 mmol) dropwise during 20 minutes at room temperature. The solution was then allowed to stir at 80 0C for 24 hours after which the solvent was evaporated. The crude product was purified with flash column chromatography (toluene, Rf ~0.6) which gave the title compound (5.08 g, 73%).
Step b) 2-Amino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester ( E-16b) Compound E-16a (14.02 g, 29.61 mmol) was dissolved in dichloromethane (72 mL) and the solution was cooled to 0 0C. TFA (58 mL) was added dropwise during 5 minutes and the solution was stirred for 30 minutes at 0 0C and for an additional 3.5 hours at room temperature. The solvents were evaporated and co-evaporated three times with toluene. The residue was dissolved in methanol (75 niL) and solid sodium hydrogen carbonate (7 g) was added and the slurry was stirred for 40 minutes. The methanol was then evaporated and the mixture was extracted with ethyl acetate and washed twice with saturated sodium hydrogen carbonate (aq) and once with brine. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified using flash column chromatography (ethyl acetate +1% MeOH saturated with NH3, Rf -0.3) which gave the title compound (4.81 g, 70%).
Step c) 2-tert-Butoxycarbonylamino-3-(3,5-difluoro-phenoxy)-propionic acid methyl ester ( E- 16c) The amine E-16b (1.643 g, 7.11 mmol) was dissolved in dichloromethane (50 mL) and BoC2O (2.33 g, 10.66 mmol) and triethylamine (1.98 mL, 14.22 mmol) dissolved in 20 mL of dichloromethane were added dropwise at room temperature during 10 minutes. The solution was then stirred at room temperature for 20 hours after which saturated sodium hydrogencorbonate (aq, -120 mL) was added. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf -0.3) which gave the title compound (2.061 g, 87%).
Step d) [l-(3.5-Difluoro-phenoxymethyl)-allyll-carbamic acid tert-butyl ester ( E-16d) Preparation of the Wittig reagent: Methyltripenylphosphonium bromide (8.182 g, 22.90 mmol) was added to dry THF (68 mL) under nitrogen atmosphere and the slurry was cooled to 0 0C.
KHMDS (0.5 M in toluene) (45.4 mL, 22.685 mmol) was added during 5 minutes and the slurry was stirred for 1.5 hours at 0 0C.
Reduction of the ester to the aldehyde: Compound E-16c (3.596 g, 10.854 mmol) was dissolved in dry toluene (45 mL) under nitrogen atmosphere and the solution was cooled to -78 0C. DIBAL
(1.0 M in hexane) (14.11 mL, 14.11 mmol) was added dropwise during 5 minutes. The reaction mixture was stirred at -78 0C until the starting material had been consumed according to TLC
(approximately 20 minutes).
The above mentioned Wittig mixture was cooled to -78 0C and the aldehyde mixture was added directly (without workup) by syringe during 3 minutes and the mixture was allowed to stir at -78
0C under nitrogen atmosphere for 25 minutes, at room temperature for 1 hour, and then the mixture was heated to 40 0C for 20 hours. The reaction allowed to attain room temperature and was then quenched by the addition of 25 mL of MeOH. The mixture was transferred to a separatory funnel and ethyl acetate and a 1 : 1 mixture of saturated Rochelle salts (aq) and water were added. The phases were separated and the aqueous phase was extracted one more time with ethyl acetate. The combined organic phases were washed once with water and once with brine and were then dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf ~0.4) which gave the title compound (1.296 g, 40%).
Step e) r2-(3,5-Difluoro-phenoxy)-l-oxiranyl-ethvH-carbamic acid tert-butyl ester ( E-16) Compound E-16d (287 mg, 0.959 mmol) was dissolved in dichloromethane (15 mL) and 3- chloroperoxybenzoic acid (mCPBA) (77%) (860 mg, 3.835 mmol) was added and the mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with diethyl ether and was transferred to a separatory funnel. The organic phase was washed with 0 0C 10% Na2SO3 (aq), saturated sodium hydrogen carbonate (aq), and brine. The organic phase was then dried (MgSO4), filtered and, concentrated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 15:1, Rf ~0.3) which gave the title compound (229 mg, 76%) as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
Epoxide E- 17
Figure imgf000056_0001
(l-Oxiranyl-2-phenoxy-ethyl)-carbamic acid tert-butyl ester (E- 17) iV-trityl-L-serine methyl ester was reacted with phenol according to method described for the preparation of Epoxide E-16, which gave the compound as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
Epoxide E- 18
Figure imgf000057_0001
Step a) (2S,3S)-3-azido-l-(tert-butyldimethylsilyloxy)-4-(3,5-difluorophenoxy)butan-2-yl methanesulfonate (E- 18a)
To a 50 0C solution of compound E-Ig (259.1 mg, 1 mmol), 4-dimethylamino pyridine (12.2 mg, 0.1 mmol) and N-ethyldiisopropylamine (284 mg, 2.2 mmol) in toluene (3-4 mL) was slowly added tert-butyldimethylchlorosilane (347 mg, 2.3 mmol) dissolved in toluene (1 mL). After 3h the reaction mixture was cooled to 0 0C and N-ethyldiisopropylamine (516 mg, 4 mmol) was added followed by slow addition of methanesulphonyl chloride (128 mg, 1.1 mmol). The reaction mixture was stirred for 3-4 h at 0 0C. The solid precipitate was filtered of and the solution was washed with aqueous hydrochloric acid (IM) and brine. Concentration under reduced pressure gave the title compound (250 mg, 55 %) which was used in the next step without further purification.
Step b) (R)-2-((S)-l-azido-2-(3.5-difiuorophenoxy)ethyl)oxirane (E-18)
Tetrabutylammoniumfluoride (0.664 mL, 1 M in THF) was added to a solution of compound E- 18a (240 mg, 0.53 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the afforded residue purified by column chromatography (SiO2, iso-hexane to isohexane-ether, 3:1) which gave the title compound (78 mg, 60 %).
General method for preparation of Amines A-I to A-23
Figure imgf000057_0002
Epoxide Amine
The Epoxide (1 eq, prepared as described above) was dissolved in isopropanol/H2O 1 :1 (0.5 mL), the amine (2 eq) was added and the mixture was stirred at a temperature between room temperature and 83 0C for 1 to 2Oh. The reaction mixture was partitioned between DCM and H2O, the organic phase was dried (Na2SO4), filtered and concentrated. The afforded residue was purified by column chromatography, dissolved in MeOH (11 mL) and triphenylphosphine (1.5 eq) and two drops OfH2O were added to the solution. The reaction mixture was stirred for 18h, and then concentrated. The afforded crude product was then either purified by column chromatography, or used directly in the next step.
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Analytical data for Amines A-I to A-5 and A-8 A-I
1H-NMR (CDCl3) δ 7.59 (app. s, IH), 7.55-7.48 (m, 2H), 7.44 (m, IH), 7.19 (m, IH), 6.97-6.88 (m, 2H), 7.78 (m, IH), 4.09 (m, IH), 3.97-3.80 (m, 3H), 3.71 (m, IH), 3.22 (m, IH), 2.92 (m, IH), 2.75 (m, IH)
A-2
1H-NMR (CDCl3) δ 7.35-7.23 (m, 3H), 7.20-7.09 (m, 2H), 6.95-6.84 (m, 2H), 6.77 (m, IH), 4.12-3.62 (m, 5H), 3.24-3.10 (m, IH), 3.95-2.65 (m, 2H), 1.36-1.20 (m, 9H)
A-3
1H-NMR (CDCl3) δ 7.40-7.21 (m, 5H), 7.17-7.07 (m, 3H), 4.18-3.52 (m, 5H), 3.29-3.10 (m,
IH), 2.99-2.67 (m, 2H), 1.37-1.21 (m, 9H)
A-4 1H-NMR (CDCl3) δ 8.28 (app. s, IH), 8.18 (m, IH), 7.59 (m, IH), 7.55-7.47 (m, 2H), 7.42 (m, IH), 7.22-7.13 (m, 2H), 4.14 (m, IH), 3.99 (m, IH), 3.93-3.81 (m, 2H), 3.76 (m, IH), 3.21 (m, IH), 2.91 (m, IH), 2.76 (m, IH)
A1S
1H-NMR (CDCl3) δ 8.31 (m, IH), 8.21 (m, IH), 7.35-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.13 (m, IH), 4.16 (m, IH), 3.98 (m, IH), 3.91-3.76 (m, 2H), 3.70 (m, IH), 3.21 (m, IH), 2.95 (m, IH), 2.75 (m, IH), 1.31 (s, 9H)
A-S
1H-NMR (CDCl3) δ 7.35-7.23 (m, 3H), 7.12 (m, IH), 6.47-6.35 (m, 3H), 4.10-3.62 (m, 5H), 3.21-3.06 (m, IH), 2.97-2.65 (m, 2H), 1.36-1.21 (m, 9H)
Amine 24
Figure imgf000063_0001
A-24a A-24
Step a^ (2R.3SV3-Azido-4-(3.5-difluorophenoxyVl-phenoxybutan-2-ol (A-24a^ Epoxide E- 18b was added to a stirred suspension of sodium hydride (4 eq) and phenol (4 eq) in dry DMF at 0 0C. The mixture was stirred at 0 0C for Ih and then at room temperature over night. Saturated NH4Cl (aq) (10 mL) was added and the mixture was stirred for 30 minutes after which the slurry was transferred to a separatory funnel and extracted with ethyl acetate. The organic phase was washed with water and brine, dried, filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ethyl acetate 15:1) which gave the title compound.
Step b) (2R3S)-3-amino-4-(3.5-difluorophenoxy)-l-ρhenoxybutan-2-ol (A-24) The azide derivative A-24a was reduced according to the method described in Example 37 step b, which gave the title compound in quantitative yield. The product was purified by column chromatography using toluene/ethyl acetate 1 :3 containing 1% MeOH saturated with NH3 as mobile phase. Amine 25
Figure imgf000064_0001
Step a) (3-Bromo-benzyl)-carbamic acid tert-butyl ester (A-25a)
3-Bromo-benzyl amine hydrochloride( 3g, 13,5 mmol) and NaHCO3 (2.3g, 27 mmol) were mixed in ethanol (20 ml). BoC2O (4.4 g, 20.3 mmol) was added and the resulting reaction mixture stirred at room temperature over night. The solvent was evaporated under vacuum and the residue dissolved in EtOAc. The mixture was washed with brine, dried (Na2SOs), filtered and concentrated in vacuo. The crude product was purified by chromatography on a silica column (EtOAc in hexane 1 :10), which gave the title compound (3.3 g, 86%). LCMS m/z 287.22 (M+H)+
Step b) Tert-butyl 3-neopentylbenzylcarbamate (A-25b)
2,2-Dimethylpropylmagnesium bromide (35 mmol, 35 ml, IM in diethyl ether) was added drop wise over 30 min to a solution of ZnCl2 in diethyl ether (35 mL, 35 mmol, IM). The reaction mixture was stirred for additionally 30 min at room temperature whereafter Pd(dppf)2Cl2 (0.6 mmol, 10 mol%) and compound A-25a (6 mmol) was added. The resulting mixture was heated to 60 0C for 3.5 hours until LC-MS analysis indicated complete conversion. The mixture was concentrated in vacuo, the residue dissolved in EtOAc, washed with brine, dried over Na2SO3, filtered and concentrated. The crude product was purified by chromatography on a silica column, using iso-hexane /EtOAc as eluent (0-40% EtOAc in hexane). LCMS m/z 278.45(M+ϋ)+
Step c) (3-neopentylphenyl)methanamine (A-25c)
Compound A-25b (650 mg, 2.3 mmol) was dissolved in 4M HCL in dioxane (5 mL) and the resulting mixture stirred at room temperature for 10 min. The reaction mixture was concentrated under vacuum and the residue dissolved in DCM (10 ml). Aq. NaHCO3 (sat. 10 ml) was added and the mixture was stirred for 30 min. The layers were separated and the organic phase dried over Na2SO3, filtered and concentrated in vacuo, which gave the title compound (420 mg, quant.). LCMS m/z 178.3 (M+H)+
Step d) (2R,3S)-3-amino-l-(3-neopentylbenzylamino)-4-(pyridin-3-yloxy)butan-2-ol (A-25) The amine A-25c (215 mg, 1.22 mmol) was reacted with the epoxide E-4 (108 mg, 0.53 mmol) according to the General method for preparation of Amines described above, which gave the title compound (74 mg, 33%). LCMS m/z 358.4 [M+H]+
Amine 26
Figure imgf000065_0001
(2R,3S)-3-amino-4-(3,5-difluorophenoxy)-l-(3-neopentylbenzylamino)butan-2-ol (A-26) The amine A-25c was reacted with the Epoxide E-Ii according to the General method for preparation of Amines described above, which gave the title compound (170 mg, 68%). MS m/z 393.2 [M+H]+
Acid l
Figure imgf000065_0002
Acid-1
2-[Methyl-(2-methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol- isonicotinic acid (Acid-1)
The title compound was prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO06/057945.
Acid 2 & 3
Figure imgf000065_0003
Acid-2
Figure imgf000065_0004
2-(((lS.2S)-2-methylcyclopropyπmethylamino)-6-(N-methylmethylsulfonamido)isonicotinic acid (Acid-2) &
2-(((lS,2S)-2-methylcvclopropyl)methylamino)-6-(N-methylpropan-2-ylsulfonamido)- isonicotinic acid (Acid-3)
The title compound were prepared from 2,6-dichloro-isonicotinic acid methyl ester and methyl- (2-methyl-cyclopropylmethyl)-amine according to a procedure similar to the one described in WO05/051914.
Acid-4
Figure imgf000066_0001
2-Chloro-6-(N-methylpropan-2-ylsulfonamido)isonicotinic acid (Acid-4)
The title compound was prepared from 2,6-dichloroisonicotinic acid methyl ester using a procedure similar to the one described in WO06/057945.
Acid 5
Figure imgf000066_0002
Acid-5b, R = CH3 Acid-5, R = H
Step a) Methyl-(4-methyl-thiazol-2-ylmethyl)-amine (Acid-5a)
Methylamine (4.7 ml, 9.3 mmol, 2 M in THF) was added to a solution of (4-methyl-2-thiazole carboxaldehyde (200 μl, 1.86 mmol) in DCM (5 ml) and the mixture was stirred at rt. After 3 days, the solvent was evaporated and the residue dissolved in MeOH (20 ml) and reduced using an H-cube with a 10% Pd on C cartridge, which gave the title compound (200 mg).
Step b) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid methyl ester (Acid-5b) Triethylamine (one drop) was added to 5-bromo-isophthalic acid monomethyl ester (230 mg, 0.888 mmol) in SOCl2 (3 ml). The mixture was stirred at 90 0C for 1 h whereafter the solvent was evaporated and the residue dissolved in DCM (3 ml). Compound Acid-5a (200 mg, 1.40 mmol) in DCM (3 ml) was added and the mixture was stirred at rt. After 30 min the solvent was evaporated and the residue purified by flash chromatography using 1-2% MeOH in DCM as eluent, which gave the title compound (188 mg, 55%). MS: 383/385.
Step c) 5-Bromo-N-methyl-N-(4-methyl-thiazol-2-ylmethyl)-isophthalamic acid (Acid-5) 1 M NaOH (1 .5 ml) was added to the methyl ester (A-5b) (188 mg, 0.491 mmol) in MeOH (5 ml) and THF (5 ml). The mixture was stirred at rt for 3 d. whereafter most of the solvent was evaporated, and IM HCl (2.5 ml) and brine was added. The mixture was extracted with EtOAc, the organic layers were combined, dried (MgSO4) and evaporated, which gave the title compound (178 mg, 98%) as a yellow solid. MS: m/z = 369/371.
Acid 6
Figure imgf000067_0001
Acid-6, R = H
Step a) 2'-Trifluoromethyl-biphenyl-3.5-dicarboxylic acid dimethyl ester (Acid-6a) An oven-dried vial containing a magnetic stir bar was charged with dimethyl-5-bromo isophthalate (500 mg, 1.83 mmol), Pd(OAc> (4 mg, 1.0 mol%), S-Phos (15.0 mg, 2.0 mol%), 2- (trifluoromethyl)-phenyl boronic acid (695 mg, 3.66 mmol, 2 equiv.) and powdered, anhydrous KsPO4 (LIo 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) S-d-Phenyl-ethylcarbamoyD-l'-trifluoromethyl-biphenyl-S-carboxylic acid methyl ester
Figure imgf000068_0001
LiOH was added to a solution of compound Acid-6a 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) 5-(l-Phenyl-ethylcarbamoyl)-2'-trifluoromethyl-biphenyl-3-carboxylic acid (Acid-6) LiOH was added to a solution of compound Acid-6b 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)+.
Acid-7
Figure imgf000068_0002
Acid-7a Acid-7b, R = CH3 Acid-7, R = H
Step a) 5-Bromo-isophthalic acid monomethyl ester (Acid-7a)
1 M NaOH (1.19 ml, 1.91 mmol) was added to a solution of dimethyl 5-bromoisophthalate (522 mg, 1.91 mmol) in THF (10 ml) and MeOH (10 ml). The mixture was stirred at ambient temperature overnight. Most of solvents were evaporated, 2 M HCl (6 ml) was added and aqueous phase was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated, which gave the title compound (484 mg, 98%) as a white solid.
Step b) 5-Bromo-N-(l-phenyl-ethyl)-isophthalamic acid methyl ester (Acid- 7b)
HATU (827 mg, 2.18 mmol) was added to a solution of 5-bromo-isophthalic acid monomethyl ester (Acid-7a) (470 mg, 1.81 mmol), R-1-phenylethylamine (257 μl, 1.99 mmol) and DIEA (1.26 ml, 7.25 mmol) in DMF (10 ml) at 0 0C. The mixture was stirred for 1 h whereafter the solvent was evaporated. The residue was purified by flash chromatography using 20% EtOAc in iso-hexanes as eluent, which gave the title compound (568 mg, 87%) as a colourless oil. Step c) 5-Bromo-N-(l-phenyl-ethyl)-isophthalamic acid (Acid-7)
1 M NaOH (2 ml) was added to a solution of 5-bromo-N-(l-phenyl-ethyl)-isophthalamic acid methyl ester (Acid- 7b) in THF (5 ml) and MeOH (5 ml). The mixture was stirred at rt for 1.5 h. Some solvent was evaporated and 1 M HCl (4 ml) was added. The aqueous phase was extracted with EtOAc and combined organic layers were dried (MgSO4) and evaporated, which gave the title compound (217 mg, 88%).
Acid-8
Figure imgf000069_0001
Step a) 5-(2-Oxo-pyrrolidin-l-yl)-N-(l-phenyl-ethyπ-isophthalamic acid methyl ester (Acid-8a) Tris(dibenzylideneacetone)palladium (8.3 mg, 0.0091 mmol) was added to a degassed mixture of 5-bromo-N-(l-phenyl-ethyl)-isophthalamic acid methyl ester (Acid- 7b) (65.8 mg, 0.182 mmol), 2-pyrrolidione (21 μl, 0.273 mmol), Cs2CO3 (148 mg, 0.455 mmol) and Xantphos (15.8 mg, 0.0273 mmol) in dioxane (5 ml). The mixture was heated at 105 0C for 4 h, whereafter the solvent was evaporated and the residue purified by flash chromatography using 3% MeOH in DCM which gave the title compound (62.2 mg, 93%) as a colourless oil.
Step b) 5-(2-Oxo-pyrrolidin-l-yl)-N-(l-phenyl-ethyπ-isophthalamic acid (Acid-8) 1 M NaOH (0.50 ml) was added to Acid-8a (62.2 mg, 0.170 mmol) in THF (3 ml) and MeOH (3 ml). The mixture was stirred at rt overnight. 1 M HCl (0.75 ml) was added and the mixture was concentrated. Brine was added and the mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated which gave the title compound (56.6 mg, (94%) as a white solid.
Acid-9
Figure imgf000070_0001
(R)-3-(Methylsulfonyloxy)-5-(l-phenylethylcarbamoyl)benzoic acid (Acid 9) The title compound was prepared as described in WO08/119772.
Acid 10
Figure imgf000070_0002
AcicMOa AcicMOb, R=CH3 AcicMOd, R=CH3 AcicMOc, R=H Acid 10, R=H
Step a) 5-Chlorosulfonyl-isophthalic acid dimethyl ester (Acid- IQa)
5-Sulfoisophthalic dimethylester sodium salt (4.08 g, 13.8 mmol) in SOCl2 (15 ml) and DMF (6 drops) was heated at 80 0C for 20 h. The mixture was cooled to rt, filtered and washed with iso- hexanes which gave the title compound (2.94 g, 73%) as a white powder.
Step b) 5-Dimethylsulfamoyl-isophthalic acid dimethyl ester (Acid- IQb) 2 M Dimethylamine in THF (2 ml) was added to a solution of Acid-lOa (223 mg, 0.762 mmol) in THF (5 ml). The mixture was stirred at rt overnight, whereafter the solvent was evaporated and the residue purified by flash chromatography using EtOAc : iso-hexanes 4:1 and 2:1 as eluents which gave the title compound (181 mg, 79%) as a white solid.
Step c) 5-Dimethylsulfamoyl-isophthalic acid monomethyl ester (Acid IQc) 1 M NaOH (0.60 ml, 0.60 mmol) was added to Acid-lOb (181 mg, 0.600 mmol) in THF (5 ml) and MeOH (5 ml). The mixture was stirred at rt overnight whereafter the solvents were evaporated and 1 M HCl (2 ml) was added. The mixture was extracted with EtOAc, the organic layers were dried (MgSO4) and evaporated. Yield: 167 mg (97%); white solid.
Step d) 5-Dimethylsulfamoyl-N-(l-phenyl-ethvD-isophthalamic acid methyl ester (Acid IQd) HATU (243 mg, 0.639 mmol) was added to a solution of Acid 10c (167 mg, 0.581 mmol), R-I- phenylethylamine (90 μl, 0.70 mmol) and DIEA (406 μl, 2.32 mmol) in DMF (5 ml) at 0 0C. The cold bath was removed after 30 min and mixture was stirred at rt for 2 h. Solvent was evaporated and the residue purified by flash chromatography using iso-hexanes : EtOAc 2:1 and 1 :1 as eluents, which gave the title compound (164 mg, 72%) as a white solid.
Step e) 5-Dimethylsulfamoyl-N-(l-phenyl-ethyl)-isophthalamic acid (Acid 10) 1 M NaOH (1 ml) was added to Acid 1Od (163 mg, 0.417 mmol) in THF (2 ml) and MeOH (2 ml). The mixture was stirred at rt for 4 h. I M HCl (2 ml) was added and the mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated, which gave the title compound (143 mg, 92%) as a white solid.
Acid 11
Figure imgf000071_0001
Step a) 5-Methanesulfonyl-isophthalic acid dimethyl ester (Acid- 1 Ia)
Acid-lOa (1.00 g, 3.38 mmol) was added to a solution of sodium sulphite (0.85 g, 6.8 mmol) and sodium bicarbonate (0.60 g, 7.1 mmol) in water. The mixture was heated at 50 0C for 2 h whereafter the solvent was evaporated and the residue dried at high vacuum overnight. The material was suspended in DMF (10 ml) and MeI (1.00 ml, 16.0 mmol) was added. The mixture was stirred at rt for 3 h, EtOAc (50 ml) was added and the organic layer was washed with sat. NaHCO3 ,water and dried (MgSO4)which gave the title compound (764 mg, 83%).
Step b) 5-Methanesulfonyl-N-π-phenyl-ethvD-isophthalamic acid (Acid-11) The compound Acid-1 Ia (251 mg, 0.921 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (206 mg, 63%)
Acid 12
Figure imgf000072_0001
Acid-12
Step a) 2-Methyl-π.2.51thiadiazolidine 1.1 -dioxide (Acid-12a)
N-Methylethylene diamine (1.02 ml, 11.6 mmol) in dioxane (4 ml) was added dropwise to sulphamide (1.12 g, 11.6 mmol) in dioxane (10 ml) over 2 h. The mixture was refluxed for 18 h, solvent evaporated and residue purified by flash chromatography using 3% MeOH in DCM as eluent which gave the title compound (259 mg, 16%) as a semisolid.
Step b) 5-(5-Methyl-l,l-dioxo-llambda*6*-ri,2,51thiadiazolidin-2-yl)-isophthalic acid dimethyl ester (Acid- 12b^ Tris(dibenzylideneacetone)palladium (27 mg, 0.029 mmol) was added to a degassed mixture of 5-bromo-isophthalic acid dimethyl ester (159 mg, 0.583 mmol), 2-methyl-[l,2,5]thiadiazolidine 1,1 -dioxide (Acid- 12a) (79 mg, 0.583 mmol), Cs2CO3 (474 mg, 1.46 mmol) and Xantphos (50.6 mg, 0.0874 mmol) in dioxane (5 ml). The mixture was heated at 105 0C under N2 for 2 h, the solvent was evaporated and the residue purified by flash chromatography using 2% MeOH in DCM as eluent, which gave the title compound (143 mg, 75%) as a yellow solid.
Step c) 5-(5-Methyl- 1.1 -dioxo- 1 lambda*6*-[ 1 ,2.51thiadiazolidin-2-ylVN-(l -phenyl-ethvO- sophthalamic acid methyl ester (Acid-12)
The compound Acid-12b (143 mg, 0.436 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (98 mg, 55%) as a pale yellow solid.
Acid 13
Figure imgf000072_0002
Step a) 5-(Piperidine-l-sulfonyl)-isophthalic acid dimethyl ester (Acid 13a) Piperidine (236 μl, 2.38 mmol) was added to a solution of 5-chlorosulfonyl-isophthalic acid dimethyl ester (Acid 10a) (279 mg, 0.953 mmol) in THF (5 ml). The mixture was stirred at rt overnight whereafter the solvent was evaporated and the residue purified by flash chromatography using EtOAc :isohexanes 4:1 and 2: 1 as eluents, which gave the title compound (83.4 mg, 26%) as a white solid.
Step b) N-d-Phenyl-ethyπ-S-fpiperidine-l-sulfonvD-isophthalamic acid methyl ester (Acid-13) The compound Acid-12b (83 mg, 0.243 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (34 mg, 88%) as a pale yellow solid.
Acid 14
Figure imgf000073_0001
Step a) 5-(2-Oxo-oxazolidin-3-yl)-isophthalic acid dimethyl ester (Acid-14a) Tris(dibenzylideneacetone)palladium (58 mg, 0.063 mmol) was added to a degassed mixture of 5-bromo-isophthalic acid dimethyl ester (345 mg, 1.26 mmol), 2-oxazolidinone (220 mg, 2.52 mmol), CS2CO3 (1.03 g, 3.16 mmol) and Xantphos (109 mg, 0.189 mmol) in dioxane (10 ml). The mixture was stirred at 105 0C under N2 for 4 h. The solvent was evaporated and the residue taken up in DCM/water. The organic phase was separated and concentrated. The residue was purified by flash chromatography using 2% MeOH in DCM which gave the title compound (264 mg, 75%) as a beige solid.
Step b) 5-(2-Oxo-oxazolidin-3-yl)-N-(l-phenyl-ethyl)-isophthalamic acid methyl ester (Acid-14) The compound Acid-14a (264 mg, 0.946 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (63 mg, 18%) as a white solid.
Acid 15
Figure imgf000074_0001
Step a) 5-Methyl-N-π-phenyl-ethvD-isophthalamic acid methyl ester (Acid-15a) Triphenylphosphine (7 mg) was added to a mixture of 5-bromo-N-(l-phenyl-ethyl)- isophthalamic acid methyl ester (Acid- 7b) (164 mg, 0.452 mmol), trimethylboroxine (64 μl, 0.452 mmol) and K2CO3 (191 mg, 1.36 mmol) in DMF (5 ml). The mixture was heated at 150 0C for 15 min in microwave reactor. The solvent was evaporated and residue purified by flash chromatography using 1% MeOH in DCM which gave the title compound (87 mg, 71%).
Step b) 5-Methyl-N-(l-phenyl-ethyl)-isophthalamic acid (Acid-15) The compound Acid- 15a (97 mg, 0.326 mmol) was treated as described in steps b to e for the preparation of Acid- 10, which gave the title compound (91 mg, 99%) as a white solid.
Acid- 16
Figure imgf000074_0002
Acid-16
The title compound was prepared as described in J. Med. Chem., 49, 21, 6147-6150, 2006.
Acid 17
Figure imgf000074_0003
2-(N-methylpropan-2-ylsulfonamido)isonicotinic acid (Acid- 17) 2-chloro-6-(N-methylpropan-2-ylsulfonamido)isonicotinic acid (40 mg, 0.13 mmol), prepared from 2,6-dichloro-isonicotinic acid methyl ester according to a procedure similar to the one described in WO06/057945, was dissolved in methanol and then subjected to catalytic hydrogenation by using an H-cube equipment and a 10%pd/C cartridge. The sample was concentrated to vacuum which gave the title compound in quantitative yield. MS m/z 259.3 (M+H)+.
Example 1
Figure imgf000075_0001
Step N-[I-O -Bromo-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- F(2-methyl-cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide
01 Acid-3 (0.260 g, 0.76 mmol) was dissolved in DMF (8 ml) and DIEA (0.529 ml, 3.0 mmol) was added. The mixture was cooled to 0 0C and HATU (0.404 g, 1.1 mmol) was added. The mixture was stirred at 0 0C for 10 min and the Amine A-12 (0.328 g, 0.76 mmol) in DMF (5 ml) was added. The reaction mixture was allowed to attain room temperature over night. The reaction was diluted with DCM and washed with aq. NaHCOs (sat.). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0-100:4) gave the title compound (0.503 g, 88%). MS m/z 755.9 (M+H)+.
Example 2
Figure imgf000075_0002
N- F2-Hydroxy- 1 -(3 -thiazol-2- yl-phenoxymethvD-3 -(3 -trifluoromethyl-benzylaminoVpropyH -2- F(2-methyl-cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide Bromo compound 1 (0.060 g, 0.08 mmol) was dissolved in dioxane (0.520 ml) and DMF (0.070 ml). 2-Thiazole tributylstannane (0.050 ml, 0.16 mmol), CuI (0.003, 0.016 mmol), LiCl (0.013 g, 0.32 mmol), and (CySP)2PdCl2 (0.009 g, 0.012 mmol) were added. The reaction was degassed and stirred under N2 at 125 0C for 15 min. The reaction mixture was diluted with CH3CN, the major Sn-residues were washed away by ώo-hexane. Concentration of the CH3CN layer and purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0-100:4) gave the title compound (0.032 g, 53%). MS m/z 761.0 (M+H)+.
Example 3
Figure imgf000076_0001
N- [2-Hydroxy- 1 -(3 -thiazol-4-yl-phenoxymethyπ-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- [(2-methyl-cyclopropylmethyπ-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide
O)
Bromo compound 1 (0.040 g, 0.053 mmol) was coupled with 4-thiazole tributylstannane (0.040 g, 0.1 mmol) according to the procedure described for compound 2 which gave the title compound (0.034 g, 83%). MS m/z 761.0 (M+H)+.
Example 4
Figure imgf000076_0002
N- r 1 -(3-Cvano-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- [(2- methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (4) Bromo compound 1 (0.04 g, 0.05 mmol) was dissolved in DMF (0.2 ml) and Zn(CN)2 (0.006 g, 0.05 mmol) and Pd(PPh3)4 (0.006 g, 0.005 mmol) were added. The reaction was degassed and stirred under N2 at 85 0C over night. The reaction mixture was diluted with DCM and washed with aq. NaHCO3 (sat.). The organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0- 100:3) gave the title compound (0.021 g, 60%). MS m/z 703.1 (M+H)+.
Example 5
Figure imgf000077_0001
N- r 1 -(3-Cvclopropylethvnyl-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)- propyll-l-ffl-methyl-cyclopropylmethyD-aminol-ό-fmethyl-fpropane-l-sulfonyD-aminol- isonicotinamide (5)
Bromo compound 1 (0.030 g, 0.04 mmol) was dissolved in DMF (0.6 ml) and CuI (0.001 g, 0.004 mmol), Pd(PPh3)4 (0.007 g, 0.006 mmol), cyclopropylacetylene (0.007 ml, 0.06 mmol), and DEA (0.071 ml) were added. The reaction was degassed and stirred under N2 at 90 0C for 40 min. and then at room temperature for 72 h. The reaction mixture was concentrated and the residue purified by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0-100:2) which gave the title compound (0.019 g, 64%). MS m/z 742.0 (M+H)+.
Example 6
Figure imgf000077_0002
N- r 1 -(3-Ethvnyl-phenoxymethyl)-2-hvdroxy-3 -(3 -trifluoromethyl-benzylamino)-propyll -2- [(2- methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (6) Bromo compound 1 (0.040 g, 0.053 mmol) was coupled with trimethylsilylacetylene (0.011 ml, 0.08 mmol) in the same way as described for compound 5. Subsequent treatment with KF (0.39 g, 6.7 mmol) in MeOH (3 ml) at room temperature over night, dilution with DCM and washing with 5% aq. Na2CO3, drying (Na2SO4) and purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0-100:2) gave the title compound (0.015 g, 48%). MS m/z 702.0 (M+H)+.
Example 7
Figure imgf000078_0001
N-ri-(3-Bromo-phenoxymethyl)-2-hvdroxy-3-(3-trifluoromethyl-benzylamino)-propyll-2- rmethyl-(2-methyl-cvcloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (7)
Acid-1 (0.110 g, 0.31 mmol) was dissolved in DMF (5 ml) and DIEA (0.216 ml, 1.2 mmol) was added. The mixture was cooled to 0 0C and HATU (0.165 g, 0.43 mmol) was added. The mixture was stirred at 0 0C for 10 min whereafter Amine A- 13 (0.133 g, 0.31 mmol) in DMF (2 ml) was added. The reaction mixture was allowed to attain room temperature over night. The reaction was diluted with DCM and washed with NaHCO3 (sat. aq.). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 1 :0-100:2) gave the title compound (0.180 g, 75%). MS m/z 769.8 (M+H)+.
Example 8
Figure imgf000078_0002
N-[I -(3-Bromo-phenoxymethyl)-2-hvdroxy-3-(3-trifluoromethyl-benzylamino)-propyll-3-(l , 1 - dioxo- 1 lambda*6*-r 1 ,21thiazinan-2-yl)-5-ethylamino-2-fluoro-benzamide (8) 3-(l,l-Dioxo-llambda*6*-[l,2]thiazinan-2-yl)-5-ethylamino-2-fluoro-benzoic acid, prepared as described in WO04/050619 (0.025 g, 0.079 mmol) was coupled to amine A-13 (0.034 g, 0.079 mmol) as described in Example 7. Purification by flash column chromatography (CHCI3/NH3 in MeOH (sat.), 100:25) and then RP-LC-MS (acetonitrile-10 mM aq. ammonium formate, 50-90% over 9 min) which gave the title compound (0.015 g, 26%). MS m/z 730.8 (M+H)+.
Example 9
Figure imgf000079_0001
Step a) 6-(3.5-Difluorophenoxy)-3-deoxy-1.2-O-isopropylidene-α-D-glucose (9a) To a solution of the epoxide 5,6-anhydro-3-deoxy-l,2-O-isopropylidene-D-glucofuranoside (0.893 g, 4.80 mmol), prepared from 3-deoxy-l,2-O-isopropyliden-D-glucofuranoside according to the procedure described by B. Samuelsson et al. in J. Med. Chem., 2004, 47, 3353-336, and 3,5-difluorophenol (0.690 g, 5.30 mmol) in DMF (20 mL) was added K2CO3 (0.332 g, 2.40 mmol). The mixture was heated to 100 0C and stirred overnight. After cooling, aqueous NH4CI (20 mL) was added and the reaction mixture was extracted with diethyl ether. The organic phase was washed twice with water, dried, concentrated and the afforded residue was purified by gradient flash chromatography (toluene/EtOAc 15:1, 9:1 and 6:1) which gave the title compound (1.16 g, 76%) as a colourless oil.
1R NMR (300 MHz, CDCl3) δl.33 (s, 3H), 1.52 (m, 3H), 1.81-1.96 (m, IH), 2.16 (dd, J = 4.2, 13.5 Hz, IH), 2.62 (d, J = 4.2 Hz, IH), 3.94 (dd, J= 6.6, 9.6 Hz, IH), 4.05 (dd, J= 3.9, 9.6 Hz, IH), 4.09-4.17 (m, IH), 4.26-4.35 (m, IH), 4.74-4.79 (m, IH), 5.82 (d, J= 3.9 Hz, IH), 6.38- 6.49 (m, 3H); 13C NMR (75.5 MHz, CDCl3) 526.1, 26.8, 34.1, 69.9, 70.1, 78.1, 80.6, 96.9 (t, JCF = 25.9 Hz), 98.5 (d, JCF = 27.8 Hz, 2C), 105.5, 111.5, 160.4, 163.6 (d, JCF = 246.6 Hz), 163.8 (d, JCF = 246.6 Hz).
Step b) 5-Azido-6-(3,5-difluorophenoxy)-3,5 dideoxy-l,2-O-isopropylidene- α -L-iodose (9b) The alcohol 9a (1.16 g, 3.65 mmol) and triphenylphosphine (1.44 g, 5.64 mmol) were dissolved in dry THF (19 rnL). The mixture was cooled to -15 0C and diisopropyl azodicarboxylate (DIAD) (1.80 mL, 9.13 mmol) was added. After stirring the solution for 10 min at -15 0C, the temperature was raised to 0 0C and diphenylphosphoryl azide (DPPA) (1.23 mL, 5.48 mmol) was added. The solution was stirred for 30 min at 0 0C and then over night at room temperature. Concentration and gradient flash chromatography (toluene, toluene/EtO Ac 24 : 1 , 15:1, 9:1) gave the title compound (1.15 g, 92%) as a colourless oil.
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.
Step c) (3£45V4-Azido-5-(3.5-difluorophenoxy)-3-hydroxy-pentanoic acid (9c)
Compound 9b (185 mg, 0.542 mmol) was refluxed (115 0C) in acetic acid/water (1 :1, 4 mL) for 1 h. The mixture was concentrated and the residual was dissolved in tert-butyi alcohol/water (2:3, 4 mL) and sodium periodate (581 mg, 2.72 mmol) was added. After stirring for 20 min at room temperature, potassium permanganate (12.8 mg, 0.081 mmol) was added and the reaction mixture was allowed to stir for an additional 1.5 h and was thereafter extracted three times with CHCl3. The combined organic extracts were dried and concentrated. The crude residual was dissolved in water (5 mL) and the mixture was cooled to 0 0C. 1 M NaOH (2.2 mL) was added drop wise and the solution was stirred at 0 0C for 30 min and for an additional 1 h at room temperature. The reaction mixture was washed twice with diethyl ether and was then acidified with 6 M HCl to pH 1-2. The acidified water phase was extracted three times with CHCl3 and the combined organic extracts were dried and concentrated. Gradient flash chromatography (toluene/EtOAc 6:1 + 1% HOAc and toluene/EtOAc 2:1 + 1% HOAc) gave the title compound (52%) as white crystals.
1H NMR (300 MHz, CD3OD) δ2.58-2.65 (m, 2H), 3.81-3.88 (m, IH), 4.14-4.31 (m, 3H), 4.94 (bs, IH), 6.47-6.64 (m, 3H); 13C NMR (75.5 MHz, CD3OD) δ39.7, 65.4, 68.7, 70.1, 97.5 (t, JCF = 26.5 Hz), 99.5 (d, JCF = 29.2 Hz, 2C), 161.9, 165.0 (d, JCF = 245.4 Hz), 165.2 (d, JCF = 245.4 Hz), 174.7.
Step d) (3£,45V4-Azido-5-(3,5-difluorophenoxy)-3-hvdroxy-pentanoic methyl ester (9d) The carboxylic acid 9c was dissolved in methanol (100 mL) at 0 0C and acetyl chloride (9 mL) was added slowly. The solution was stirred for 20 minutes at 0 0C and for an additional 48 hours at room temperature. The solvent was evaporated and the residue co-evaporated with toluene and then purified by flash column chromatography, which gave the title compound.
Step e) 4-Azido-5-(3,5-difluoro-phenoxy)-pentane-l,3-diol (9e)
Compound 9d (500 mg, 1.66 mmol) was dissolved in 100 ml ethanol (95%) and the solution was cooled to 0 °C. Sodium borohydride (94 mg, 2.49 mmol) was added and the reaction mixture was allowed to react for 16h, allowing the solution to slowly reach RT. The reaction was followed by LCMS. HCl was added to reach pH 7. The solution was concentrated, dissolved in DCM and purified by flash chromatography (DCM: MeOH 100:0-80:20) which gave the title compound (305 mg, 1.09 mmol, 66%). MS m/z 274.3 (M+H)+, 275.2 (M-H)."
Step f) 2-Azido-l-(3.5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (9f)
Dibutyltin oxide (170 mg, 0.68 mmol) was added to a solution of the diol 9e (145 mg, 0.53 mmol) in toluene (40 mL), whereafter the solution was refluxed at 125 °C with a Dean-Stark adapter for 4h. The solution was allowed to cool to 90 °C followed by addition of methyl iodide (23.6 μL, 0,53 mmol) and tetrabutylammonium bromide (195 mg, 0.85 mmol). The reaction mixture was stirred at 90 °C for 16h. The solution was carefully concentrated, dissolved in DCM (3 mL) and applied to a silica column (10 g). The crude product was purified by flash chromatography (heptane: ethyl acetate 80:20-20:80) which gave the title compound (23 mg, 0.08 mmol, 15%). MS m/z 288.3 (M+H)+.
Step g) 2-Amino-l-(3,5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (9g) Polymer supported triphenylphosphine (270 mg, 1.48 mmol/g) was added to a solution of the azide 9f (23 mg, 0.08 mmol) in THF:MeOH (10:1.5, 11.5 ml) and the mixture was shaken for 16 h. The solution was filtered from the resin and concentrated which gave the title compound (15.6 mg, 0.06 mmol, 75%). MS m/z 262.2 (M+H)+. Step h) N-[l-(3.5-Difluoro-phenoxymethyπ-2-hydroxy-4-methoxy-butyll-2-[methyl-(2-methyl- cyclopropylmethyD-aminol-ό-fmethyl-fpropane-l-sulfonyπ-aminol-isonicotinamide (9h) Acid-1 (34 mg, 0.72 mmol) was dissolved in dry DMF (4 mL) together with HATU (36.5 mg, 0.72 mmol) and then stirred for 5 minutes. Amine 9g (15 mg, 0.06 mmol) was added to the solution followed by addition of DIEA (70 μL, 0.3 mmol). The reaction mixture was stirred for 5h, diluted with DCM (30 mL) and washed with a saturated solution of sodium bicarbonate (15 mL). The organic layer was collected, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum and purified by preparative HPLC-MS which gave the title compound (4 mg, 10%). MS m/z 598.9 (M+H)+.
Example 10
Figure imgf000082_0001
Step a) 4-Azido-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro-phenoxy)-pentanoic acid methyl ester (IQa)
Compound 9d (720 mg, 2.36 mmol) was dissolved in dry DCM (100 mL) and cooled to 0 0C. Triethylamine (980 μL, 7 mmol) was added followed by drop wise addition of tøt-butyldimethyl silyl triflate (620 μL, 3.54 mmol). The reaction was stirred for Ih at 0 0C and then concentrated to vacuum. Purification by flash chromatography (hexane: ethyl acetate, 100:0- 75:25) gave the title compound (970 mg, 98%).
Step b) 4-Azido-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro-phenoxy)-pentan-l-ol (IQb) DIBAL (5.3 mL, 5.3 mmol, IM in hexane) was added to a solution of the ester 10a (880 mg, 2.12 mmol) in hexane (7 mL). The reaction mixture was agitated at RT for 2h, and then quenched by addition of water. The solution was diluted with DCM and washed with water. The organic phase was separated, concentrated and the residue purified by flash chromatography (hexane: ethyl actetate 100:0-75:25) which gave the title compound (313 mg, 38%).
Step c) r2-Azido-3-(3,5-difluoro-phenoxy)-l-(2-methoxy-ethyl)-propoxyl-tert-butyl-dimethyl- silane (IQc)
Alcohol 10b (313 mg, 0.8 mmol) was dissolved in dry DMF (5 mL), cooled to 0 °C and hexane washed sodium hydride (60% oil suspension, 25.5 mg, 1.04 mmol) was added, followed by addition of methyl iodide (500 μL, 8 mmol). The reaction mixture was stirred for 1.5h, quenched with methanol, diluted with DCM and washed with water. The organic phase was collected, dried over sodium sulphate and the residue was purified by flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (226 mg, 70%).
Step d) 2-Azido-l-(3.5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (IQd) Ammonium fluoride (38 mg, 0.64 mmol) was added to a solution of silane derivative 10c (130 mg, 0.32 mmol) in methanol (10 mL). The reaction mixture was refluxed at 65 0C for 16h, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0-50:50) which gave the title compound (77.3 mg, 84%).
Step e) 2-Azido-l-(3.5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (IQe) Triphenyl phosphine (70 mg, 0.28 mmol), DIAD (69 μL, 0.35 mmol) and 4-nitrobenzoic acid (53.7 mg, 0.31 mmol) were dissolved in dry THF (3 mL), cooled to 0 0C and stirred for 20 minutes, whereafter alcohol 1Od (77mg, 0.26 mmol) was added. The reaction temperature was slowly increased to reach RT and the mixture was stirred for 16h. The solution was concentrated, dissolved in 1-2 mL DCM and purified by flash chromatography (hexane:ethyl acetate 100:0- 75:25) which gave the nitrobenzoic acid ester 63.7 mg (55%). This afforded intermediate (30.5 mg, 0.069 mmol) was dissolved in MeOH (5 mL) and sodium methoxide (1.88 mg, 0.035 mmol) was added. The reaction was stirred at RT for 16h, neutralized by cone, acetic acid till pH 6-7 and concentrated. The residue was dissolved in DCM and washed with an aqueous solution of sodium bicarbonate. The organic phase was separated, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 95:5-75:25) which gave the title compound (12 mg, 0.04 mmol). Step f) 2-Amino-l-(3.5-difluoro-phenoxy)-5-methoxy-pentan-3-ol (IQf) The azide compound 1Oe (25 mg, 0.087 mmol) was dissolved in methanol (10 mL), and then hydrogenated using an H-Cube equipment and a 10% Pd/C cartridge at 25 0C. The solution was concentrated which gave the title compound (11.2 mg, 49%). MS m/z 262.2 (M+H)+.
Step g) N-ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-2-rmethyl-(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (IQg) Acid-1 (19 mg, 0.51 mmol) was dissolved in dry DMF (4 mL) together with HATU (20 mg, 0.61 mmol) and the solution was stirred for 5 minutes. Amine 1Of (11 mg, 0.043 mmol) was added followed by DIEA (40 μL, 0.25 mmol). The reaction mixture was stirred for 2h, diluted with DCM (30 mL) and washed with a saturated solution of sodium bicarbonate (15 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and purified by preparative HPLC-MS which gave the title compound (10.3mg, 37%). MS m/z 598.9 (M+H)+.
Example 11
Figure imgf000084_0001
Step a) r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-methoxy-butyll- carbamic acid tert-butyl ester (1 Ia) Azide derivative 10c (140 mg, 0.345 mmol) was dissolved in ethyl acetate (25 rnL) together with Boc-anhydride (380 mg, 1.73 mmol) and then subjected to catalytic hydrogenation using an H- Cube equipment and a 10% Pd/C cartridge at 25 0C. The solution was concentrated and purified by silica flash chromatography (Hexane 100:0-80:20which gave the title compound (134 mg, 82%). MS m/z 476 (M+H)+, 376 (M-Boc)+
Step b) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-carbamic acid tert-butyl ester (l ib)
Ammonium fluoride (21 mg, 0.56 mmol) was added to a solution of the silane derivative 1 Ia (134 mg, 0.28 mmol) in methanol (15 mL). The reaction mixture was refluxed at 65 0C for 16 h, concentrated and the residue was purified by silica flash chromatography (hexane: ethyl acetate 100:0-50:50) which gave the title compound (84 mg, 83%). MS m/z 362.3 (M+H)+
Step c) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-methoxy-butyll-carbamic acid tert-butyl ester (l ie)
The alcohol l ib (52.4 mg, 0.145 mmol), triphenylphosphine (42 mg, 0.16 mmol), DIAD (35 μL, 0.174 mmol) and p-nitrobenzoic acid (29 mg, 0.17 mmol) were dissolved in dry THF (30 mL) and cooled to 0 0C. The reaction was allowed to reach RT during 16h. The solution was concentrated and the residues was purified by silica flash chromatography. The afforded intermediate was dissolved in a solution of sodium methoxide (4 mg, 0.068 mmol) in methanol and the solution was stirred for Ih at RT, neutralized, concentrated and purified by silica chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (25 mg, 50%). MS m/z 362.3 (M+H)+
Step d) [2-Azido-l-(3.5-difluoro-phenoxymethyl)-4-methoxy-butyll-carbamic acid tert-butyl ester (l id)
Alcohol 1 Ic (20 mg, 0.055 mmol) was dissolved in dry THF (1 mL) together with triphenylphosphine (21 mg, 0.082 mmol) and then cooled to 0 0C. DIAD (16 μL, 0.82 mmol) was added drop wise, and the mixture was stirred at 0 0C for 5 min, followed by drop wise addition of DPPA (36 μL, 0.165 mmol). The reaction was stirred at 0 0C and allowed to reach RT overnight. The solution was concentrated, and purified by silica flash chromatography (hexane: ethyl acetate (100:0-75:25) which gave the title compound (9.8 mg, 46%). MS m/z 387.3 (M+H)+ Step e) 2-Azido-l-(3.5-difluoro-phenoxymethyl)-4-methoxy-butylamine (l ie) The boc protected derivative 1 Id (9.8 mg, 0.025 mmol) was dissolved in dioxanexonc. HCl (3:1, 4 rnL), and the reaction mixture was stirred at RT for Ih. The solution was concentrated under vacuum and co-evaporated with toluene which gave the title compound (100%).
Step f) N-r2-Azido-l-(3,5-difluoro-phenoxymethyl)-4-methoxy-butyll-2-r(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (Hf) Acid-3 (10 mg, 0.025 mmol) was dissolved in dry DMF (6 mL) whereafter HATU (12.5 mg, 0.033 mmol), the amine l ie (9.8 mg, 0.025 mmol) and DIEA (22 μL, 0.125 mmol) were added. The reaction mixture was stirred at RT for 2h, concentrated and purified by prep LCMS which gave the title compound (4.3 mg, 28%). MS m/z 609.95 (M+H)+
Example 12
Figure imgf000086_0001
Step a) 4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro- phenoxy)-pentanoic acid methyl ester (12a)
Azide compound 10a (210 mg, 0.505 mmol) was dissolved in ethyl acetate (25 mL) together with Boc-anhydride (551 mg, 2.52 mmol) and then subjected to catalytic hydrogenation using an H-Cube equipment and a 10% Pd/C cartridge at 25 0C. The solution was concentrated and the residue purified by silica flash chromatography (Hexane 100:0-80:20) which gave the title compound (146 mg, 59%). MS m/z 489 (M+H)+, 389 (M-Boc)+
Step b) r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-hvdroxy-butyll- carbamic acid tert-butyl ester (12b)
Methyl ester 12a (146 mg, 0.298 mmol) was dissolved in hexane (30 mL) followed by addition of lithium borohydride (2M in THF, 600 μL, 1.2 mmol). The reaction mixture was stirred at RT for 2h, quenched with methanol, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0-75:25) which gave the title compound (140 mg, 100%). MS m/z 462.5 (M+H)+.
Step c) r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-(3- trifluoromethyl-benzylaminoVbutvH-carbamic acid tert-butyl ester (12c)
Water (3.7 μL, 0.2 mmol) was added to a solution of alcohol 12b (95 mg, 0.2 mmol) in DCM (6 mL), the reaction mixture was vigorously stirred, and a slurry of Dess- martin reagent (122 mg, 0.28 mmol) in DCM was added. After 2h the reaction was quenched by addition of sodium bicarbonate sat. aq. and Na2S2O3 10% aq. The mixture was diluted with DCM and washed with water, the organic phase was separated and concentrated. The afforded residue was dissolved in TMOF: DCE (1 :1, 3mL) and 3-trifluorobenzylamine (23 μL, 0.24 mmol) was added to the solution. The reaction was stirred for 2h and then sodium triacetoxy borohydride (36 mg, 0.34 mmol) and acetic acid (300 μL) were added. The reaction was stirred for 16h, concentrated and partitioned between DCM and water. The organic phase was collected, dried and concentrated under vacuum. The afforded residue was dissolved in dioxanexonc. HCl (3:1, 4mL), stirred for 15 minutes and concentrated which gave the title compound. MS m/z 405 (M+H)+.
Step d) N-ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-(3-trifluoromethyl-benzylamino)- butyll -2- rmethyl-(2-methyl-cvclopropylmethyl)-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (12d) The amine 12c (0.1 mmol) was reacted with Acid-1 (35mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (100 μL, 0.5 mmol) in dry DMF. The reaction mixture was stirred for 16h, concentrated and the residue was purified by prep LCMS which gave the title compound (5mg, 67%). MS m/z 742.01 (M+H)+.
Example 13
Figure imgf000088_0001
N-r2-Amino-l -(3, 5-difluoro-phenoxymethyl)-4-methoxy-butyll-2-r(2 -methyl- cvclopropylmethyD-aminol-ό-rmethyl-fpropane-l-sulfonvπ-aminol-isonicotinamide (13) The azide derivative Hf (2 mg, 0.003 3mmol) was dissolved in methanol (5 mL) and then subjected to catalytic hydrogenation using an H-Cube equipment, in the presence of Lindlar's catalyst (Pd CaCO3 (Pb)). The solution was concentrated which gave the title compound (2.1 mg, 100%). MS m/z 584 (M+H)+.
Example 14
Figure imgf000088_0002
Step a) 4-Amino-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro-phenoxy)-pentan-l-ol (14a) DIBAL (3.74 mL, 3.74 mmol, IM in hexane) was added to a solution of compound 10a (622 mg, 1.49 mmol) in hexane (10 mL). The reaction mixture was agitated at RT for 4h, and then quenched by addition of water. The solution was diluted with DCM and washed with water. The organic phase was separated, concentrated and purified by flash chromatography (hexane:ethyl acetate 100:0-75:25) which gave the title compound (136.5 mg, 25%), MS m/z 362.8 (M+H)+.
Step b) N- r2-(tert-Butyl-dimethyl-silanyloxy)- 1 -(3 ,5 -difluoro-phenoxymethvO-4-hvdroxy- butyll -2- r(2-methyl-cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (14b)
The amine 14a (45 mg, 0.124 mmol), Acid-3 (53 mg, 0.124 mmol) HATU (47 mg, 0.124 mmol) and DIEA (81 μL, 0.5 mmol) were dissolved in dry DMF (4 mL) The solution was stirred at RT for 16h and then diluted with DCM and washed with water. The organic phase was separated, dried over sodium sulfate, concentrated and purified by silica flash chromatography
(hexane:ethyl acetate 100:0-70:30) which gave the title compound (69.2 mg, 81%). MS m/z 685.06 (M+H)+.
Step c) N-r2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,5-difluoro-phenoxymethyl)-4-oxo-butyll-2- [(2-methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (14c)
The alcohol 14b (69.2 mg, 0.1 mmol) was dissolved in dry dichloroethane (3 mL), followed by the addition of Dess- Martin reagent (59 mg, 0.14 mmol). The reaction mixture was stirred at RT for Ih, quenched with a saturated solution of sodium bicarbonate and Na2S2O3 10% aq, diluted with DCM and washed with water. The organic phase was separated, concentrated and used in next step without further purification.
Step d) N-[4-Cyclopropylamino-l-(3.5-difluoro-phenoxymethyl)-2-hydroxy-butyll-2-[(2- methyl-cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (14<ft
Aldehyde 14c (0.05 mmol) was dissolved in dry dichloroethane (3 mL), together with cyclopropylamine (10 μL, 0.06 mmol) and sodium triacetoxy borohydride (40 mg, 0.085 mmol). The solution was stirred at RT for 16h and then diluted with DCM (20 mL) and washed with water (5 mL). The organic phase was separated, dried over sodium sulfate and concentrated. MS m/z 724.09 (M+H)+. The crude product was dissolved in dioxanexonc. HCl (3:1, 4 mL), and stirred at RT for 30 min. The solution was concentrated and the residue dissolved in DCM and washed with NaOH IM. The organic phase was concentrated and purified by prep LCMS which gave the title compound (0.9 mg, 3% over 3 steps). MS m/z 610.2 (M+H)+. Example 15
Figure imgf000090_0001
N-ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-(3-trifluoromethyl-benzylamino)-butyll-2-r(2- methyl-cvclopropylmethyπ-aminol-ό-rmethyl-fpropane-l-sulfonvD-aminol-isonicotinamide (15) The title compound was synthesized from aldehyde 14c, using the procedure described in Example 14d, but using 3-(trifluoro)-benzylamine (15μL, 0.06 mmol) instead of cylopropylamine, which gave the title compound (0.7 mg, 2% over 3 steps). MS m/z 728.2 (M+H)+.
Example 16
Figure imgf000090_0002
N- [ 1 -(3.5 -Difluoro-phenoxymethyl)-2-hydroxy-4-methoxy-butyll -2- [(2-methyl- cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide (16) Compound 1 Ib (47 mg, 0.13 mmol) was dissolved in dioxanexonc. HCl (3:1, 4 mL) for Ih, concentrated and co-evaporated with toluene. The product obtained was dissolved in dry DMF (3 mL), together with Acid-3 (54 mg, 0.13 mmol) and HATU (64 mg, 0.17 mmol) and DIEA (112 μL, 0.65 mmol). The reaction mixture was stirred at RT for 4h, diluted with DCM and washed with water. The organic phase was dried over sodium sulphate, concentrated and purified by flash chromatography (hexane: ethyl acetate 100:0-75:25) followed by purification by prep LCMS which gave the title compound (17 mg, 23%). MS m/z 585.5 (M+H)+. Example 17
Figure imgf000091_0001
Step a) 4-( Bis-tert-butoxycarbonylamino)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3.5-difluoro- phenoxyVpentanoic acid methyl ester (17a)
Boc anhydride (251mg, 1.14 mmol) and DMAP (0.57 mmol) were added to a solution of compound 12a (282 mg, 0.57 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at RT for 16h, concentrated and the residue was purified by silica flash chromatography which gave the title compound (86 mg, 25%). MS m/z 590.2 (M+H)+.
Step b) 4-(Bis-tert-butoxycarbonylamino)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3,5-difluoro- phenoxy)-pentan-l-ol (17b)
Lithium borohydride (2M in THF, 770 μL, 1.52 mmol) was added to a solution of compound 17a (225 mg, 0.382 mmol) in hexane (15 mL). The reaction mixture was stirred at RT for 16h. The solution was quenched with methanol, and then concentrated under vacuum. The residue was portioned between DCM and water, the organic phase was separated dried over sodium sulfate, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0- 70:30) which gave the title compound (101 mg, 56%). MS m/z 562.2 (M+H)+. Step c) Bis-tert-butoxycarbonyl-[2-(tert-butyl-dimethyl-silanyloxy)-l-(3.5-difluoro- phenoxymethyπ-4-methoxy-butyll -amine (17c)
Sodium hydride (60% oil suspension, 9 mg, 0.23 mmol, prewashed with hexane) was added at 0 0C to a solution of alcohol 17b (101.4 mg, 0.18 mmol) in dry DMF (3 mL) was added followed by addition of methyl iodide (112 μL, 1.8 mmol). The reaction mixture was stirred for 2h, quenched with methanol, diluted with DCM and washed with water. The organic phase was collected, dried over sodium sulphate and purified by flash chromatography (hexane :ethyl acetate 100:0-85:15) which gave the title compound (63.8 mg, 61%). MS m/z 576.2 (M+H)+.
Step d) 2-(Bis-tert-butoxycarbonyl-amino)-l-(3,5-difluorophenoxy)-5-methoxy-pentan-3-ol (17(D
Ammonium fluoride (8.5 mg, 0.22 mmol) was added to a solution of compound 17c (64 mg, 0.11 mmol) in methanol (15 mL). The reaction mixture was refluxed at 65 0C for 16 h, concentrated and purified by silica flash chromatography (hexane: ethyl acetate 100:0-80:20) which gave the title compound (41 mg, 80%). MS m/z 462.3 (M+H)+
Step e) [2-Azido-l-(3.5-difluoro-phenoxymethyl)-4-methoxy-butyll-bis-tert-butoxycarbonyl- amine (17e)
Alcohol 17d (41 mg, 0.089 mmol) was dissolved in dry THF (1 mL) together with triphenyl phosphine (35 mg, 0.13 mmol) and the solution was cooled to 0 0C. DIAD (26 μL, 0.13 mmol) was added drop wise, and the mixture was stirred at 0 0C for 5 min, followed by drop wise addition of DPPA (58 μL, 0.26 mmol). The reaction was stirred at 0 0C and then allowed to attain room temperature overnight. The solution was concentrated, and the residue purified by silica flash chromatography (hexane:ethyl acetate (100:0-75:25) which gave the title compound (28.5 mg, 66%). MS m/z 487.3 (M+H)+
Step f) N-r2-Azido-l-(3,5-difluoro-phenoxymethyl)-4-methoxy-butyll-2-r(2-methyl- cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide ( 17f) Compound 17e (26.5 mg, 0.058 mmol) was dissolved in dioxanexonc. HCl (3:1, 4 mL) after Ih stirring, the solution was concentrated and co-evaporated with toluene. The obtained residue was dissolved in dry DMF (3 mL), together with Acid-3 (20 mg, 0.058 mmol), HATU (27 mg, 0.07 mmol) and DIEA (41 μL, 0.23 mmol). The reaction mixture was stirred at RT for 16h, diluted with DCM and washed with water. The organic phase was dried over sodium sulphate, concentrated and purified by prep LCMS which gave the title compound (18.3 mg, 52%). MS m/z 609.9 (M+H)+.
Example 18
Figure imgf000093_0001
N-r2-Amino-l-(3,5-difluoro-phenoxymethyl)-4-methoxy-butyll-2-r(2-methyl- cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide (18) Compound 17f 10 mg, 0.0164 mmol) was dissolved in methanol (5 mL) and then subjected to catalytic hydrogenation using an H-Cube equipment in the presence of Lindlar's catalyst (Pd CaCO3 (Pb)). Concentrated of the solution gave the title compound (8 mg, 84%). MS m/z 584.04 (M+H)+.
Example 19
Figure imgf000093_0002
Step l) N-r3-Cvclopropylamino-l-(3,5-difluoro-phenoxymethyl)-2-hvdroxy-propyll-2-rmethyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (19)
The Amine A-9 (30 mg, 0.11 mmol) and Acid-1 (39.2 mg, 0.11 mmol) were dissolved in DMF (2-3 mL) and cooled on an ice-bath. HATU (59 mg, 0.16 mmol) and diisopropyl amine (107 μL 0.44 mmol) were then added and the mixture was left with cooling for two hours. The cooling was then removed and the mixture was allowed to attain room temperature. Sodium bicarbonate (aq) was added and the mixture was extracted with ether. Purification by chromatography on silica gel (2 - 5 % methanol in ether) gave pure title compound (12 mg, 18 %). HPLC-MS: 610.3 (MH+)
The following compounds were prepared according to the procedure described in Example 19 using the appropriate Acid and Amine.
Figure imgf000094_0001
Figure imgf000095_0001
Example 26
Figure imgf000095_0002
N- [ 1 -(4-Cyano-phenoxymethyO-2-hydroxy-3 -(3 -trifluoromethyl-benzylaminoVpropyl] -2- [(2- methyl-cyclopropylmethyπ-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (26) Bromo compound 23 (32 mg, 0.042 mmol), zinc cyanide (5.9 mg, 0.05 mmol) and tetrakistriphenylphospine palladium (0) (5 mg, 0.0043 mmol) were mixed in N, N-diethyl- formamide (0.2 mL) and degassed under argon atmosphere. The mixture was heated at 85 0C over night then quenched with saturated sodium bicarbonate, extracted with ether and purified by prep. HPLC, which gave the pure title compound (5mg, 17 %). HPLC-MS: 703.2 (MH+)
Example 27
Figure imgf000096_0001
N-r2-Hvdroxy-l-(4-thiazol-2-yl-phenoxymethyl)-3-(3-trifluoromethyl-benzylamino)-propyll-2-
[(l-methyl-cvclopropylmethyπ-aminol-ό-rmethyl-fpropane-l-sulfonvD-aminol-isonicotinamide (27)
Bromo compound 23 (60 mg, 0.08 mmol), CuI (3 mg, 0.06 mmol), LiCl ( 13,4 mg, 0.32 mmol), 2-tributylstannanyl-thiazole (50 μL, 0.16 mmol) and dichlorobis(tricyclohexylphosphine)- palladium(II) (9 mg, 0.12 mmol) were dissolved in a degassed solution of dioxane (520 μL) and DMF (70 μL). The mixture was heated at 125 0C for 6 hours under inert atmosphere. The reaction mixture was then diluted with acetonitrile (5 mL) and washed several times with small portions of ώo-hexane. Purification by prep-HPLC gave the title compound (3 mg). HPLC-MS: 761.2 (MH+)
Example 28
Figure imgf000096_0002
Step f) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-3-methoxy-propyll-carbamic acid tert-butyl ester (28 a)
Sodium hydride (60% dispersion in mineral oil) (192mg, 4.795 mmol) was added to dry methanol (3 mL) at 0 0C and the mixture was stirred for 5 minutes. The disatereomeric epoxide E-16e (252 mg, 0.799 mmol) dissolved in dry methanol (3 mL) was added and the mixture was stirred for 1 hour at 0 0C and then at room temperature overnight. Saturated NH4Cl (aq) (10 mL) was added and the mixture was stirred for 30 minutes after which the slurry was transferred to a separatory funnel and extracted with ethyl acetate. The organic phase was washed once with water and once with brine, and was thereafter dried, filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ethyl acetate 2:1, Rf ~0.3) which gave the title compound (212 mg, 76%) as a diastereomeric mixture; 3.5:1 in favour of the R isomer. (M-Boc+H)+ calcd: 248.1; found: 248.3.
N-[I-0 ,5 -Difluoro-phenoxymethyl)-2-hvdroxy-3 -methoxy-propyll -2- [methyl-(2-methyl- cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (28b) Compound 28a (112 mg, 0.322 mmol) was dissolved in dioxane (4.5 mL) and concentrated HCl (1.5 mL) was added. After 20 minutes the solvents were evaporated and co-evaporated three times with toluene. The remainder was dissolved in DMF (8 mL) and Acid-1 (114 mg, 0.322 mmol) and DIEA (224 μL, 1.288 mmol) were added after which the mixture was cooled to 0 0C. HATU (184 mg, 0.483 mmol) was added and the mixture was stirred at 0 0C for 30 minutes and then for an additional hour at room temperature. The solvent was evaporated and the remainder was extracted with ethyl acetate and washed twice with saturated NaHCO3 (aq) and once with brine after which the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ethyl acetate 1 :1) provided the title compound (153 mg, 81%) as a diastereomeric mixture; 3.5:1 in favour of the R isomer. (M+H)+ calc: 585.3; found: 585.7.
Example 29
Figure imgf000097_0001
N- F 1 -(3 ,5 -Difluoro-phenoxymethyl)-2-hydroxy-3 -methoxy-propyll -2- F(2-methyl- cvclopropylmethyl)-aminol-6-Fmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (28) Compound 28a and Acid-3, were reacted as described in Example 28 step b, which gave the title compound in 88% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer. Column chromatography mobile phase: toluene/ethyl acetate 1:1. (M+H)+ calc: 571.2; found: 571.4.
Example 30
Figure imgf000098_0001
Step a) ri-Azido-l-O^-difluoro-phenoxymethyπ-S-methoxy-propyll-carbamic acid tert-butyl ester (30a)
Compound 28a (184 mg, 0.530 mmol) and triphenylphosphine (208 mg, 0.795 mmol) were dissolved in dry THF (8 mL) and the solution was cooled to 0 0C. DIAD (157 μL, 0.795 mmol) was added followed by dropwise addition of DPPA (342 μL, 1.589 mmol) during 5 minutes. The mixture was stirred at 0 0C for 20 minutes and was thereafter stirred at room temperature overnight. The solvents were evaporated and the crude mixture was purified by flash column chromatography (toluene - toluene/ ethyl acetate 15:1) which gave the title compound (197 mg, -100%) as a diastereomeric mixture; 3.5:1 in favour of the S isomer. (M-Boc+H)+ calcd: 273.1; found: 273.2.
Step b) N-[2-Azido-l-(3.5-difluoro-phenoxymethyl)-3-methoxy-propyll-2-[(2-methyl- cyclopropylmethyD-amino] -6- [methyl-(propane-2-sulfonyl)-aminol -isonicotinamide (3 Ob) The title compound was prepared from compound 30a and Acid-3, in 67% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer, according to the method described in Example 28 step b. Column chromatography mobile phase: toluene/ethyl acetate 5:1 - 3:1. (M+H)+ calcd: 596.2; found: 596.4.
Example 31
Figure imgf000098_0002
N-((2RV3-Amino-l-(3.5-difluorophenoxyV4-methoxybutan-2-ylV2-(((lS.2SV2- methylcyclopropyπmethylamino)-6-(N-methylpropan-2-ylsulfonamido)isonicotinamide (31) To a solution of compound 30b (54 mg, 0.091 mmol) in methanol (5 mL) and a few drops of water was added triphenylphosphine (36 mg, 0.136 mmol) and the mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the crude material was purified by flash column chromatography (toluene/ ethyl acetate 1 :3 containing 1% MeOH saturated with NH3 - ethyl acetate/ MeOH 9:1 containing 1% MeOH saturated with NH3) to afford the title compound (12 mg, 23%) as a diastereomeric mixture; 3.5:1 in favour of the S isomer. (M+H)+ calcd: 570.3; found: 570.4.
Separation of diastereomers
Figure imgf000099_0001
N-((2R.3R)-3-Amino-l-(3.5-difiuorophenoxy)-4-methoxybutan-2-yl)-2-(((lS.2S)-2- methylcyclopropyl)methylamino)-6-(N-methylpropan-2-ylsulfonamido)isonicotinamide (3 IR) & N-((2R.3S)-3-amino-l-(3.5-difiuorophenoxy)-4-methoxybutan-2-yl)-2-(((lS.2S)-2- methylcyclopropyl)methylamino)-6-(N-methylpropan-2-ylsulfonamido)isonicotinamide (31 S) The diastereomeres obtained in Example 31 were separated using flash column chromatography (ethyl acetate containing 1% MeOH saturated with NH3) which gave compound 3 IR as the first eluting compound and compound 3 IR as the second eluting compound. 3 IR: (M+H)+ calcd: 570.3; found: 570.3; 3 IS: (M+H)+ calcd: 570.3; found: 570.4.
Example 32
Figure imgf000100_0001
N-[I-Q ,5 -Difluoro-phenoxymethyl)-2-hydroxy-3 -methoxy-propyll -2-(methanesulfonyl-methyl- amino)-6-rmethyl-(2-methyl-cvclopropylmethyl)-aminol-isonicotinamide (32) The title compound was prepared from compound 28a and Acid-2 in 84% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer according to the method described in Example 28 Step b. Column chromatography mobile phase: toluene/ethyl acetate 1 :1. (M+H)+ calcd: 557.2; found: 557.2.
Example 33
Figure imgf000100_0002
Step b) (2-Hydroxy-3-methoxy-l-phenoxymethyl-propyπ-carbamic acid tert-butyl ester (33 a) Epoxide E-17 was reacted according to the procedure described in Example 28 step a, which gave the title compound in 80% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer.
Step c) N-(2-Hvdroxy-3-methoxy-l-phenoxymethyl-propyl)-2-r(2-methyl-cvclopropylmethyl)- aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (33b)
Compound 33a and Acid-3, were reacted according to the procedure described in Example 28 step b, which gave the title compound in 86% yield as a diastereomeric mixture; 3.5:1 in favour of the R isomer Column chromatography mobile phase: toluene/ethyl acetate 1 :1. (M+H)+ calcd: 535.3; found: 535.3. Example 34
Figure imgf000101_0001
^-Azido^-methoxy-l-phenoxymethyl-propyO-carbamic acid tert-butyl ester (34a) Compound 33a was reacted according to the method described in Example 30 step a which gave the title compound in -100% yield as a diastereomeric mixture; 3,5:1 in favour of the S isomer.
Step b) N-(2-Azido-3-methoxy- 1 -phenoxymethyl-propyl)-24(2-methyl-cyclopropylmethyl)- aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (34b) Compound 34a and Acid-3 were reacted according to the method described in Example 28 step b, which gave the title compound in 96% yield as a diastereomeric mixture; 3.5:1 in favour of the S isomer. Column chromatography mobile phase: toluene/ethyl acetate 5:1. (M+H)+ calcd: 560.3; found: 560.2.
Example 35
Figure imgf000101_0002
N-(2-Amino-3-methoxy-l-phenoxymethyl-propyl)-2-r(2-methyl-cvclopropylmethyl)-aminol-6- rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (35R & 35S)
To compound 34b (72 mg, 0.129 mmol) dissolved in ethanol (5 mL) were added palladium on charcoal (10%) (10 mg) and palladium hydroxide (2 mg). The mixture was subjected to catalytic hydrogenation conditions (atmospheric pressure) for 3 hours after which the mixture was filtered through Celite and the solvent vas evaporated. The crude mixture was purified by flash column chromatography (ethyl acetate containing 1% MeOH saturated with NH3) which gave the pure R and S isomers of the title compound 35R (8 mg, 12%) and 35S (31 mg, 45%) respectively. (M+H)+ calcd: 534.3; found: 534.3 (both compounds).
Example 36
Figure imgf000102_0001
Step a) 4-(3.5-Difluoro-phenoxymethyl)-5-isobutoxymethyl-oxazolidin-2-one (36a)
Sodium hydride (60% dispersion in mineral oil) (40mg, 1.002 mmol) was added to dry z-BuOH (2 mL) at 0 0C and the mixture was stirred for 5 minutes. The diastereomeric mixture of epoxide 28e (79 mg, 0.251 mmol) dissolved in dry z-BuOH (2 mL) was added and the mixture was stirred for 30 minutes at 0 0C and then at room temperature overnight. To get complete conversion of the starting material the mixture was then heated to 50 0C for 5 hours. Saturated NH4CI (aq) (10 mL) was added and the mixture was stirred for 30 minutes after which the slurry was transferred to a separatory funnel and extracted with ethyl acetate. The organic phase was washed once with water and once with brine, and was thereafter dried, filtered, and concentrated. The crude material was purified by flash column chromatography (toluene/ethyl acetate 2:1) which gave the desired R isomer cyclic carbamate 36a (50 mg, 63%) and the undesired S isomer (10 mg, 13%). In this chromatographic system the R isomer is the first compound that elutes followed by the S isomer. (M+H)+ calcd: 316.1; found: 316.2.
Step b) N-ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-3-isobutoxy-propyll-2-r(2-methyl- cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide (36b) Compound 36a (50 mg, 0.159 mmol) was dissolved in THF/H2O/MeOH 4:2:1 (7 mL) and LiOH (23 mg, 0.960 mmol) and cesium carbonate (112 mg, 0.318 mmol) were added. The mixture was then stirred at room temperature for 24 hours followed by an additional 24 hours at 70 0C. The mixture was the neutralized by addition of IM HCl and the solvents were evaporated. The remainder was dissolved in DMF (6 mL) and Acid-3 (50 mg, 0.146 mmol) and DIEA (102 μL, 0.584 mmol) were added after which the mixture was cooled to 0 0C. HATU (72 mg, 0.190 mmol) was added and the mixture was stirred at 0 0C for 30 minutes and then for an additional 2 hours at room temperature. The solvent was evaporated and the remainder was extracted with ethyl acetate and washed three times with brine after which the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ethyl acetate 2:1) gave the title compound (76 mg, 85%). (M+H)+ calcd: 613.3; found: 613.3.
Example 37
Figure imgf000103_0001
Step a) 3-Azido-4-(3.5-difluoro-phenoxy)-l-isobutoxy-butan-2-ol (37a) The epoxide E-Ii was opened with sodium hydride according to the conditions described in Example 28 step , but using ώo-butanol instead of methanol. The title compound was achieved in 84% yield after column chromatography using toluene/ ethyl acetate 15:1 as mobile phase.
Step b) 3-Amino-4-(3.5-difluoro-phenoxy)-l-isobutoxy-butan-2-ol (37b)
To compound 37a (257 mg, 0.815 mmol) dissolved in MeOH (12 mL) and a few drops of water was added triphenylphosphine (321 mg, 1.223 mmol) and the mixture was stirred overnight. The mixture was concentrated and the crude product was purified by flash column chromatography (ethyl acetate containing 1% MeOH saturated with NH3) which gave the title compound (234 mg, 99%).
Step c) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-3-isobutoxy-propyll-carbamic acid tert- butyl ester (37c)
To compound 37b (234 mg, 0.809 mmol) dissolved in DCM (12 mL) under nitrogen atmosphere were added TEA (169 μL, 1.214 mmol) and BoC2O (212 mg, 0.971 mmol) and the mixture was stirred overnight. Saturated NaHCCh (aq) was added and the mixture was extracted with DCM and the organic phase was washed once with brine and thereafter dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ ethyl acetate 7:1) provided the title compound (280 mg, 89%).
Step d) r2-Azido-l-(3,5-difluoro-phenoxymethyl)-3-isobutoxy-propyll-carbamic acid tert-butyl ester (37d)
The title compound was prepared from compound 37c in 69% yield according to the procedure described for the synthesis of compound 30a. Column chromatography mobile phase: toluene - toluene/ ethyl acetate 15:1.
Step e) N- [2- Azido- 1 -(3 ,5 -difluoro-phenoxymethyl)-3 -isobutoxy-propyll -2- [(2-methyl- cycloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide (37e) The title compound was prepared from compound 37d and Acid-3 in 70% yield according to the method described for the synthesis of compound 28b. Column chromatography mobile phase: toluene/ethyl acetate 7:1. (M+H)+ calcd: 638.3; found: 638.3.
Example 38
Figure imgf000104_0001
N-r2-Amino-l-(3,5-difluoro-phenoxymethyl)-3-isobutoxy-propyll-2-r(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (38) The title compound was prepared from compound 37e in 60% yield according to the method described for the synthesis of compound 35. Column chromatography mobile phase: toluene/ethyl acetate 1:1 containing 1% MeOH saturated with NH3. (M+H)+ calcd: 612.3; found: 612.3.
Example 39
Figure imgf000105_0001
N-r2-Amino-l-(3,5-difluoro-phenoxymethyl)-3-isobutoxy-propyll-3-fluoro-6-r(2-methyl- cycloprop ylmethvD-aminol -2- rmethyl-(propane-2-sulfonyl)-aminol -isonicotinamide (39) Compound 38 (15 mg, 0.0245 mmol) was dissolved in DMF (1 niL) and Selectfluor (9 mg, 0.0257 mmol) was added. The mixture was stirred at room temperature for 30 hours whereafter the solvent was evaporated. The crude material was purified by flash column chromatography (toluene/ ethyl acetate 3:1 containing 1% MeOH saturated with NH3) which gave the title compound (9 mg, 58%). (M+H)+ calcd: 630.3; found: 630.3.
Example 40
Figure imgf000105_0002
Step a) 3-Azido-4-(3,5-difluoro-phenoxy)-l-fluoro-butan-2-ol (40a) Epoxide E-Ii (105.5 mg, 0.437 mmol) was dissolved in chlorobenzene (3 mL) and potassiumhydrogen fluoride (68 mg, 0.875 mmol) and TBAF (IM in THF) (0.875 mL, 0.875 mmol) were added and the mixture was stirred at 120 0C for 90 minutes. The mixture was diluted with ethyl acetate and washed twice with brine whereafter the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ ethyl acetate 9:1) provided the title compound (72 mg, 63%). Step b) 3-Amino-4-(3.5-difluoro-phenoxy)-l-fiuoro-butan-2-ol (40b)
The title compound was prepared from compound 40a in 92% yield according to the procedure described for the synthesis of compound 37b. Chromatography mobile phase: ethyl acetate containing 1% MeOH saturated with NH3. (M+H)+ calcd: 236.1; found: 236.1.
Step c) ri-(3,5-Difluoro-phenoxymethyl)-3-fluoro-2-hydroxy-propyll-carbamic acid tert-butyl ester (40c)
The title compound was prepared from compound 40b in 84% yield according to the procedure described for the synthesis of compound 37c. Chromatography mobile phase: toluene/ ethyl acetate 7:1.
Step d) r2-Azido-l-(3,5-difluoro-phenoxymethyl)-3-fluoro-propyll-carbamic acid tert-butyl ester (4Od)
The title compound was prepared from compound 40c in 80% yield according to the procedure described for the synthesis of compound 30a. Chromatography mobile phase: toluene - toluene/ ethyl acetate 15:1.
Step e) N-[2-Azido-l-(3.5-difluoro-phenoxymethyl)-3-fluoro-propyll-2-[(2-methyl- cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (4Oe) The title compound was prepared from compound 4Od and Acid-1, in 88% yield according to the method described for the synthesis of compound 28b. Column chromatography mobile phase: toluene/ethyl acetate 5:1. (M+H)+ calcd: 584.2; found: 584.3.
Example 41
Figure imgf000106_0001
N-r2-Amino-l-(3,5-difluoro-phenoxymethyl)-3-fluoro-propyll-2-r(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (41) Compound 4Oe (64 mg, 0.1097 mmol) was dissolved in MeOH (7 mL) and the solution was run through an H-Cube hydrogen generating device using a Lindlar's catalyst cartridge (25 0C, ambient pressure, 1 mL/ min). To get complete conversion the procedure was repeated once more. The solvent was evaporated and the crude material was purified by flash column chromatography (toluene/ ethyl acetate 1 :1 containing 1% MeOH saturated with NH3) which gave the title compound (39 mg, 63%). (M+H)+ calcd: 558.2; found: 558.2.
Example 42
Figure imgf000107_0001
Step a) [2-(3.5-Difluoro-phenoxy)-l-(methoxy-methyl-carbamoyl)-ethyll-carbamic acid tert- butyl ester (42a)
To compound 28a (6.932 g, 20.923 mmol) dissolved in dioxane/ water 1 :1 (140 mL) at 0 0C was added IM LiOH (62.77 mL, 62.77 mmol) and the mixture was stirred at 0 0C for 30 minutes and then at room temperature for 2 hours. After neutralization with 1 M HCl the solvents were evaporated and co-evaporated three times with toluene. The remainder was dissolved in DMF (100 mL) and 7V,O-dimethylhydroxylamine hydrochloride (2.245 g, 23.015 mmol) and NMM (6.60 mL, 60.03 mmol) were added. The mixture was cooled to 0 0C after which EDC (4.412 g, 23.015 mmol) and HATU (7.96 g, 20.923 mmol) were added. The mixture was stirred at 0 0C for 30 minutes followed by an additional 4 hours at room temperature. The solvent was evaporated the remainder was extracted with ethyl acetate and washed three times with brine. The organic phase was dried, filtered, and concentrated and the crude material was purified by flash column chromatography (toluene/ ethyl acetate 7:1) which gave the title compound (3.05 g, 40%).
Step b) ri-(3,5-Difluoro-phenoxymethyl)-2-oxo-hexyH-carbamic acid tert-butyl ester (42b) To compound 42a (269 mg, 0.746 mmol) dissolved in dry ether (6 mL) at 0 0C was added butylmagnesium chloride (2M in THF) (149 μL, 2.99 mmol) dropwise during 5 minutes. The solution was stirred at 0 0C for 1.5 hours and the reaction was subsequently quenched by the addition of saturated NH4Cl (aq) (15 rnL). The mixture was extracted with ethyl acetate and washed twice with saturated NH4CI (aq) and the organic phase was dried, filtered and concentrated. Purification by flash column chromatography (toluene - toluene/ ethyl acetate 15:1) provided the title compound (224 mg, 84%).
Step c) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-hexyll-carbamic acid tert-butyl ester (42c) To compound 42b (114 mg, 0.319 mmol) in MeOH (6 rnL) at 0 0C was added sodium borohydride (14.5 mg, 0.383 mmol) and the mixture was stirred at 0 0C for 1 hour. Saturated NH4Cl (aq) was added and the methanol was evaporated. The mixture was extracted with ethyl acetate and washed twice with saturated NH4CI (aq) and the organic phase was dried, filtered, and concentrated. Purification by flash column chromatography (toluene/ ethyl acetate 7:1) provided the title compound (106 mg, 92%) as a diastereomeric mixture; 3:1 in favor of the R isomer.
Step d) N-[l-(3.5-Difluoro-phenoxymethyl)-2-hydroxy-hexyll-2-[methyl-(2-methyl- cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyl)-aminol-isonicotinamide (42d) Compound 42d was prepared from compound 42c and Acid-1 in 90% yield as a diastereomeric mixture; 3:1 in favour of the R isomer according to the method described for the synthesis of compound 28b. Column chromatography mobile phase: toluene/ethyl acetate 5:1 - 3:1. (M+H)+ calcd: 597.3; found: 597.3.
Example 43
Figure imgf000108_0001
Step a) l-(3,5-Difluoro-phenoxymethyl)-2-oxo-3-phenyl-propyll-carbamic acid tert-butyl ester (43a)
Compound 42a was reacted with benzylmagnesium chloride (2M in THF) according to the method described in Example 42 step b, which gave the title compound in 89% yield. Column chromatography mobile phase: toluene - toluene/ethyl acetate 15:1. Step b) [l-O.S-Difluoro-phenoxymethyD-l-hydroxy-S-phenyl-propyll-carbamic acid tert-butyl ester (43b)
Compound 43b was prepared from compound 43a in 95% yield as a diastereomeric mixture; 5:1 in favor of the R isomer according to the method described for the synthesis of compound 42c. Column chromatography mobile phase: toluene/ethyl acetate 7:1.
Step c) N- 1" 1 -(3 ,5 -Difluoro-phenoxymethyl)-2-hvdroxy-3 -phenyl-propyll -2- [(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (43c) Compound 43c was prepared from compound 43b and Acid-3 in 93% yield as a diastereomeric mixture; 5:1 in favour of the R isomer according to the method described for the synthesis of compound 28b. Column chromatography mobile phase: toluene/ethyl acetate 3:1. (M+H)+ calcd: 617.3; found: 617.2.
Example 44
Figure imgf000109_0001
Step a) [l-(3,5-Difluoro-phenoxvmethvl)-2-oxo-4-phenvl-butvll-carbamic acid tert-butvl ester
(44a)
Compound 42a was reacted with phenethylmagnesium chloride (IM in THF) according to the method described for the synthesis of compound 42b, which gave the title compound in 88% yield. Column chromatography mobile phase: toluene - toluene/ethyl acetate 15:1.
Step b) ri-(3,5-Difluoro-phenoxymethyl)-2-hvdroxy-4-phenyl-butyll-carbamic acid tert-butyl ester (44b) The title compound was prepared from compound 44a in 90% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 42c. Column chromatography mobile phase: toluene/ethyl acetate 7:1. Step c) N- [ 1 -(3.5 -Difluoro-phenoxymethylV 2-hydroxy-4-phenyl-butyr| -2- [(2-methyl- cyclopropylmethyl)-aminol-6-[methyl-(propane-2-sulfonyπ-aminol-isonicotinamide (44c) The title compound was prepared from compound 44b and Acid-3 in 82% yield as a diastereomeric mixture; 2.9:1 in favour of the R isomer according to the method described for the synthesis of compound 28b. Column chromatography mobile phase: toluene/ethyl acetate 3:1. (M+H)+ calcd: 631.3; found: 631.3.
Example 45
Figure imgf000110_0001
Step a) [2-Hydroxy-l-phenoxymethyl-3-(3-trifluoromethyl-benzylamino)-propyll-carbamic acid tert-butyl ester (45 a)
3-(Trifluoromethyl)benzylamine (0.242 ml, 1.68 mmol) was added to a solution of diastereomer mixture 28e (157 mg, 0.562 mmol; ratio of R to S was 7:2) in ethanol (2.5 ml). The reaction mixture was stirred at 50-78 0C for 4 Vi h, and was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (stepwise gradient of 1-4 % CH3OH in CH2Cl2 containing 0.1 % triethylamine) which gave the title compound as a mixture of diastereomers 45a-R/S (219 mg, 86%). ESI+, m/z: 455 (M+-HH).
Step b) 3-Amino-4-phenoxy-l-(3-trifluoromethyl-benzylamino)-butan-2-ol (45b) Diastereomer mixture 45a (218 mg, 0.480 mmol) was dissolved in a solution of 4M HCl in dioxane (8 ml). The reaction mixture was stirred at room temperature for 1 1/2 h and then concentrated under reduced pressure. The residue was dried by evaporation of added toluene (2x10 ml) and CH3CN (10 ml), to afford crude title compound.
Step c) N- [2-Hydroxy- 1 -phenoxymethyl-3 -(3 -trifluoromethyl-benzylaminoVpropyH -2- [methyl- (2-methyl-cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (45c) The crude amine 45b and Acid-1 (171 mg, 0.480 mmol) were dissolved in dry DMF (8 ml) and diisopropylethylamine (416 μl, 2.40 mmol) was added. The solution was cooled on an ice-water bath and HATU (237 mg, 0.623 mmol) was then added. The reaction mixture was stirred at 0-5 0C for 1 h and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (25 ml) and washed with saturated aqueous NaHCO3 (25 ml). The aqueous layer was washed with CH2Cl2 (2x10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (stepwise gradient of 1-2.5% CH3OH in CH2Cl2 containing 0.1 % triethylamine) to give the title compound as a mixture of diastereomers (total yield 319 mg, 96%). NMR-analysis of various collected product containing fractions showed that a partial separation of the diastereomers was obtained. In order to increase the proportion of the R- isomer, late fractions were collected separately which gave 45c-S and 45c-R in a ratio of 4:6 (5 mg). ESI+, m/z: 692 (M++H).
Example 46
Figure imgf000111_0001
Step a [2-Hydroxy-l-phenoxymethyl-3-(3-trifluoromethyl-phenylamino)-propyll-carbamic acid tert-butyl ester (46a)
To a solution of epoxide E- 17 (53.3 mg, 0.19 mmol) in ethanol (0.76 mL) was added 3- (trifluoromethyl)aniline (71.5 μL, 0.57 mmol, 3 equiv.). The mixture was refluxed 4 h, cooled down rt and concentrated in vacuo. The slurry was diluted in EtOAc, washed with a sat. aq. solution OfNaHCO3 three times, dried and concentrated to yield the title compound as a colourless oil. LCMS m/z 441 (MH)+.
Step b) 3-Amino-4-phenoxy-l-(3-trifluoromethyl-phenylamino)-butan-2-ol (46b) To a solution of compound 46a (67 mg, 0.15 mmol) in acetonitrile (0.75 mL) was added pTSA (86.8 mg, 0.46 mmol, 3 equiv.). The mixture was stirred at rt for 15 h and then filtered which gave the title compound as a white solid. LCMS m/z 341 (MH)+. Step c) 2'-Trifluoromethyl-biphenyl-3.,5-dicarboxylic acid 5-([2-hydroxy-l-phenoxymethyl-3-(3- trifluoromethyl-phenylamino)-propyl"|-amidel 3-[(l-phenyl-ethyl)-amide1 (46c) To a solution of Acid-6 (62 mg, 0.15 mmol) in anhyd. DMF (0.3 mL) was added HATU (68 mg, 0.18 mmol, 1.2 equiv.). The mixture was stirred at rt for 30 min and then cooled down to 0 0C and amine 46b (62.6 mg, 0.15 mmol) and DIEA (52.2 μL, 0.3 mmol, 2 equiv.) were added. The resulting mixture was stirred 30 min at 0 0C and then warmed up to rt and stirred for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc The organic phase was concentrated and the residue purified by RP-LC-MS (acetonitrile-10 mM aq. ammonium formate, 50-95% ) which gave the title compound in 82% yield. MS m/z 736 (M+H)+.
Example 47
OH O HO /
BocNH^ /L /R BocNI-L JL ,C\ BocNhk X -Cl
Figure imgf000112_0001
47a, R = OH 47d 47e 47b, R = OTs
Figure imgf000112_0002
Step a (2,3-Dihvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47a) To a solution of (l-phenoxymethyl-allyl)-carbamic acid tert-butyl ester (200 mg, 0.76 mmol), prepared from N-trityl-L-serine methyl ester in as described in Example E- 16 steps a-d, but using phenol instead of 3,5-difluorophenol, in acetone:water (10:1 mL) was added a catalytic amount OfOsO4 and NMO (0.16 mL, 1.52 mmol, 2 equiv., wt 50% in water). The mixture was stirred at rt overnight, diluted with water and extracted with CH2Cl2. The organic phase was washed with brine, dried and concentrated. Purification by flash chromatography (EtOAc/n-Heptane, 6/4) afforded the pure title compound in 89% yield. LCMS m/z 198 (MH-Boc)+. Step b Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-2-hydroxy-4-phenoxy-butyl ester (47^
To a solution of compound 47a (364 mg, 1.22 mmol) in CH2Cl2 (2.6 rnL) were added n- (dibutyltin)oxide (61 mg, 0.02 equiv.), tosylchloride (231 mg, 1 equiv.) and triethylamine (169 μL, 1 equiv.). The mixture was stirred at rt overnight, filtered and concentrated in vacuo which gave the title compound. LCMS m/z 352 (MH-Boc)+.
Step c (3-Chloro-2-hvdroxy-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47c) To a solution of compound 47b (550.8 mg, 1.22 mmol) in acetone (11 rnL) was added LiCl (1.24 g, 29.3 mmol, 24 equiv.) and the mixture was refluxed overnight. After cooling down to rt, the mixture was concentrated, diluted with CH2Cl2 and washed with water. The organic phase was dried and evaporated, which gave the title compound which was used in the next step without further purification. LCMS m/z 216 (MH-Boc)+.
Step d) (3-Chloro-2-oxo-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47d)
To a solution of compound 47c (385 mg, 1.22 mmol) in CH2Cl2 (12 rnL) was added Dess-Martin reagent (806 mg, 1.9 mmol, 1.5 equiv.). The mixture was stirred at rt for 2 h and then quenched with NaHCO3 (10%, aq.) and Na2S2O4. The solution was washed with water, and brine. The organic phase was dried and evaporated and the afforded residue was purified by flash chromatography (EtOAc/n-Heptane, 2/8) which gave the title compound in 92% yield. LCMS m/z 214 (MH-BoC)+.
Step e) 3-Chloro-2-hydroxy-2-methyl-l-phenoxymethyl-propyl)-carbamic acid tert-butyl ester (47e) To a solution of compound 47d (100 mg, 0.32 mmol) in THF (0.8 rnL) methylmagnesium bromide (0.32 mL, 3 equiv., 3 M in Et2O) was added dropwise at -78 0C. The mixture was stirred 1 h at -78 0C, and then slowly warmed up to rt overnight. The reaction was then quenched with a sat aqueous, solution of sodium chloride and extracted with EtOAc. The organic phase was dried and evaporated and the afforded residue was purified by flash chromatography (EtO Ac/n- Heptane, 2/8) which gave the title compound in 55% yield). LCMS m/z 230 (MH-Boc)+.
Step f) r2-Hvdroxy-2-methyl-3-(3-methyl-benzylamino)- 1 -phenoxymethyl-propyll-carbamic acid tert-butyl ester (47f) To a solution of compound 47e (23.4 mg, 0.071 mmol) in EtOH (0.28 mL) was added 3- (trifluoromethyl)benzyl amine (31 μL, 0.21 mmol, 3 eq.). The mixture was refluxed overnight, cooled down to rt and concentrated. EtOAc was added and the solution was washed with a sat aq. solution of NaHCOs. The organic phase was dried and evaporated and the afforded residue was used in the next step without any further purification. LCMS m/z 469 (MH)+.
Step g) 3-Amino-2-methyl-l-(3-methyl-benzylamino)-4-phenoxy-butan-2-ol (47g) To a solution of Boc protected aminoalcohol 47f (33 mg, 0.07 mmol) in acetonitrile (0.34 mL) was added pTSA (41 mg, 0.21 mmol, 3 equiv.). The mixture was stirred at rt for 15 h and then filtered which gave the title compound as a white solid. LCMS m/z 369 (MH)+.
Step h) N-r2-Hvdroxy-2-methyl-3-(3-methyl-benzylamino)- 1 -phenoxymethyl-propyll-2- rmethyl-(2-methyl-cvcloprop ylmethvD-aminol -6- rmethyl-(propane-2-sulfonyl)-aminol - isonicotinamide (47h) To a solution of Acid- 1 (21 mg, 0.059 mmol) in anhyd. DMF (0.12 mL) was added HATU (27 mg, 0.07 mmol, 1.2 equiv.). The mixture was stirred at rt for 30 min and then cooled down to 0 0C. Compound 47g (80 mg, 0.07 mmol, 1.2 equiv) and DIEA (51.4 μL, 0.3 mmol, 5 equiv.) were added. The resulting mixture was stirred 30 min at 0 0C and then warmed up to rt and stirred 18 h, diluted with water and extracted with EtOAc. The organic phase as concentrated and the afforded residue purified by RP-LC-MS (acetonitrile- 10 mM aq. ammonium formate, 40-90% ) which gave the title compound in 84% yield. MS m/z 706 (M+H)+'
Example 48
Figure imgf000114_0001
Step a) ri-(3,5-Difluoro-phenoxymethyl)-3-hvdroxy-propyll-carbamic acid tert-butyl ester(48a) To a solution of compound E-16d (200 mg, 0.67 mmol) in THF (8 mL) was added 9-BBN (3.76 niL, 2.8 equiv., 0.5 M in THF) at 0 0C under N2. The mixture was stirred overnight and then NaOH (3.34 mL, 3 N), and H2O2 (3.34 mL, 30%) were added at 0 0C. The mixture was stirred at rt overnight, quenched with MeOH (3.34 mL) and extracted with EtOAc. Purification by flash chromatography (EtOAc/n-Heptane, 1/1) afforded the pure title compound in 80% yield. LCMS m/z 340 (MNa)+.
Step b) 3-Amino-4-(3,5-difluorophenoxy)-butan-l-ol (48b)
To a solution of Boc protected aminoalcohol 48a (70 mg, 0.22 mmol) in acetonitrile (1.1 mL) was added pTSA (125.5 mg, 0.66 mmol, 3 equiv.). The mixture was stirred at rt for 15 h and then filtered which gave the title compound as a white solid. LCMS m/z 218 (MH)+.
Step c) N- r 1 -(3 ,5 -Difluoro-phenoxymethyl)-3 -hvdroxy-propyll -2- [(2-methyl- cvclopropylmethyl)-aminol-6-rmethyl-(propane-2-sulfonyl)-aminol-isonicotinamide (48c) To a solution of Acid-3 (19 mg, 0.059 mmol) in anhyd. DMF (0.12 mL) was added HATU (25 mg, 0.07 mmol, 1.2 equiv.). The mixture was stirred at rt for 30 min and then cooled down to 0 0C. The amine 48b (22.5 mg, 0.055 mmol, 1 equiv) and DIEA (48 μL, 0.27 mmol, 5 equiv.) were added. The resulting mixture was stirred 30 min at 0 0C and then warmed up to rt and stirred 18 h. The mixture was diluted with H2O and extraction with EtOAc, the organic phase was concentrated and the afforded residue was purified by flash chromatography (EtOAc/n-Heptane, 1/1) which gave the title compound in 94% yield. MS m/z 541 (M+H)+
Example 49
Figure imgf000115_0001
49a , R = N3 49c
49b , R = NH2
Step a) 3-Amino-4-(3,5-difluoro-phenoxy)-l-(3-iodo-benzylamino)-butan-2-ol (49a) To a solution of the epoxide E-Ii (100 mg, 0.42 mmol) in ethanol (1.7 mL) was added 3- iodobenzyl amine (166 μL, 1.24 mmol, 3 equiv.). The mixture was refluxed overnight, cooled to rt and concentrated in vacuo. The slurry was diluted in EtOAc, washed with a sat. aq. solution of NaHCOs three times, dried and concentrated. Purification by flash chromatography (EtO AcIn- Heptane, 2/8) afforded pure title compound (66%). LCMS m/z Al 5 (MH)+
Step b) 3-Azido-4-(3,5-difluoro-phenoxy)-l-(3-iodo-benzylamino)-butan-2-ol (49b) To a solution of compound 49a (125 mg, 0.26 mmol) in methanol (7.31 mL) was added PPI13 (103.2 mg, 0.39 mmol, 1.5 equiv.) and water (3 drops). The mixture was stirred at rt overnight and concentrated. Purification by flash chromatography (toluene/npropanol/Nϊ^OH, 8/2/0.1) afforded pure title compound (73%). LCMS m/z 449 (MH)+.
Step c) N- r 1 -(3 ,5 -Difluoro-phenoxymethyl)-2-hvdroxy-3 -(3 -iodo-benzylamino)-propyll -3 - dipropylamino-5-methyl-benzamide (49c)
To a solution of 3-dipropylamino-5-methyl-benzoic acid (42 mg, 0.16 mmol) in anhyd. DMF (0.32 mL) was added HATU (72 mg, 0.19 mmol, 1.2 equiv.). The mixture was stirred at rt for 30 min and then cooled down to 0 0C. The amine 49b (86 mg, 0.19 mmol, 1.2 equiv) and DIEA (56 μL, 0.32 mmol, 2 equiv.) were added. The resulting mixture was stirred 30 min at 0 0C and then warmed to rt and stirred for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc, the organic phase was concentrated and the afforded residue was purified by RP-LC-MS (acetonitrile-10 mM aq. ammonium formate, 40-90% ) which gave the title compound in 78% yield. MS m/z 694 (M+H)+.
Intermediate 1
Figure imgf000116_0001
Step a) (26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-3-(4-methoxy-benzyloxy)-5-methoxy-6- phenoxy-hexane (I- Ia)
DIAD (28 μL, 0.141 mmol, 1.4 equiv) was added drop wise at 0 0C to a stirred solution of 1-14 (44 mg, 0.101 mmol), phenol (14.3 mg, 0.152 mmol, 1.5 equiv) and Ph3P (37 mg, 0.141 mmol, 1.4 equiv) in freshly distilled DCM (3 mL). The reaction mixture was allowed to reach room temperature. After 16 h the reaction mixture was evaporated and purified by column chromatography (toluene) to give the title compound product (32.5 mg, 0.063 mmol, 63%) as a clear oil. MS (ESI) m/z 536.2 ([M+Na]+ calcd for C27H29F2N3NaO5 536.2).
Step b) (26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-5-methoxy-6-phenoxy-hexan-3-ol (I-lb) DDQ (11.5 mg, 0.051 mmol, 1.3 equiv) was added at 0 0C to a stirred solution of I- Ia (20 mg, 0.039 mmol) in DCM:H20 (19:1, 10 mL). The reaction was allowed to reach room temperature then stirred for an additional 3 h. The reaction mixture was washed with saturated NaHCO3 (aq) and water, dried over Na2SO4, evaporated and purified by column chromatography (toluene- EtOAc, 50:1) to give the title compound (13.7 mg, 0.035 mmol, 89%) as a clear oil. MS (ESI) m/z 416.1 ([M+Na]+ calcd for Ci9H2IF2N3NaO4 + 416.1).
Intermediate 2
Figure imgf000117_0001
Step a) N-(4-Fluoro-phenyO-2-nitro-benzenesulfonamide (I-2a) Nosylchloride (177 mg, 0.8 mmol) and pyridine (194 μL, 2.4 mmol, 3 equiv) were added to a solution of 4-flouranilin (154 μL, 1.6 mmol, 2 equiv) in freshly distilled DCM (2mL). The reaction was stirred at room temperature for two hours then quenched with 10% HCl (aq), the pH was set to ~1 before extracting with DCM (2x). The combined organic phases was washed with brine, dried over MgSO4, concentrated and purified by silica column chromatography (toluene- EtOAc, 50:1) to give the title compound (165mg, 0.56 mmol, 70%) as a pale yellow oil.
1H-NMR (400 MHz, CDCl3) δ 7.86 (dd, IH, J= 1.3, 8.0 Hz), 7.76 (dd, IH, J= 1.4, 7.8 Hz), 7.71 (dt, IH, J= 1.4, 7.8 Hz), 7.58 (dt, IH, J= 1.3, 7.7 Hz) 7.16 (m, 2H), 6.96 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 161.4 (d, JCF = 246.8 Hz), 148.4, 134.2, 132.7, 132.0, 131.9, 131.4 (d, JCF = 3.4 Hz), 126.1 (d, JCF = 8.6 Hz), 125.4, 116.5 (d, JCF = 22.9 Hz); MS (ESI) m/z 319.0 ([M+Na]+ calcd for Ci2H9FN2NaO4S+ 319.0).
Step b) r(2iM£55V5-Azido-6-(3,5-difluoro-phenoxy)-2-methoxy-4-(4-methoxy-benzyloxy)- hexyl1-(4-fluoro-t>henyl)-amine (I-2b) DIAD (32 μL, 0.164 mmol, 1.4 equiv) was added drop wise at 0 0C to a stirred solution of 1-14 (51 mg, 0.117 mmol), I-2a (47 mg, 0.159 mmol, 1.36 equiv) and Ph3P (43 mg, 0.164 mmol, 1.4 equiv) in freshly distilled DCM (3 mL). The reaction mixture was allowed to reach room temperature, then left stirring over night. The solvent was evaporated and the crude product was used dissolved in MeCN and thiophenol (36μL, 0.351 mmol, 3 equiv) was added followed by potassium carbonate (48 mg, 0.351 mmol, 3 equiv). The reaction was heated to 50 0C and followed by TLC. After 3h all starting material was consumed. The reaction mixture was evaporated, co-evaporated with toluene and then filtered through a short silica plug using ethyl acetate as eluent and then concentrated and purified by silica column chromatography (toluene- EtOAc, 50:1) which gave the title compound (30 mg, 0.056 mmol, 48%) as a pale yellow oil. MS (ESI) m/z 531.2 ([M+H]+ calcd for C27H30F3N4O4 + 531.2).
Step c) (26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-,6-(4-fluoro-phenylamino)-5-methoxy- hexan-3-ol (I-2c)
Compound I-2b (50 mg, 0.094 mmol) was stirred in a solution of TFA (10%) in freshly distilled DCM (1 ml) at room temperature for 40 minutes. The reaction was evaporated then co- evaporated 5 times with toluene before purification by silica column chromatography (toluene- EtOAc, 30:1 - 5:1) which gave the title compound (38mg, 0.093 mmol, 99%) as a clear oil. MS (ESI) m/z 411.2 ([M+H]+ calcd for Ci9H22F3N4O3 + 411.2).
Intermediate 3
Figure imgf000118_0001
Step a) Methyl 5-azido-3,5-dideoxy-6-O-(3,5-difluorobenzyl)-L-/vxo-hexofuranoside (I-3a)
Compound 9b (2.586 g, 7.28 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 (1.816 g, 5.53 mmol, 76%). Step b) Methyl 5-azido-3.5-dideoxy-6-O-(3.5-difluoroberizylV2-O-methyl-L-/vxo- hexofuranoside (I-3b)
Compound I-3a (1.816 g, 5.51 mmol) was dissolved in DMF, methyl iodide (8 eq.) and Ag2O (2 eq.) were added. The reaction was stirred at room temperature over night, then quenched with CHCI3 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) which gave the title compound (1.449 g, 4.25 mmol, 77%).
Step c) 5-Azido-3,5-dideoxy-6-Q-(3,5-difluorobenzyl)-2-Q-methyl-L-/vxo-hexofuranoside (I-3c) The methyl glycoside I-3b (1.449 g, 4.22 mmol) was dissolved in 1, 4-dioxane/ 0.5 M H2SO4 1 :1 and heated to reflux. After complete reaction (~1 hour according to TLC), the reaction was cooled to room temperature and then neutralized with Na2CO3 (aq). The volatile solvents were evaporated under vacuum and the afforded residue 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 (876 mg, 2.66 mmol, 63%). MS m/z 352.11 [(M+Na)+ calcd for Ci4Hi7F2N3NaO4 + 352.11]
Step d) (2i?.46'.55)-5-Azido-6-(3.5-difluoro-phenoxyV2-methoxy-hexane-1.4-diol (I-3cD LiBH4 (200 mg, 9.22 mmol, 2 equiv) was added under an argon atmosphere at 0 0C to a stirred solution of compound I-3c (1.45 g, 4.61 mmol) in dry THF (20 mL). After 1 h the reaction was quenched with water, extracted with EtOAc, dried over Na2SO4 and concentrated. The afforded residue was purified by silica gel chromatography (toluene-EtOAc, gradient 20:1 - 5:1), which gave the title compound (1.39 g, 4.38 mmol, 95%) as a clear oil. [α]20 D -5.8 (c 1.00, MeOH); 1H-NMR (400 MHz, CDCl3) δ 6.50-6.41 (m, 3H), 4.26 (dd, IH, J= 4.1, 9.7 Hz), 4.15 (dd, IH, J = 8.0, 9.8 Hz), 4.05 (m, IH), 3.88 (m, IH), 3.71 (m, IH), 3.36-3.23 (m, 2H). 3.45 (s, 3H), 2.01- 1.90 (m, IH), 1.80 (m, IH), 1.64 (bs, IH); 13C-NMR (100 MHz, CDCl3) δ 165.0 (d, JCF = 15.4 Hz), 162.5 (d, JCF = 16.2 Hz), 160.2, (t, JCF = 13.9 Hz), 98.6, (dd, JCF = 12.4, 29.1 Hz), 97.1, (t, JCF = 25.7 Hz), 80.4, 69.4, 64.6, 62.8, 57.1, 34.8; MS (ESI) m/z 340.1 ([M+Na]+ calcd for Ci3HnF2N3NaO4 + 340.1).
General method for preparation of Intermediates 4-10
Figure imgf000120_0001
l-3d 1-4 - 1-10
NaH (60% in mineral oil) (1.2 equiv) was added to a stirred solution of diol I-3d in dry DMF at 0 0C. After 30 min the halide (R-X) (1.5 equiv) and tert-butyi ammonium iodide (0.1 equiv.) were added. The reaction was allowed to reach room temperature and then left stirring for an additional 16 h. The reaction was quenched with MeOH, concentrated and purified by silica column chromatography (toluene-EtOAc, gradient 30:1 - 5:1) which gave intermediates 1-4 - I- 10.
Figure imgf000120_0002
Intermediate 11
Figure imgf000121_0001
(26',36',5i?)-2-Azido-6-benzyloxy-l-(3,5-difluoro-phenoxy)-5-methoxy-hexan-3-ol (I- 11) Under argon atmosphere, dibutyltinoxide (85 mg, 0.341 mmol, 1.32 equiv) was added to a stirred solution of I-3d (82 mg, 0.258 mmol) in dry toluene (3 mL). The reaction was refluxed for two hours with a Dean-Starke trap. After 2 h benzylbromide (61 μL, 0.517 mmol, 2 equiv) and tert- butyl ammonium iodide (126 mg, 0.341 mmol, 1.32 equiv) were added. The reaction mixture was refluxed Ih before it was concentrated and purified by silica column chromatography (toluene-EtOAc, gradient 30:1 - 5:1) which gave the title compound (40 mg, 0.098 mmol, 38%). MS (ESI) m/z 430.2 ([M+Na]+ calcd for C20H23F2N3NaO4 + 430.2).
Intermediate 12
Figure imgf000121_0002
(46'.6i?)-4-r(iy)-l-Azido-2-(3.5-difluoro-phenoxy)-ethyl1-6-methoxy-2-(4-methoxy-phenyl)- [1.3]dioxepane (1-12) Anisaldehyde dimethylacetal (228 μL, 1.34 mmol, 1.5 equiv) and p-TsOH (8mg, 0.045 mmol, 0.05 equiv) were added to a stirred solution of I-3d (283 mg, 0.892 mmol) in freshly distilled DMF (10 mL). The reaction mixture was heated to 50 0C under reduced pressure. After approximately 1.5h, TLC indicated that all starting material was consumed. A couple of drops of TEA was added and the reaction mixture was concentrated and purified by silica column chromatography (toluene-EtOAc, gradient 100:1 - 10:1) to give the title compound (382 mg, 0.877 mmol, 98%). MS (ESI) m/z 458.2 ([M+Na]+ calcd for C2IH23F2N3NaO5 + 458.2).
Intermediates 13 and 14
Figure imgf000122_0001
(26',36',5i?)-2-Azido-l-(3,5-difluoro-phenoxy)-5-methoxy-6-(4-methoxy-benzyloxy)-hexan-3-ol (1-13) and
(2i?,46',5y)-5-Azido-6-(3,5-difluoro-phenoxy)-4-(4-methoxy-benzyloxy)-hexan-l-ol (I-14) A solution OfMe3SiCl (483 μL, 3.846 mmol, 6 equiv) in MeCN (3mL) , kept at 0 0C, was added drop wise to a stirred mixture of 1-12 (279 mg, 0.641 mmol), NaCNBH3 (242 mg, 3.846 mmol, 6 equiv) and 3A molecular sieves in MeCN (7.5 mL). The reaction mixture was stirred at 0 0C for 30 min, then allowed to reach room temperature before it was filtrated through Celite and evaporated. The residue was dissolved in DCM and washed with NaHCO3(aq), the organic phase was dried over Na2SO4, evaporated and purified by silica column chromatography (toluene- EtOAc, gradient 60:1 - 3:1) which gave the title compounds 1-13 (124 mg, 0.283 mmol, 44%) (ESI) m/z 460.2 ([M+Na]+ calcd for C2IH25F2N3NaO5 + 460.2) and 1-14 (91 mg, 0.208 mmol, 32%). MS (ESI) m/z 460.2 ([M+Na]+ calcd for C2IH25F2N3NaO5 + 460.2).
General method for preparation of compounds 50-54
Figure imgf000122_0002
Palladium on charcoal (~5%) was added to a solution of the azide (N3-R) (1 equiv) in MeOH under argon atmosphere. The flask was evacuated followed by addition of hydrogen gas (1 atm). The reaction mixture was stirred over night. The Pd/C was filtered off and the filtrate was concentrated to yield the crude product which was used in the next step without further purification. 5-(Methanesulfonyl-methyl-amino)-N-(l-phenyl-ethyl)-isophthalamic acid (1 equiv) was dissolved in dry DCM and pyBOP (1 equiv) was added followed by DIPEA (1 equiv). After 30 minutes the crude amine (1 equiv dissolved in DCM) was added to the mixture, followed by DIPEA (1 equiv). After 2 h, the reaction mixture was diluted with DCM, washed with Na2CCh (sat.) and NH4Cl (aq). The aqueous layers was extracted with DCM (3x), and the combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by silica column chromatography (Toluene-EtOAc gradient 10:1 - 1 :6) to yield the crude compounds 17-21 which was further purified by LC-MS.
N11R
Example
Yield
JV-[(15,25,4R)-l-(3,5-Difluoro- I-3d phenoxymethyl)-2,5-dihydroxy-4-methoxy- 21% pentyl] -5 -(methanesulfonyl-methylamino)- N'-((i?)-l-phenylethyl)-isophthalamide (50)
JV-[(l£,2£,4R)-l-(3,5-Difluoro- 1-4 phenoxymethyl)-2-hydroxy-4,5-dimethoxy- 43% pentyl] -5 -(methanesulfonyl-methylamino)- N'-((i?)-l-phenylethyl)-isophthalamide (51)
JV-[(15,25,4R)-l-(3,5-Difluoro- 1-5 phenoxymethyl)-2-hydroxy-5-isobutoxy-4- 85% methoxy-pentyl] -5 -(methanesulfonyl- methylamino)-7V'-((i?)- 1 -phenylethyl)- isophthalamide (52)
N-[(lS,2S,4i?)-5-Cyclopropylmethoxy-l- 1-6 (3,5-difluoro-phenoxymethyl)-2-hydroxy-4- 65% methoxy-pentyl] -5 -(methanesulfonyl- methylamino)-7V'-((i?)- 1 -phenylethyl)- isophthalamide (53)
Figure imgf000123_0001
N11R
Example
Yield
JV-[(l£,2£,4R)-l-(3,5-Difluoro- 1-7 phenoxymethyl)-2-hydroxy-4-methoxy-5- 39% (4,4,4-trifluoro-butoxy)-pentyl]-5- (methanesulfonylmethylamino)-N'-((i?)- 1 - phenyl-ethyl)-isophthalamide (54)
Figure imgf000124_0001
Analytical data for compounds of Examples 50-54 Ex. 50
1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.6 Hz), 8.04 (m, 2H), 7.44-7.08 (m, 5H), 6.65- 6.47 (m, 3H), 5.25 (m, IH), 4.55 (m, IH), 4.27 (dd, IH, J= 6.5, 9.9 Hz), 4.17 (m, 2H), 3.69 (dd, IH, J= 3.4, 11.4 Hz), 3.54-3.44 (m, 2H). 3.39 (s, 3H), 3.38 (s, 3H), 2.97 (s, 3H), 1.78 (m, 2H), 1.64 (d, 3H, J= 7.0 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.1, 167.8, 166.4 (d, JCF = 15.9 Hz), 164.0 (d, JCF = 16.1 Hz), 162.3 (t, JCF = 13.9 Hz), 145.1, 143.8, 137.5, 137.1, 129.6, 129.4, 129.3, 129.2, 128.2, 127.3, 125.9, 98.6 (dd, JCF = 13.2, 29.1 Hz), 97.2 (t, JCF = 26.4 Hz), 80.8, 68.8, 68.2, 63.6, 57.4, 54.2, 51.0, 38.3, 36.3, 35.9, 22.1; HRMS (ESI) m/z 650.2340 ([M+H]+ calcd for C3IH38F2N3O8S+ 650.2342).
Ex. 51
1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.6 Hz), 8.04 (m, 2H), 7.43-7.18 (m, 5H), 6.62 (m, 2H), 6.51 (m, IH), 5.25 (dd, IH, J= 7.0, 14.0 Hz), 4.54 (m, IH), 4.26 (dd, IH, J= 6.5, 9.8
Hz), 4.16 (m, 2H), 3.60 (m IH), 3.50 (dd, IH, J= 3.6, 10.5 Hz), 3.43 (dd, IH, J= 5.2, 10.5 Hz).
3.39 (s, 3H), 3.37 (s, 3H), 3.33 (s, 3H), 2.97 (s, 3H), 1.77 (m, 2H), 1.58 (d, 3H, J= 7.1 Hz); 13C-
NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 16.1 Hz), 164.0 (d, JCF = 16.1 Hz),
162.3 (t, JCF = 13.6 Hz), 145.1, 143.8, 137.5, 137.1, 129.6, 129.3, 129.3, 129.2, 128.2, 127.3, 125.9, 99.6 (dd, JCF = 12.3, 28.7 Hz), 97.2 (t, JCF = 26.4 Hz), 79.1, 75.0, 68.8, 68.2, 59.4, 57.6,
54.2, 51.0, 38.3, 36.6, 35.9, 22.1; HRMS (ESI) m/z 686.2302 ([M+Na]+ calcd for
C32H39F2N3NaO8S+ 686.2318).
Ex. 52 1H-NMR (400 MHz, CD3OD) δ 8.25 (t, IH, J= 1.6 Hz), 8.05 (m, 2H), 7.40 (m, 2H), 7.33 (m, 2H), 7.23 (m, IH), 6.62 (m, 2H), 6.51 (m, IH), 5.25 (dd, IH, J= 7.1, 14.1 Hz), 4.55 (m, IH), 4.26 (dd, IH, J= 6.6, 9.8 Hz), 4.17 (m, 2H), 3.60 (m, IH), 3.49 (m, 2H). 3.40 (s, 3H), 3.37 (s, 3H), 3.19 (m, 2H), 2.97 (s, 3H), 1.79 (m, 3H), 1.58 (d, 3H, J= 7.1 Hz), 0.85 (d, 6H, J=6.7 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 16.1 Hz), 164.0 (d, JCF = 16.1 Hz), 162.3 (t, JCF = 13.9 Hz), 145.0, 143.8, 137.4, 137.0. 129.6, 129.3, 128.2, 127.3, 125.9, 99.6 (dd, JCF = 12.8, 28.8 Hz), 97.2 (t, JCF = 26.3 Hz), 79.4, 79.2, 73.4, 68.7, 68.2, 57.7, 54.1, 51.0, 38.3, 36.9, 35.9, 29.6, 19.7, 19.7; HRMS (ESI) m/z 728.2790 ([M+Na]+ calcd for C35H45F2N3NaO8S+ 728.2778).
Ex. 53
1H-NMR (400 MHz, CD3OD) δ 8.25 (t, IH, J= 1.5 Hz), 8.04 (m, 2H), 7.44-7.08 (m, 5H), 6.62 (m, 2H), 6.51 (m, IH), 5.25 (dd, IH, J= 7.0, 14.0 Hz), 4.55 (m, IH), 4.27 (dd, IH, J= 6.5, 9.9 Hz), 4.17 (m, 2H), 3.58 (m, 2H), 3.50 (m, IH). 3.40 (s, 3H), 3.37 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 1.79 (t, 2H, J= 6.5 Hz), 1.58 (d, 3H, J= 7.1 Hz), 0.97 (m, IH), 0.46 (m, 2H), 0.16 (m, 2H); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 16.2 Hz), 164.0 (d, JCF = 16.2 Hz), 162.3 (t, JCF = 14.0 Hz), 145.0, 143.8, 137.5, 137.0, 129.9, 129.6, 129.3, 129.3, 128.2, 127.3, 125.9, 99.6 (dd, JCF = 12.6, 29.0 Hz), 97.2 (t, JCF = 26.3 Hz), 79.2, 77.0, 72.7, 68.7, 68.2, 57.6, 54.2, 51.0, 38.3, 36.7, 35.9, 22.1, 11.4, 3.4, 3.4; HRMS (ESI) m/z 726.2647 ([M+Na]+ calcd for C35H43F2N3O8SNa+ 726.2631).
Ex. 54
1H-NMR (400 MHz, CD3OD) δ 8.25 (t, IH, J= 1.6 Hz), 8.04 (m, 2H), 7.42-7.20 (m, 5H), 6.62
(m, 2H), 6.51 (m, IH), 5.25 (dd, IH, J= 7.0, 14.0), 4.55 (m, IH), 4.26 (dd, IH, J= 6.5, 9.89 Hz), 4.17 (m, 2H), 3.65 -3.45 (m, 5H). 3.40 (s, 3H), 3.37 (s, 3H), 2.97 (s, 3H), 2.18 (m, 2H), 1.77 (m, 4H), 1.59 (d, 3H, J= 7.1 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 16.0 Hz), 164.0 (d, JCF = 15.9 Hz), 162.3 (t, JCF = 13.8 Hz), 145.1, 143.8, 137.5, 137.0, 129.6, 129.4, 129.3, 128.2, 127.3, 125.9, 99.6 (dd, JCF = 12.7, 28.9 Hz), 97.2 (t, JCF = 26.4 Hz), 79.1, 73.2, 70.6, 68.8, 68.2, 57.7, 54.1, 51.0, 38.3, 36.7, 35.9, 31.4 (dd, JCF = 28.7, 86.5 Hz), 23.5 (dd, JCF = 3.1, 9.1 Hz), 22.1; HRMS (ESI) m/z 760.2677 ([M+H]+ calcd for C35H43F5N3O8S+ 760.2686).
General method for preparation of compounds 55-61
Figure imgf000126_0001
Triphenyl phosphine (1.5 equiv) was added together with a drop of water to a solution of the azide (1 equiv) in MeOH. The reaction mixture was stirred for 16 h, concentrated to yield the crude compound which was used in the next step without further purification. Acid A (I equiv) was dissolved in dry DCM and pyBOP (1 equiv) was added followed by DIPEA (1 equiv). After 30 minutes the crude amine (1 equiv, dissolved in DCM) was added to the mixture, followed by DIPEA (1 equiv). After 2 h, the reaction mixture was diluted with DCM, washed with Na2CO3 (sat.) and NH4Cl (aq). The aqueous layers was extracted with DCM (3x), and the combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by silica column chromatography (Toluene-EtOAc gradient 10:1 - 1 :6) to yield the crude compounds 22- 28 which was further purified by LC-MS.
Azide
Example Yield
JV-[(15,25,4R)-5-AUyloxy-l-(3,5-difluoro- 1-8 phenoxymethyl)-2-hydroxy-4-methoxy- 82% pentyl] -5 -(methanesulfonyl-methyl-amino)- N'-((i?)-l-phenyl-ethyl)-isophthalamide (55)
JV-[(15,25,4R)-l-(3,5-Difluoro- 1-9 phenoxymethyl)-5-(4-fluoro-benzyloxy)-2- 70% hydroxy-4-methoxy-pentyi] -5 - (methanesulfonyl-methyl-amino)-iV'-((i?)- 1 - phenyl-ethyl)-isophthalamide (56)
Figure imgf000126_0002
Azide
Example Yield
JV-[(l£,2£,4R)-l-(3,5-Difluoro- 1-10 phenoxymethyl)-2-hydroxy-4-methoxy-5 -(3 - 92% methoxy-benzyloxy)-pentyl] -5 - (methanesulfonyl-methyl-amino)-N'-((i?)- 1 - phenyl-ethyl)-isophthalamide (57)
N-[(lS,2S,4i?)-5-Benzyloxy-l-(3,5-difluoro- 1-11 phenoxymethyl)-2-hydroxy-4-methoxy- 83% pentyl] -5 -(methanesulfonyl-methyl-amino)- N '-((R)- 1 -phenyl-ethyl)-isophthalamide (58)
JV-[(l£,2£,4R)-l-(3,5-Difluoro- 1-13 phenoxymethyl)-2-hydroxy-4-methoxy-5-(4- 3% methoxy-benzyloxy)-pentyl] -5 - (methanesulfonyl-methyl-amino)-N'-((i?)- 1 - phenyl-ethyl)-isophthalamide (59)
JV-[(l£,2£,4R)-l-(3,5-Difluoro- I-lb phenoxymethyl)-2-hydroxy-4-methoxy-5- 61% phenoxy-pentyl] -5 -(methanesulfonyl-methyl- amino)-N'-((R)- 1 -phenyl-ethyl)- isophthalamide (60)
JV-[(l£,2£,4R)-l-(3,5-Difluoro- I-2c phenoxymethyl)-5-(4-fluoro-phenylamino)-2- 40% hydroxy-4-methoxy-pentyl] -5 - (methanesulfonyl-methyl-amino)-N'-((i?)- 1 - phenyl-ethyl)-isophthalamide (61)
Figure imgf000127_0001
Analytical data for compounds of Examples 55-61 Ex. 55 1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.6 Hz), 8.04 (m, 2H), 7.43-7.21 (m, 5H), 6.65- 6.48 (m, 3H), 5.86 (m, IH), 5.24 (m, 2H), 5.11 (m, IH), 4.55 (m, IH), 4.26 (dd, IH, J= 6.5, 9.9 Hz), 4.17 (m, 2H), 3.98 (m, 2H), 3.61 (m, IH), 3.56 (dd, IH, J= 3.7, 10.5 Hz), 3.48 (dd, IH, J = 5.1, 10.5 Hz), 3.40 (s, 3H), 3.37 (s, 3H), 2.97 (s, 3H), 1.79 (t, 2H, J= 6.6 Hz), 1.58 (d, 3H, J = 7.1 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 15.9 Hz), 164.0 (d, JCF = 16.0 Hz), 162.3 (t, JCF = 13.8 Hz), 145.0, 143.8, 137.5, 137.0, 136.0, 129.6, 129.3, 128.2, 127.2, 125.9, 117.2, 99.6 (dd, JCF = 13.0, 28.8 Hz), 97.2 (t, JCF = 26.4 Hz), 79.2, 73.2, 72.4, 68.8, 68.2, 57.7, 54.1, 51.0, 38.3, 36.7, 35.9, 22.1; HRMS (ESI) m/z 712.2496 ([M+Na]+ calcd for C34H4IF2N3O8SNa+ 712.2475).
Ex. 56
1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.5 Hz), 8.04 (m, 2H), 7.40 (m, 2H), 7.30 (m, 4H), 7.22 (m, 2H), 7.12 (m, IH), 6.98 (m, 2H), 6.60 (m, 2H), 6.50 (m, 2H), 5.24 (dd, IH, J= 7.0, 14.1), 4.54 (s, IH), 4.47 (d, 2H, J= 4.5 Hz), 4.25 (dd, IH, J= 6.6, 10.0 Hz), 4.17 (m, 2H), 3.64 (m, IH), 3.58 (dd, IH, J= 3.7, 10.4 Hz), 3.51 (dd, IH, J= 5.0, 10.4 Hz), 3.38 (s, 3H), 3.35 (s,
3H), 2.94 (s, 3H), 1.81 (m, 2H), 1.58 (d, 3H, J= 7.0 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.7, 166.4 (d, JCF = 15.9 Hz), 164.9, 163.9 (d, JCF = 16.0 Hz), 162.5, 162.3 (t, JCF = 13.8 Hz), 145.0, 143.8, 137.4, 137.0, 135.6 (d, JCF = 3.3 Hz), 130.7 (d, JCF = 8.2 Hz), 129.9, 129.6, 129.4, 129.3, 129.2, 128.2, 127.3, 126.3, 125.9, 116.0 (d, JCF = 21.8 Hz), 99.6 (dd, JCF = 12.4, 28.7 Hz), 97.2 (t, JCF = 26.3 Hz), 79.1, 73.4, 72.3, 68.8, 68.2, 57.7, 54.1, 60.0, 38.3, 36.7, 35.9, 22.1; HRMS (ESI) m/z 758.2683 ([M+H]+ calcd for C38H43F3N3O8S+ 758.2717).
Ex. 57
1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.5 Hz), 8.04 (m, 21H), 7.40 (m, 2H), 7.32 (m, 2H), 7.26-7.09 (m, 2H), 6.85 (m, 2H), 6.78 (m, IH), 6.60 (m, 2H), 6.50 (m, IH), 5.24 (dd, IH, J = 7.0, 14.0 Hz), 4.59 (bs, IH), 4.55 (m, IH), 4.48 (d, 2H, J= 5.4 Hz), 4.24 (dd, IH, J= 6.5, 9.9 Hz), 4.15 (m, 2H), 3.73 (s, 3H), 3.67-3.56 (m, 2H), 3.51 (dd, IH, J= 4.8, 10.5 Hz), 3.39 (s, 3H), 3.35 (s, 3H), 2.94 (s, 3H), 1.81 (m, 2H), 1.58 (d, 3H, J= 7.1 Hz); 13C-NMR (IOO MHz, CD3OD) δ 169.0, 167.7, 166.4 (d, JCF = 16.0 Hz), 166.3, 164.0, (d, JCF = 15.8 Hz), 162.3 (t, JCF = 13.9 Hz), 161.2, 145.0, 143.8, 141.1, 137.4, 137.0, 130.4, 129.6, 129.3, 129.2, 128.2, 127.3, 125.9, 120,9, 114.1, 99.6 (dd, JCF = 12.4, 28.6 Hz), 97.2 (t, JCF = 26.5 Hz), 79.1, 74.1, 72.2, 68.8, 68.2, 57.7, 55.6, 54.2, 51.0, 38.3, 36.8, 35.9, 22.1; HRMS (ESI) m/z 792.2709 ([M+Na]+ calcd for C39H45F2N3O9S+ 792.2737). Ex. 58
1H-NMR (400 MHz, CD3OD) δ 8.24 (t, IH, J= 1.5 Hz), 8.04 (m, 2H), 7.44-7.19 (m, 10H), 6.64- 6.47 (m, 3H), 5.25 (dd, IH, J= 7.0, 14.1), 4.54 (m, 3H), 4.25 (dd, IH, J= 6.4, 9.8 Hz), 4.17 (m, 2H), 3.62 (m, 2H), 3.52 (dd, IH, J= 4.9, 10.4 Hz), 3.39 (s, 3H), 3.36 (s, 3H), 2.95 (s, 3H), 1.81 (m, 2H), 1.58 (d, 3H, J= 7.0 Hz); 13C-NMR (100 MHz, CD3OD) δ 169.0, 167.8, 166.4 (d, JCF = 16.0 Hz), 164.0 (d, JCF = 15.8 Hz), 162.3 (t, JCF = 13.9 Hz), 145.1, 143.8, 139.6, 137.4, 137.0, 129.6, 129.4, 129.3, 128.8, 128.7, 128.2, 127.3, 125.9, 99.6 (dd, JCF = 12.5, 29.0 Hz), 97.2 (d, JCF = 26.5 Hz), 79.1, 74.3, 72.3, 68.8, 68.2, 57.7, 54.1, 50.9, 38.3, 36.8, 35.9, 22.1; HRMS (ESI) m/z 740.2837 ([M+H]+ calcd for C38H44F2N3O8S+ 740.2812).
Ex. 59
1H-NMR (400 MHz, CD3OD) δ 8.44 (t, IH, J= 1.5 Hz), 8.21 (m, IH), 8.08 (m, IH), 7.39 (m, 2H), 7.32 (m, 2H), 7.23 (m, 3H), 6.83 (m, 2H), 6.62 (m, 2H), 6.54 (m, IH), 5.21 (dd, IH, J= 7.1, 14.2 Hz), 4.45 (d, 2H, J= 4.7 Hz), 4.28 (d, 2H, J= 6.0 Hz), 3.74 (s, 3H), 3.63-3.50 (m, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 3.08 (dd, IH, J= 6.0, 12.3 Hz), 2.93 (m, 4H), 2.02 (m, IH), 1.91 (m, IH), 1.49 (d, 3H, J= 7.0 Hz); 13C-NMR (125 MHz, CD3OD) δ 179.6, 167.7, 166.1 (d, JCF = 15.9 Hz), 164.2 (d, JCT = 15.8 Hz), 162.1 (t, JCF = 13.8 Hz), 160.8, 145.1, 143.8, 137.6, 135.6, 131.5, 131.1, 130.6, 129.6, 129.6, 128.1, 127.7, 127.2, 114.8, 99.6 (dd, JCF = 15.1, 28.9 Hz), 97.4 (t, JCF = 26.5 Hz), 79.8, 74.0, 71.8, 68.6, 58.5, 55.7, 51.0, 41.8, 40.1, 38.2, 35.8, 31.5, 22.0;; HRMS (ESI) m/z 770.2916 ([M+H]+ calcd for C39H46F2N3O9S+ 770.2917).
Ex. 60
1H-NMR (400 MHz, CDCl3) δ 8.15 (m, IH), 7.98 (m, 2H), 7.37 (m, 4H), 7.28 (m, 2H), 6.95 (m,
2H), 6.87 (m, 2H), 6.60 (d, IH, J= 7.6 Hz), 6.51 (m, 2H), 6.42 (m, IH), 5.32 (m, IH), 4.47 (m, IH), 4.37 (m, IH), 4.15 (m, IH), 4.08 (dd, IH, J= 5.2, 9.3 Hz), 4.03 (dd, IH, J= 4.6, 9.8 Hz),
3.94 (m, 2H), 3.55 (s, 3H), 3.37 (s, 3H), 2.86 (s, 3H), 1.89 (m, 2H), 1.63 (d, 3H, J= 7.0 Hz); 13C- NMR (125 MHz, CDCl3) δ 165.8, 164.8 (d, JCF = 15.7 Hz), 164.6, 162.8 (d, JCF = 15.6 Hz), 160.4 (t, JCT = 13.5 Hz), 158.4, 142.8, 142.5, 136.2, 135.5, 129.7, 129.0, 127.9, 127.8, 127.6, 126.4, 124.1, 121.4, 114.6. 98.7 (dd, JCF = 15.1, 28.8 Hz), 96.9 (t, JCF = 25.9 Hz), 80.3, 69.2, 69.1, 67.0, 58.1, 53.1, 50.0, 38.1, 36.3, 35.6, 21.8; HRMS (ESI) m/z 726.2627 ([M+H]+ calcd for C37H42F2N3O8S+ 726.2655).
Ex. 61 1H-NMR (400 MHz, CDCl3) δ 8.52 (d, IH, J= 5.5 Hz), 8.13 (t, IH, J= 1.5 Hz), 7.95 (m, 2H), 7.40-7.22 (m, 5H), 7.17 (m, IH), 6.90 (m, 2H), 6.62 (m, 2H) 6.55 (m 2H), 6.46 (m, IH) 5.31 (m, IH), 4.81 (m, IH), 4.48 (dd, IH, J= 3.8, 9.9 Hz), 4.41 (m, IH), 4.18 (m, IH), 3.95 (t, IH, J= 9.5 Hz), 3.74 (d, IH, J= 11.1 Hz), 3.54 (s, 3H), 3.33 (s, 3H), 3.29 (dd IH, J= 4.8, 11.1 Hz), 2.84 (s, 3H), 2.43 (m, 2H), 1.70 (bs, IH), 1.60 (d, 3H, J= 9.7 Hz); 13C-NMR (100 MHz, CDCl3) δ 166.7, 165.1 (d, JCF = 15.8 Hz), 164.7, 162.7 (d, JCF = 15.5 Hz), 160.3 (t, JCF = 13.6 Hz), 155.8 (d, JCF = 235.9 Hz), 143.5 (d, JCF = 2.2 Hz), 142.8, 142.3, 136.1, 135.9, 129.2, 128.9, 128.4, 127.8, 127.8, 127.8, 126.4, 125.4, 124.4, 116.0 (d, JCF = 22.1 Hz), 113.5 (d, JCF = 15.5 Hz), 98.7 (dd, JCF = 12.8, 28.5 Hz), 97.0 (t, JCF = 25.8 Hz), 80.1, 67.4, 58.0, 57.6, 55.5, 49.8, 49.3, 38.2, 35.5, 32,3, 21.8; HRMS (ESI) m/z 743.2697 ([M+H]+ calcd for C37H42F3N4O7S+ 743.2721).
The following compounds were prepared according to the procedure described in Example 1 using the appropriate Acid and Amine.
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Acid.
Example Amine Yield. MS
Nl-((2S,3R)-l-(3,5-difluorophenoxy)- Acid-8 3-hydroxy-4-(3- Amine- 10
(trifluoromethyl)benzylamino)butan-2- 29% yl)-5-(2-oxopyrrolidin- 1 -yl)-N3-((R)- 1 - m/z 725 phenylethyl)isophthalamide (72)
3-((2S,3R)-l-(3,5-difluorophenoxy)-3- Acid-9 hydroxy-4-(3- Amine- 10
(trifluoromethyl)benzylamino)butan-2- 54% ylcarbamoyl)-5 -((R)-I- m/z 736 phenylethylcarbamoyl)phenyl methanesulfonate (73)
Nl-((2S,3R)-l-(3,5-difluorophenoxy)- Acid- 11 3-hydroxy-4-(3- Amine- 10
(trifluoromethyl)benzylamino)butan-2- 72% yl)-5-(methylsulfonyl)-N3-((R)- 1 - m/z 720 phenylethyl)isophthalamide (74)
Nl-((2S,3R)-l-(3,5-difluorophenoxy)- Acid- 10 3-hydroxy-4-(3- Amine- 10
(trifluoromethyl)benzylamino)butan-2- 83% yl)-5-(N,N-dimethylsulfamoyl)-N3- m/z 749 ((R)- 1 -phenylethyl)isophthalamide (75)
N-[l-(3,5-Difluoro-phenoxymethyl)-2- Acid- 12 hydroxy-3 -(3 -methyl-benzylamino)- Amine- 10 propyl]-5-(5-methyl- 1 , 1 -dioxo- 40% llambda*6*-[l,2,5]thiadiazolidin-2-yl)- m/z 776 N'-( 1 -phenyl-ethyl)-isophthalamide (76)
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
NMR data for some of the compounds of Examples 62-88
Ex. 62
1H-NMR (CDCl3) δ 7.58 (m, IH), 7.54-7.48 (m, 2H), 7.43 (m, IH), 7.20 (m, IH), 6.98-6.90 (m,
2H), 6.83-6.79 (m, 2H), 6.45 (app. s, IH), 4.77-4.69 (m, IH), 4.42-4.31 (m, 3H), 4.06 (m, IH), 3.95-3.73 (m, 3H), 3.40 (s, 3H), 3.24-3.15 (m, IH), 3.12-3.04 (m, IH), 2.89-2.75 (m, 2H), 1.39- 1.30 (m, 6H), 1.09-1.04 (m, 3H), 0.79 (m, IH), 0.66 (m, IH), 0.40 (m, IH), 0.29 (m, IH).
Ex. 63 1H-NMR (CDCl3) δ 7.46 (m, IH), 7.34-7.23 (m, 3H), 7.18 (m, IH), 7.12 (m, IH), 6.94 (m, IH), 6.89 (m, IH), 6.83-6.77 (m, 2H), 6.44 (m, IH), 4.73 (m, IH), 4.43-4.27 (m, 2H), 4.00 (m, IH), 3.95-3.74 (m, 4H), 3.38 (s, 3H), 3.18 (m, IH), 3.07 (m, IH), 2.90-2.82 (m, 2H), 1.38-1.33 (m, 6H), 1.28 (s, 9H), 1.09-1.03 (m, 3H), 0.79 (m, IH), 0.66 (m, IH), 0.39 (m, IH), 0.28 (m, IH).
Ex. 64
1H-NMR (CDCl3) δ 7.42 (m, IH), 7.37 (m, IH), 7.33-7.23 (m, 4H), 7.17-7.10 (m, 3H), 6.84 (m, IH), 6.47 (m, IH), 4.72 (m, IH), 4.46-4.31 (m, 2H), 4.03 (m, IH), 3.94-3.74 (m, 4H), 3.51 (br. s, IH), 3.40 (m, 3H), 3.20 (m, IH), 3.08 (m, IH), 2.91-2.81 (m, 2H), 1.38-1.33 (m, 6H), 1.28 (m, 9H), 1.09-1.05 (m, 3H), 0.79 (m, IH), 0.67 (m, IH), 0.40 (m, IH), 0.29 (m, IH).
Ex. 65
1H-NMR (CDCl3) δ 8.32 (br. s, IH), 8.24 (m, IH), 7.58 (app. s, IH), 7.54-7.49 (m, 2H), 7.44 (m, IH), 7.28-7.18 (m, 3H), 6.83 (app. s, IH), 6.46 (m, IH), 4.74 (m, IH), 4.46 (m, IH), 4.38 (m, IH), 4.13 (m, IH), 3.98-3.85 (m, 3H), 3.77 (m, IH), 3.40 (s, 3H), 3.20 (m, IH), 3.09 (m, IH), 2.91-2.79 (m, 2H), 1.40-1.30 (m, 6H), 1.10-1.03 (m, 3H), 0.79 (m, IH), 0.67 (m, IH), 0.40 (m, IH), 0.29 (m, IH).
Ex. 66
1H-NMR (CDCl3) δ 8.30 (m, IH), 8.23 (m, IH), 7.43 (m, IH), 7.35-7.18 (m, 5H), 7.13 (m, IH), 6.83 (app. s, IH), 6.45 (app. s, IH), 4.70 (m, IH), 4.45-4.36 (m, 2H), 4.09 (m, IH), 3.93 (m, IH), 3.90-3.77 (m, 3H), 3.39 (s, 3H), 3.19 (m, IH), 3.08 (m, IH), 2.91-2.85 (m, 2H), 1.88-1.23 (m, 15H), 1.09-1.03 (m, 3H), 0.79 (m, IH), 0.66 (m, IH), 0.39 (m, IH), 0.29 (m, IH).
Ex. 67 1H-NMR (CDCl3) δ 8.78 (m, IH), 8.07-7.95 (m, 2H), 7.61 (m, IH), 7.58-7.40 (m, 3H), 7.39-7.31 (m, 3H), 7.14 (m, IH), 6.86 (app. s, IH), 6.48 (app. s, IH), 4.75 (m, IH), 4.53 (m, IH), 4.45 (m, IH), 4.21 (m, IH), 4.06-3.73 (m, 4H), 3.39 (s, 3H), 3.19 (m, IH), 3.08 (m, IH), 2.98-2.84 (m, 2H), 1.38-1.31 (m, 6H), 1.08-1.04 (m, 3H), 0.78 (m, IH), 0.65 (m, IH), 0.39 (m, IH), 0.28 (m, IH). Ex. 68
1H-NMR (CDCl3) δ 8.20 (m, IH), 8.18 (m, IH), 7.44 (m, IH), 7.33-7.22 (m, 4H), 7.39-7.31 (m, 3H), 7.12 (m, IH), 6.84 (app. s, IH), 6.46 (app. s, IH), 4.72 (m, IH), 4.46-4.31 (m, 2H), 4.06 (m, IH), 3.94-3.85 (m, 2H), 3.84-3.74 (m, 2H), 3.54 (br. S, IH), 3.39 (s, 3H), 3.20 (m, IH), 3.08 (m, IH), 2.93-2.80 (m, 2H), 1.39-1.23 (m, 15H), 1.09-1.04 (m, 3H), 0.79 (m, IH), 0.67 (m, IH), 0.40 (m, IH), 0.29 (m, IH).
Ex. 87
1H NMR (500 MHz, CDCl3) δ 8.31 (m, IH), 8.24 (m, IH), 7.32-7.18 (m, 4H), 7.15 (m, IH), 7.09-6.98 (m, 2H), 6.83 (s, IH), 6.49 (s, IH), 4.70 (t, J= 5.3, IH), 4.46-4.32 (m, 2H), 4.16-4.02 (m, IH), 3.97-3.87 (m, IH), 3.87-3.74 (m, 3H), 3.40 (s, 3H), 3.26-3.14 (m, IH), 3.13-3.02 (m, IH), 2.88-2.83 (m, 2H), 2.45 (s, 2H), 1.40 (m, 6H), 1.07 (m, 3H), 0.93 (s, 9H), 0.84-0.74 (m, IH), 0.72-0.59 (m, IH), 0.44-0.35 (m, IH), 0.34-0.22 (m, IH).
Ex.
1H NMR (500 MHz, CDCl3) δ 7.25-7.19 (m, 2H), 7.15 (d, IH), 7.11-6.89 (m, 2H), 6.79 (m, IH), 6.60-6.16 (m, 4H), 4.70 (m, IH), 4.45-4.29 (m, 2H), 4.01 (m, IH), 3.94-3.67 (m, 4H), 3.49 (s, 3H), 3.31 (m, IH), 3.07 (m, IH), 2.84 (m, 2H), 2.60 (s, 2H), 1.46-1.31 (m, 6H), 1.01 (d, J= 6.0, 3H), 0.97 (s, 9H), 0.86-0.76 (m, IH), 0.74-0.60 (m, IH), 0.54-0.33 (m, IH), 0.40-0.22 (m, IH).
Example 94
Figure imgf000139_0001
N-[I-0 ,5 -Difluoro-phenoxymethyl)-2-hydroxy-3 -(3 -trifluoromethyl-benzylaminoVpropyli -N'- ( 1 -phenyl-ethvD-isophthalamide (94)
Compound 71 (16.7 mg, 0.0231 mmol) in MeOH (30 ml) was reduced in an H-cube using a Lindlar catalyst cartridge, four cycles. The solvent was evaporated and the residue purified by flash chromatography using 3% MeOH sat. with NH3 in CHCl3 as eluent, which gave the title compound (8.1 mg, 55%) as a white solid. MS: m/z = 642. Example 95
Figure imgf000140_0001
N-[I-Q ,5 -Difluoro-phenoxymethyl)-2-hydroxy-3 -(3 -trifluoromethyl-benzylaminoVpropyli -
N'-methyl-N'-(4-methyl-thiazol-2-ylmethyl)-isophthalamide (95)
A solution of compound 80 in MeOH (15 ml) was reduced in H-cube using Lindlars catalyst.
The crude material was purified by flash chromatography using 3% MeOH sat. with NH3 in
CHCI3 as eluent, which gave the title compound (10.9 mg, 61%) as a white solid. LC-MS: 95%, m/z = 663.
Example 96
Figure imgf000140_0002
N-((2S.3R)-4-((3-Tert-butylbenzyπ(methyπamino)-l-(3.5-difluorophenoxy)-3-hydroxybutan-2- yl)-2-(((lS.2S)-2-methylcyclopropyl)methylamino)-6-(N-methylpropan-2- ylsulfonamido)isonicotinamide (96) Compound 22 (17.3 mg, 0.024 mmol) was dissolved in dry DCE (1.5 mL). Formaldehyde (37% aqueous solution, 1.95 μL, 0.024 mmol) was added followed by addition of sodium triacetoxy borohydride (20.8 mg, 0.096 mmol). The solution was stirred at room temperature for 16h whereafter a saturated solution of aqueous sodium hydrogen carbonate was added. The reaction mixture was extracted with ethyl acetate, the organic phase was concentrated and the afforded crude product was purified by column chromatography on silica gel (elution system: DCM- sat NH3/MeOH, 100:0-80:20) which gave the title compound (15 mg, 87%). MS m/z 716.21 [M+H]+.
Example 97
Figure imgf000141_0001
N-((2S,3S)-4-((3-tert-butylbenzyl)(methyl)amino)-l-(3,5-difluorophenoxy)-3-hvdroxybutan-2- yl)-2-(((lS,2S)-2-methylcvclopropyl)methylamino)-6-(N-methylpropan-2- ylsulfonamido)isonicotinamide (97)
Compound 93 (7.3 mg, 0.01 mmol) was treated as described in Example 96, which gave the title compound (3 mg, 42%), MS m/z 716.2 [M+H]+.
The following compounds were prepared according to the procedure described in Example 1 using the appropriate Acid and Amine.
Figure imgf000141_0002
Biological Examples To evaluate the enzymatic inhibition of BACEl exhibited by the compounds of the invention, a TruPoint™ Beta-Secretase Assay Kit was used. The assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanide fluorescence can be measured by time-resolved fluorometry (TRF).
The enzyme used in the assay is recombinant BACEl (produced in house) and the substrate is a 10 amino acids long peptide with a fluorescent europium chelate coupled to one end and a quencher of europium fluorescence (QSY 7) coupled via lysine to the other end; EU- CEVNLDAEFK-QSY 7. The cleavage site by BACEl is the peptide bond between L and D. A spectroscopic response is generated by peptidase cleavage, and the activity was measured by a continuous detection of increased fluorescence intensity exhibited by the cleavage product. The compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed. The assay used employs the enzyme at a concentration of 10 nM in a reaction buffer consisting of 50 mM sodium acetate, CHAPS, 0.05% Triton X-100 and EDTA at pH=4.5. The substrate was prepared at a 120 μM stock solution in distilled water. The stock solution was diluted to 400 nM in an amount which was needed for the day. To each well of a 96-well half area polystyrene plate was added the enzyme containing reaction buffer (15 μl) and inhibitor of different concentrations in DMSO (1 μl). To control wells were added reaction buffer (15 μl) and DMSO (1 μl). The enzyme with inhibitor in DMSO was preincubated at room temperature (20-25 0C) for 30 min whereafter the reactions were started by addition of substrate, 15 μl/well, thus giving a total volume of 31 μl/well and a substrate concentration of 200 nM. Product TR- fluorescence was monitored during 90 min with a 1420 VICTOR and presented as Relative Fluorescence units (RFu). The IC50 value was calculated with GraFit software. Activity of the inhibitors was determined by measuring the TR-fluorescence at λgX 330 nm and λgm 615 nm. The inhibition is calculated as follows:
( ^Uinhibitor~^ background \ 1 x 100 = % inhibition R ^^F^n enzyme controll R ^^F^n background '
The compound of Example 68, which is a representative compound of the invention, exhibited an enzymatic inhibition of 6.5 nm, when tested in a BACE enzyme assay such as the one described above. Table 1 shows the enzymatic inhibition represented as intervals exhibited by the compounds according to the invention. Category A indicates an IC50 value of < 1 μM, category B indicates 1 - 5 μM and category C indicates > 5 μM. TABLE 1
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000143_0003
Figure imgf000144_0001
Figure imgf000144_0002

Claims

Claims
1. A compound of formula (I) :
Figure imgf000145_0001
wherein
A is CR or N;
D is H, Ci-Cβalkyl, C2-C6alkenyl, C2-Cealkynyl or
/
Figure imgf000145_0002
R1 is H, Ci-Cβalkyl, Ci-Cβalkoxy, N3 or halo;
R2 is H or Ci-C6alkyl;
R is Ci-Cβalkyl, C2-Cealkenyl, C2-C3alkynyl, Ci-Cβalkoxy, Ci-CealkoxyCi-Cβalkoxy, arylCi-Cβalkoxy, heterocyclylCi-Cβalkoxy, NRaRb or N3;
R6 is hydrogen, Ci-C6alkyl, aryl, NRaRb, N(Ra)S(=O)rRc, N(Ra)S(=O)rNRaRc, S(=O)rCi-
C6alkyl, N(Ra)C(=O)Rc, N(Ra)C(=O)ORc, N(Ra)C(=O)NRaRc, OS(=O)2CiC6alkyl, halo or cyano;
R7 is Ci-Cβalkyl, Cs-C6Cy cloalkyl, Cs-CδCycloalkylCi-Csalkyl, aryl, arylCi-Csalkyl, heterocyclyl, heterocyclylCi-Csalkyl, hydroxyCi-Csalkyl, Ci-CδalkoxyCi-Csalkyl, arylCo-
C3alkoxyCi-C3alkyl, heterocyclylC0-C3alkoxyCi-C3alkyl, N(Ra)(Rb)Ci -C3alkyl; wherein, when present, the Ci-C3alkyl moiety of R7 is optionally substituted with Ci- C6alkyl;
R8 is H, Ci-C6alkyl; or
R7 and R8 together with the N atom to which they are attached define a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with
Figure imgf000145_0003
or fluoro; R9 is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi-C3alkyl; R10 is H or Ci-Cβalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci-Cδalkyl, C2-Cealkenyl, C2-Cealkynyl and phenyl;
Q is C2-C6alkenyl, C2-C6alkynyl, aryl or heterocyclyl; W is H, Ci-Cβalkyl, C2-C6alkenyl, haloCi-C3alkyl, hydroxyCi-C3alkyl, Cs-C6Cy cloalkyl, aryl or heterocyclyl; one of X' and X" is H or CH3, the other is Ci-C3alkyl, F, OH, NRaRb, CF3 or N3; or
X' and X" are both F;
Y is a bond, CH2, NRa, O, CH2CH2, CH2NRa, CH2O or S(=O)r; Z is O, S(=O)r or NRa; 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 methylene may alternatively be a 1,1-cyclopropyl group; r is 0, 1 or 2;
Ra is independently H or Ci-Cβalkyl;
Rb is independently H or Ci-Cβalkyl; or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb together with the nitrogen atom to which they are attached may form a 3 to 6 membered cyclic amine, which cyclic amine is optionally substituted with Ci-C4alkyl or fluoro;
Rc is independently Ci-Cδalkyl; or Rc and Ra together with the atoms to which they are attached may form a 3 to 6 membered heterocyclic ring;
Rd is H or Ci-C3alkyl; and wherein aryl is independently phenyl, naphthyl or phenyl fused to C^CδCycloalkyl or C4-
CδCycloalkenyl; heterocyclyl is independently a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N; and wherein each occurrence of Ci-Cβalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cecycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as arylalkyl or heterocyclylalkyl) is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, C2-C6alkenyl, C2-
Cδalkynyl, C3-C6Cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi- C3alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, NRaRb,
NRaRbCi -C4alkyl, C(=O)NRaRb, NRaC(=O)Rb, cyano, azido, Ci-C4alkylcarbonyl, C3-
C4cyc loalkyl'Co-Csalkyl, aryl'Co-Csalkyl, heterocyclyl1 Co-C3alkyl, C3-C4CyClOaIkVl^-
C3alkenyl, aryl1C2-C3alkenyl, heterocyclyl1C2-C3alkenyl, C3-C4CyC loalkyl1C2-C3alkynyl, aryl1C2-C3alkynyl or heterocyclyl1C2-C3alkynyl, or a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro); where aryl1 is independently phenyl, naphthyl, or phenyl fused to Cs-Cβcycloalkyl or C5-
C6cycloalkenyl; heterocyclyl1 is independently a 5 or 6 membered, saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from S, O and N, and wherein each occurrence of C3-C4cycloalkyl1, aryl1 and heterocyclyl1 above (including those in composite expressions such as C3-C4cycloalkyl1Co-C3alkyl, ary^Co-Csalkyl and heterocyclyl1 Co-C3alkyl), the cycloalkyl1, aryl1 and heterocyclyl1 is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C4alkyl, C3-C4cycloalkyl, halo, haloCi-C4alkyl and polyhaloCi-C4alkyl; or a pharmaceutically acceptable salt, hydrate, quaternary amine, metal complex or N- oxide thereof.
2. A compound according to claim 1, wherein
R1 is H or F;
R2 is H;
R6 is N(Ra)S(=O)2Rc, N(Ra)S(=O)2NRaRc, OS(=O)2CiC6alkyl or halo; R7 is Ci-C6alkyl, C3-C6Cy cloalkyl, C3-C6Cy cloalkylCi-C3alkyl, aryl, arylCi-C3alkyl, heterocyclyl, heterocyclylCi -C3alkyl; wherein, when present, the Ci-C3alkyl moiety of R7 is optionally substituted with C1-
C6alkyl;
R8 is H, Ci-Cealkyl; Q is optionally substituted aryl or optionally substituted heterocyclyl;
W is C3-C6Cy cloalkyl, C2-C6alkenyl, aryl or heterocyclyl, any of which is optionally substituted; one of X' and X" is OH;
Y is O or NH; Z is O or NH; n is 0 or 1 ; r is 2.
3. A compound according to claim 1 or 2, wherein R1 is H.
4. A compound according to any preceding claim, wherein R2 is H.
5. A compound according to any preceding claim, wherein R6 is N(Co-C2alkyl)S(=0)2Rc and Rc is Ci-C4alkyl, preferably methyl or isopropyl.
6. A compound according to any preceding claim, wherein one of X' and X" is OH and the other is H.
7. A compound according to any preceding claim, wherein n is 0.
8. A compound according to any of the preceding claims, wherein Q is an optionally substituted 5 or 6-membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one, two or three substituents.
9. A compound according to any preceding claim, wherein Q is optionally substituted phenyl.
10. A compound according to any preceding claim, wherein Q is mono- or di-halophenyl, such as mono- or di- fluorophenyl or mono- or di-bromophenyl.
11. A compound according any preceding claim, wherein Q is phenyl substituted with heteroaryl, C2-Cealkenyl, C2-Cealkynyl, cyano or cyclopropylethynyl.
12. A compound according to any preceding claim, wherein p is 1 and R3 is Ci-C4alkoxy, preferably methoxy.
13. A compound according to any of claims 1-11, wherein p is 0.
14. A compound according to claim 13, wherein Y is NH.
15. A compound according to any preceding claim, wherein W is optionally substituted phenyl.
16. A compound according to claim 15, wherein the optional substituents to W are selected from fluoro, chloro, methyl, trifluoromethyl and tert. butyl.
17. A compound according to any of claims 1-14, wherein W is Cs-Cβcycloalkyl.
18. A compound according to any preceding claim, wherein q is 0 or 1.
19. A compound according to any preceding claim, wherein D is
Figure imgf000149_0001
20. A compound according to claim 19, wherein R7 is arylCi-Csalkyl such as phenylmethyl or 1-phenylethyl, and wherein the phenyl ring is optionally substituted.
21. A compound according to any of claims 1-18, wherein D is
R9
R 10 y.
22. A compound according to claim 21, wherein A is N.
23. A compound according to claim 21, wherein R9 is Cs-CβcycloalkylCi-Csalkyl, wherein the cycloalkyl moiety is optionally substituted with Ci-C3alkyl.
24. A compound according to claim 23, wherein R9 is cyclopropylmethyl or 2- methylcyclopropylmethyl, and R10 is H or methyl.
25. 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.
26. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 24, for use in therapy.
27. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 24, in the manufacture of a medicament for use in the treatment or prevention of Alzheimer's disease.
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