WO2013004290A1 - Cyclic amine derivatives as ep4 receptor antagonists - Google Patents

Cyclic amine derivatives as ep4 receptor antagonists Download PDF

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Publication number
WO2013004290A1
WO2013004290A1 PCT/EP2011/061226 EP2011061226W WO2013004290A1 WO 2013004290 A1 WO2013004290 A1 WO 2013004290A1 EP 2011061226 W EP2011061226 W EP 2011061226W WO 2013004290 A1 WO2013004290 A1 WO 2013004290A1
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WIPO (PCT)
Prior art keywords
trifluoromethyl
carboxamido
benzyl
cyclopropyl
methyl
Prior art date
Application number
PCT/EP2011/061226
Other languages
French (fr)
Inventor
Manuela Borriello
Sabrina Pucci
Luigi Piero Stasi
Lucio Rovati
Original Assignee
Rottapharm S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DK11743035.5T priority Critical patent/DK2729445T3/en
Priority to PCT/EP2011/061226 priority patent/WO2013004290A1/en
Priority to RU2014103587/04A priority patent/RU2565596C2/en
Priority to ES11743035.5T priority patent/ES2559513T3/en
Priority to JP2014517473A priority patent/JP5813223B2/en
Priority to PL11743035T priority patent/PL2729445T3/en
Priority to US14/130,451 priority patent/US9181279B2/en
Application filed by Rottapharm S.P.A. filed Critical Rottapharm S.P.A.
Priority to IN719CHN2014 priority patent/IN2014CN00719A/en
Priority to BR112014000087-5A priority patent/BR112014000087B1/en
Priority to CA2839116A priority patent/CA2839116C/en
Priority to HUE11743035A priority patent/HUE028439T2/en
Priority to EP11743035.5A priority patent/EP2729445B1/en
Priority to CN201180072023.8A priority patent/CN103702980B/en
Priority to KR1020147001964A priority patent/KR101760164B1/en
Priority to AU2011372747A priority patent/AU2011372747B2/en
Priority to TW101121493A priority patent/TWI546285B/en
Priority to ARP120102418A priority patent/AR087052A1/en
Publication of WO2013004290A1 publication Critical patent/WO2013004290A1/en
Priority to HK14109116.4A priority patent/HK1195901A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
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    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to novel cyclic amine derivative compounds, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
  • Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
  • the cyclic amine derivative compounds of the invention are selective EP 4 receptor antagonists.
  • Prostaglandin E 2 is a member of the prostanoid family with a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in stomach, generation of fever, hyperalgesia, inflammation and immunity. These actions of prostaglandin PGE 2 are mediated by four G-protein-coupled PGE 2 receptors, EP-i , EP 2 , EP 3 and EP 4 . The prostaglandin PGE 2> in fact, has affinity for all of these EP receptors (SubTypes EP ; EP 2 , EP 3 , EP 4 , respectively).
  • the EP 4 receptor is a 7-transmembrane receptor whose activation is normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels.
  • PGE 2 -activated EP 4 receptor signalling may be involved in various pathologic states, such as pain (in particular inflammatory, neuropathic and visceral), inflammation, neuroprotection, cancer, dermatitis, bone disease, immune system dysfunction promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
  • Patent application publications WO2005021508, WO2005105732, WO2005105733, WO2007121578 and WO2009139373 disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
  • One of the objects of the present invention is the provision of compounds having an EP 4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases.
  • the inventors of the present application have discovered novel compounds that are selective antagonists of the EP 4 subtype of PGE 2 receptors. Specifically, the compounds according to the invention are provided with analgesic and antinflammatory activity.
  • the present invention provides a cyclic amine compound of Formula (I):
  • Ri and R 2 are independently of each other hydrogen, linear or branched d- 3 alkyl or are joined together to form a cyclopropyl ring;
  • A is s
  • n 0, 1 or 2
  • R 3 is H or linear or branched Ci -3 alkyl
  • R 4 and R 5 are independently hydrogen, fluorine, linear or branched Ci -3 alkyl or joined together they form a cyclopropyl ring,
  • both R 4 and R 5 are fluorine, linear or branched C-i-
  • ii.c. A is D and m is 1 .
  • 6-membered heteroaromatic ring containing 1 to 3 N.
  • the 6-membered heteroaromatic ring is substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom. In certain embodiments the halogen is chlorine or fluorine.
  • C-i -3 alkyl refers to a linear or branched saturated hydrocarbon group containing of 1 to 3 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl.
  • compounds of Formula (I) may exist as R and S enantiomers and as racemic mixture.
  • This invention includes in its scope of protection all the possible isomers and racemic mixtures. Wherever should be present further symmetry centres, this invention includes all the possible diastereoisomers and relative mixtures as well.
  • the invention concerns a compound of Formula (I) as medicament, in particular it concerns its use for the treatment of pathologies where an antagonist of the EP 4 receptor is needed, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid artrhritis, cancer endometriosis and migraine.
  • an antagonist of the EP 4 receptor such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid artrhritis, cancer endometriosis and migraine.
  • the invention thus concerns, in a general aspect, cyclic amine derivatives of Formula (I):
  • Ri and R 2 are independently hydrogen, linear or branched (C 1 -3 )alkyl or joined together they form a cyclopropyl ring;
  • A is selected from the group consisting of:
  • n 0, 1 or 2
  • R 3 is H or linear or branched Ci -3 alkyl
  • R 4 and R 5 are independently hydrogen, fluorine, linear or branched Ci -3 alkyl or joined together they form a cyclopropyl ring,
  • A is B, and both R 4 and R 5 are fluorine, linear or branched d- 3 alkyl or are joined together to form a cyclopropyl ring, ii.b.
  • A is C and m is 0,
  • ii.c. A is D and m is 1 .
  • Ar is phenyl substituted in 4 position with halogen, cyano, or trifluoromethyl.
  • Ar is phenyl substituted in 4 position with trifluoromethyl.
  • heteroatom of the 5-membered heteroaromatic ring is N.
  • either the 5- membered heteroaromatic and the 6- membered heterocyclic rings are substituted with halogen, cyano or trifluoromethyl.
  • said halogen preferably is fluorine or chlorine and according to an embodiment the halogen is fluorine.
  • Examples of a suitable 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, include pyrrolyl, imidazolyl, pirazolyl, triazolyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl and the like.
  • Examples of a 6-membered heteroaromatic ring containing 1 to 3 N include pyridyl, pyrimidinyl, pyrazinyl and triazinyl.
  • the 6-membered heteroaromatic ring is pyridyl.
  • the pyridyl ring is substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl .
  • references to the compounds of Formula (I) are meant to include the compounds of Formulae (IB), (IC), (ID), (IE) as described hereinafter, where appropriate.
  • cyclic amine derivative of Formula (I) contains A which is the ring B.
  • n 0, 1 or 2
  • Ri and R 2 are independently hydrogen, linear o branched Ci -3 alkyl, or joined together they form a cyclopropyl ring.
  • R 3 is H or linear or branched (Ci -3 )alkyl
  • R 4 and R 5 are independently hydrogen, fluorine, linear or branched (d-
  • - phenyl having: i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
  • n is 1 or 2 and preferably is 2.
  • Ri and R 2 are joined together to form a cyclopropyl ring.
  • R 3 is H or methyl and preferably is H.
  • R 4 and R 5 are independently hydrogen, fluorine, a linear or branched Ci -3 alkyl, tipically methyl, or joined together they form a cyclopropyl ring.
  • R and R 5 are both methyl.
  • the halogen is fluorine or chlorine and according to specific embodiment the halogen is fluorine.
  • R 4 and R 5 are H and Ar is phenyl having in 4- position one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
  • R 4 and R 5 are togheter, halogen, preferably fluorine, a linear or branched Ci -3 alkyl, or are fused to form a cyclopropyl and Ar is phenyl having in 3 or 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl.
  • Ar is phenyl having in 3-position one substituent selected from trifluoromethyl or fluorine.
  • either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted with halogen, cyano or trifluoromethyl.
  • said halogen preferably is fluorine or chlorine.
  • the 6-membered heteroarocyclic ring is pyridyl.
  • n is 1 ; R 4 and R 5 are independently selected from H, fluorine or methyl, or both R 4 and R 5 are fluorine or methyl.
  • n is 2, both R 4 and R 5 are fluorine.
  • n 2
  • R 4 and R 5 are joined together to form a cyclopropyl ring.
  • n 2
  • Ar is phenyl substituted in 4-position with one substituent selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, preferably trifluoromethyl and R-i , R 2 , R3, R4, R5, are as defined above.
  • the cyclic amine derivative of Formula (I) contains A which is the ring C.
  • m is 1 .
  • Ri and R 2 are independently hydrogen, linear or branched Ci -3 alkyl, tipically methyl, or joined together they form a cyclopropyl ring.
  • R 3 is H or linear 0 branched C-i -3 alkyl, tipically methyl.
  • R 3 is H.
  • Ar is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
  • the 6-membered heteroarocyclic ring is pyridyl.
  • m is 0 and Ar is phenyl substituted in 4 position with fluorine, chlorine, cyano, or trifluoromethyl, preferably with trifluoromethyl, and R-i, R 2 , R3 are as defined above.
  • the cyclic amine derivative of Formula (I) contains A which is the ring D.
  • m is 1 .
  • Ri and R 2 are independently hydrogen, linear or branched Ci -3 alkyl, or joined together they form a cyclopropyl ring.
  • R 3 is H or linear 0 branched C-i -3 alkyl, tipically methyl.
  • R 3 is H.
  • Ar is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Ar is phenyl as defined above and having in one or both 2 and 6 positions a moiety selected from the group consisting of H, halogen, cyano, trifluoromethyl, or linear or branched Ci -3 alkyl.
  • either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
  • the 6-membered heteroarocyclic ring is pyridyl.
  • m is 1 and Ar is phenyl substituted in 4 position with one substituent selected from the group consisting of halogens, cyano, trifluorormethyl, preferably trifluoromethyl and R-i , R 2 , R3 are as defined above.
  • the cyclic amine derivative of Formula (I) contains A which is the ring E.
  • Ri and R 2 are independently hydrogen, linear 0 branched Ci -3 alkyl, or joined together they form a cyclopropyl ring.
  • R 3 is H or linear or branched Ci -3 alkyl, preferably R 3 is H.
  • Ar is phenyl, substituted in 4 position with one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
  • Ar is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • - phenyl having in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl.
  • Ar is phenyl, having in 4-position one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
  • Ar is phenyl as defined above and having in one or both 2 and 6 positions a moiety selected from the group consisting of H, halogen, cyano, trifluoromethyl, or linear or branched Ci -3 alkyl.
  • either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
  • the 6-membered heteroarocyclic ring is pyridyl.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, quaternary ammonium salts and internally formed salts.
  • Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganous, potassium, sodium, zinc, and the like. Preferred are the ammonium, calcium, magnesium, litium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • references to the compounds of Formula (I) are meant to also include the pharmaceutically acceptable salts or derivatives.
  • the compound of the formula (I) may form an acid addition salt or a salt with a base, depending on the kind of the substituents, and these salts are included in the present invention, as long as they are pharmaceutically acceptable salts.
  • the compounds (I) of the invention may be in crystalline forms.
  • the crystalline forms of the compounds (I) are polymorphs.
  • the compound of the invention and “the compounds of the present invention” refer to each of the compounds of formulae (I), (IB), (IC), (ID), (IE) and are meant to include their pharmaceutically acceptable salts, hydrates, solvates, and crystalline forms and also any suitable forms as illustrated hereinafter.
  • the compound of the Formula (I) may exist in the form of other tautomers or geometrical isomers in some cases, depending on the kinds of the substituents.
  • the compound may be described in only one form of such isomers, but the present invention includes such isomers, isolated forms of the isomers, or a mixture thereof.
  • the compound of the Formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and correspondingly, it may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like.
  • the present invention includes both a mixture and an isolated form of these optical isomers.
  • stereoisomeric forms including enantiomers, diastereoisomers, and mixtures thereof, including racemates and the general reference to the compounds of formulae (I), (IB), (IC), (ID), (IE) include all the stereoisomeric forms, unless otherwise indicated.
  • the pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into an amino group, OH, CO2H, or the like, by solvolysis or under a physiological condition.
  • Examples of the groups for forming a prodrug include those as described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163- 198.
  • the present invention in certain embodiments also includes various hydrates or solvates, and polymorphism of the compound of the formula (I) and a pharmaceutically acceptable salt thereof. Furthermore, the present invention also includes the compounds labelled with various radioactive isotopes or nonradioactive isotopes.
  • the present invention provides a compound selected from the group consisting of: lithium 4-((1 S)-1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate lithium 4-((S)-1 -((/ ⁇ -l -(4-fluorobenzyl)piperidine-2- carboxamido)ethyl)benzoate
  • Preferred compounds of the invention are selected from the group consisting of: lithium(/ : ?)-4-(1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl) benzoate
  • a further aspect of this invention concerns a process for the preparation of a compound of Formula (I) comprising the following steps represented in the general scheme below:
  • R-i , R 2 , R3, Ar are as defined in formula (I),
  • R is selected from the group consisting of hydrogen, linear or branched Ci -3 alkyl and benzyl groups,
  • W is selected from the group consisting of hydrogen, benzyl group and t- Butyl carbamate group, It will be appreciated that compounds of formula (II), (IV) and (VII), may be converted into other compounds of formula (II), (IV) and (VII), by synthetic methods known to the skilled person in the art.
  • the hydrolysis is carried out in the presence of a base, for example lithium hydroxide, typically in presence of a suitable ether system, such as aqueous 1 ,4-dioxane.
  • a base for example lithium hydroxide
  • a suitable ether system such as aqueous 1 ,4-dioxane.
  • the compounds of the present invention may be prepared according to the following schemes.
  • protecting group means an amino protecting group which is selected from typical amino protecting groups as described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999);
  • Compounds of formula (I) may be prepared by hydrolysis reaction of ester compounds of formula (VI) according to the reaction scheme 1 .
  • Hydrolysis can be carried out in presence of a base, for example lithium hydroxide in a suitable solvent such as in aqueous 1 ,4-dioxane.
  • a base for example lithium hydroxide in a suitable solvent such as in aqueous 1 ,4-dioxane.
  • this reaction may be carried out at room temperature.
  • Compounds of formula (IV), wherein W is hydrogen, may be prepared from corresponding compounds of formula (IV) wherein W preferably is benzyl group or f-butyl carbamate group.
  • the deprotection step can be carried out in presence of trifluoroacetic acid in a suitable solvent such as dichloromethane.
  • the deprotection step can be carried out by hydrogenolysis typically in a suitable solvent such as ethanol.
  • the compounds of formula (II), wherein R is hydrogen and W is a benzyl group or f-butyl carbamate are reacted with compounds of formula (III) in the presence of a suitable coupling reagent, for example selected from (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetramethylaminium hexafluorophosphate) (HCTU), 0-(7-Azabenzotriazol-1 -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (HATU), (1 -Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride) and 1 -Hydroxybenzotriazole and mixtures thereof.
  • HCTU (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetra
  • the reaction is carried out in an aprotic solvent, for example a halohydrocarbon, such as dichloromethane, ⁇ , ⁇ -dimethylformamide, or acetonitrile or mixture thereof, typically at room temperature, in presence of a suitable base, such as N,N-diisopropylamine.
  • a halohydrocarbon such as dichloromethane, ⁇ , ⁇ -dimethylformamide, or acetonitrile or mixture thereof
  • a suitable base such as N,N-diisopropylamine.
  • the compounds of formula (VII), wherein R is H are reacted with compounds of formula (III) in the presence of a suitable coupling reagent, for example selected from (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetramethylaminium hexafluorophosphate) (HCTU), 0-(7-Azabenzotriazol-1 -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (HATU), (1 -Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride) and 1 -Hydroxybenzotriazole or mixtures thereof.
  • a suitable coupling reagent for example selected from (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetramethylaminium hexafluoro
  • reaction is carried out in an aprotic solvent, for example a halohydrocarbon, such as dichloromethane, ⁇ , ⁇ -dimethylformamide, or acetonitrile or mixtures thereof, typically at room temperature, in presence of a suitable base.
  • a halohydrocarbon such as dichloromethane, ⁇ , ⁇ -dimethylformamide, or acetonitrile or mixtures thereof
  • the compounds of formula (VII), wherein R is hydrogen may be prepared by hydrolysis of the corresponding compounds of formula (VII), wherein R is C(1 -3) alkyl.
  • the hydrolysis is carried out in the presence of a base for example lithium hydroxide, typically in suitable solvent such as aqueous 1 ,4-dioxane.
  • the compounds of formula (VII) may be prepared according to reaction scheme 5.
  • the compounds of formula (II), wherein R is C(1 -3) alkyl and W is a benzyl group or f-butyl carbamate may be reacted with compounds of formula (V) in the presence of a suitable base such as cesium carbonate and a suitable solvent such as acetonitrile.
  • a suitable base such as cesium carbonate
  • a suitable solvent such as acetonitrile.
  • the reaction is carried out at room temperature, in other embodiments the reaction is carried out under heating, for example at around 60 °C.
  • the compounds of formula (II) wherein A is D, R is hydrogen, W is f-butyl carbamate and m is 1 may be prepared according to the reaction scheme 6.
  • the compounds of formula (II) wherein A is C, m is 0 or 1 , R is ethyl and W is f-butyl carbamate may be prepared according to reaction scheme 7.
  • the compounds of formula (II) wherein A is C, m is 0, R is ethyl and W is f-butyl carbamate may be prepared according to reaction scheme 8.
  • the compounds of formula (II) wherein A is B, n is 1 , R and R 5 are independently selected from hydrogen or fluorine or both R 4 and R 5 are fluorine, may be prepared according to reaction scheme 9.
  • the compounds of formula (II) wherein A is B, n is 1 , R 4 and R 5 are methyl, R and R 3 are hydrogen and W is f-butyl carbamate, may be prepared according synthetic route described in scheme 10.
  • the compounds of formula (II) wherein A is B, W, R, R 4 and R 5 are hydrogen, n is 0, 1 and 2, R 3 is methyl, may be prepared according synthetic route described in scheme 1 1 .
  • Scheme 12 describes an alternative synthetic route to products of formula (II) wherein A is B, W, R 4 and R 5 are hydrogen, n is 1 , R and R 3 are methyl.
  • the compounds (I) are obtained using a simple process, easy to scale-up and avoiding lengthy and expensive preparation steps, obtaining high yield of a stable pharmaceutical grade compound of formula (I).
  • the various methods described above may be useful for the introduction of the desired group at any stage in the stepwise formation of the required compound, and it will appreciated that these general methods can be combined in different way in such multi-stage processes.
  • the sequence of the reactions in multi-stage processes are chosen so that the reaction conditions used do not affect groups in the molecule which are in the final product.
  • an enantiomer of a compound of the general formula (I) may be obtained by resolution of a corresponding enantiomeric mixture of such compound of formula (I) by using conventional methods such as by chiral HPLC procedure.
  • the compounds of general formula (I) are in the form of salts, specifically pharmaceutically acceptable salts. These salts may be obtained using conventional methods, for example by reacting the compound having general formula (I) in the form of a free base with a suitable acid in a suitable solvent for example an alcohol, such as ethanol or an ether such as diethyl ether or an ester such as ethyl acetate.
  • a suitable solvent for example an alcohol, such as ethanol or an ether such as diethyl ether or an ester such as ethyl acetate.
  • the compounds of general formula (I) may be isolated in association with solvent molecules for example by evaporation or crystallisation from a suitable solvent to provide the corresponding solvates.
  • the Inventors have found that the general family of the compounds of formula (I) as well the sub-families of the compounds of formulae (IB), (IC), (ID), (IE) as above, have affinity for and are specific antagonists of PGE 2 receptors, in particular of EP 4 subtype of PGE 2 receptors.
  • the compounds of general formula (I) and the specific compounds of (IB), (IC), (ID), (IE) are useful in the treatment of Prostaglandin E mediated conditions or diseases.
  • the invention concerns compounds of Formulae (I), (IB), (IC), (ID), (IE) for use as a medicament the treatment of pathologies or disorders where an antagonist of the EP 4 receptor is needed.
  • the pathologies or disorders are selected from acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder such as arthritis, rheumatoid arthritis, cancer endometriosis and migraine.
  • the compounds of the invention are useful as analgesics.
  • they are useful in the treatment of chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic articular pain e.g. rheumatoid arthritis, osteoarthritis, rheum
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Compounds of the invention are also useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD); gastrointestinal tract disorders (e.g.
  • an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic an
  • Compounds of the invention are also useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • the compounds of the invention are also effective in increasing the latency of HIV infection.
  • Compounds of the invention are also useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
  • diseases of abnormal platelet function e.g. occlusive vascular diseases.
  • Compounds of the invention are also useful for the preparation of a drug with diuretic action.
  • Compounds of the invention are also useful in the treatment of impotence or erectile dysfunction.
  • Compounds of the invention are also useful in the treatment of bone disease characterized by abnormal bone metabolism or resorption such as osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gout and ankylosing spondylitis, tendinitis and bursitis.
  • compounds of the invention may be useful in inhibiting bone resorption and/or promoting bone generation.
  • Compounds of the invention are also useful for attenuating the hemodynamic side effects of NSAIDs and COX-2 inhibitors.
  • Compounds of the invention are also useful in the treatment of cardiovascular diseases such as hypertension or myocardiac ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • cardiovascular diseases such as hypertension or myocardiac ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • Compounds of the invention are also useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chores, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chores, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins;
  • the compounds of Formula (I), (IB), (IC), ID) and (IE) are also useful in the treatment of neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • Compounds of the invention are also useful for the treatment of stroke and multiple sclerosis.
  • Compounds of the invention are also useful in the treatment of tinnitus. Compounds of the invention are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent.
  • dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • Compounds of the invention are also useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
  • Type 1 diabetes e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy
  • kidney dysfunction nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome
  • liver dysfunction hepatitis, cirrhosis
  • gastrointestinal dysfunction diarrhoea
  • Treatment includes partial or total inhibition of the neoplasia growth, spreading or metastasis, as well as partial or total destruction of the neoplastic cells and/or symptoms associated with neoplasia including pain, anorexia or weight loss.
  • prevention includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinical ⁇ evident stage of neoplasia in individuals at risk.
  • the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells is also intended to be encompassed by this definition.
  • the term "subject" for purposes of treatment includes any human or mammal subject who has any one of the known neoplasias, and preferably is a human subject.
  • the subject is any human or animal subject, and preferably is a human subject who is at risk for obtaining a neoplasia.
  • the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to have the neoplasia, and the like.
  • neoplasia includes both benign and cancerous tumors, growths and polyps.
  • the compounds of the invention are useful for treating or preventing benign tumors, growths and polyps including squamous cell papilloma, basal cell tumor, transitional cell papilloma, adenoma, gastrinoma, cholangiocellular adenoma, hepatocellular adenoma, renal tubular adenoma, oncocytoma, glomus tumor, melanocyte nevus, fibroma, myxoma, lipoma, leiomyoma, rhabdomyoma, benign teratoma, hemangioma, osteoma, chondroma and meningioma.
  • the compounds of the invention are also useful for treating or preventing cancerous tumors, growths and polyps including squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, adenocarcinoma, malignant gastrinoma, cholangiocelleular carcinoma, hepatocellular carcinoma, renal cell carcinoma, malignant melanoma, fibrosarcoma, myxosarcoma, liposarcoma, leimyosarcoma, rhabdomyosarcoma, malignant teratoma, hemangiosarcoma, Kaposi sarcoma, lymphangiosarcoma, ostreosarcoma, chondrosarcoma, malignant meningioma, non-Hodgkin lymphoma, Hodgkin lymphoma and leukemia.
  • neoplasia includes brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, rectal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial, mesenchymal or blood cells throughout the body.
  • the compounds of the invention are useful for treating or preventing any of the aforementioned cancers.
  • the compounds of the invention are useful for treating or preventing benign and cancerous tumors, growths and polyps of the following cell types: squamous epithelium, basal cells, transitional epithelium, glandular epithelium, G cells, bile ducts epithelium, hepatocytes, tubules epithelium, melanocytes, fibrous connective tissue, cardiac skeleton, adipose tissue, smooth muscle, skeletal muscle, germ cells, blood vessels, lymphatic vessels, bone, cartilage, meninges, lymphoid cells and hematopoietic cells.
  • the compounds can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP).
  • the compounds can be used to prevent polyps from forming in patients at risk of FAP.
  • the compounds of the invention are useful for treating or preventing the following cancers: colorectal, esophagus stomach, breast, head and neck, skin, lung, liver, gall bladder, pancreas, bladder, endometrium cervix, prostate, thyroid and brain. It is to be understood that reference to a treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
  • the present invention concerns a compound of Formulae (I), (IB), (IC), (ID), (IE) for use as a medicament.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) (IB), (IC), (ID), (IE) and a pharmaceutically acceptable carrier.
  • the compound of Formula (I) may be used in combination with a pharmaceutically acceptable carrier and, optionally, with suitable excipients, to obtain pharmaceutical compositions.
  • pharmaceutically acceptable carrier means solvents, carrier agents, diluting agents and the like which are used in the administration of compounds of the invention.
  • the pharmaceutical compositions of the invention may be in solid or liquid form.
  • the pharmaceutical compositions in solid form may contain suitable excipients such as fillers, lubricants, binding agents, wetting agents, disintegrants, colorants and flavouring agents and mixtures thereof.
  • suitable excipients such as fillers, lubricants, binding agents, wetting agents, disintegrants, colorants and flavouring agents and mixtures thereof.
  • the tablets may contain pre-gelatinised starch, microcrystalline cellulose, sodium glycolate starch, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
  • compositions in liquid form typically may be provided as solutions, suspensions, emulsion, syrups, elixir.
  • the compositions in liquid form may contain suspending agents, emulsifying agents, carriers, preservatives and colorants, flavouring agents.
  • compositions of the invention can be administered by parenteral, oral, buccal, sublingual, nasal, rectal, topical or transdermal administration.
  • Pharmaceutical compositions for oral administration are generally preferred.
  • compositions of the invention suitable for the oral administration typically, will be discrete units in solid form such as in the form of tablets, capsules, cachets, powders, granules, lozenges, patches, suppositories, pellets, or in liquid form such as liquid preparations, injectable or infusible solutions or suspensions.
  • compositions for parenteral administration typically include sterile preparations in the forms of solutions or suspensions.
  • compositions for parenteral administration are aqueous based solution suitable for injection or infusion.
  • compositions for parenteral administration includes one or more adjuvants such as buffering agents, preservatives, antibacterial agents, surfactants and mixtures thereof.
  • compositions for topical administration may be formulated as creams, pastes, oils, ointments, emulsions, foams, gels, drops, spray solutions and transdermal patches.
  • the pharmaceutical composition of the invention includes 0.1 to 99% by weight of the compound of formula (I) as active ingredient. In certain embodiments the amount of the compound of formula (I) is 1 to 30% by weight.
  • the dosage of the compound of formula (I) to be administered depends on the severity of the disease, the weight, the age and general conditions of the patient in need of treatment.
  • a suitable unit dosage may vary of from 0.01 to 1000 mg or typically of 1 .0 to 300 mg to be administered one or more in a day, for example twice a day usually at regular intervals.
  • the duration of the therapy depends on the severity of the illness and general condition of the patients and may be varied by the physician an extended for certain weeks or months.
  • a compounds of the general formula (I) for the manufacture of a medicament for the treatment of pathologies or diseases which require the administration of an antagonist of the EP 4 receptor, such as the treatment of inflammatory pain, osteoarthritis, arthritis.
  • the present invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or (IB), (IC), (ID), (IE), in association with an additional active ingredient and a pharmaceutically acceptable excipient.
  • Said additional active ingredients may be an additional compound of formula (I) or a different chemical entity having similar or different activity.
  • said additional active ingredients is selected from the antinflammatory compounds, such as FANS or cortisonic compounds.
  • enantiomer 1 is used for the single stereoisomer with the minor retention time in the conditions of the chiral separation.
  • enantiomer 2 is used for the single stereoisomer with the major retention time in the conditions of the chiral separation.
  • diastereoisomer 1 is used for the single diastereoisomer with the minor retention time in the conditions of the chiral separation or the first eluting in flash chromatography column.
  • diastereoisomer 2 is used for the single diastereoisomer with the major retention time in the conditions of the chiral separation or the second eluting in flash chromatography column.
  • Reagents used in the following examples were commercially available from various suppliers (for example Sigma-Aldrich, Acros, Matrix scientific, Manchester or Apollo) and used without further purifications.
  • Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP-Si cartridges), Waters PoraPak RXN RP cartridges, Biotage SNAP-C18.
  • SPE-Si cartridges are silica solid phase extraction columns.
  • PoraPakRXN RP cartridges are polimer based reverse phase resin.
  • Biotage SNAP C18 Gold cartridges are silica based reverse phase column.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is dichloromethane and methanol or only methanol followed by 2N ammonia solution in methanol.
  • the collected fractions are those eluted with ammonia solution in methanol.
  • Thin layer chromatography was carried out using Merck TLC plates Kieselgel 60F-254, visualized with UV light, aqueous permanganate solution, iodine vapours.
  • MS refers to Mass Spectra taken by Direct infusion Mass or to a mass Spectra associated with peaks taken by UPLC/MS or HPLC/MS analysis, where the Mass Spectrometer used is as mentioned below.
  • MS Direct infusion Mass Spectra
  • HPLC spectra were performed on a Waters Alliance 2965 instrument equipped with a Waters 2996 UV-Vis detector using a Phenomenex Luna C18 column (150x4.6mm, 5 ⁇ particle size).
  • UV detection wavelenght range from 220 up to 300 nm]
  • TIC Total ion current
  • DAD UV chromatografic traces together with MS and UV spectra were taken on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM Mass Spectrometer operating in positive or negative electrospray ionisation mode.
  • reaction mixture was then charged with TFAA (0.3 ml, 2.1 1 mmol) keeping the temperature below -45 °C. After complete addition, the reaction mixture was warmed to 20-25 °C within one hour and kept for an additional 4 hrs at this temperature. Reaction mixture was quenched by slow addition of water. Phases were separated and the organics washed with water, dried over Na 2 S0 4 and concentrated to obtain a clear oil, which was used as such to be subjected to the same procedure once again to afford the title compound (D20) (260 mg).
  • Dioxane was evaporated off and water was washed with Et 2 0 (2x40 ml) then the pH was adjusted to ⁇ 4 by addition of citric acid and the resulting aqueous phase was extacted with DCM (200 ml), washed with water (20 ml), dried over Na 2 S0 4 and evaporated in vacuo to afford the title compound (D27) (2.75 g) as diastereoisomer mixture with syn-anti ratio 10/2.
  • reaction mixture was stirred at -78 °C for 3 hrs then quenched by the slow addition of saturated NaHC0 3 and water.
  • the reaction mixture was extracted with DCM (3x10 ml), the organic layers washed with NaCI sat sol, dried over Na 2 S0 4 and evaporated to afford the title compound (D40) (168 mg).
  • the crude material was purified on SPE-Si cartridge or SNAP-Si column eluting with a mixture of DCM/MeOH 98:2 or DCM/EtOAc from 100:0 to 70:30 affording the title amide compound.
  • the title compound (D53) (650 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (F?)-1 -(terf- butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #516341 ), and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (470 mg). Reaction time: 18 hrs.
  • the title compound (D54) (290 mg) was prepared according to the general procedure for amides preparation (Method B) starting from 6-(terf-butoxycarbonyl)- azaspiro[2.5]octane-5-carboxylic acid (D1 ) (200 mg) and methyl 4-(1 - aminocyclopropyl)benzoate hydrochloride (214 mg). Reaction time: 18 hrs.
  • the title compound (D56) (130 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 6-(terf-butoxycarbonyl)- azaspiro[2.5]octane-5-carboxylic acid (D1 ) (80 mg) and (S)-methyl 4-(1 - aminoethyl)benzoate hydrochloride (67.6 mg). Reaction time: 18 hrs.
  • the title compound (D68) (688 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1 -(terf-butoxycarbonyl)- 4,4-difluoropiperidine-2-carboxylic acid (600 mg; described in WO2010148197) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (566.5 mg). Reaction time: 5 hrs
  • the title compound (D72) (81 5 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (F?)-1 -(terf- butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #43381 8), and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (501 mg). Reaction time: 1 8 hrs
  • the title compound (D81) (1 .02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy- D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na 2 C0 3 : 2.5 eq; Reaction time: 24 hrs; 60 °C).
  • the title compound (D100) (155 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 4-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-3-azabicyclo[4.1 .0]heptane-3- carboxylate (D69) (260 mg).
  • the title compound (D104) (1 .8 g) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (1 R,3R,5R)-tert-butyl 3-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[3.1 .0]hexane-2-carboxylate (syn diastereoisomer) (D73a) (2.6 g).
  • the title compound (D111 ) (45 mg) was prepared according to the general procedure for for esters hydrolysis (Method C) starting from ethyl 2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylate (D78) (420 mg). (LiOH : 2 eq; reaction time: 1 8hrs; RT).
  • the title compound (D125) (60.7 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1 -(6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (single unknown enantiomer) (D90) (50 mg, 0.1 1 mmol) and 3- (Trifluoromethyl)benzyl bromide (0.020 ml, 0.12 mmol). (Cs 2 C0 3 :2 eq; reaction time: 4 hrs; reaction temperature: RT.

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Abstract

There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP4 subtype of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.

Description

"Cyclic amine derivatives as EP4 receptor antagonists"
********************
FIELD OF THE INVENTION
The present invention relates to novel cyclic amine derivative compounds, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
The cyclic amine derivative compounds of the invention are selective EP4 receptor antagonists. BACKGROUND OF THE INVENTION
A number of review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists; Eicosanoids: From Biotechnology to therapeutic Applications, Folco, Samuelson, Maclouf and Velo eds, Plenum Press, New York, 1996, chap.14, 137-154; "Molecular aspects of the structures and functions of the prostaglandin E receptors", Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; "Function of prostanoid receptors: studies on knockout mice", Prostaglandins & other Lipid Mediators, 2002, 68-69, 557-573 and "Prostanoid receptor antagonists: development strategies and therapeutic applications", British Journal of Pharmacology (2009), 158, 104-145. Prostaglandin E2 (PGE2) is a member of the prostanoid family with a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in stomach, generation of fever, hyperalgesia, inflammation and immunity. These actions of prostaglandin PGE2 are mediated by four G-protein-coupled PGE2 receptors, EP-i , EP2, EP3 and EP4. The prostaglandin PGE2> in fact, has affinity for all of these EP receptors (SubTypes EP ; EP2, EP3, EP4, respectively). The EP4 receptor is a 7-transmembrane receptor whose activation is normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels. PGE2-activated EP4 receptor signalling may be involved in various pathologic states, such as pain (in particular inflammatory, neuropathic and visceral), inflammation, neuroprotection, cancer, dermatitis, bone disease, immune system dysfunction promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
In The Journal of Immunology (2008, 181 , 5082-5088) studies suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in osteoarthritic chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for osteoarthritis disease modification.
In European Journal of Pharmacology (2008, 580, 1 16-121 ) studies suggest that that a pharmacological blockade of the prostanoid EP4 receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
Patent application publications WO2005021508, WO2005105732, WO2005105733, WO2007121578 and WO2009139373 disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
One of the objects of the present invention is the provision of compounds having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases.
The inventors of the present application have discovered novel compounds that are selective antagonists of the EP4 subtype of PGE2 receptors. Specifically, the compounds according to the invention are provided with analgesic and antinflammatory activity.
In accordance with a general aspect, the present invention provides a cyclic amine compound of Formula (I):
Figure imgf000004_0001
(I)
or a pharmaceutically acceptable salt or derivative thereof,
wherein:
Ri and R2 are independently of each other hydrogen, linear or branched d- 3 alkyl or are joined together to form a cyclopropyl ring;
A is s
Figure imgf000004_0002
B C D E
wherein:
n= 0, 1 or 2
m= 0 or 1
R3 is H or linear or branched Ci-3 alkyl
R4 and R5 are independently hydrogen, fluorine, linear or branched Ci-3 alkyl or joined together they form a cyclopropyl ring,
Ar is
- phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that
ii.a. when A is B, both R4 and R5 are fluorine, linear or branched C-i-
3 alkyl or joined together they form a cyclopropyl ring,
ii.b. A is C and m is 0
ii.c. A is D and m is 1 .
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N. In certain embodiments, the 6-membered heteroaromatic ring is substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
The term "halogen" as used herein refers to a fluorine, chlorine, bromine or iodine atom. In certain embodiments the halogen is chlorine or fluorine.
The term "C-i-3 alkyl" as used herein refers to a linear or branched saturated hydrocarbon group containing of 1 to 3 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl.
In this invention compounds of Formula (I) may exist as R and S enantiomers and as racemic mixture. This invention includes in its scope of protection all the possible isomers and racemic mixtures. Wherever should be present further symmetry centres, this invention includes all the possible diastereoisomers and relative mixtures as well.
In another aspect the invention concerns a compound of Formula (I) as medicament, in particular it concerns its use for the treatment of pathologies where an antagonist of the EP4 receptor is needed, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid artrhritis, cancer endometriosis and migraine. DETAILED DESCRIPTION OF THE INVENTION
The invention thus concerns, in a general aspect, cyclic amine derivatives of Formula (I):
Figure imgf000005_0001
(I)
or a pharmaceutically acceptable salt thereof,
wherein:
Ri and R2 are independently hydrogen, linear or branched (C1 -3)alkyl or joined together they form a cyclopropyl ring;
A is selected from the group consisting of:
Figure imgf000006_0001
B C D E
wherein:
n= 0, 1 or 2
m= 0 or 1
R3 is H or linear or branched Ci-3 alkyl,
R4 and R5 are independently hydrogen, fluorine, linear or branched Ci-3 alkyl or joined together they form a cyclopropyl ring,
Ar is
- phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that
ii.a. A is B, and both R4 and R5 are fluorine, linear or branched d- 3 alkyl or are joined together to form a cyclopropyl ring, ii.b. A is C and m is 0,
ii.c. A is D and m is 1 .
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
In certain embodiments Ar is phenyl substituted in 4 position with halogen, cyano, or trifluoromethyl.
In certain embodiments Ar is phenyl substituted in 4 position with trifluoromethyl.
In certain embodiments the heteroatom of the 5-membered heteroaromatic ring is N.
In certain embodiments, either the 5- membered heteroaromatic and the 6- membered heterocyclic rings are substituted with halogen, cyano or trifluoromethyl. In these embodiments said halogen preferably is fluorine or chlorine and according to an embodiment the halogen is fluorine.
Examples of a suitable 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, include pyrrolyl, imidazolyl, pirazolyl, triazolyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl and the like.
Examples of a 6-membered heteroaromatic ring containing 1 to 3 N include pyridyl, pyrimidinyl, pyrazinyl and triazinyl.
In one embodiment the 6-membered heteroaromatic ring is pyridyl. In this embodiment the pyridyl ring is substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
It will be understood that, as used herein, references to the compounds of Formula (I) are meant to include the compounds of Formulae (IB), (IC), (ID), (IE) as described hereinafter, where appropriate. In a first aspect of the invention, cyclic amine derivative of Formula (I) contains A which is the ring B.
In accordance with this aspect a subset of compounds of Formula (IB) is provided
Figure imgf000007_0001
and/or pharmaceutically acceptable derivatives or salts thereof, wherein: n= 0, 1 or 2
Ri and R2 are independently hydrogen, linear o branched Ci-3 alkyl, or joined together they form a cyclopropyl ring.
R3 is H or linear or branched (Ci-3)alkyl,
R4 and R5 are independently hydrogen, fluorine, linear or branched (d-
3)alkyl or joined together they form a cyclopropyl ring,
Ar is
- phenyl having: i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that both R4 and R5 are fluorine, linear or branched Ci-3 alkyl or joined together they form a cyclopropyl ring,
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
In certain embodiments n is 1 or 2 and preferably is 2.
In accordance to certain embodiments Ri and R2 are joined together to form a cyclopropyl ring.
In certain embodiments R3 is H or methyl and preferably is H.
In certain embodiments, R4 and R5 are independently hydrogen, fluorine, a linear or branched Ci-3 alkyl, tipically methyl, or joined together they form a cyclopropyl ring.
In certain embodiments R and R5 are both methyl.
In certain embodiments wherein Ar is phenyl, the halogen is fluorine or chlorine and according to specific embodiment the halogen is fluorine.
In certain embodiments, R4 and R5 are H and Ar is phenyl having in 4- position one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
In certain embodiments R4 and R5 are togheter, halogen, preferably fluorine, a linear or branched Ci-3 alkyl, or are fused to form a cyclopropyl and Ar is phenyl having in 3 or 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl.
In certain embodiments Ar is phenyl having in 3-position one substituent selected from trifluoromethyl or fluorine.
In certain embodiments, either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted with halogen, cyano or trifluoromethyl. In these embodiments said halogen preferably is fluorine or chlorine. In certain embodiments the 6-membered heteroarocyclic ring is pyridyl.
In certain embodiments n is 1 ; R4 and R5 are independently selected from H, fluorine or methyl, or both R4 and R5 are fluorine or methyl.
In other embodiments n is 2, both R4 and R5 are fluorine.
According to an embodiment n is 2, R4 and R5 are joined together to form a cyclopropyl ring.
In certain embodiments n is 2, Ar is phenyl substituted in 4-position with one substituent selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, preferably trifluoromethyl and R-i , R2, R3, R4, R5, are as defined above.
In a second aspect of the invention, the cyclic amine derivative of Formula (I) contains A which is the ring C.
In accordance with this aspect a subset of compounds of Formula (IC) is provided:
Figure imgf000009_0001
(IC)
and/or pharmaceutically acceptable salts or derivatives thereof,
wherein m, R R2, R3 and Ar are as above described in general, unless otherwise specified.
In certain embodiments m is 1 .
In certain embodiments, Ri and R2 are independently hydrogen, linear or branched Ci-3 alkyl, tipically methyl, or joined together they form a cyclopropyl ring.
In certain embodiments R3 is H or linear 0 branched C-i-3 alkyl, tipically methyl.
In certain embodiments R3 is H.
In certain embodiments, Ar is
- phenyl having
in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, wherein halogen typically is fluorine, or
in 3-position one substituent selected from group consisting of halogen, cyano, trifluoromethyl, provided that m is 0;
In certain embodiments, either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
In one embodiment the 6-membered heteroarocyclic ring is pyridyl.
In certain embodiments m is 0 and Ar is phenyl substituted in 4 position with fluorine, chlorine, cyano, or trifluoromethyl, preferably with trifluoromethyl, and R-i, R2, R3 are as defined above.
In a third aspect of the invention, the cyclic amine derivative of Formula (I) contains A which is the ring D.
In accordance with this aspect a subset of compounds of Formula (ID) is provided:
Figure imgf000010_0001
and/or pharmaceutically acceptable derivatives or salts thereof,
wherein m, R ; R2, R3 and Ar are as above described in general, unless otherwise specified,
In certain embodiments of this aspect, m is 1 .
In certain embodiments, Ri and R2 are independently hydrogen, linear or branched Ci-3 alkyl, or joined together they form a cyclopropyl ring.
In certain embodiments R3 is H or linear 0 branched C-i-3 alkyl, tipically methyl.
In certain embodiments R3 is H.
In certain embodiments, Ar is
phenyl, having - in 4-position one substituent selected from the group consisting of
halogen, cyano, trifluoromethyl,
- in 3-position one substituent selected from group consisting of halogen,
cyano, trifluoromethyl, provided that m is 1 .
In certain embodiments Ar is phenyl as defined above and having in one or both 2 and 6 positions a moiety selected from the group consisting of H, halogen, cyano, trifluoromethyl, or linear or branched Ci-3 alkyl.
In certain embodiments, either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
In one preferred embodiment the 6-membered heteroarocyclic ring is pyridyl.
In certain embodiments m is 1 and Ar is phenyl substituted in 4 position with one substituent selected from the group consisting of halogens, cyano, trifluorormethyl, preferably trifluoromethyl and R-i , R2, R3 are as defined above.
In a fourth aspect of the invention, the cyclic amine derivative of Formula (I) contains A which is the ring E.
In accordance with this aspect a subset of compounds of Formula (IE) is provided:
Figure imgf000011_0001
(IE)
and/or pharmaceutically acceptable derivatives or salts thereof,
wherein R-i , R2, R3 and Ar are as above described in general, unless otherwise specified.
In certain embodiments, Ri and R2 are independently hydrogen, linear 0 branched Ci-3 alkyl, or joined together they form a cyclopropyl ring. In certain embodiments R3 is H or linear or branched Ci-3 alkyl, preferably R3 is H.
In certain embodiments, Ar is phenyl, substituted in 4 position with one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
In certain embodiments, Ar is
- phenyl, having in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl.
In certain embodiments, Ar is phenyl, having in 4-position one substituent selected from the group consisting of halogen, cyano and trifluoromethyl.
In certain embodiments Ar is phenyl as defined above and having in one or both 2 and 6 positions a moiety selected from the group consisting of H, halogen, cyano, trifluoromethyl, or linear or branched Ci-3 alkyl.
In certain embodiments, either the 5-membered heteroaromatic and the 6- membered heterocyclic rings are substituted, preferably in 4 position, with halogen, cyano or trifluoromethyl.
In one preferred embodiment the 6-membered heteroarocyclic ring is pyridyl.
The term "pharmaceutically acceptable salts" as used herein, refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, quaternary ammonium salts and internally formed salts.
Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganous, potassium, sodium, zinc, and the like. Preferred are the ammonium, calcium, magnesium, litium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2- diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of Formula (I) are meant to also include the pharmaceutically acceptable salts or derivatives.
Furthermore, the compound of the formula (I) may form an acid addition salt or a salt with a base, depending on the kind of the substituents, and these salts are included in the present invention, as long as they are pharmaceutically acceptable salts.
The compounds (I) of the invention may be in crystalline forms. In certain embodiments, the crystalline forms of the compounds (I) are polymorphs.
The terms "the compound of the invention" and "the compounds of the present invention" refer to each of the compounds of formulae (I), (IB), (IC), (ID), (IE) and are meant to include their pharmaceutically acceptable salts, hydrates, solvates, and crystalline forms and also any suitable forms as illustrated hereinafter.
In certain embodiments, the compound of the Formula (I) may exist in the form of other tautomers or geometrical isomers in some cases, depending on the kinds of the substituents. In the present specification, the compound may be described in only one form of such isomers, but the present invention includes such isomers, isolated forms of the isomers, or a mixture thereof.
Furthermore, the compound of the Formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and correspondingly, it may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like. The present invention includes both a mixture and an isolated form of these optical isomers.
Within the scope of the present invention are therefore included all stereoisomeric forms, including enantiomers, diastereoisomers, and mixtures thereof, including racemates and the general reference to the compounds of formulae (I), (IB), (IC), (ID), (IE) include all the stereoisomeric forms, unless otherwise indicated.
Additionally, the pharmaceutically acceptable prodrugs of the compound of the formula (I) are also included in the present invention. The pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into an amino group, OH, CO2H, or the like, by solvolysis or under a physiological condition. Examples of the groups for forming a prodrug include those as described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163- 198.
Additionally, the present invention in certain embodiments also includes various hydrates or solvates, and polymorphism of the compound of the formula (I) and a pharmaceutically acceptable salt thereof. Furthermore, the present invention also includes the compounds labelled with various radioactive isotopes or nonradioactive isotopes.
Compounds according to the present invention include examples 1 - 40 as shown herein below, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the present invention provides a compound selected from the group consisting of: lithium 4-((1 S)-1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate lithium 4-((S)-1 -((/^-l -(4-fluorobenzyl)piperidine-2- carboxamido)ethyl)benzoate
lithium 4-((S)-1 -((R)-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate lithium (f?)-4-(1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate
lithium (R)-4-(1 -(1 -(4-chlorobenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate lithium (R)-4-(1 -(1 -(4-cyanobenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoic acid
4-(1 -(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoic acid
4-(1 -(6-(3-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid
4-((1 S)-1 -(5-methyl-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid
4-(1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid
4-((1 S)-1 -((2fl)-4-fluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid
4-(1 -((2/:?)-4-fluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-((S)-1 -((/:?)-4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid
(f?)-4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid 4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoic acid
4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoic acid
4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoic
4-(1 -(3-(3-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoic acid
4-(1 -((3fl)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)ethyl)benzoic acid
lithium 4-((S)-1 -((fl)-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoate
lithium 4-((S)-1 -((RH -(4-fluorobenzyl)pyrrolidine-2-carboxamido)ethyl)
4-(1 -((1 f?,3/:?!5/:?)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
4-(1 -((1 R,3R,5R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
4-(1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)ethyl)benzoic acid
4-((1 S)-1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)ethyl)benzoic acid
(f?)-4-(1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -(1 -(4-(trifluoromethyl)benzyl)azetidine-2-carboxamido)ethyl)benzoic acid 4-((1 S)-1 -(1 -(4-(trifluoromethyl)benzyl)azetidine-2-carboxamido)ethyl)benzoic acid 4-((1 S)-1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2- carboxamido)ethyl)benzoic acid 4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -(2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3- carboxamido)ethyl)benzoic acid
4-(1 -(2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3- carboxamido)cyclopropyl)benzoic acid
(f?)-4-(1 -(2-methyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-((S)-1 -((/:?)-2-methyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid
(R)-4-(1 -(2-methyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoic acid
lithium 4-((S)-1 -((2fl,4S)-4-fluoro-1 -(3-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoate
4-((S)-1 -((fl)-4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoic acid
Preferred compounds of the invention are selected from the group consisting of: lithium(/:?)-4-(1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl) benzoate
4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)
benzoic acid
4-((1 S)-1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid
4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid
4-((S)-1 -((fl)-4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid (R)-4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid
4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoic
4-(1 -((3fl)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)ethyl)benzoic acid
lithium 4-((S)-1 -((fl)-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoate
4-(1 -((1 f?,3/:?!5/:?)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
4-(1 -((1 R,3R,5R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
A further aspect of this invention concerns a process for the preparation of a compound of Formula (I) comprising the following steps represented in the general scheme below:
Figure imgf000019_0001
a) reacting a compound of formula (II) with a compound of formula (III) in the presence of a coupling reagent and a base thus obtaining a compound of Formula
(IV);
b) reacting a compound (IV) with compound of (V) in presence of a suitable base thus obtaining a compound of Formula (VI);
c) hydrolysing an ester compound (VI) with strong bases such us lithium hydroxide in a suitable solvent system such as 1 ,4-dioxane/H20, thus obtaining a compound of Formula (I);
d) reacting a compound (II) with a compound of (V) in presence of a suitable base thus obtaining a compound of Formula (VII);
e) reacting a compound of formula (VII) with a compound of formula (III) in the presence of a coupling reagent and in the presence of a base thus obtaining a compound of Formula (VI).
In the above general scheme:
A, R-i , R2, R3, Ar are as defined in formula (I),
R is selected from the group consisting of hydrogen, linear or branched Ci-3 alkyl and benzyl groups,
W is selected from the group consisting of hydrogen, benzyl group and t- Butyl carbamate group, It will be appreciated that compounds of formula (II), (IV) and (VII), may be converted into other compounds of formula (II), (IV) and (VII), by synthetic methods known to the skilled person in the art.
Examples of such conversion reactions are:
i) Compounds of formula (II) wherein R is Ci-3 alkyl, may be prepared by reacting corresponding compounds wherein R is hydrogen with alcohols, for example ethanol, in the presence of a suitable reactive reagent such as thionyl chloride.
ii) Compounds of formula (II), when R is hydrogen, may be prepared by hydrolysis of the corresponding compounds of formula (II), wherein R is
C-i -3 alkyl. The hydrolysis is carried out in the presence of a base, for example lithium hydroxide, typically in presence of a suitable ether system, such as aqueous 1 ,4-dioxane.
iii) Compounds of formula (IV) wherein W is hydrogen, may be prepared by corresponding compounds of formula (IV) wherein W is benzyl group, by hydrogenolysis or by reacting compound formula (IV), wherein W is t- Butyl carbamate group, with trifluoroacetic acid.
iv) Compounds of formula (VII), when R is hydrogen, may be prepared by hydrolysis of the corresponding compounds of formula (VII), wherein R is C-i -3 alkyl. The hydrolysis is carried out in the presence of a base, for example lithium hydroxide in aqueous 1 ,4-dioxane.
METHOD OF SYNTHESIS
As above shown, according to a further aspect of this invention there is provided a process for the preparation of compound of formula (I).
In a more detailed way, the compounds of the present invention may be prepared according to the following schemes.
Unless otherwise indicated R-i , R2, R3, W and Ar in the reaction schemes and discussion that follow are as defined above, in formula (I).
The term "protecting group", as used hereinafter, means an amino protecting group which is selected from typical amino protecting groups as described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999);
Compounds of formula (I) may be prepared by hydrolysis reaction of ester compounds of formula (VI) according to the reaction scheme 1 .
Figure imgf000021_0001
(VI) ( I )
Hydrolysis can be carried out in presence of a base, for example lithium hydroxide in a suitable solvent such as in aqueous 1 ,4-dioxane.
In certain embodiments, this reaction may be carried out at room temperature.
Compounds of formula (VI) may be prepared according to reaction scheme
2.
SCHEME 2
Compounds of formula (IV), wherein W is hydrogen, may be reacted with compounds of formula (V) in the presence of a suitable base, such as cesium carbonate and in a suitable solvent such as acetonitrile. In certain embodiments the reaction is carried out at room temperature or in others by heating, for example at 60°C.
Compounds of formula (IV), wherein W is hydrogen, may be prepared from corresponding compounds of formula (IV) wherein W preferably is benzyl group or f-butyl carbamate group. In certain embodiments wherein W is f-butyl carbamate, the deprotection step can be carried out in presence of trifluoroacetic acid in a suitable solvent such as dichloromethane.
In other embodiments wherein W is a benzyl group, the deprotection step can be carried out by hydrogenolysis typically in a suitable solvent such as ethanol.
Compounds of formula (IVa) may be prepared according to reaction scheme 3.
SCHEME 3
Figure imgf000022_0001
In certain embodiments, the compounds of formula (II), wherein R is hydrogen and W is a benzyl group or f-butyl carbamate, are reacted with compounds of formula (III) in the presence of a suitable coupling reagent, for example selected from (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetramethylaminium hexafluorophosphate) (HCTU), 0-(7-Azabenzotriazol-1 -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (HATU), (1 -Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride) and 1 -Hydroxybenzotriazole and mixtures thereof. Typically, the reaction is carried out in an aprotic solvent, for example a halohydrocarbon, such as dichloromethane, Ν,Ν-dimethylformamide, or acetonitrile or mixture thereof, typically at room temperature, in presence of a suitable base, such as N,N-diisopropylamine.
Compounds of formula (III) are known, for example from the International Patent applications WO 2005105733 and WO2008104055.
Alternatively compound of formula (VI) may be prepared according to reaction scheme 4.
Figure imgf000023_0001
(VII) (VI)
In certain embodiments, the compounds of formula (VII), wherein R is H, are reacted with compounds of formula (III) in the presence of a suitable coupling reagent, for example selected from (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3- tetramethylaminium hexafluorophosphate) (HCTU), 0-(7-Azabenzotriazol-1 -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (HATU), (1 -Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride) and 1 -Hydroxybenzotriazole or mixtures thereof.
In certain embodiments the reaction is carried out in an aprotic solvent, for example a halohydrocarbon, such as dichloromethane, Ν,Ν-dimethylformamide, or acetonitrile or mixtures thereof, typically at room temperature, in presence of a suitable base.
In certain embodiments, the compounds of formula (VII), wherein R is hydrogen, may be prepared by hydrolysis of the corresponding compounds of formula (VII), wherein R is C(1 -3) alkyl. In certain embodiments, the hydrolysis is carried out in the presence of a base for example lithium hydroxide, typically in suitable solvent such as aqueous 1 ,4-dioxane.
In certain embodiments, the compounds of formula (VII) may be prepared according to reaction scheme 5.
Figure imgf000023_0002
(ll) (V) (VII)
In certain embodiments, the compounds of formula (II), wherein R is C(1 -3) alkyl and W is a benzyl group or f-butyl carbamate, may be reacted with compounds of formula (V) in the presence of a suitable base such as cesium carbonate and a suitable solvent such as acetonitrile. In certain embodiments the reaction is carried out at room temperature, in other embodiments the reaction is carried out under heating, for example at around 60 °C.
In certain embodiments the compounds of formula (II) wherein A is D, R is hydrogen, W is f-butyl carbamate and m is 1 , may be prepared according to the reaction scheme 6.
SCHEME 6
Figure imgf000024_0001
In certain embodiments the compounds of formula (II) wherein A is C, m is 0 or 1 , R is ethyl and W is f-butyl carbamate, may be prepared according to reaction scheme 7.
SCHEME 7
Figure imgf000024_0002
In other embodiments, the compounds of formula (II) wherein A is C, m is 0, R is ethyl and W is f-butyl carbamate, may be prepared according to reaction scheme 8.
SCHEME 8
Figure imgf000024_0003
In accordance with certain embodiments, the compounds of formula (II) wherein A is B, n is 1 , R and R5 are independently selected from hydrogen or fluorine or both R4 and R5 are fluorine, may be prepared according to reaction scheme 9.
SCHEME 9
Figure imgf000025_0001
In certain embodiments the compounds of formula (II) wherein A is B, n is 1 , R4 and R5 are methyl, R and R3 are hydrogen and W is f-butyl carbamate, may be prepared according synthetic route described in scheme 10.
SCHEME 10
Figure imgf000025_0002
In accordance with certain embodiments, the compounds of formula (II) wherein A is B, W, R, R4 and R5 are hydrogen, n is 0, 1 and 2, R3 is methyl, may be prepared according synthetic route described in scheme 1 1 .
SCHEME 11
Figure imgf000025_0003
Scheme 12 describes an alternative synthetic route to products of formula (II) wherein A is B, W, R4 and R5 are hydrogen, n is 1 , R and R3 are methyl.
SCHEME 12
Figure imgf000025_0004
According to certain embodiments of the invention, the compounds (I) are obtained using a simple process, easy to scale-up and avoiding lengthy and expensive preparation steps, obtaining high yield of a stable pharmaceutical grade compound of formula (I).
Typically, the various methods described above may be useful for the introduction of the desired group at any stage in the stepwise formation of the required compound, and it will appreciated that these general methods can be combined in different way in such multi-stage processes. Typically, the sequence of the reactions in multi-stage processes are chosen so that the reaction conditions used do not affect groups in the molecule which are in the final product.
In certain embodiments where an enantiomer of a compound of the general formula (I) is required, this may be obtained by resolution of a corresponding enantiomeric mixture of such compound of formula (I) by using conventional methods such as by chiral HPLC procedure.
In certain embodiments the compounds of general formula (I) are in the form of salts, specifically pharmaceutically acceptable salts. These salts may be obtained using conventional methods, for example by reacting the compound having general formula (I) in the form of a free base with a suitable acid in a suitable solvent for example an alcohol, such as ethanol or an ether such as diethyl ether or an ester such as ethyl acetate.
In certain embodiments the compounds of general formula (I) may be isolated in association with solvent molecules for example by evaporation or crystallisation from a suitable solvent to provide the corresponding solvates.
The Inventors have found that the general family of the compounds of formula (I) as well the sub-families of the compounds of formulae (IB), (IC), (ID), (IE) as above, have affinity for and are specific antagonists of PGE2 receptors, in particular of EP4 subtype of PGE2 receptors.
The compounds of general formula (I) and the specific compounds of (IB), (IC), (ID), (IE) are useful in the treatment of Prostaglandin E mediated conditions or diseases. Thus, according to an additional aspect the invention concerns compounds of Formulae (I), (IB), (IC), (ID), (IE) for use as a medicament the treatment of pathologies or disorders where an antagonist of the EP4 receptor is needed.
In certain embodiments the pathologies or disorders are selected from acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder such as arthritis, rheumatoid arthritis, cancer endometriosis and migraine.
In certain embodiments, the compounds of the invention are useful as analgesics. For example they are useful in the treatment of chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
Compounds of the invention are useful in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
Compounds of the invention are also useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux disease); organ transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, polymyositis, tendinitis, bursitis, and Sjogren's syndrome.
Compounds of the invention are also useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation. The compounds of the invention are also effective in increasing the latency of HIV infection.
Compounds of the invention are also useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
Compounds of the invention are also useful for the preparation of a drug with diuretic action.
Compounds of the invention are also useful in the treatment of impotence or erectile dysfunction.
Compounds of the invention are also useful in the treatment of bone disease characterized by abnormal bone metabolism or resorption such as osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gout and ankylosing spondylitis, tendinitis and bursitis. In a further aspect, compounds of the invention may be useful in inhibiting bone resorption and/or promoting bone generation.
Compounds of the invention are also useful for attenuating the hemodynamic side effects of NSAIDs and COX-2 inhibitors.
Compounds of the invention are also useful in the treatment of cardiovascular diseases such as hypertension or myocardiac ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
Compounds of the invention are also useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chores, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
The compounds of Formula (I), (IB), (IC), ID) and (IE) are also useful in the treatment of neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like. Compounds of the invention are also useful for the treatment of stroke and multiple sclerosis.
Compounds of the invention are also useful in the treatment of tinnitus. Compounds of the invention are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent. Examples of dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
Compounds of the invention are also useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
Compounds of the invention are also useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.
Compounds of the invention are also useful for treating or preventing a neoplasia in a subject in need of such treatment or prevention. The term "treatment" includes partial or total inhibition of the neoplasia growth, spreading or metastasis, as well as partial or total destruction of the neoplastic cells and/or symptoms associated with neoplasia including pain, anorexia or weight loss. The term also includes the use of compounds as sensitizing agents for other chemotherapies. The term "prevention" includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinical^ evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia. The term "subject" for purposes of treatment includes any human or mammal subject who has any one of the known neoplasias, and preferably is a human subject. For methods of prevention, the subject is any human or animal subject, and preferably is a human subject who is at risk for obtaining a neoplasia. The subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to have the neoplasia, and the like. The term "neoplasia" includes both benign and cancerous tumors, growths and polyps. Thus, the compounds of the invention are useful for treating or preventing benign tumors, growths and polyps including squamous cell papilloma, basal cell tumor, transitional cell papilloma, adenoma, gastrinoma, cholangiocellular adenoma, hepatocellular adenoma, renal tubular adenoma, oncocytoma, glomus tumor, melanocyte nevus, fibroma, myxoma, lipoma, leiomyoma, rhabdomyoma, benign teratoma, hemangioma, osteoma, chondroma and meningioma. The compounds of the invention are also useful for treating or preventing cancerous tumors, growths and polyps including squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, adenocarcinoma, malignant gastrinoma, cholangiocelleular carcinoma, hepatocellular carcinoma, renal cell carcinoma, malignant melanoma, fibrosarcoma, myxosarcoma, liposarcoma, leimyosarcoma, rhabdomyosarcoma, malignant teratoma, hemangiosarcoma, Kaposi sarcoma, lymphangiosarcoma, ostreosarcoma, chondrosarcoma, malignant meningioma, non-Hodgkin lymphoma, Hodgkin lymphoma and leukemia. For purposes of this specification, "neoplasia" includes brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, rectal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial, mesenchymal or blood cells throughout the body. The compounds of the invention are useful for treating or preventing any of the aforementioned cancers. The compounds of the invention are useful for treating or preventing benign and cancerous tumors, growths and polyps of the following cell types: squamous epithelium, basal cells, transitional epithelium, glandular epithelium, G cells, bile ducts epithelium, hepatocytes, tubules epithelium, melanocytes, fibrous connective tissue, cardiac skeleton, adipose tissue, smooth muscle, skeletal muscle, germ cells, blood vessels, lymphatic vessels, bone, cartilage, meninges, lymphoid cells and hematopoietic cells. The compounds can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the compounds can be used to prevent polyps from forming in patients at risk of FAP. Preferably, the compounds of the invention are useful for treating or preventing the following cancers: colorectal, esophagus stomach, breast, head and neck, skin, lung, liver, gall bladder, pancreas, bladder, endometrium cervix, prostate, thyroid and brain. It is to be understood that reference to a treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
In a further aspect, the present invention concerns a compound of Formulae (I), (IB), (IC), (ID), (IE) for use as a medicament.
In another aspect the invention provides a pharmaceutical composition comprising a compound of Formula (I) (IB), (IC), (ID), (IE) and a pharmaceutically acceptable carrier.
The compound of Formula (I) may be used in combination with a pharmaceutically acceptable carrier and, optionally, with suitable excipients, to obtain pharmaceutical compositions.
The term "pharmaceutically acceptable carrier" means solvents, carrier agents, diluting agents and the like which are used in the administration of compounds of the invention.
In certain embodiments, the pharmaceutical compositions of the invention may be in solid or liquid form.
The pharmaceutical compositions in solid form may contain suitable excipients such as fillers, lubricants, binding agents, wetting agents, disintegrants, colorants and flavouring agents and mixtures thereof. For example the tablets may contain pre-gelatinised starch, microcrystalline cellulose, sodium glycolate starch, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
The pharmaceutical compositions in liquid form, typically may be provided as solutions, suspensions, emulsion, syrups, elixir. Typically, the compositions in liquid form may contain suspending agents, emulsifying agents, carriers, preservatives and colorants, flavouring agents.
Typically, the pharmaceutical compositions of the invention can be administered by parenteral, oral, buccal, sublingual, nasal, rectal, topical or transdermal administration. Pharmaceutical compositions for oral administration are generally preferred.
The pharmaceutical compositions of the invention suitable for the oral administration typically, will be discrete units in solid form such as in the form of tablets, capsules, cachets, powders, granules, lozenges, patches, suppositories, pellets, or in liquid form such as liquid preparations, injectable or infusible solutions or suspensions.
The pharmaceutical compositions for parenteral administration typically include sterile preparations in the forms of solutions or suspensions. In certain embodiments the compositions for parenteral administration are aqueous based solution suitable for injection or infusion. In certain embodiments such compositions for parenteral administration includes one or more adjuvants such as buffering agents, preservatives, antibacterial agents, surfactants and mixtures thereof.
The pharmaceutical compositions for topical administration may be formulated as creams, pastes, oils, ointments, emulsions, foams, gels, drops, spray solutions and transdermal patches.
In certain embodiments the pharmaceutical composition of the invention includes 0.1 to 99% by weight of the compound of formula (I) as active ingredient. In certain embodiments the amount of the compound of formula (I) is 1 to 30% by weight.
The dosage of the compound of formula (I) to be administered depends on the severity of the disease, the weight, the age and general conditions of the patient in need of treatment.
For example a suitable unit dosage may vary of from 0.01 to 1000 mg or typically of 1 .0 to 300 mg to be administered one or more in a day, for example twice a day usually at regular intervals. The duration of the therapy depends on the severity of the illness and general condition of the patients and may be varied by the physician an extended for certain weeks or months.
According to another aspect, the use of a compounds of the general formula (I) for the manufacture of a medicament for the treatment of pathologies or diseases which require the administration of an antagonist of the EP4 receptor, such as the treatment of inflammatory pain, osteoarthritis, arthritis.
In accordance to certain embodiments, the present invention provides for a pharmaceutical composition comprising a compound of formula (I) or (IB), (IC), (ID), (IE), in association with an additional active ingredient and a pharmaceutically acceptable excipient. Said additional active ingredients may be an additional compound of formula (I) or a different chemical entity having similar or different activity.
In certain embodiments said additional active ingredients is selected from the antinflammatory compounds, such as FANS or cortisonic compounds.
The invention will be now detailed by means of the following examples relating to the preparation of some embodiments of the compounds of the invention and to the evaluation of their activity against EP4 receptor.
The following Descriptions relating to intermediate products and Examples illustrating the preparation of certain compounds of formula (I) or salts thereof follow below. The descriptions illustrate the preparation of intermediates used to make compounds of formula (I) or salts thereof.
In the procedures that follow, after each starting material, reference to a description is provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the Description referred to. The stereochemistry of Descriptions and Examples has been assigned on the assumption that the absolute configuration centres are retained. Relative stereochemistry has been determined by using NMR Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, as for example in the descriptions D73a, D73b, D140a and D140b.
When a chiral HPLC separation of a racemic mixture was accomplished, it has been decide to use the term enantiomer 1 or enantiomer 2 depending on the retention time in the corresponding chiral HPLC separation. The term enantiomer 1 is used for the single stereoisomer with the minor retention time in the conditions of the chiral separation. Conversely the term enantiomer 2 is used for the single stereoisomer with the major retention time in the conditions of the chiral separation.
When a chiral HPLC separation or a separation by flash chromatography of a diastereoisomeric mixture was accomplished, it has been decide to use the term diastereoisomer 1 or diastereoisomer 2 depending on the retention time in the corresponding chiral HPLC separation or on the retention time in the corresponding flash chromatography column. The term diastereoisomer 1 is used for the single diastereoisomer with the minor retention time in the conditions of the chiral separation or the first eluting in flash chromatography column. Conversely the term diastereoisomer 2 is used for the single diastereoisomer with the major retention time in the conditions of the chiral separation or the second eluting in flash chromatography column.
The yields are calculated assuming that products were 100% pure if not stated otherwise.
Compound are named using ChemBioDraw Ultra 12.0 (CambridgeSoft Corp., 100 CambridgePark Drive, Cambridge, MA 02140)
Reagents used in the following examples were commercially available from various suppliers (for example Sigma-Aldrich, Acros, Matrix scientific, Manchester or Apollo) and used without further purifications.
Reactions in anhydrous environment were run under a positive pressure of dry N2 and solvents were used in dry form.
For reaction involving microwave irradiation, an Initiator 2.5 System was used.
Purification was performed using Biotage automatic flash chromatography systems (Sp1 and Isolera systems), Companion CombiFlash (ISCO) automatic flash chromatography, Flash Master or Vac Master systems.
Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP-Si cartridges), Waters PoraPak RXN RP cartridges, Biotage SNAP-C18.
SPE-Si cartridges are silica solid phase extraction columns.
PoraPakRXN RP cartridges are polimer based reverse phase resin.
Biotage SNAP C18 Gold cartridges are silica based reverse phase column. SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian. The eluent used with SPE-SCX cartridges is dichloromethane and methanol or only methanol followed by 2N ammonia solution in methanol. The collected fractions are those eluted with ammonia solution in methanol. Thin layer chromatography was carried out using Merck TLC plates Kieselgel 60F-254, visualized with UV light, aqueous permanganate solution, iodine vapours.
Proton Nuclear Magnetic Resonance (1H NMR) spectra were recorded on Bruker Avance 400 MHz instrument and on Bruker Avance III plus 400MHz. TMS was used as internal standard. Chemical shifts are reported in ppm (δ) using the residual solvent line as internal standard. Splitting patterns are designated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad signal. The NMR spectra were recorded at temperature ranging from 25 °C to 90 °C. When more than one conformer was detected the chemical shifts of the most abundant one is usually reported.
In the analytical characterisation of the described compounds "MS" refers to Mass Spectra taken by Direct infusion Mass or to a mass Spectra associated with peaks taken by UPLC/MS or HPLC/MS analysis, where the Mass Spectrometer used is as mentioned below.
Direct infusion Mass Spectra (MS) were run on a Ion Trap Thermo LCQ classic spectrometer, operating in positive ES (+) and negative ES (-) ionization mode using different columns and operating procedures listed below:
Phenomenex Gemini-NX C18 column (100x2mm, 3μιτι particle size), column T= 35 °C. Mobile phase: A (water + 0,1 % formic acid)/ B (acetonitrile + 0,1 % formic acid), Gradient: 10% B at t=0min up to 90% B at t=12min using different gradient curves, flow rate: 0.3 ml/min;
Acquity™UPLC-BEH C18 column (50x21 mm, 1 .7μΜ particle size), column T = 35 °C. Mobile phase: A (water + 0,1 % formic acid)/ B (acetonitrile + 0,1 % formic acid), Gradient: 5% B at t=0min up to 100% B at t=4.5min, using different gradient curves, flow rate: 0.5 ml/min;
Zorbax SB C18 column (2.1 x 50mm, 3,5 μιτι particle size) column T= 35 °C. Mobile phase: A (water + 0,1 % formic acid)/ B (acetonitrile + 0,1 % formic acid), Gradient: 10% B at t=0min up to 90% B at t=12min using different gradient curves, flow rate: 0.4 ml/min.
HPLC spectra were performed on a Waters Alliance 2965 instrument equipped with a Waters 2996 UV-Vis detector using a Phenomenex Luna C18 column (150x4.6mm, 5μιη particle size). [Mobile phase: different mixtures of acetonitrile/methanol/KH2P04 (20mM pH 2.5); Elution time: 35 min; column T= 30 °C; flow rate= 0.6 ml/min. UV detection wavelenght range from 220 up to 300 nm]
Total ion current (TIC) and DAD UV chromatografic traces together with MS and UV spectra were taken on a UPLC/MS Acquity™ system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQ™ Mass Spectrometer operating in positive or negative electrospray ionisation mode. UPLC analysis were performed using an Acquity™UPLC-BEH C18 column (50x21 mm, 1 .7μΜ particle size), column T= 35 °C. Mobile phase: A (water + 0,1 % formic acid)/ B (acetonitrile + 0,1 % formic acid), Gradient: 5% B at t=0min, up to 100% B at t=2 min or 4.5 min using different gradient curves, flow rate: 0.5 ml/min.
LCMS were taken on a quadrupole Mass spectrometer on Agilent LC/MSD 1200 Series using Column: Welchrom XB-C18 (50x4.6mm, 5μιη) operating in ES (+) or (-) ionization mode at T=30°C and with a flow rate=1 .5 ml/min.
HPLC spectra for chiral purity determinations were performed on Agilent 1200 instrument and UV detector DAD G1315D using a Daicel Chiralpack IC column [5μιτι particle size (250x4.6mm)] or a Daicel Chiralpack AD-H column [5μιτι particle size (250x4.6mm)] or a DAICEL OD-H [5μιη particle size (250x4.6mm)] or a Regis Welk 01 (SS) [5μιτι particle size (250x4.6mm)] and the following general isocratic conditions: Mobile phases: A: n-heptane or n-hexane from 90% to 50% (+0.1 % DEA or +0.2% TFA) B: ethanol or IPA from 10% to 50%; time: up to 60 min of elution; Column Temperature: 30 °C; flow rate: 0.5 ml/min.
Purifications by means of preparative chiral HPLC were performed on Shimadzu Preparative Liquid Chromatograph LC-8A apparatus and UV detector SPD-20A using a Daicel Chiralpack IC column [(250x4.6mm), 5μιτι particle size] or a Daicel Chiralpack AD-H column [(250x4.6mm), 5μιτι particle size] and the following general isocratic conditions: Mobile phase: premixed mixture of n- heptane or n-hexane from 90% to 50%, and ethanol or IPA from 10% to 50% (+0.1 % DEA or +0.2% TFA); time: up to 60 min of elution; Column Temperature: RT; flow rate: 10 ml/min.
Specific Mobile phase and operating conditions will be specified each time. ABBREVIATIONS:
BAIB - bis(acetoxy)iodobenzene
BF3.OEt2 - Boron trifluoride diethyl etherate
Boc20 - Di-terf-butyl dicarbonate
cHex - Cyclohexane
s-BuLi - sec-Butyllithium
f-Buli - tert- Butyl lithium
DAST - Diethylaminosulfur trifluoride
1 ,2 DCE - 1 ,2-Dichloroethane
DCM - dichloromethane
DEA - diethylamine
DMAP - 4-Dimethylaminopyridine
DMF - Dimethylformamide
DIPEA - Λ/,/V-Diisopropylethylamine
EDC HCI - 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide)
EtOAc - Diethylacetate
Et20 - Diethylether
Et3SiH - Triethylsilane
HATU - O-iy-azabenzotriazol-l -y -^^^/V'-tetramethyluronium hexafluorophosphate
HBTU - 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate
HCTU - (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 , 1 ,3, 3- tetramethylaminium hexafluorophosphate)
HOBT - N-Hydroxybenzotriazole
IPA - 2-propanol
LDA - Lithium diisopropylamide
LiEt3BH - Lithium triethylborohydride
LiHMDS - Lithium bis(trimethylsilyl)amide
MeCN - Acetonitrile
MTBE - Methyl tert-butyl ether NaBH(OAc)3 Sodium triacetoxyborohydride
NaBH4 Sodium borohydride
PTSA p-Toluene sulfonic acid
Py Pyridine
RT Room Temperature
TBAF Tetra-n-butylammonium fluoride
TBDMSCI terf-Butyldimethylsilyl chloride
TBDPSCI terf-butyldiphenylsilyl chloride
TEA Triethylamine
TEMPO 2,2,6,6-Tetramethylpiperidinyloxy
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
TMEDA Tetramethylethylenediamine
TMSCHN2 Trimethylsilyldiazomethane
p-TSA p-Toluenesulfonic acid
THF Tetrahydrofuran
DESCRIPTIONS Description 1 : 6-(ferf-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (racemic mixture) (D1)
Figure imgf000039_0001
To a solution of terf-butyl 6-azaspiro[2.5]octane-6-carboxylate (2.1 g, 9.9 mmol; for preparation see published International Patent application WO201 1006960) in dry Et2O (40 ml), cooled to -78°C, TMEDA (3.6 ml, 23.85 mmol) was added followed by addition of sec-BuLi 1 .4M sol in cHex (17.04 ml, 23.85 mmol). The reaction mixture was stirred at -78 °C for 1 .5 hrs then slowly warmed at -25 °C and further stirred at this temperature for 30 min. The solution was cooled to -78 °C and quenched by bubbling dry ice into the reaction mixture via cannula for 15 min. The solution was then further stirred for 15 min the allowed to slowly warm to RT prior addition of NH4CI sat sol (40 ml). Phases were separated then the aqueous was acidified to pH~3 by addition of citric acid 1 M sol and extracted with EtOAc. Collected organic phases after drying and solvent evaporation afforded a residue which was purified by SPE-Si cartridge (50g) eluting with a mixture DCM/MeOH from 100/0 to 98/2. Collected fractions after solvent evaporation afforded the title compound (D1) (1 .93 g).
MS: (ES/+) m/z: 254.1 [MH"] C13H21 N04 requires 255.15
1 H NMR (400MHz ,CHCI3-d) δ (ppm10.62 (br. s, 1 H), 5.15 - 4.70 (m, 1 H), 4.23 - 3.86 (m, 1 H), 3.37 - 3.02 (m, 1 H), 2.29 - 2.14 (m, J = 5.4, 13.0 Hz, 1 H), 2.02 - 1 .85 (m, J = 3.4 Hz, 1 H), 1 .67 - 1 .54 (m, 1 H), 1 .49 (br. s., 9 H), 0.88 - 0.77 (m, 1 H), 0.52 - 0.25 (m, 4 H).
Description 2: N-benzyl-1-phenylethanaminium 6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylate (single unknown enantiomer) (D2)
Figure imgf000040_0001
To an ice cooled solution of 6-(terf-butoxycarbonyl)-6-azaspiro[2.5]octane-5- carboxylic acid (racemic mixture) (D1 ) (41 g, 160.8 mmol) in anhydrous MeOH (400 ml) (f?)-N-benzyl-1 -phenylethanamine (34 g, 160.8 mmol) was added and the resulting reaction mixture was stirred at 0°C for 1 .5 hrs. The reaction mixture was warmed at RT and further stirred for 5 hours. Solvent was evaporated in vacuo to afford (f?)-N-benzyl-1 -phenylethanaminium 6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylate (racemic salt) (75 g). To a solution of the above compound (75 g, 160.8 mmol) in anhydrous EtOH (400 ml), H20 (1 .2 L) was added and the resulting suspension was warmed to reflux untill the mixture turned into clear solution. The mixture was cooled slowly to 50°C until formation of a precipitate which was filtered at 50 °C. The aqueous layer was extracted with EtOAc twice, and the collected organic layers were dried over anhydrous Na2S04, filtered and evaporated in vacuo to afford 20 g of salt which was recrystallized from H20/EtOH (300/100 ml) at 50°C to afford the title compound (D2) (10 g). Description 3: 6-(ferf-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (single unknown enantiomer)
Figure imgf000041_0001
To a suspension of N-benzyl-1 -phenylethanaminium 6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylate (single unknown enantiomer) (D2) (10 g, 24 mmol) in EtOAc (100 ml_) stirred at 0°C was slowly added aqueous HCI 0.5N (100 ml) saturated with NaCI. After addition was completed, dissolution was observed. The organic layer was decanted, washed with saturated NaCI, dried (Na2S04) and evaporated in vacuo to afford 5 g of acid which was recrystallized from petroleum ether/EtOAc (60 ml/20 ml) to afford the tile compound (D3) (2.8g) as white solid.
Description 4: 6-ferf-butyl 5-methyl 6-azaspiro[2.5]octane-5,6-dicarboxylate (racemic mixture) (D4)
Figure imgf000041_0002
To an ice cooled solution of 6-(terf-butoxycarbonyl)-6-azaspiro[2.5]octane-5- carboxylic acid (racemic mixture) (D1 ) (500 mg, 0.78 mmol) in Et20/MeOH (10/5ml), TMSCHN2 2M sol in Et20 (1 .5 ml, 2.94 mmol) was added and the resulting mixture was stirred 2 hrs at 0°C then 18 hrs at RT. After solvent evaporation the crude residue was loaded onto SPE-Si cartridge (1 Og) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D4) (420 mg) as a clear oil.
MS: (ES/+) m/z: 170 [MH-Boc+] C14H23N04 requires 269.16
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 5.07 - 4.63 (m, 1 H), 4.16 - 3.88 (m, 1 H), 3.74 (br. s., 3 H), 3.34 - 3.04 (m, 1 H), 2.18 (dd, J = 6.0, 13.6 Hz, 1 H), 2.02 - 1 .81 (m, 1 H), 1 .61 - 1 .37 (m, 10 H), 0.81 (br. s., 1 H), 0.44 - 0.19 (m, 4 H)
Description 5: 6-iert-butyl 5-methyl 5-methyl-6-azaspiro[2.5]octane-5,6- dicarboxylate (D5) ■ COOMe
Boc
6-terf-butyl 5-methyl 6-azaspiro[2.5]octane-5,6-dicarboxylate (D4) (420 mg, 1 .56 mmol) was dissolved in THF (25 ml) and the solution was cooled at -78°C prior addition of LDA 2M sol in THF/heptane (1 .16 ml, 2.34 mmol). The red solution was left stirring at -78°C for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and left stirring for 3 hrs. The resulting yellow-orange solution was treated with NH4CI sat. sol. (5 ml) and extracted with Et2O (3x50ml). Collected organic phases were washed with NaCI sat. sol. and dried over Na2SO4. Collected organics after solvent evaporation, afforded a residue which was purified by Biotage SNAP-Si (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D5) (320 mg) MS: (ES/+) m/z: 306.3 [MH+Na+] C15H25NO4 requires 283.18
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 4.03 - 3.85 (m, 1 H), 3.73 (s, 3 H), 3.28 - 3.1 1 (m, 1 H), 2.33 - 2.14 (m, 1 H), 2.01 - 1 .85 (m, 1 H), 1 .45 (s, 12 H), 1 .17 - 1 .09 (m, 1 H), 0.56 - 0.41 (m, 2 H), 0.40 - 0.21 (m, J = 6.2 Hz, 3 H).
Description 6: 6-(iert-butoxycarbonyl)-5-methyl-6-azaspiro[2.5]octane-5- carboxylic acid (D6)
Figure imgf000042_0001
6-tert-butyl 5-methyl 5-methyl-6-azaspiro[2.5]octane-5,6-dicarboxylate (D5) (320 mg, 1 .13 mmol) was partitioned between dioxane/water (8/8 ml) prior addition of LiOH H2O (190 mg, 4.52 mmol). The mixture was stirred at RT for 18 hrs then heated at 150°C under microwave irradiation 40 min (4 cycles of 10 min each). Organic solvent was evaporated off and the aqueous solution washed with EtOAc (2x10ml), acidified to pH~4 with citric acid sat. sol. and extracted with EtOAc (3x10ml). The organic phases were washed with NaCI sat. sol, dried over Na2SO4 and evaporated to reduced pressure to afford the title compound (D6) (1 14 mg). MS: (ES/+) m/z: 292 [MH+Na+] C14H23NO4 requires 269.16 1 H NMR (400MHz ,CHCI3-d) δ (ppm): 4.01 - 3.88 (m, 1 H), 3.24 - 3.1 1 (m, 1 H), 2.41 - 2.30 (m, 1 H), 2.04 - 1 .91 (m, 1 H), 1 .47 (s, 12 H), 1 .16 (d, J = 13.2 Hz, 2 H), 0.51 (br. s., 2 H), 0.37 (d, J = 6.4 Hz, 2 H). Description 7: 2-aminopent-4-en-1-
Figure imgf000043_0001
To an ice cooled solution of (±)-2-Amino-4-pentenoic acid (6 g, 0.052 mmol; available from Fluka #05960) in THF (250 ml), LiAIH4 (2.37g, 0.065 mmol) was added portionwise. The resulting reaction mixture was allowed to warm to RT then stirred overnight. Water (2.36 g), NaOH 1 M (3.56 g) and water (7.2 g) were added in sequence to the reaction mixture previously cooled at 0°C. The precipitate was filtered off and the phases were separated. The aqueous layer was evaporated under reduced pressure to afford a yellow-brown oil (5 g). The previously filtered solid was treated with boiling THF (500 ml) for 30 min prior filtration. The filtrate was evaporated and the resulting residue was taken up in water and extracted with DCM (3x200ml). After solvent evaporation, a yellow-brown oil (3.3 g) was isolated. Both obtained oils were collected together to afford a single batch of the desired compound (D7) (8.3 g).
MS: (ES/+) m/z: 102.1 [MH+] C5H1 1 NO requires 101 .08
1 H NMR (400MHz ,DMSO-d) δ (ppm): 5.91 - 5.73 (m, 2 H), 5.08 - 4.92 (m, 4 H), 3.34 - 3.25 (m, 1 H), 3.16 - 3.1 1 (m, 1 H), 2.72 - 2.61 (m, 1 H), 2.19 - 2.02 (m, 1 H), 1 .96 - 1 .83 (m, 1 H).
Description 8: A/-(1-hydroxypent-4-en-2-yl)-4-methylbenzenesulfonamide (D8)
Figure imgf000043_0002
A solution of Na2C03 (9.22 g, 86.92 mmol) in water (50 ml) was left under stirring at RT for 20 min prior addition of 2-aminopent-4-en-1 -ol (D7) (8.3 g) and EtOAc (160 ml). After 30 minutes stirring, a solution of p-toluenesulfonyl chloride (12.9 g, 67.85 mmol) in EtOAc/THF (24/24 ml) was added over 15 minutes. The reaction mixture was stirred at RT for a weekend. Water (30ml) and EtOAc (100ml) were added to the reaction mixture, the phases were separated and the aqueous layer was extracted with EtOAc (2x80ml). The combined organic phases were evaporated and the residue was purified by Biotage SNAP-Si (100g) cartridge eluting with a mixture cHex/EtOAc from 80/20 to 50/50. Collected fractions after solvent evaporation afforded the title compound (D8) (5.5 g)
MS: (ES/+) m/z: 256.1 [MH+] C12H17N03S requires 255.09
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.82 - 7.75 (m, 2 H), 7.37 - 7.30 (m, J = 8.8 Hz, 2 H), 5.57 - 5.44 (m, 1 H), 5.05 (s, 1 H), 5.04 - 4.98 (m, 1 H), 4.79 (d, J = 7.3 Hz, 1 H), 3.65 - 3.59 (m, 1 H), 3.59 - 3.52 (m, 1 H), 3.36 - 3.22 (m, 1 H), 2.46 (s, 3 H), 2.28 - 2.14 (m, 2 H).
Description 9: /V-(1-((feri-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4- methylbenzenesulfonamide (D9)
Figure imgf000044_0001
DPS
To a solution of /V-(1 -hydroxypent-4-en-2-yl)-4-methylbenzenesulfonamide (D8) (6.5 g, 25.45 mmol) in DMF (95 ml), imidazole (4.5 g, 66.17 mmol) and TBDPSCI (7.9 ml, 30.54 mmol) were added and the reaction was stirred at RT for 3 hrs. The mixture was diluted with brine (50 ml) and extracted with EtOAc (3x60ml). The combined organic phases after solvent evaporation afforded a residue which was purified by Biotage SNAP-Si (100g) cartridge eluting with a mixture cycloexane/EtOAc from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D9) (13 g).
MS: (ES/+) m/z: 494.2 [MH+] C28H35NO3SSi requires 493.21
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.76 - 7.20 (m, 14 H), 5.64 - 5.43 (m, 1 H), 5.02 (s, 1 H), 5.00 - 4.94 (m, 1 H), 4.76 (d, J = 7.8 Hz, 1 H), 3.62 - 3.54 (m, 1 H), 3.50 - 3.40 (m, 1 H), 3.39 - 3.25 (m, 1 H), 2.43 (s, 3 H), 2.34 (t, J = 6.8 Hz, 2 H), 1 .07 - 1 .01 (m, 9 H). Description 10: /V-allyl-N-(1-((feri-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4- methylbenzenesulfonamide (D10)
Figure imgf000045_0001
To a solution of /V-(1 -((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4- methylbenzenesulfonamide (D9) (13 g, 26.33 mmol) in DMF (80 ml), Cs2C03 (12.86 g, 39.49 mmol) and allyl bromide (1 .8 ml, 21 .06 mmol) were added and the mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with water (40ml) and extracted with EtOAc (3x60ml). The combined organic phases were evaporated and the resulting residue was was purified by Biotage SNAP-Si (100g) cartridge eluting with a mixture cycloexane/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D10) (10.7 g). MS: (ES/+) m/z: 534.2 [MH+] C31 H39N03SSi requires 533.24
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.72 - 7.67 (m, J = 8.3 Hz, 2 H), 7.64 - 7.57 (m, 4 H), 7.50 - 7.43 (m, 2 H), 7.43 - 7.35 (m, 4 H), 7.23 - 7.17 (m, J = 8.3 Hz, 2 H), 5.79 (tdd, J = 6.4, 10.4, 17.0 Hz, 1 H), 5.55 (tdd, J = 6.8, 10.3, 17.1 Hz, 1 H), 5.14 - 4.89 (m, 4 H), 4.03 - 3.92 (m, 2 H), 3.87 - 3.78 (m, 1 H), 3.71 - 3.60 (m, 2 H), 2.50 - 2.42 (m, 1 H), 2.40 (s, 3 H), 2.33 - 2.23 (m, 1 H), 1 .04 (s, 9 H).
Description 11 : 2-(((feri-butyldiphenylsilyl)oxy)methyl)-1-tosyl-1 ,2,3,6- tetrahydropyridine (D11)
Figure imgf000045_0002
To a solution of /V-allyl-N-(1 -((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4- methylbenzenesulfonamide (D10) (7.12 g, 13.33 mmol) in DCM (64 ml), Grubb's catalyst (1 .09 g, 1 .32 mmol) was added and the mixture was stirred at RT overnight. After solvent evaporation, the residue was loaded on KP-Si (100g) cartridge eluting with a mixture cHex/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D11) (8.9 g).
MS: (ES/+) m/z: 506.2 [MH+] C29H35N03SSi requires 505.74
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.67 - 7.58 (m, 6 H), 7.50 - 7.35 (m, 6 H), 7.18 (d, J = 7.8 Hz, 2 H), 5.60 (dd, J = 2.0, 5.4 Hz, 1 H), 5.55 (br. s., 1 H), 4.32 (d, J = 7.8 Hz, 1 H), 4.04 (d, J = 18.1 Hz, 1 H), 3.63 - 3.53 (m, 2 H), 3.51 - 3.41 (m, 1 H), 2.40 (s, 3 H), 2.33 - 2.24 (m, 1 H), 2.22 - 2.1 1 (m, 1 H), 1 .05 (s, 9 H).
Description 12: 4-(((feri-butyldiphenylsilyl)oxy)methyl)-3-tosyl-3- azabicyclo[4.1.0]heptane (racemi mixture) (D12)
Figure imgf000046_0001
To an ice cooled solution of diethylzinc 1 M in hexane (93.64 ml) in DCM (50 ml) TFA (7.17 ml, 93.64 mmol) was added dropwise. After 20 min stirring, diiodomethane (7.54 ml, 93.64 mmol) was added and the mixture stirred for further 20 min. A solution of 2-(((ferf-butyldiphenylsilyl)oxy)methyl)-1 -tosyl-1 ,2,3,6- tetrahydropyridine (D1 1 ) (5.92 g, 1 1 .7 mmol) in DCM (25 ml) was added then the reaction mixture was allowed to warm to RT and stirred for 6 hrs. A solution of diethylzinc 1 M in hexane (93.64 ml), TFA (7.17 ml, 93.64 mmol) and diiodomethane (7.54 ml, 93.64 mmol) in DCM (50 ml) was prepared as described above and added to the previous mixture at 0°C. The resulting reaction mixture was allowed to warm to RT and stirred overnight. NH4CI solution (100ml) was added to the reaction mixture, the phases were separated and the aqueous layer was extracted twice with EtOAc (2x60ml). After solvent evaporation, the residue was was purified by Biotage SNAP-Si (2100g) cartridge eluting with a mixture cHex/ EtOAc from 100/0 to 95/05. Collected fractions after solvent evaporation afforded the title compound (D12) (5.12 g).
MS: (ES/+) m/z: 520.2 [MH+] C30H37NO3SSi requires 519.23
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.68 - 7.61 (m, 4 H), 7.61 - 7.55 (m, J = 7.8 Hz, 2 H), 7.50 - 7.35 (m, 6 H), 7.21 - 7.15 (m, J = 8.3 Hz, 2 H), 3.92 - 3.83 (m, 1 H), 3.71 - 3.59 (m, 2 H), 3.42 - 3.26 (m, 2 H), 2.40 (s, 3 H), 2.26 (ddd, J = 1 .5, 8.3, 14.7 Hz, 1 H), 1 .41 (td, J = 5.3, 14.3 Hz, 1 H), 1 .1 1 - 1 .03 (m, 9 H), 0.93 - 0.82 (m, 1 H), 0.82 - 0.71 (m, 1 H), 0.70 - 0.58 (m, 1 H), 0.03 (q, J = 4.9 Hz, 1 H)
Description 13: 4-(((fert-butyldiphenylsilyl)oxy)methyl)-3- azabicyclo[4.1.0]heptane (racemic mixture) (D13)
Figure imgf000047_0001
To a solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-tosyl-3- azabicyclo[4.1 .0]heptane (D12) (3.12 g, 6 mmol) in MeOH (430 ml), under a nitrogen atmosphere, magnesium turnings (previously flame dried) (8.46 g, 348 mmol) and NH4CI (8.9 g, 168 mmol) were added sequencially and the mixture was stirred at 23 °C. Two further additions of magnesium (4.3g), each one after 2 hrs stirring, were done. DCM (210 ml) and NH4CI sat. sol. (285 ml) were added to the reaction mixture. The formed emulsion was filtered through a celite pad. The organic layer was separated and washed with brine (2x55ml). The combined organic layers were evaporated and the resulting residue was purified by SPE- SCX (20g) cartridge. Collected ammonia fractions after solvent evaporation afforded the title compound (D13) (1 .65 g).
MS: (ES/+) m/z: 365.7 [MH+] C23H31 NOSi requires 365.22
1 H NMR (400MHz, CHCI3-d) δ (ppm): 7.67 (d, J = 6.8 Hz, 4 H), 7.49 - 7.36 (m, 6 H), 3.64 - 3.51 (m, 3 H), 2.82 (dd, J = 2.7, 12.5 Hz, 1 H), 2.40 (tdd, J = 3.9, 7.5, 1 1 .1 Hz, 1 H), 1 .72 (dd, J = 3.9, 13.2 Hz, 1 H), 1 .57 (ddd, J = 5.6, 1 1 .1 , 13.1 Hz, 1 H), 1 .19 - 0.99 (m, 1 1 H), 0.67 (dt, J = 4.6, 8.7 Hz, 1 H), 0.21 (q, J = 5.4 Hz, 1 H).
Description 14: ferf-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3- azabicyclo[4.1.0]heptane-3-carboxylate (racemic mixture) (D14)
Figure imgf000047_0002
To a solution of 4-(((ie f-butyldiphenylsilyl)oxy)methyl)-3-azabicyclo[4.1 .0]heptane (D13) (1 .65g, 4.51 mmol) and TEA (1 .25 ml, 9.02 mmol) in DCM (30 ml), Boc20 (1 .08 g, 4.96 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solution was diluted with H20 (50ml), washed with 1 N HCI (2x35ml) then with NaHC03 sat. sol. (2x35ml). The combined organic layers were evaporated in vacuo and the resulting residue was loaded on SPE-Si cartridges (50g) and eluted with a mixture cycloexane/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D14) (2.10 g).
MS: (ES/+) m/z: 488.2 [MH+Na+] C28H39N03Si requires 465.7 1 H NMR (400MHz , DMSO-d6) δ (ppm): 7.62 (ddd, J = 2.0, 3.9, 5.9 Hz, 4 H), 7.54 - 7.36 (m, 6 H), 4.09 - 3.84 (m, 1 H), 3.74 (d, J = 12.2 Hz, 1 H), 3.70 - 3.55 (m, 2 H), 3.32 - 3.26 (m, 1 H), 2.09 - 1 .81 (m, 1 H), 1 .63 (ddd, J = 3.4, 6.8, 14.7 Hz, 1 H), 1 .40 - 1 .25 (m, 9 H), 1 .00 (s, 9 H), 0.88 (br. s., 2 H), 0.63 - 0.47 (m, 1 H), -0.02 (d, J = 3.9 Hz, 1 H).
Description 15: ieri-butyl 4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3- carboxylate (racemic mixture) (D15
Figure imgf000048_0001
To a solution of terf-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3- azabicyclo[4.1 .0]heptane-3-carboxylate (D14) (2.1 Og, 4.5 mmol) in THF (80 ml), TBAF 1 M sol. in THF (9.01 ml) was added and the reaction mixture was stirred at RT for 18 hrs. Solvents were evaporated in vacuo and the resulting residue was purified on SPE-Si (5g) cartridge eluting with a mixture cHex/EtOAc from 90/10 to 40/60. Collected fractions after solvent evaporation afforded the title compound (D15) (0.93 g).
MS: (ES/+) m/z: 172.1 [MH-56+] C12H21 N03 requires 277.15
1 H NMR (400MHz , DMSO-d6) δ (ppm): 4.66 (br. s., 1 H), 3.78 (br. s., 1 H), 3.71 (d, J = 13.7 Hz, 1 H), 3.47 - 3.31 (m, 2 H), 3.28 (br. s., 1 H), 1 .96 - 1 .83 (m, 1 H), 1 .59 - 1 .49 (m, 1 H), 1 .42 - 1 .34 (m, 9 H), 0.89 (s, 2 H), 0.59 (dt, J = 4.4, 8.3 Hz, 1 H), -0.08 (q, J = 4.9 Hz, 1 H).
Description 16: ieri-butyl 4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (racemic mixture) (D16)
Figure imgf000048_0002
To a solution of terf-butyl 4-(hydroxymethyl)-3-azabicyclo[4.1 .0]heptane-3- carboxylate (D15) (820 mg, 3.6 mmol) and TEMPO (1 12.7 mg, 0.72 mmol) in DCM (8 ml), BAIB (1 .27 g, 3.96 mmol) was added and the resulting mixture was stirred at RT 4hrs. The reaction mixture was diluted with DCM (35 ml), washed with Na2S2O3 sat sol (35 ml) and extracted with DCM (2x35ml). The combined organic extracts were washed with NaHC03 sat sol (35ml) and brine (35ml), dried and evaporated under reduce pressure. The remaining residue was loaded on SPE-Si (25g) cartridge and eluted with a mixture cHex/EtOAC from 95/05 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D16) (0.62 g).
MS: (ES/+) m/z: 170.1 [MH-56+] C12H19N03 requires 225.14
1 H NMR (400MHz , DMSO-d6) δ (ppm): 9.46 (d, J = 19.1 Hz, 1 H), 4.13 - 3.95 (m, 1 H), 3.75 - 3.60 (m, 1 H), 3.59 - 3.35 (m, 1 H), 2.30 - 2.19 (m, 1 H), 1 .76 - 1 .59 (m, 1 H), 1 .47 - 1 .29 (m, 9 H), 1 .14 - 0.84 (m, 2 H), 0.62 (dt, J = 4.9, 8.3 Hz, 1 H), 0.24 - 0.05 (m, 1 H).
Description 17: 3-(ferf-butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-4- carboxylic acid (racemic mixture)
Figure imgf000049_0001
To a mixture of terf-butyl 4-formyl-3-azabicyclo[4.1 .0]heptane-3-carboxylate (D16) (615 mg, 2.73 mmol) in acetone/water (30/20 ml) NaH2P04.2H20 (426 mg, 2.73 mmol), 2-methyl-2-butene (1 .3 ml, 12.28 mmol) and NaCI02 (864 mg, 9.55 mmol) were added and the reaction mixture was stirred at RT overnight. Solvents were evaporated in vacuo and the remaining residue was taken up into EtOAc (10 ml) and water (10 ml). Phases were separated and the aqueous layer was extracted with EtOAc (2x10ml). The combined organic extracts after solvent evaporation afforded the title compound (D17) (0.5 g).
MS: (ES/+) m/z: 264.1 [MH+Na+] C12H19NO4 requires 241 .13
1 H NMR (400MHz , DMSO-d6) δ (ppm): 12.51 (br. s., 1 H), 4.25 - 4.01 (m, 1 H), 3.65 - 3.51 (m, 1 H), 3.37 (dd, J = 4.6, 13.4 Hz, 1 H), 2.31 - 2.16 (m, 1 H), 1 .81 - 1 .67 (m, 1 H), 1 .42 - 1 .32 (m, 9 H), 1 .12 - 0.85 (m, 2 H), 0.67 - 0.53 (m, 1 H), 0.19 - 0.04 (m, 1 H).
Description 18: (fi)-ethyl 6-oxopiperidine-2-carboxylate (D18)
Figure imgf000049_0002
A 2-necked flask was charged with EtOH (60 ml) and cooled to -5°C. Thionyl chloride (2.8 ml, 38.4 mmol) was added dropwise in a manner that the temperature did not exceed 0°C. D-6-oxopipecolic acid (5 g, 34.9 mmol, available from Fluorochem #040124) was added in portions and the resulting mixture was left warming to RT and stirred for 18 hrs. EtOH was evaporated down to 15% of its volume and toluene (60 ml) was added followed by addition of TEA (10.6 ml, 76.8 mmol) in a manner that the temperature did not exceed 10°C. The slurry was left stirring for 30 min, before filtering the white salt. The filtrate was evaporated in vacuo and the resulting residue was re-dissolved in Et2O (80 ml). The white solid formed was filtrated off and the filtrate was evaporated in vacuo to afford the title compound (D18) (6.4g)
MS: (ES/+) m/z: 172.1 [MKT] C8H13NO3 requires 171 .09
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 7.34 - 7.09 (m, 2 H), 6.51 (br. s., 1 H), 4.24 (q, J = 7.2 Hz, 2 H), 4.08 (t, J = 5.9 Hz, 1 H), 2.51 - 2.29 (m, 3 H), 2.26 - 2.12 (m, 1 H), 2.02 - 1 .70 (m, 3H).
Description 19: (fi)-1-ferf-butyl 2-ethyl 6-oxopiperidine-1 ,2-dicarboxylate (D19)
Figure imgf000050_0001
(f?)-ethyl 6-oxopiperidine-2-carboxylate (D18) (5.97 g, 34.9 mmol) was dissolved in toluene (30 ml) prior addition of DMAP (213 mg, 1 .74 mmol). After 10 minutes, a solution of Boc2O (7.61 g, 34.9 mmol) in toluene (20 ml) was added dropwise and the resulting mixture left stirring at RT for 7 hrs. Boc2O (1 .52 g, 6.97 mmol) was added and the mixture further stirred for 18 hrs. The reaction mixture was then charged with half-saturated NaHCO3 solution (100ml) and stirred for 10 min before separating the two phases. The separated organic phase was washed with water (2 x 50 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D19) (9.06g).
MS: (ES/+) m/z: 294.1 [MH+Na+] C13H21 NO5 requires 271 .14 1 H NMR (400MHz ,CHCI3-d) δ (ppm): 4.77 - 4.63 (m, 1 H), 4.24 (dd, J = 2.7, 7.1 Hz, 2 H), 2.68 - 2.42 (m, 2 H), 2.26 - 2.13 (m, 1 H), 2.12 - 1 .97 (m, 1 H), 1 .88 - 1 .69 (m, 2 H), 1 .59 - 1 .44 (m, 9 H), 1 .30 (t, J = 7.1 Hz, 3 H). Description 20: (H)-1-ieri-butyl 2-ethyl 3,4-dihydropyridine-1 ,2(2H)- dicarboxylate (D20)
Figure imgf000051_0001
A solution of -ie -butyl 2-ethyl 6-oxopiperidine-1 ,2-dicarboxylate (D19) (0.5g, 1 .84 mmol) in toluene (5 ml) was cooled at -50°C. LiEt3BH 1 M solution in THF (1 .93 ml, 1 .93 mmol) was added dropwise in a manner that the reaction temperature did not exceed -45 °C. After complete addition the mixture was stirred at -45 °C for 30 minutes. DIPEA (1 .38 ml, 7.92 mmol) was added to the reaction maintaining the temperature below -45 °C followed by the addition of DMAP (3.4 mg, 0.027 mmol). The reaction mixture was then charged with TFAA (0.3 ml, 2.1 1 mmol) keeping the temperature below -45 °C. After complete addition, the reaction mixture was warmed to 20-25 °C within one hour and kept for an additional 4 hrs at this temperature. Reaction mixture was quenched by slow addition of water. Phases were separated and the organics washed with water, dried over Na2S04 and concentrated to obtain a clear oil, which was used as such to be subjected to the same procedure once again to afford the title compound (D20) (260 mg).
MS: (ES/+) m/z: 278.1 [MH+Na+] C13H21 N04 requires 255.15
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 6.98 - 6.71 (m, 1 H), 4.99 - 4.86 (m, 1 H), 4.86 - 4.65 (m, 1 H), 4.32 - 4.12 (m, 2 H), 2.44 - 2.24 (m, 1 H), 2.08 - 1 .76 (m, 3 H), 1 .65 - 1 .44 (m, 9 H), 1 .38 - 1 .17 (m, 3 H).
Description 21 : (3fi)-2-ferf-butyl 3-ethyl 2-azabicyclo[4.1.0]heptane-2,3- dicarboxylate (diastereoisomers mixture) (D21)
Figure imgf000051_0002
To a solution of -ferf-butyl 2-ethyl 3,4-dihydropyridine-1 ,2(2H)-dicarboxylate (D20) (260 mg, 1 .02 mmol) in toluene (5 ml), cooled to -30°C, diethyl zinc 1 M solution in heptane (2.04 ml, 2.04 mmol) was added dropwise followed by addition of diiodomethane (0.33ml, 4.07 mmol) in toluene (1 ml). (During reactant additions the reaction temperature was maintained between -25 °C and -30 °C). The reaction mixture was stirred at -20 °C for 24 hrs. Diethyl zinc 1 M solution in heptane (2.04 ml, 2.04 mmol) and diiodomethane (0.33ml, 4.07 mmol) were added and the reaction left stirring at -20 C for other 24 hrs. The reaction was quenched with half saturated NaHC03 (10ml) and left stirring for 30 min. The white precipitate was filtered off. The organic phase was washed with water (2x20 ml), dried over Na2S04 and evaporated in vacuo to afford the title compound (D21) (600 mg) used as such without purification.
MS: (ES/+) m/z: 292.1 [MH+Na+] C14H23N04 requires 269.16
Description 22: (3fi)-2-(ferf-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3- carboxylic acid (diastereoisomer mixture) (D22)
Figure imgf000052_0001
(3fl)-2-ieri-butyl 3-ethyl 2-azabicyclo[4.1 .0]heptane-2,3-dicarboxylate (D21 ) (600mg, 2.22 mmol) was partitioned between dioxane (10 ml) and water (5 ml) prior addition of LiOH H20 (370 mg, 8.9 mmol). The mixture was stirred at RT for 18 hrs. Water (10 ml) and LiOH H2O (740 mg, 18 mmol) were added and the mixture left at RT for 66h. Dioxane was evaporated off and remaining aqueous was washed with Et2O (3x20 ml). Aqueous solution was acidified with acetic acid up to pH 4 and extracted with EtOAc (3x30ml). Collected organics were washed with NaCI sat., dried over Na2SO4 and evaporated in vacuo to afford the title compound (D22) (210 mg).
MS: (ES/+) m/z: 264.1 [MH+Na+] C12H19NO4 requires 241 .13
Description 23: (fi)-ethyl 5-oxopyrrolidine-2-carboxylate (D23)
Figure imgf000052_0002
To a solution of (f?)-5-oxopyrrolidine-2-carboxylic acid (10 g, 69.84 mmol; available from Aldrich#422614) in EtOH (100 ml) cooled at -5°C, thionyl chloride (10 ml, 139.68 mmol) was added and the resulting mixture was stirred at RT for 3 hrs. Solvents were evaporated in vacuo and the resulting residue was taken up with EtOAc (350 ml), washed with water/TEA (40/12ml), then with water (40 ml). Collected organics were dried over Na2S04 and evaporated to afford a residue that was loaded on a SNAP-Si cartridge (50 g) and eluted with a mixture DCM/EtOAc from 90/10 to 50/50. Collected fractions after solvent evaporation afforded a first batch of title compound (D23) (6.4 g). The aqueous were saturated with NaCI and extracted with EtOAc (400 ml). The organic was washed with water (20 ml) dried over Na2SO4 and evaporated in vacuo to afford a second batch of title compound (D23) (3.7 g).
1 H NMR (400MHz , CHCI3-d) δ (ppm): 6.58 (br. s., 1 H), 4.29 - 4.17 (m, 3 H), 2.53 - 2.29 (m, 3 H), 2.28 - 2.17 (m, 1 H), 1 .35 - 1 .22 (m, 3 H).
Description 24: (H)-1-feri-butyl 2-ethyl 5-oxopyrrolidine-1 ,2-dicarboxylate (D24)
Figure imgf000053_0001
To a solution of (f?)-ethyl 5-oxopyrrolidine-2-carboxylate (D23) (10 g, 63.62 mmol) in toluene (50 ml), DMAP (390 mg, 3.2 mmol) was added before addition, after 10 min, of a solution of Boc2O (13.9 g, 63.62 mmol) in toluene (50 ml). The reaction mixture was stirred at RT overnight then diluted with EtOAc (200 ml), charged with half-saturated NaHCO3 solution (60ml) and stirred for 10 min. Phases were separated and the organics washed with water (40 ml), dried over Na2SO4 and evaporated in vacuo to afford a residue which was triturated in heptane. After filtration and drying under reduced pressure, 13.7 g of title compound (D24) were isolated.
MS: (ES/+) m/z: 280 [MH+ Na+] C12H19NO5 requires 257.13
1 H NMR (400MHz , CHCI3-d) δ (ppm): 4.68 - 4.57 (m, 1 H), 4.26 (q, J = 1.3 Hz, 2 H), 2.72 - 2.58 (m, 1 H), 2.57 - 2.43 (m, 1 H), 2.42 - 2.26 (m, 1 H), 2.12 - 1 .99 (m, 1 H), 1 .52 (s, 9 H), 1 .32 (t, J = 7.1 Hz, 3 H). Description 25: (H)-1-ieri-butyl 2-ethyl 2,3-dihydro-1 H-pyrrole-1 ,2- dicarboxylate (D25)
Figure imgf000054_0001
To a solution of (H)-1 -ferf-butyl 2-ethyl 5-oxopyrrolidine-1 ,2-dicarboxylate (D24) (14.3 g, 55.58 mmol) in toluene (100 ml) cooled at -50°C, LiEt3BH 1 M sol in THF (58.4 ml, 58.36 mmol) was added dropwise maintaining the reaction temperature below -45 °C. After complete addition the mixture was stirred at -45 °C for 30 min. DIPEA (42 ml, 239 mmol), DMAP (102 mg, 0.83 mmol) and TFAA (8.9 ml, 63.92 mmol) were added sequentially maintaining the reaction temperature below -45 °C. After complete addition, the reaction mixture was warmed to 20-25 °C within one hour and kept for an additional 2 hrs at this temperature. The reaction mixture was slowly charged with water (8 ml) so that the temperature did not exceed 5°C and diluted with EtOAc (50 ml). Aqueous and organic phases were then separated and the organics washed again with water (8 ml), dried over Na2S04 and evaporated to obtain residue which was purified by Biotage SNAP-Si cartridge (50g) eluting with cHex/EtOAc from 90/10 to 50/50. Collected fractions, after solvent evaporation afforded the title compound (D25) (10.4 g).
MS: (ES/+) m/z: 264 [MH+ Na+] C12H19N04 requires 241 .13
1 H NMR (400MHz , CHCI3-d) δ (ppm): 6.73 - 6.44 (m, 1 H), 4.93 (d, J = 19.1 Hz, 1 H), 4.73 - 4.49 (m, 1 H), 4.36 - 4.09 (m, 2 H), 3.19 - 2.94 (m, 1 H), 2.77 - 2.54 (m, 1 H), 1 .57 - 1 .37 (m, 9 H), 1 .37 - 1 .18 (m, 3 H).
Description 26: (3fi)-2-ferf-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (diastereoisomers mixture) (D26)
N "COOEt
Boc
A flamed three-necked flask was charged with diethyl zinc solution 1 .0 M in hexane (62 ml, 62 mmol) and toluene (100 ml). The resulting solution was cooled to -10°C and charged dropwise with diiodomethane (5 ml, 62 mmol) and stirred at 0°C for 10 min. The reaction mixture was cooled to -10°C, charged with a solution of (R)-l -tert-butyl 2-ethyl 2, 3-dihydro-1 H-pyrrole-1 ,2-dicarboxylate (D25) (5 g, 21 mmol) in toluene (30 ml) and kept at 0°C. After 6h the mixture was quenched with half saturated NaHC03 (80ml); a white precipitate was formed which was filtered off and washed with AcOEt (500 ml). Aqueous and organic phase was separated and the organic phase washed with water (60ml), dried over Na2S04 and evaporated to afford 4.5 g of yellow oil. This material dissolved in toluene (30 ml) was added, over a period of 45 min, to a solution of diethylzinc 1 M in hexane (62 ml), and diiodomethane (5 ml) in toluene (100 ml) prepared as described above (T= -10°C) and the resulting mixture was stirred at 0°C for 4 hrs. After 4h the mixture was quenched with half saturated NaHC03 (80ml); a white precipitate was formed which was filtered off and washed with AcOEt (500 ml). Aqueous and organic phase were separated and the organic phase washed with water (60ml), dried over Na2S04 and evaporated to afford 3.85 g of yellow oil which was loaded on a SPE-Si cartridge (50 g) and eluted with a mixture cHex/AcOEt 95/5. Collected fractions after solvent evaporation afforded the title compound (D26) (1 .19 g) as diastereoisomer mixture with syn-anti ratio 8/2.
MS: (ES/+) m/z: 278 [MH+Na+] C13H21 N04 requires 255.15
1 H NMR (400MHz , CHCI3-d) δ (ppm): 4.66 - 4.46 (m, 1 H), 4.26 - 3.93 (m, 5 H), 3.62 - 3.40 (m, 2 H), 2.70 - 2.50 (m, 1 H), 2.42 - 2.17 (m, 2 H), 2.10 - 1 .99 (m, 1 H), 1 .69 - 1 .58 (m, 2 H), 1 .56 - 1 .40 (m, 18 H), 1 .32 - 1 .21 (m, 6 H), 0.96 - 0.64 (m, 3 H), 0.48 (br. s., 1 H).
Description 27: (3fi)-2-(ferf-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (diastereoisomer mixture) (D27)
1ST ""COOH
Boc
To a mixture of (3R)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1 .0]hexane-2,3- dicarboxylate (D26) (diastereoisomer mixture) (3.4 g, 13.3 mmol) in dioxane (15 ml) and water (15 ml), LiOH H20 (2.2 g, 53 mmol). The mixture was stirret at RT for 18h. Dioxane was evaporated off and water was washed with Et20 (2x40 ml) then the pH was adjusted to ~4 by addition of citric acid and the resulting aqueous phase was extacted with DCM (200 ml), washed with water (20 ml), dried over Na2S04 and evaporated in vacuo to afford the title compound (D27) (2.75 g) as diastereoisomer mixture with syn-anti ratio 10/2.
MS: (ES/+) m/z: 226 [M"] C1 1 H17N04 requires 227.12 1 H NMR (400MHz ,DMSO-d6) δ (ppm): 12.69 - 12.41 (m, 2 H), 4.45 - 4.32 (m, 1 H), 3.89 (br.s. 1 H), 3.42 - 3.32 (m, 2 H), 2.65 - 2.54 (m, 1 H), 2.35 - 2.24 (m, 1 H), 2.09 (m, 1 H), 1 .95 - 1 .73 (m, 1 H), 1 .60 - 1 .46 (m, 2 H), 1 .44 - 1 .30 (m, 18 H), 0.76 - 0.60 (m, 3 H), 0.46 (dt, J = 2.4, 4.9 Hz, 1 H).
Description 28: (H)-5-(((iefi-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2-one (D28)
Figure imgf000056_0001
To an ice cooled solution of f?-(5)-hydroxymethyl-2pyrrolidinone (4 g, 34.7 mmol; available from Aldrich#366358) in DMF (30 ml), imidazole (2.6 g, 38.2 mmol) and TBDPSiCI (9.4 ml, 38.2 mmol) were added and the resulting mixture was stirred at RT for 3 hrs. After solvent evaporation, water was added and the mixture extracted with MTBE (2x50ml). Collected organics were washed with NaCI sat., dried over Na2S04 and evaporated. The residue was purified by Biotage SNAP-Si column (50g) eluting with a mixture Et20/Acetone from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D28) (9.75 g)
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.72 - 7.59 (m, 4 H), 7.53 - 7.37 (m, 6 H), 5.82 (br. s., 1 H), 3.83 (dd, J = 4.2, 5.1 Hz, 1 H), 3.69 - 3.61 (m, 1 H), 3.53 (dd, J = 7.8, 10.3 Hz, 1 H), 2.42 - 2.28 (m, 2 H), 1 .80 - 1 .60 (m, 2 H), 1 .13 - 1 .01 (m, 9 H).
Description 29: (H)-feri-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- oxopyrrolidine-1 -carboxylate (D29)
O^A^/OTBDPS
Boc
To an ice cooled solution of (f?)-5-(((ie f-butyldiphenylsilyl)oxy)methyl)pyrrolidin-2- one (D28) (8 g, 22.6 mmol) in DCM (40 ml), pyridine (2.5 ml) and DMAP (0.55 g, 4.52 mmol) were added followed by addition of Boc20 (4.98 g, 22.8 mmol). The solution was left warming to RT. After 3 hrs stirring, Boc20 (1 .48 g, 6.78 mmol) was added and the mixture stirred for 18 hrs. NH4CI sat sol (30 ml) was added then the mixture was acidified to pH~4 by addition of 2N HCI. The organic phase was separated and the aqueous extracted with MTBE. The organic phases were collected and washed sequentially with H3P04, water and brine then dried and evaporated. Combined organics after solvent evaporation were purified by Biotage SNAP-Si column (25g) eluting with Et20. Collected fractions after solvent evaporation afforded the title compound (D29) (8 g).
MS: (ES/+) m/z: 454.4 [MH+] C26H35N04Si requires 453.65
1 H NMR (400MHz , CHCI3-d) δ (ppm): 7.64 (dd, J = 7.0, 12.9 Hz, 4 H), 7.51 - 7.36 (m, 6 H), 4.28 - 4.19 (m, 1 H), 3.96 - 3.86 (m, 1 H), 3.79 - 3.66 (m, 1 H), 2.87 - 2.72 (m, 1 H), 2.52 - 2.38 (m, 1 H), 2.23 - 2.08 (m, 2 H), 1 .46 (s, 9 H), 1 .07 (s, 9 H). Description 30: (5H)-ieri-butyl 5-(((ieri-butyldiphenylsilyl)oxy)methyl)-2-oxo- 3-((trimethylstannyl)methyl)pyrrolidine-1-carboxylate (diastereoisomer mixture) (D30)
Figure imgf000057_0001
To a solution of (F?)-terf-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- oxopyrrolidine-1 -carboxylate (D29) (6 g, 13.23 mmol) in THF (80 ml) cooled at - 70°C, LiHMDS 1 M solution in THF (17.2 ml) was added dropwise over a period of 15 minutes. The reaction was kept at -78 °C for 1 h before adding (iodomethyl)trimethylstannane (6.04 g, 19.84 mmol) over a period of 5 minutes. The mixture was allowed to warm at -35 and stirred at this temperature for 2 hrs. NH4CI sat. sol (15 ml) was added and the mixture diluted with EtOAc (40 ml). The organic layer was separated and the aqueous phase acidified to pH~4 with 0.5N HCI and the latter re-extracted with EtOAc (3x50ml). The organic phases were combined, dried over Na2S04 and evaporated in vacuo. The residue was purified by Biotage SNAP-Si (50 g) eluting with a mixture cHex/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D30) as diastereoisomer mixture (3.2 g).
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 7.69 - 7.59 (m, 8 H), 7.46 - 7.38 (m, 12 H), 4.16 - 4.09 (m, 2 H), 4.09 - 4.01 (m, 1 H), 3.86 (d, J = 4.4 Hz, 2 H), 3.75 - 3.69 (m, 1 H), 3.05 - 2.90 (m, 1 H), 2.69 - 2.56 (m, 1 H), 2.45 - 2.33 (m, 2 H), 1 .82 - 1 .70 (m, 2 H), 1 .44 (s, 9 H), 1 .41 (s, 9 H), 1 .28 (s, 1 H), 1 .23 - 1 .13 (m, 1 H), 1 .08 (s, 9 H), 1 .06 (s, 9 H), 0.99 - 0.94 (m, 1 H), 0.94 - 0.86 (m, 1 H), 0.24 - 0.04 (m, 18 H) Description 31 : (3H)-ieri-butyl 3-(((iert-butyldiphenylsilyl)oxy)methyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (diastereoisomers mixture) (D31)
Figure imgf000058_0001
To a solution of (5F?)-terf-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxo-3- ((trimethylstannyl)methyl)pyrrolidine-1 -carboxylate (D30) (3.1 g, 6.86 mmol) in THF (200 ml) cooled at -78°C, LiEt3BH 1 M sol in THF (17.2 ml) was added dropwise. The reaction was left at -78 °C for 2 hrs then water (50 ml) and the reaction extracted with Et20 (3x100ml). The organic phases were combined, dried over Na2S04 and evaporated in vacuo to afford a residue which was dissolved in DCM (120 ml) and cooled at 0°C. TFA (1 .31 ml, 17.2 mmol) was added and the reaction was stirred 10 min at this temperature. K2C03 sat sol (100 ml) was added and the mixture extracted with DCM (3x100ml). The organic phases were collected, dried over Na2S04 and evaporated in vacuo to afford a residue which was purified by BiotageSNAP-Si column (50g) eluting with a mixture cHex/EtOAc 95/5. Collected fractions after solvent evaporation afforded the title compound (D31) (2.1 g).
MS: (ES/+) m/z: 474.4 [MH+Na+] C27H37N03Si requires 451 .25
1 H NMR (400MHz , CHCI3-d) δ ppm: 7.78 - 7.56 (m, 4 H), 7.48 - 7.35 (m, 6 H), 3.88 (br. s., 1 H), 3.73 (br. s., 1 H), 3.21 (br. s., 1 H), 2.44 - 2.28 (m, 1 H), 2.1 1 - 1 .98 (m, 1 H), 1 .52 (br. s., 2 H), 1 .45 (s, 9 H), 1 .08 (s, 9 H), 0.97 - 0.77 (m, 1 H), 0.37 (br. s., 1 H).
Description 32: (3H)-ieri-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (diastereoisomers mixture) (D32)
Boc
To a solution of (3F?)-terf-butyl 3-(((ieri-butyldiphenylsilyl)oxy)methyl)-2- azabicyclo[3.1 .0]hexane-2-carboxylate (D31 ) (2.1 g, 4.6 mmol) in THF (130 ml), TBAF 1 M sol in THF (9.2 ml) was added and the solution was stirred at RT for 18 hours. Solvent was evaporated and the residue purified by Biotage SNAP-Si column (50g), eluting with DCM/Et20 from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D32) (490 mg).
MS: (ES/+) m/z: 236.3 [MH+Na+] C1 1 H19N03 requires 213.14
1 H NMR (400MHz, CHCI3-d) δ (ppm): 3.78 - 3.67 (m, 1 H), 3.65 - 3.61 (m, 2 H), 3.28 (dt, J = 2.4, 6.1 Hz, 1 H), 3.23 - 2.89 (br. s., 1 H), 2.17 (dd, J = 8.3, 13.2 Hz, 1 H), 1 .88 - 1 .78 (m, 1 H), 1 .54 - 1 .43 (m, 10 H), 0.78 - 0.69 (m, 1 H), 0.42 (dt, J = 2.4, 5.3 Hz, 1 H).
Description 33: (3fi)-2-(ferf-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (diastereoisomers mixture) (D33)
Figure imgf000059_0001
To a solution of (3F?)-terf-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1 .0]hexane-2- carboxylate (D32) (440 mg, 2.06 mmol) in a mixture MeCN/CCI4/H20 (6/6/9ml), sodium periodate (1 .76 g, 8.25 mmol) was added and the reaction stirred vigorously for 5 min before addition of Ruthenium trichloride (12.8 mg, 0.062 mmol). The resulting solution was stirred 18 hrs at RT then quenched by addition of isopropanol (6 ml). The resulting black mixture was diluted with Et20 (50 ml) and filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in water, the pH was adjusted to pH~9-10 with K2C03 and the aqueous was washed with Et20 (3x30 ml). Aqueous was then acidified to pH~4-5 and re- extracted with EtOAc (3x30 ml). Collected organics after solvent evaporation afforded the title compound (D33) (216 mg).
MS: (ES/+) m/z: 250.2 [MH+] C1 1 H17N04 requires 227.12 Description 34: (H)-3,3-dimethyltetrahydropyrrolo[1 ,2-c]oxazol-5(3H)-one (D34)
To a stirred suspension of (f?)-(-)-5-(hydroxymethyl)pyrrolidin-2-one (2 g, 17.4 mmol; available from Aldrich#366358) and p-TSA (16 mg, 0.08 mmol) in toluene (50 ml), 2,2-dimethoxypropane (6.4 ml, 52.1 mmol) was added in one portion and the reaction mixture refluxed for 2 hrs. The reaction flask was equipped with a Dean Stark apparatus then 2,2-dimethoxypropane (6.4 ml, 52.1 mmol) was added and the reaction was refluxed overnight. Solvent was evaporated in vacuo affording the title compound (D34) (2.4 g).
MS: (ES/+) m/z: 156.1 [MH +] C8H13N02 requires 155.09
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.26 (ddd, J = 2.7, 5.9, 9.0 Hz, 1 H), 4.14 - 4.02 (m, 1 H), 3.53 - 3.37 (m, 1 H), 2.88 - 2.71 (m, 1 H), 2.62 - 2.47 (m, 1 H), 2.27 - 2.1 1 (m, 1 H), 1 .86 - 1 .69 (m, 1 H), 1 .67 (d, J = 2.9 Hz, 3 H), 1 .47 (d, J = 2.9 Hz, 3 H).
Description 35: (H)-3,3,6,6-tetramethyltetrahydropyrrolo[1 ,2-c]oxazol-5(3H)- one (D35)
Figure imgf000060_0001
To a solution of (f?)-3,3-dimethyltetrahydropyrrolo[1 ,2-c]oxazol-5(3H)-one (D34) (1 .3 g, 8.37 mmol) in dry THF (120 ml) cooled to -78°C, LDA 2M sol in THF/heptane (6.28 ml, 12.6 mmol) was added. The red solution was stirred at this temperature for 40 min before adding iodomethane (0.78 ml, 12.6 mmol). The reaction mixture was warmed to RT (40 min) then cooled to -78 °C prior addition of LDA 2M sol in THF/heptane (6.28 ml, 12.6 mmol). The mixture was stirred at - 78°C for 1 h before adding iodomethane (0.78 ml, 12.6 mmol) then the mixture was slowly warmed to RT and stirred overnight. The resulting solution was treated with NH4CI sat sol (10 ml) and extracted with Et20 (3x10 ml). The organic phases were collected and washed with NaCI sat. sol, dried over Na2S04 and evaporated in vacuo to afford the title compound (D35) (1 .2 g ).
MS: (ES/+) m/z: 184.1 [MH +] C10H17NO2 requires 183.13
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.24 - 4.10 (m, 2 H), 3.42 (t, J = 8.6 Hz, 1 H), 2.04 (dd, J = 5.9, 12.2 Hz, 1 H), 1 .68 (s, 3 H), 1 .60 (dd, J = 3.2, 8.6 Hz, 1 H), 1 .49 (s, 3 H), 1 .26 (s, 3 H), 1 .21 (s, 3 H). Description 36: (H)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (D36)
Figure imgf000061_0001
To a stirred suspension of (fl)-3,3,6,6-tetramethyltetrahydropyrrolo[1 ,2-c]oxazol- 5(3H)-one (D35) (714 mg, 3.89 mmol) in MeOH (15 ml), p-TSA (74 mg, 0.39 mmol) was added and the resulting mixture was heated at reflux for 2 hrs. Solvent was evaporated off and the residue was loaded on SPE-SCX cartridge (5g). The cartridge was washed with MeOH (3 column volume). The methanolic phase was collected and evaporated to afford the title compound (D36) (690 mg)
MS: (ES/+) m/z: 144.1 [MH +] C7H13NO2 requires 143.09
1 H NMR (400MHz, CHCI3-d) δ (ppm): 3.91 - 3.82 (m, 1 H), 3.77 (dd, J = 2.4, 1 1 .6 Hz, 1 H), 3.51 - 3.44 (m, 2 H), 2.02 (dd, J = 7.5, 12.7 Hz, 1 H), 1 .71 (dd, J = 7.8, 12.7 Hz, 1 H), 1 .24 (s, 6 H).
Description 37: (H)-feri-butyl 2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1- carboxylate (D37)
Figure imgf000061_0002
To an ice cooled suspension of LiAIH4 (219 mg, 5.78 mmol) in THF (10 ml) under N2, a solution of (f?)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (D36) (690 mg, 4.82 mmol) in THF (10 ml) was added dropwise. The reaction was allowed to warm to RT over 30 min then refluxed for 5 hrs. LiAIH4 (219 mg, 5.78 mmol) was added to the mixture and the reaction stirred for 18 hrs then a further addition of LiAIH4 (219 mg, 5.78 mmol) was done and the reaction refluxed for additional 5 hrs. The reaction mixture was cooled to 0°C prior sequentially addition of water (0.87 ml), 15% NaOH (0.87 ml) and water (2.58 ml). The resulting slurry solution was filtered off; the filtrated was diluted with water (10 ml) and basified to pH~12 with Na2CO3 before adding dropwise a solution of Boc2O (1 .37 g, 6.26 mmol) in THF (10 ml). The resulting mixture was stirred for 24 hrs then extracted with EtOAc (3x30ml). The organic phases were washed with NaCI sat., dried onto Na2SO4 and evaporated in vacuo to afford the title compound (D37) (435 mg). MS: (ES/+) m/z: 252.2 [MH+Na+] C12H23NO3 requires 229.17 1 H NMR (400MHz, CHCI3-d) δ (ppm): 5.25 - 5.09 (m, 1 H), 4.13 - 3.99 (m, 1 H), 3.62 (d, J = 7.9 Hz, 2 H), 3.39 - 3.23 (m, 1 H), 3.08 - 2.92 (m, 1 H), 1 .87 - 1 .73 (m, 1 H), 1 .49 (s, 9 H), 1 .38 - 1 .25 (m, 1 H), 1 .09 (s, 3 H), 1 .03 (s, 3 H) Description 38: (H)-1-(fefi-butoxycarbonyl)-4,4-dimethyl-5-oxopyrrolidine-2- carboxylic acid (D38)
Figure imgf000062_0001
To a solution of (F?)-terf-butyl 2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1 - carboxylate (D37) (385 mg, 1 .68 mmol) in CH3CN/CCI4/H20 (6/6/9 ml) Nal04 (1 .43 g6.71 mmol) was added and the resulting mixture was stirred vigorously for 5 min before addition of RuCI3 (10 mg, 0.05 mmol). The resulting brown solution was stirred 18 hrs at RT then the reaction was quenched with isopropanol (0.6 ml) and diluted with Et20 (10 ml). The mixture was filtered through a celite pad and the filtarte was washed with Et20 (4x20ml) then with DCM (2x5ml). Collected organic phases after drying over Na2S04 and solvent evaporation afforded the title compound (D38) (293 mg).
MS: (ES/+) m/z: 280.2 [MH+Na+] C12H19N05 requires 257.13
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.63 - 4.54 (m, 1 H), 2.34 - 2.22 (m, 1 H),
2.04 - 1 .95 (m, 1 H), 1 .53 (s, 9 H), 1 .25 (d, J = 4.9 Hz, 6 H).
Description 39: (fi)-2-benzyl 1-ferf-butyl 4,4-dimethyl-5-oxopyrrolidine-1 ,2- dicarboxylate (D39)
Figure imgf000062_0002
To a solution of (f?)-1 -(ie f-butoxycarbonyl)-4,4-dimethyl-5-oxopyrrolidine-2- carboxylic acid (D38) (320 mg, 1 .24 mmol) in acetone (10 ml), TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1 .86 mmol) were added and the resulting mixture was stirred at RT for 18 hrs. TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1 .86 mmol) were added and the reaction stirred for 24 hrs prior addition of further TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1 .86 mmol). The final mixture was then refluxed for 18 hrs. Solvents were evaporated off and the resulting residue was re-dissolved in EtOAc, washed with water (3x10 ml), dried over Na2S04 and evaporated in vacuo to afford a residue that was purified by Biotage SNAP-Si column (25g) eluting with a mixture DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D39) (260 mg).
MS: (ES/+) m/z: 248.2 [MH-Boc+] C19H25N05 requires 347.17
1 H NMR (400MHz, CHCI3-d) δ (ppm): 7.38 (br. s., 5 H), 5.25 (d, J = 1 .0 Hz, 1 H), 5.20 (d, J = 1 .0 Hz, 1 H), 4.63 - 4.55 (m, 1 H), 2.27 - 2.18 (m, 1 H), 1 .95 - 1 .87 (m, 1 H), 1 .47 (s, 9 H), 1 .20 (d, J = 14.5 Hz, 6 H).
Description 40: (fi)-2-benzyl 1-ferf-butyl 4,4-dimethylpyrrolidine-1 ,2- dicarboxylate (D40)
Figure imgf000063_0001
To a solution of (f?)-2-benzyl 1 -terf-butyl 4,4-dimethyl-5-oxopyrrolidine-1 ,2- dicarboxylate (D39) (210 mg, 0.6 mmol) in THF (10 ml) cooled at -78°C, LiEt3BH 1 M sol in THF (0.6 ml) was added and the mixture stirred 2 hrs at -78°C. The reaction was warmed to 0°C and quenched with slow addition of NaHC03 sat sol (4 ml) and 1 drop of H202. Stirring was continued for 20 min then THF was removed under reduced pressure and the remaining residue was taken up in water (5 ml) and extracted with DCM (3x10ml). The organic phases were collected, dried over Na2S04 and evaporated in vacuo. The obtained residue was dissolved in DCM (10 ml) and cooled at -78°C under N2. Et3SiH (0.09 ml, 0.6 mmol) was added followed by addition of BF3.OEt2 (0.1 ml, 0.63 mmol) and the reaction stirred 30 min, prior further addition of Et3SiH (0.09 ml, 0.6 mmol) and BF3.OEt2 (0.1 ml, 0.63 mmol). The final reaction mixture was stirred at -78 °C for 3 hrs then quenched by the slow addition of saturated NaHC03 and water. The reaction mixture was extracted with DCM (3x10 ml), the organic layers washed with NaCI sat sol, dried over Na2S04 and evaporated to afford the title compound (D40) (168 mg).
MS: (ES/+) m/z: 356.3 [MH+Na+] C19H27N04 requires 333.19 (H)-1-(iefi-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-
Figure imgf000064_0001
To a mixture of (f?)-2-benzyl 1 -feri-butyl 4,4-dimethylpyrrolidine-l ,2-dicarboxylate (D40) (198 mg, 0.59 mmol) in dioxan/water (4/4ml), LiOH.H20 (100 mg, 2.37 mmol) was added and the mixture was left stirring at RT for 18hrs. Organic solvent was evaporated off and the reaction mixture was diluted with water (8 ml), washed with Et2O (2x10ml), acidified with acetic acid to pH~4-5 and extracted with Et2O (3x10ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D41) (84 mg).
MS: (ES/+) m/z: 144.1 [MH-Boc+] C12H21 NO4 requires 243.15
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.51 - 4.20 (m, 1 H), 3.45 - 3.05 (m, 2 H),
2.32 - 1 .81 (m, 2 H), 1 .62 - 1 .39 (m, 9 H), 1 .19 - 1 .03 (m, 6 H) Description 42: methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (racemic mixture (D42)
Figure imgf000064_0002
To an ice cooled solution of 3-azabicyclo[3.1 .0]hexane-2-carboxylic acid (racemic mixture with relative stereochemistry syn) (500 mg, 3.93 mmol; available from ABCR#AB156920), thionyl chloride (0.57 ml, 7.86 mmol) was added dropwise and the resulting mixture was stirred at RT overnight. Solvent evaporation under reduced pressure afforded the title compound (D42) 700 mg) as racemic mixture with relative stereochemistry syn.
MS: (ES/+) m/z: 142.1 [MH-Boc+] C7H1 1 NO2 requires 141 .08
1 H NMR (400MHz, METHANOL-d4) δ (ppm): 4.67 (d, J = 4.2 Hz, 1 H), 3.90 (s, 3 H), 3.54 (d, J = 3.6 Hz, 1 H), 3.51 - 3.42 (m, 1 H), 2.23 - 2.10 (m, 1 H), 1 .94 (d, J = 3.4 Hz, 1 H), 0.86 (d, J = 7.5 Hz, 1 H), 0.61 (d, J = 6.0 Hz, 1 H).
Description 43: (2S,5S)- iert-butyl 2-(feri-butyl)-3,5-dimethyl-4- oxoimidazolidine-1-carboxylate (D43)
Figure imgf000065_0001
To a solution of (S)-tert-butyl 2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1 - carboxylate (0.5 g, 1 .95 mmol; available from Aldrich#337595) in dry THF (15 ml) cooled to -78°C, LDA 2M in THF/heptane (0.97 ml, 1 .95 mmol) was added and the reaction mixture stirred at this temperature for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and stirred for 18 hrs. The reaction mixture was cooled again at -78 °C then LDA 2M in THF/hepatane (0.3 ml) and iodomethane (0.04 ml, 0.6 mmol) were added in sequence. The mixture was allowed to reach RT and further stirred for 5 hrs. The resulting solution was treated with NH4CI sat sol (5 ml) and extracted with Et20. The organic phases were collected and washed with NaCI sat sol, dried over Na2S04 and evaporated in vacuo to afford a residue which was purified by Biotage SNAP-Si column (25g) eluting with cHex/Et20 60/40. Collected fractions after solvent evaporation afforded the title compound (D43) (430 mg).
MS: (ES/+) m/z: 271 .2 [MKT] C14H26N203 requires 270.19
Description 44: (2S,5R)- feri-butyl 2-(feri-butyl)-5-(4-chlorobutyl)-3,5-dimethyl- 4-oxoimidazolidine-1 -carboxylate (D44)
Figure imgf000065_0002
To a solution of {2S,5S)- terf-butyl 2-(teri-butyl)-3,5-dimethyl-4-oxoimidazolidine-1 - carboxylate (D43) (430 mg, 1 .59 mmol) in dry THF (15 ml) cooled to -78°C, LDA 2M in THF/heptane (1 .2 ml, 2.38 mmol) was added and the reaction mixture stirred at this temperature for 40 min before adding 1 -bromo-4-chloro-butane (0.27 ml, 2.38 mmol). The reaction was allowed to warm to RT and left stirring for 3 hrs. The resulting solution was treated with NH4CI sat sol (5 ml) and extracted with Et20 (3x10ml). The organic phases were collected and washed with NaCI sat sol, dried over Na2S04 and evaporated in vacuo to afford a residue which was purified by Biotage SNAP-Si column (25g) eluting with cHex/Et20 60/40. Collected fractions after solvent evaporation afforded the title compound (D44) (465 mg). MS: (ES/+) m/z: 361 .3 [MH+] C18H33CIN203 requires 360.22
1 H NMR (400MHz, CHCI3-d) δ (ppm): 3.56 - 3.37 (m, 2 H), 3.02 (s, 3 H), 2.28 -
2.15 (m, 1 H), 1 .86 - 1 .60 (m, 4 H), 1 .51 (s, 1 1 H), 1 .28 - 0.80 (m, 12 H). Description 45: (2R,5H)-2-(feri-butyl)-5-(4-chlorobutyl)-3,5- dimethylimidazolidin-4-one (D4
Figure imgf000066_0001
To an ice cooled of {2S,5R)-tert-buiy\ 2-(teri-butyl)-5-(4-chlorobutyl)-3,5-dimethyl- 4-oxoimidazolidine-1 -carboxylate (D44) (465 mg, 1 .28 mmol) in dry DCM (2 ml), TFA (1 ml, 12.8 mmol) was added and the solution stirred for 12 hrs at RT. The reaction mixture was treated with NaHC03 sat sol with vigorous stirring until pH~7. The resulting mixture was poured into water and the aqueous phase extracted with DCM (3x10ml), dried over Na2S04 and evaporated in vacuo to afford the title compound (D45) (310 mg).
MS: (ES/+) m/z: 261 .2 [MFT] C13H25CIN20 requires 260.22
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.1 1 (s, 1 H), 3.54 (t, J = 6.5 Hz, 2 H), 2.94 (s, 3 H), 1 .86 - 1 .73 (m, 2 H), 1 .59 (br. s., 5 H), 1 .33 (s, 3 H), 1 .01 (s, 9 H).
Description 46: (3H,SaH)-3-(iert-butyl)-2,8a-dimethylhexahydroimidazo[1 ,5- a]pyridin-1 (5H)-one (D46)
Figure imgf000066_0002
To a solution of (2f?,5/:?)-2-(ie f-butyl)-5-(4-chlorobutyl)-3,5-dimethylimidazolidin-4- one (D45) (310 mg, 1 .18 mmol) in dry MeCN (4 ml), anhydrous Na2C03 (63 mg, 0.6 mmol) and Nal (178 mg, 1 .18mmol) were added sequentially. The solution was heated at 80 °C for 12 hrs. The reaction was allowed to cool at RT, poured into water (10ml) and extracted with Et20 (3x10ml). The organic phases were collected, washed with NaCI sat sol, dried over Na2S04 and evaporated in vacuo to afford the title compound (D46) (220mg) MS: (ES/+) m/z: 225.2 [MH+] C13H24N20 requires 224.19
1 H NMR (400MHz, CHCI3-d) δ (ppm): 4.10 - 3.90 (m, 1 H), 3.79 (d, J = 5.3 Hz, 1 H), 3.74 - 3.60 (m, 1 H), 3.02 (br. s., 3 H), 2.97 - 2.79 (m, 1 H), 1 .95 - 1 .32 (m, 1 1 H), 1 .10 (br. s., 6 H).
Description 47: (fi)-2-methylpiperidine-2-carboxylic acid hydrochloride (D47)
Figure imgf000067_0001
(3f?,Sa/:?)-3-(ie f-butyl)-2,8a-dimethylhexahydroimidazo[1 ,5-a]pyridin-1 (5H)-one (D46) (220 mg, 0.98 mmol) was dissolved in HCI 6M (2 ml) into a thick-walled glass tube which was sealed and heated at 108°C for 70 hrs. The reaction was cooled and the extracted with DCM (3x5ml). The aqueous solution was evaporated to afford the title compound (D47) (180 mg).
MS: (ES/+) m/z: 144.1 [MH+] C7H13N02 requires 143.09
1 H NMR (400MHz, METHANOL-d4) δ (ppm): 3.27 (br. s., 2 H), 2.57 (s, 3 H), 2.32 - 2.21 (m, 1 H), 1 .91 - 1 .68 (m, 4 H), 1 .57 (m, 1 H).
Description 48: (7afi)-3-(trichloromethyl)tetrahydropyrrolo[1 ,2-c]oxazol- 1 (3H)-one (D48)
Figure imgf000067_0002
To a solution of D-proline (0.4 g, 3.48 mmol) in MeCN (8 ml) the trifluoroacetaldehyde (0.68 ml, 6.94 mmol) was added and the resulting mixture was stirred at RT for 8 hrs. Solvents were evaporated and the residue was triturated with diethyl ether. After solvent filtration and drying, 0.23 g of title compound (D48) was isolated.
MS: (ES/+) m/z: 244.0 [MH+] C7H8CI3N02 requires 242.96
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 4.15 (dd, J = 4.5, 8.6 Hz, 1 H), 3.52 - 3.36 (m, J = 7.0, 7.0, 10.5 Hz, 1 H), 3.22 - 3.07 (m, 1 H), 2.33 - 2.20 (m, 1 H), 2.19 - 2.08 (m, 1 H), 1 .96 (quind, J = 5.9, 12.1 Hz, 1 H), 1 .84 - 1 .69 (m, 1 H), 1 .61 (br. s., 1 H). Description 49: (7a/7)-7a-methyl-3-(trichloromethyl)tetrahydropyrrolo[1 ,2- c]oxazol-1 (3H)-one (D49)
Figure imgf000068_0001
To a solution of (7af?)-3-(trichloromethyl)tetrahydropyrrolo[1 ,2-c]oxazol-1 (3H)-one (D48) (0.2 g, 0.82 mol) in THF (10 ml) cooled at -78°C LDA 2M sol in THF/heptane (0.58 ml, 1 .17 mol) was added and the mixture stirred 30 min. Diiodomethane (0.185 ml, 2.97 mol) was added and the temperature was allowed to warm to - 40 °C over a period of 2 hrs then left at this temperature for an additional hour. The resulting mixture was partitioned between DCM and H20. The aqueous phase was extracted with DCM (2x10 ml); the organic phases were collected, dried over Na2S04 and evaporated in vacuo. The residue was purified by SPE-Si cartridge (25g) eluting with DCM. Collected fractions after solvent evaporation afforded title compound (D49) in mixture (4:1 ) with starting material (1 10 mg).
MS: (ES/+) m/z: 258.0 [MKT] C8H10CI3NO2 requires 256.98
Description 50: (fi)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride (D50)
Figure imgf000068_0002
To a solution of (7af?)-7a-methyl-3-(trichloromethyl)tetrahydropyrrolo[1 ,2-c]oxazol- 1 (3H)-one (D49) (0.1 1 g, 0.42 mol) in dry MeOH (2 ml), HCI 1 M sol in MeOH (0.3 ml, 0.85 mol) was added and the mixture refluxed under a constant current of nitrogen for 1 h. Solvent was evaporated to afford the title compound (D50) 60 mg. MS: (ES/+) m/z: 144.1 [MKT] C7H13N02 requires 143.09
General procedure for amides preparation
Method A
Selected acid (1 eq), HOBT.H20 (1 eq) and EDC.HCI (1 .5 eq) were suspended in DCM and the resulting mixture was stirred 1 h at RT. A solution of a selected amine (1 eq) and TEA (1 eq) in DCM was added and the mixture was stirred at RT for 1 /48 hrs. Solvents were evaporated in vacuo and the resulting residue was re- dissolved in DCM. The mixture was then added to a saturated aqueous solution of NaHC03 and extracted with dichloromethane. The organic phase was dried over Na2S04 and the solvent was removed under reduced pressure. The crude material was purified on SPE-Si cartridge or SNAP-Si column eluting with a mixture of DCM/MeOH 98:2 or DCM/EtOAc from 100:0 to 70:30 affording the title amide compound.
Method B
To a solution of selected acid (1 eq) in DMF, HATU (1 .2 eq) and DIPEA (2.5 eq) were added in sequence. The mixture was stirred 30 min before addition of the selected amine (1 .2 eq). The mixture was left stirring at RT for 18 hrs. The reaction was partitioned between EtOAc and H20 and the aqueous phase was washed with EtOAc. The organic phases were collected and washed several times with H20, dried over Na2S04 and evaporated under reduced pressure. The crude material was purified on SPE-Si cartridge or Biotage SNAP-Si column eluting with a mixture of DCM/EtOAc from 100:0 to 80:20 affording the title amide compound. Method C
To a solution of selected acid (1 eq) in DMF, HCTU (1 .1 eq) and DIPEA (2.5 eq) were added in sequence and the resulting mixture was stirred 30 min before adding the selected amine (1 .1 eq). The mixture was left stirring at RT for 1 -18 hrs then the reaction mixture was partitioned between EtOAc and H2O and the organic phase was separated. The aqueous phase was washed with EtOAc. All the collected organic phases were washed with NaCI sat. sol., dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified on SPE-Si cartridge or Biotage SNAP-Si column eluting with a mixture of DCM/EtOAc from 100:0 to 95:5 affording the title amide compound.
Description 51 : iert-butyl 2-(((S)-1 -(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl) piperidine-1-carboxylate (diastereoisomers mixture) (D51)
Figure imgf000069_0001
The title compound (D51) (1 .95 g) was prepared according to the general procedure for amides preparation (Method A) starting from 1 -(ieri- butoxycarbonyl)piperidine-2-carboxylic acid (1 .17g, available from Sigma Aldrich #495875), and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (1 .1 g, for preparation see published International Patent application WO 2005/105733). Reaction time: 18hrs.
MS: (ES/+) m/z: 391 .3 [MH+] C21 H30N2O5 requires 390.22
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% IPA; DAD: 237 nm]: Peak 1 retention time: 1 1 .6 min; peak 2 retention time:16.16 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.01 (d, 4 H) 7.36 (t, 4 H) 6.12 - 6.82 (m, 2 H) 5.17 (br. s., 2 H) 4.74 (br. s., 2 H) 3.81 - 4.25 (m, 8 H) 2.81 (br. s., 1 H) 2.66 (t, 1 H) 2.28 (br. s., 2 H) 1 .42 - 1 .75 (m, 4 H). Description 52: (R)-tert-bu\y\ 2-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl) piperidine-1 -carboxylate (D52)
Figure imgf000070_0001
The title compound (D52) (405 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (F?)-1 -(terf- butoxycarbonyl)piperidine-2-carboxylic acid (250 mg, available from Sigma Aldrich #516341 ), and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (235 mg). Reaction time: 18hrs.
MS: (ES/+) m/z: 391 .3 [MH+] C21 H30N2O5 requires 390.22
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% EtOH; DAD: 237 nm]: Peak retention time: 9.6 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (d, J = 8.3 Hz, 2 H), 7.36 (d, J = 7.8 Hz, 2 H), 6.75 - 6.40 (m, 1 H), 5.23 - 5.1 1 (m, 1 H), 4.81 - 4.70 (m, 1 H), 4.10 - 3.95 (m, 1 H), 3.93 (s, 3 H), 2.72 - 2.60 (m, 1 H), 2.36 - 2.20 (m, 1 H), 1 .67 - 1 .61 (m, 1 H), 1 .58 - 1 .47 (m, 15 H), 1 .46 - 1 .36 (m, 1 H). Description 53: (7? ferf-butyl 2-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl) piperidine-1-carboxylate (D53)
Figure imgf000071_0001
The title compound (D53) (650 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (F?)-1 -(terf- butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #516341 ), and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (470 mg). Reaction time: 18 hrs.
MS: (ES/+) m/z: 403 [MH+] C22H30N2O5 requires 402.22
Chiral HPLC [DAICEL OD-H; Mobile phase A: 80% n-hexane (+0.1 % DEA), B: 20% IPA; DAD: 248 nm]: Peak retention time: 13.04 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.96 (d, J = 8.1 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.02 - 6.74 (m, 1 H), 4.81 - 4.68 (m, 1 H), 4.19 - 4.00 (m, 1 H), 3.92 (s, 3 H), 2.88 - 2.69 (m, 1 H), 2.39 - 2.17 (m, 1 H), 1 .66 (br. s., 3 H), 1 .52 (s, 9 H), 1 .34 (d, J = 18.6 Hz, 6 H).
Description 54: ferf-butyl 5-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (racemic mixtur
Figure imgf000071_0002
The title compound (D54) (290 mg) was prepared according to the general procedure for amides preparation (Method B) starting from 6-(terf-butoxycarbonyl)- azaspiro[2.5]octane-5-carboxylic acid (D1 ) (200 mg) and methyl 4-(1 - aminocyclopropyl)benzoate hydrochloride (214 mg). Reaction time: 18 hrs.
MS: (ES/+) m/z: 429 [MH+] C24H32N205 requires 428.52
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.1 Hz, 2 H), 7.28 (d, J = 2.7 Hz, 2 H), 6.76 (br. s., 1 H), 4.90 - 4.76 (m, 1 H), 4.17 (br. s., 1 H), 3.92 (s, 3 H), 3.08 - 2.88 (m, 1 H), 2.05 - 1 .99 (m, 1 H), 1 .97 - 1 .86 (m, 1 H), 1 .83 - 1 .75 (m, 1 H), 1 .51 (s, 9 H), 1 .45 - 1 .31 (m, 4 H), 0.88 - 0.79 (m, 1 H), 0.60 - 0.44 (m, 1 H), 0.43 - 0.27 (m, 2 H), 0.28 - 0.20 (m, 1 H).
Description 55: ieri-butyl 5-((1-(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (single unknow enantiomer) (D55)
Figure imgf000072_0001
6-(terf-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (D3) (16 g, 62.6 mol) HOBT.H20 (9.59 g, 62.6 mol) and EDC.HCI (18.00 g, 94 mol) were suspended in DCM (225 ml) and the resulting mixture was stirred 30 min at RT. A solution of methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (14.3 g, 62.6 mol) and TEA (8.73 ml, 62.6 mol) in DCM (96 ml) was added and the mixture was stirred at RT for 3 hrs. The solution was washed with water (1 x100 ml), NaHC03 (2x100 ml) citric acid 1 M (1 x100 ml), sat NaCI (500 ml), dried over Na2S04 and evaporated to afford a yellow solid 29 g which was triturated in a mixture Et20/cHex 9/1 to afford the title compound (D55) (19.7 g).
MS: (ES/+) m/z: 429.3 [MH+] C24H32N205 requires 428.52
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.3 Hz, 2 H), 7.28 (d, 5 H ubder solvent), 6.74 (br. s., 1 H), 4.96 - 4.70 (m, 1 H), 4.32 - 4.1 1 (m, 1 H), 3.92 (s, 3 H), 3.08 - 2.88 (m, 1 H), 2.12 - 1 .97 (m, 1 H), 1 .97 - 1 .84 (m, 1 H), 1 .84 - 1 .73 (m, 1 H), 1 .52 (s, 9 H), 1 .43 - 1 .31 (m, 4 H), 0.90 - 0.77 (m, 1 H), 0.62 - 0.46 (m, 1 H), 0.43 - 0.29 (m, 2 H), 0.28 - 0.19 (m, 1 H).
Description 56: iert-butyl 5-(((S)-1-(4- (methoxycarbonyl)phenyl)ethyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (diastereoisomers mixture) (D56)
Figure imgf000072_0002
The title compound (D56) (130 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 6-(terf-butoxycarbonyl)- azaspiro[2.5]octane-5-carboxylic acid (D1 ) (80 mg) and (S)-methyl 4-(1 - aminoethyl)benzoate hydrochloride (67.6 mg). Reaction time: 18 hrs.
MS: (ES/+) m/z: 317 [MH-Boc+] C23H32N205 requires 416.23
Chiral HPLC [Phenomens LUX-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% IPA; DAD: 248 nm]: Peak 1 retention time: 13.01 min, peak 2 retention time: 19.4 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (t, 4 H) 7.39 (dd, 4 H) 6.29 (br. s., 2 H) 5.16 - 5.28 (m, 2 H) 4.82 (br. s., 2 H) 4.14 (d, 1 H) 3.93 (d, 6 H) 3.00 (br. s., 1 H) 2.84 - 2.95 (m, 1 H) 2.01 (dt, 2 H) 1 .73 - 1 .96 (m, 4 H) 1 .41 - 1 .57 (m, 24 H) 0.72 - 0.95 (m, 3 H) 0.58 (d, 1 H) 0.21 - 0.45 (m, 6 H) 0.09 (br. s., 1 H).
Description 57: fert-butyl 5-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)-5-methyl-6-azaspiro[2.5]octane- 6-carboxylate (diastereoisomers mixture) (D57)
Figure imgf000073_0001
The title compound (D57) (25 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 6-(terf-butoxycarbonyl)- 5-methyl-6-azaspiro[2.5]octane-5-carboxylic acid (D6) (57 mg) and (S)-methyl 4- (l -aminoethyl)benzoate hydrochloride (46 mg). EDC.HCI: 1 .1 eq, Reaction time: 48 hrs.
MS: (ES/+) m/z: 431 [MH+] C24H34N205 requires 430.25
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.09 - 7.94 (m, 2 H), 7.52 - 7.31 (m, 2 H), 5.33 - 5.07 (m, 1 H), 3.93 (s, 3 H), 3.91 - 3.79 (m, 1 H), 3.28 - 2.83 (m, 1 H), 2.07 (s, 1 H), 1 .98 - 1 .84 (m, 1 H), 1 .66 - 1 .42 (m, 12 H), 1 .36 - 1 .29 (m, 3 H), 1 .19 (d, J = 13.9 Hz, 1 H), 1 .00 - 0.74 (m, 1 H), 0.65 - 0.12 (m, 4 H).
Description 58: iert-butyl 2-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpiperidine-1- carboxylate (racemic mixtur
Figure imgf000073_0002
The title compound (D58) (250 mg) was prepared according to the general procedure for amides preparation (Method C) starting from l -(terf-butoxycarbonyl)- 4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491 -2501 ) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (312 mg). Reaction time: 18 hrs
MS: (ES/+) m/z: 431 .4 [MH+] C24H34N205 requires 430.25
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.96 (d, J = 8.2 Hz, 2 H), 7.32 - 7.29 (m, 2 H), 6.82 - 6.59 (m, 1 H), 4.65 (d, J = 4.4 Hz, 1 H), 4.02 (br. s., 1 H), 3.92 (s, 3 H), 3.00 (d, J = 10.6 Hz, 1 H), 2.18 (d, J = 12.9 Hz, 1 H), 1 .50 (s, 9 H), 1 .43 - 1 .29 (m, 7 H), 0.96 (s, 3 H), 0.84 (s, 3 H).
Description 59: iert-butyl 2-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4,4-dimethylpiperidine-1- carboxylate (diastereoisomers mixture) (D59)
Figure imgf000074_0001
The title compound (D59) (230 mg) was prepared according to the general procedure for amides preparation (Method C) starting from l -(terf-butoxycarbonyl)- 4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491 -2501 ) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (295 mg). Reaction time: 18 hrs
MS: (ES/+) m/z: 419.4 [MH+] C23H34N205 requires 418.25
Description 60: (fi)-ferf-butyl 2-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4-oxopiperidine-1-carboxylate (D60)
Figure imgf000074_0002
The title compound (D60) (300 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (F?)-1 -(terf- butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg; available from Aldrich#701 130) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (195 mg). Reaction time: 1 h
MS: (ES/+) m/z: 405.5 [MH+] C21 H28N206 requires 404.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.99 (d, J = 7.6 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.25 - 7.09 (m, 1 H), 5.17 - 5.02 (m, 1 H), 5.02 - 4.85 (m, 1 H), 3.93 (s, 3 H), 3.89 - 3.73 (m, 1 H), 3.57 - 3.36 (m, 1 H), 2.66 - 2.46 (m, 2 H), 2.46 - 2.31 (m, 1 H), 1 .51 (br. s., 13 H).
Description 61 : (2H)-fert-butyl 4-hydroxy-2-(((S)-1-(4- (methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D61) (diastereoisomer mixture)
Figure imgf000075_0001
To an ice cooled solution of (F?)-terf-butyl 2-(((S)-1 -(4- (methoxycarbonyl)phenyl)ethyl)carbamoyl)-4-oxopiperidine-1 -carboxylate (D60) (300 mg, 0.75 mmol) in MeOH (25 ml) under nitrogen, NaBH4 (142 mg, 3.75 mmol) was added portionwise and the resulting mixture was stirred at RT for 18 hrs. The mixture was diluted with water (10 ml) and extracted with EtOAc (3x10 ml). The organic phases were collected, washed with NaCI sat. (20 ml) dried over Na2S04 and evaporated in vacuo to afford the title compound (D61) (261 mg). MS: (ES/+) m/z: 407.2 [MH+] C21 H30N2O6 requires 406.21
Description 62: (2H)-fert-butyl 4-fluoro-2-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate
(diastereoisomer mixture) (D
Figure imgf000075_0002
A solution of (2F?)-terf-butyl 4-hydroxy-2-(((S)-1 -(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1 -carboxylate (D61 ) (261 mg, 0.64 mmol) in DCM (10 ml) cooled at -20 °C was treated with DAST (0.17 ml, 1 .28 mmol) and the reaction mixture stirred 1 h at -20°C then at RT for 18 hrs. DAST (0.17 ml, 1 .28 mmol) was added and the mixture further stirred 24 hrs. The reaction was quenched with NaHC03 sat. sol. and extracted with DCM (3x10 ml), dried over MgS04 and evaporated in vacuo. The residue was loaded onto a SPE- Si cartridge (20 g) eluting with a mixture DCM/EtOAc 90/10. Collected fractions after solvent evaporation afforded the title compound (D62) (89 mg)
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.96 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 5.27 - 4.96 (m, 1 H), 4.96 - 4.80 (m, 1 H), 4.20 - 4.02 (m, 1 H), 3.92 (s, 3 H), 2.97 - 2.77 (m, 1 H), 2.63 - 2.47 (m, 1 H), 2.07 (s, 1 H), 1 .75 - 1 .46 (m, 12 H), 1 .44 - 1 .21 (m, 4 H)
Description 63: (H)-iert-butyl
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4-oxopiperidine-1- carboxylate (D63)
Figure imgf000076_0001
The title compound (D63) (295 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (F?)-1 -(terf- butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg) and methyl 4-(1 - aminocyclopropyl)benzoate hydrochloride (206 mg). Reaction time: 18 hrs
MS: (ES/+) m/z: 417.5 [MH+] C22H28N206 requires 416.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.95 (d, J = 7.9 Hz, 2 H), 7.51 - 7.37 (m, 1 H), 7.22 (d, J = 7.6 Hz, 2 H), 4.97 - 4.80 (m, 1 H), 3.92 (s, 4 H), 3.66 - 3.54 (m, 1
H), 2.58 (d, J = 5.6 Hz, 2 H), 2.52 - 2.37 (m, 1 H), 1 .55 (s, 9 H), 1 .46 - 1 .24 (m, 5
H)
Description 64: (2fi)-ferf-butyl 4-hydroxy-2-((1-(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (diastereoisomer mixture) (
Figure imgf000076_0002
The title compound (D64) (266 mg) was prepared according to the experimental procedure described in Description 61 starting from starting from (F?)-terf-butyl 2- ((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4-oxopiperidine-1 - carboxylate (D63) (300 mg, 0.72 mmol).
MS: (ES/+) m/z: 419.2 [MH+] C22H30N2O6 requires 418.21 Description 65: (2R)-tert-butyl 4-fluoro-2-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (diastereoisomer mixture) (D
Figure imgf000077_0001
The title compound (D65) (39 mg) was prepared according to the experimental procedure described in Description 59 starting from starting from (2F?)-terf-butyl 4- hydroxy-2-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1 - carboxylate (D64) (266 mg, 0.63 mmol).
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.00 (d, J = 7.8 Hz, 2 H), 7.34 - 7.26 (m, 2 H), 5.18 - 5.03 (m, 1 H), 4.96 - 4.86 (m, 1 H), 4.08 - 3.96 (m, 1 H), 3.93 (s, 3 H), 2.77 - 2.64 (m, 1 H), 2.64 - 2.49 (m, 1 H), 2.05 - 1 .96 (m, 1 H), 1 .73 - 1 .53 (m, 3 H), 1 .53 - 1 .44 (m, 13 H).
Description 66: (H)-iert-butyl 4,4-difluoro-2-(((S)-1-(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D66)
Figure imgf000077_0002
A solution of (F?)-terf-butyl 2-(((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)- 4-oxopiperidine-1 -carboxylate (D60) (300 mg, 0.74 mmol) in DCM (30 ml) cooled at -20 °C was treated with DAST (0.49 ml, 3.71 mmol) and the reaction mixture stirred 1 h at -20 °C and at RT for 18 hrs. The reaction was quenched with NaHC03 sat. sol. and extracted with DCM (3x5 ml), dried over MgS04 and evaporated in vacuo. The residue was loaded onto a SPE-Si cartridge (15g) eluting with a mixture DCM/EtOAc from 100/0 to 95/5. Collected fractions after solvent evaporation afforded the title compound (D66) (98 mg)
MS: (ES/+) m/z: 427.4 [MH+] C21 H28F2N205 requires 426.45 Description 67: (H)-iert-butyl 4,4-difluoro-2-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (single enantiomer) (D67)
Figure imgf000078_0001
The title compound (D67) (68 mg) was prepared according to the experimental procedure described in Description 66 starting from starting from (F?)-terf-butyl 2- ((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4-oxopiperidine-1 - carboxylate (D63) (295 mg, 0.70 mmol).
MS: (ES/+) m/z: 339.4 [MH-Boc+] C22H28F2N205 requires 438.20
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.96 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 6.67 (br. s., 1 H), 5.06 - 4.93 (m, 1 H), 4.33 - 4.22 (m, 1 H), 3.91 (s, 4 H), 3.26 - 3.05 (m, 1 H), 3.05 - 2.88 (m, 1 H), 2.01 - 1 .85 (m, 2 H), 1 .59 - 1 .31 (m, 13 H) Description 68: ieri-butyl 4,4-difluoro-2-((1-(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (racemic mixture) (D68)
Figure imgf000078_0002
The title compound (D68) (688 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1 -(terf-butoxycarbonyl)- 4,4-difluoropiperidine-2-carboxylic acid (600 mg; described in WO2010148197) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (566.5 mg). Reaction time: 5 hrs
MS: (ES/+) m/z: 439.2 [MH+] C22H28F2N205 requires 438.46
Chiral HPLC [Daicel IC; Mobile phase A: 70% n-heptane (+0.1 % DEA), B: 30% EtOH; DAD: 248 nm]: Peak 1 retention time: 1 1 .46 min; Peak 2 retention time: 13.48 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.3 Hz, 2 H), 7.23 (d, J = 8.3 Hz, 2 H), 6.63 (s, 1 H), 4.97 (d, J = 6.8 Hz, 1 H), 4.29 (br. s., 1 H), 3.92 (s, 3 H), 3.20 - 3.06 (m, 1 H), 3.04 - 2.89 (m, 1 H), 2.1 3 - 1 .83 (m, 3 H), 1 .52 (s, 9 H), 1 .47 - 1 .32 (m, 4 H).
Description 69: ferf-butyl 4-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-3- azabicyclo[4.1.0]heptane-3-carboxylate (racemic mixture) (D69)
Figure imgf000079_0001
The title compound (D69) (270 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(terf-butoxycarbonyl)- 3-azabicyclo[4.1 .0]heptane-4-carboxylic acid (D1 7) (200 mg) and methyl 4-(1 - aminocyclopropyl)benzoate hydrochloride (1 57 mg). HOBT.H20: 1 .2eq; Reaction time: 3 hrs.
MS: (ES/+) m/z: 41 5.2 [MH+] C23H30N2O5 requires 414.22
Chiral HPLC [Daicel AD-H ; Mobile phase A: 60% n-heptane (+0.1 % DEA), B: 40% IPA; DAD: 248 nm] : Peak 1 retention time: 1 3.36 min, peak 2 retention time: 1 9.1 8 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm) : 8.64 - 8.47 (m, 1 H), 7.89 - 7.70 (m, 2 H), 7.28 (d, J = 7.8 Hz, 2 H), 4.04 - 3.92 (m, 1 H), 3.83 (s, 3 H), 3.77 - 3.62 (m, 1 H), 3.47 - 3.20 (m, 1 H, under water peak), 2.22 - 2.1 2 (m, 1 H), 1 .83 - 1 .66 (m, 1 H), 1 .45 - 1 .34 (m, 9 H), 1 .30 - 1 .06 (m, 5 H), 0.85 (br. s., 1 H), 0.61 (d, J = 4.9 Hz, 1 H), 0.1 9 (d, J = 3.9 Hz, 1 H).
Description 70: (3R)-tert-buty\ 3-((1 -(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[4.1.0]heptane-2-carboxylate (diastereoisomers mixture) (D70)
Figure imgf000079_0002
The title compound (D70) (28 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert- butoxycarbonyl)-2-azabicyclo[4.1 .0]heptane-3-carboxylic acid (D22) (1 00 mg) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (1 03 mg). Reaction time: 1 h MS: (ES/+) m/z: 41 5.3 [MH+] C24H30N2O5 requires 414.22
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.95 (d, J = 7.7 Hz, 2 H), 7.34 - 7.14 (m, 2 H), 4.67 - 4.14 (m, 1 H), 3.91 (br. s., 3 H), 2.99 - 2.76 (1 H under residual solvent), 2.27 - 1 .08 (m, 1 8 H), 0.88 (d, J = 7.3 Hz, 1 H), 0.53 - 0.20 (m, 1 H).
Description 71 : (3R)-fert-butyl 3-(((S)-1 -(4-
(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[4.1.0]heptane-2- carboxylate (diastereoisomers mixture) (D71 )
Figure imgf000080_0001
The title compound (D71 ) (46 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert- butoxycarbonyl)-2-azabicyclo[4.1 .0]heptane-3-carboxylic acid (D22) (1 00 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (1 1 5 mg). Reaction time: 1 h MS: (ES/+) m/z: 403.2 [MH+] C22H30N2O5 requires 402.22
1 H NMR (400 MHz, CHCI3-d) δ (ppm) : 8.01 (d, J = 6.4 Hz, 2 H), 7.38 (d, J = 6.9 Hz, 2 H), 5.28 - 5.04 (m, 1 H), 4.66 - 4.21 (m, 1 H), 3.93 (s, 3 H), 3.06 - 2.66 (m, 1 H), 2.25 - 1 .1 1 (m, 1 7 H), 1 .02 - 0.64 (m, 1 H), 0.56 - 0.1 5 (m, 1 H).
Description 72: (fi)-ferf-butyl 2-(((S)-1 -(4- (methoxycarbonyl)phenyl)ethyl)carbamoyl) pyrrolidine-1 -carboxylate (D72)
Figure imgf000080_0002
The title compound (D72) (81 5 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (F?)-1 -(terf- butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #43381 8), and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (501 mg). Reaction time: 1 8 hrs
MS: (ES/+) m/z: 377 [MH+] C20H28N2O5 requires 376.20
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 70% n-hexane (+0.1 % DEA), B: 30% EtOH ; DAD: 254 nm] : Peak retention time: 7.93 min. 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.00 (d, J = 7.3 Hz, 2 H), 7.80 - 7.53 (m, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 5.15 (br. s., 1 H), 4.35 (br. s., 1 H), 3.93 (s, 3 H), 3.37 (br. s., 2 H), 2.07 (s, 4 H), 1 .50 (s, 12 H). Description 73a and 73b:
( 1R,3R,5R)-tert-buty\ 3-((1-(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (syn diastereoisomer) (D73a) and
(1 S,3fl,5S)-tert-butyl 3-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[3.1. hexane-2-carbox late (anti diastereoisomer) (D73b)
Figure imgf000081_0001
To a solution of (3R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1 .0]hexane-3- carboxylic acid (syn-anti diastereoisomer mixture 10/2) (D27) (3.06 g, 13.5 mmol) in dry DMF (15 ml) under N2 atmosphere HOBT.H20 (2.06 g, 13.46 mmol), EDC.HCI (3.87 g, 20.20 mmol), methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (3.06 g, 13.46 mmol) and TEA (4.7 ml, 33.7 mmol) were added in sequence. The mixture was stirred for 2 hrs at RT, then the solvent was evaporated in vacuo and the residue taken up in AcOEt (500ml), washed twice with water (50 ml), dried over Na2SO4 and evaporated to afford a residue which was loaded on a SNAP-Si cartridge (100g) and eluted with a mixture DCM/AcOEt from 10/0 to 9/1 . Collected fractions after solvent evaporation afforded the two diastereoisomer (D73a) (2.55 g) and (D73b) (880 mg).
(D73a) (syn diastereoisomer)
MS: (ES/+) m/z: 401 .4 [MH+] C22H28N2O5 requires 400.20
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1 H), 7.90 - 7.76 (m, 2 H), 7.34 - 7.19 (m, 2 H), 4.52 - 4.35 (m, 1 H), 3.84 (s, 3 H), 3.43 - 3.32 (m, 1 H), 2.67 -2.39 (m, 1 H), 1 .88 - 1 .74 (m, 1 H), 1 .52 - 1 .33 (m, 10 H), 1 .27 - 1 .12 (m, 4 H), 1 .09 - 0.92 (m, 1 H), 0.66 - 0.53 (m, 1 H).
(D73b) (anti diastereoisomer)
MS: (ES/+) m/z: 401 .4 [MH+] C22H28N2O5 requires 400.20 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 - 8.52 (s, 1 H), 7.90 - 7.73 (m, 2 H), 7.35 - 7.19 (m, 2 H), 3.93 - 3.75 (m, 4 H), 3.36 - 3.30 (m, 1 H), 2.35 - 2.19 (m, 1 H), 2.12 - 2.02 (m, 1 H), 1 .90 - 1 .74 (m, 1 H), 1 .47 - 1 .30 (m, 9 H), 1 .25 - 1 .07 (m, 4 H), 0.73 (td, J = 5.4, 8.8 Hz, 1 H), 0.39 (br. s., 1 H).
Description 74a and 74b:
(3H)-ieri-butyl 3-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (diastereoisomer mixture) (D74a) and 3-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (single diastereoisomer) (D74b)
Figure imgf000082_0001
The title compounds (D74a) (15 mg) and (D74b) (65 mg) were prepared according to the general procedure for amides preparation (Method C) starting from (3f?)-2- (terf-butoxycarbonyl)-2-azabicyclo[3.1 .0]hexane-3-carboxylic acid (D33) (108 mg) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (1 13 mg). Reaction time: 18 hrs.
(D74a) (diastereoisomer mixture)
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.00 (d, J = 8.1 Hz, 4 H), 7.36 (d, J = 8.1 Hz, 4 H), 5.27 - 5.05 (m, 2 H), 4.13 (2 H, under residual solvent), 3.92 (s, 6 H), 3.35 - 3.12 (m, 2 H), 2.65 - 2.38 (m, 2 H), 2.35 - 2.12 (m, 2 H), 1 .69 - 1 .58 (m, 2 H), 1 .49 (s, 24 H), 0.94 - 0.74 (m, 2 H), 0.50 - 0.34 (m, 2 H)
(D74b) (single diastereoisomer)
MS: (ES/+) m/z: 289.3 [MH-Boc+] C21 H28N205 requires 388.20
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.01 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 5.23 - 5.07 (m, 1 H), 4.22 - 4.06 (m, 1 H), 3.93 (s, 3 H), 3.33 - 3.18 (m, 1 H), 2.62 - 2.42 (m, 1 H), 2.32 - 2.12 (m, 1 H), 1 .67 - 1 .57 (m, 1 H), 1 .50 (s, 12 H), 0.90 - 0.79 (m, 1 H), 0.47 - 0.36 (m, 1 H)
Description 75: (H)-iert-butyl 2-((1-(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpyrrolidine-1- carboxylate (D75 )
Figure imgf000083_0001
The title compound (D75) (94 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (F?)-1 -(terf- butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (D41 ) (84 mg) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (79 mg). HCTU: 1 .05 eq; Reaction time: 2 hrs.
MS: (ES/+) m/z: 417.3 [MH+] C23H32N205 requires 416.23
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.04 (s, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.28 (s, 2 H, under solvent), 4.32 (br. s., 1 H), 3.91 (s, 3 H), 3.65 - 3.25 (m, 1 H), 3.08 (d, J = 10.7 Hz, 1 H), 2.35 - 2.07 (m, 1 H), 1 .95 - 1 .74 (m, 1 H), 1 .49 (br. s., 9 H), 1 .34 (d, J = 12.3 Hz, 4 H), 1 .18 - 0.95 (m, 6 H).
Description 76: methyl 4-(( 7S)-1-(1-benzylazetidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D76)
Figure imgf000083_0002
The title compound (D76) (98 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1 -benzylazetidine-2- carboxylic acid (100 mg, available from Apollo#OR7040) and (S)-methyl 4-(1 - aminoethyl)benzoate hydrochloride (1 13 mg). Reaction time: 1 h
MS: (ES/+) m/z: 353.3 [MH+] C21 H24N203 requires 352.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (d, J = 8.1 Hz, 2 H), 7.94 (d, J = 8.1 Hz, 2 H), 7.39 - 7.21 (m, 14 H), 7.06 (d, J = 8.1 Hz, 2 H), 5.07 - 4.87 (m, 2 H), 3.93 (s, 6 H), 3.78 - 3.67 (m, 3 H), 3.65 - 3.56 (m, 3 H), 3.44 (d, J = 8.1 Hz, 2 H), 3.1 1 (d, J = 8.0 Hz, 2 H), 2.48 (br. s., 2 H), 2.15 (br. s., 1 H), 2.07 (s, 1 H), 1 .47 (d, J = 6.9 Hz, 3 H), 1 .16 (d, J = 6.9 Hz, 3 H).
General procedure for substituted benzyl amines preparation
To a solution of selected cyclic amino-acid, cyclic amino-ester or cyclic amino- amide (1 eq) in ACN, Na2C03 or Cs2C03 (1 .2-8 eq) and selected benzyl bromide (2eq) were added sequentially and the resulting mixture was heated at 60-68 °C for 4-24 hrs or stirred at RT 18 hrs. After filtration of solids, the filtrate was evaporated in vacuo. The resulting residue was taken up in EtOAc and the organic phase was washed with water, dried over Na2S04 and evaporated in vacuo. The crude material was purified on SPE-Si cartridge or Biotage SNAP-Si column eluting with mixtures of cHex/EtOAc or cHex/DCM or DCM/EtOAc affording the title substituted benzyl amine compound.
Description 77: methyl 3-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxylate (syn relative stereochemistry) (D77)
Figure imgf000084_0001
The title compound (D77) (345 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 3- azabicyclo[3.1 .0]hexane-2-carboxylate hydrochloride (D42) (300 mg). (Na2C03: 6 eq; reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 300.0 [MH+] C15H16F3N02 requires 299.1 1
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.57 (d, J = 7.8 Hz, 2 H), 7.46 (d, J = 7.6 Hz, 2 H), 3.96 (d, J = 13.4 Hz, 1 H), 3.74 (s, 3 H), 3.52 - 3.41 (m, 2 H), 3.00 (d, J = 7.5 Hz, 1 H), 2.49 (d, J = 4.9 Hz, 1 H), 1 .72 (d, J = 3.1 Hz, 1 H), 1 .50 - 1 .36 (m, 1 H), 1 .1 1 - 0.96 (m, 1 H), 0.41 (d, J = 4.7 Hz, 1 H).
Description 78: ethyl 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane- 3-carboxylate (D78)
Figure imgf000084_0002
The title compound (D78) (430 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from ethyl 2- azabicyclo[2.2.2]octane-3-carboxylate (300 mg; for preparation see published International Patent application US2005009808). (Cs2C03: 3eq; reaction time: 18hrs; 68 °C)
MS: (ES/+) m/z: 342 [MH+] C1 8H22F3N02 requires 341 .1 6 Description 79: (R)-4-(trifluoromethyl)benzyl 2-methyl-1 -(4- (trifluoromethyl)benzyl)piperidine-2-carboxylate (D79)
Figure imgf000085_0001
The title compound (D79) (70 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from {R)-2- methylpiperidine-2-carboxylic acid (D47) (60 mg) and 4-(Trifluoromethyl)benzyl bromide (0.1 26 ml). (Na2C03: 8 eq; reaction time 48 hrs; 68 °C)
MS: (ES/+) m/z: 460.3 [MH+] C23H23F6N02 requires 459.1 6
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.78 - 7.40 (m, 8 H), 5.24 (d, J = 4.3 Hz, 2 H), 4.00 (d, J = 1 5.4 Hz, 1 H), 3.82 - 3.53 (m, 2 H), 2.79 - 2.56 (m, 1 H), 2.55 - 2.39 (m, 1 H), 2.31 - 2.1 1 (m, 1 H), 1 .72 - 1 .45 (m, 7 H)
Description 80: (fi)-methyl 2-methyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine- 2-carboxylate (D80)
Figure imgf000085_0002
The title compound (D80) (50 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (F?)-methyl 2- methylpyrrolidine-2-carboxylate hydrochloride (D50) (60 mg) and 4- (Trifluoromethyl)benzyl bromide (0.1 26 ml). (Na2C03: 4 eq; reaction time 1 8 hrs; 68 °C)
MS: (ES/+) m/z: 302.2 [MH+] C1 5H1 8F3N02 requires 301 .1 3 Description 81 : (2fl,4fi)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81 )
Figure imgf000086_0001
The title compound (D81) (1 .02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy- D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na2C03: 2.5 eq; Reaction time: 24 hrs; 60 °C).
MS: (ES/+) m/z: 448.2 [MH+] C21 H19F6N03 requires 447.13
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.70 - 7.34 (m, 8 H), 5.28 - 5.06 (m, 2 H), 4.51 (br. s., 1 H), 4.02 (d, J = 13.3 Hz, 1 H), 3.81 - 3.64 (m, 2 H), 3.34 (dd, J = 5.4, 10.1 Hz, 1 H), 2.52 (dd, J = 2.9, 10.1 Hz, 1 H), 2.30 (td, J = 7.0, 13.6 Hz, 1 H), 2.23 - 2.10 (m, 1 H), 1 .76 (br. s., 1 H).
Description 82: (2fl,4S)-3-(trifluoromethyl)benzyl 4-fluoro-1-(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D82)
Figure imgf000086_0002
A solution of (^F^/^-itrifluoromethy benzyl 4-hydroxy-1 -(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81 ) (200 mg, 0.45 mmol) in DCM (20 ml) cooled at -20 °C was treated with DAST (0.148 ml, 1 .1 1 mmol) and the mixture was first stirred 1 h at -20°C then 18 hrs at RT. The reaction was quenched with NaHC03 sat. sol. and the aqueous phase extracted with DCM (3x5ml), dried over MgS04 and evaporated. The residue was purified by Biotage SNAP-Si column (25g) eluting with petroleum ether/EtOAc from 90/10 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D82) (1 10 mg)
MS: (ES/+) m/z: 450.2 [MH+] C21 H18F7N02 requires 449.12 Chiral HPLC [Daicel OD-H; Mobile phase A: 80% n-hexane (+0.1 % DEA); B: 20% IPA; DAD: 265 nm]: Peak retention time: 10.82 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.77 - 7.36 (m, 8 H), 5.37 - 5.04 (m, 3 H), 4.14 (d, J = 13.3 Hz, 1 H), 3.77 - 3.58 (m, 1 H), 3.46 (br. s., 1 H), 3.38 - 3.17 (m, 1 H), 2.86 - 2.49 (m, 2 H), 2.49 - 2.25 (m, 1 H).
Description 83: (fi)-3-(trifluoromethyl)benzyl 4-oxo-1-(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D83)
Figure imgf000087_0001
A solution of (^F^/^-itrifluoromethy benzyl 4-hydroxy-1 -(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81 ) (469 mg, 1 .05 mmol) in dry DCM (10 ml) was treated with Dess-Martin periodinane (0.57 mg, 1 .34 mmol) and stirred at RT 4 hrs. The reaction was quenched with 10% aqueous sodium sulphite solution (10 ml) and extracted with EtOAc (3x10ml). The organic phases were collected, washed with NaCI sat. sol, dried over Na2S04 and evaporated to afford a residue which was purified by SPE-Si cartridge (1 Og) eluting with a mixture cHex/EtOAc 90/10. Collected fractions after solvent evaporation afforded the title compound (D83) (290 mg).
MS: (ES/+) m/z: 446.2 [MH+] C21 H17F6N03 requires 445.1 1
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.75 - 7.37 (m, 8 H), 5.25 (s, 2 H), 4.06 - 3.87 (m, 2 H), 3.78 (d, J = 13.4 Hz, 1 H), 3.36 (d, J = 17.1 Hz, 1 H), 3.06 (d, J = 17.1 Hz, 1 H), 2.80 (dd, J = 7.9, 18.1 Hz, 1 H), 2.69 - 2.47 (m, 1 H).
Description 84: (fi)-3-(trifluoromethyl)benzyl 4,4-difluoro-1-(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D84)
Figure imgf000087_0002
A solution of (F?)-4-(trifluoromethyl)benzyl 4-oxo-1 -(4-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D83) (90 mg, 0.20 mmol) in DCM (10 ml) cooled at -20 °C was treated with DAST (0.133 ml, 1 .01 mmol) and the mixture was first stirred 1 h at -20 °C then 18 hrs at RT. The reaction was quenched with NaHC03 sat. sol. and the aqueous phase extracted with DCM (3x5ml), dried over MgS04 and evaporated. The residue was purified by SPE-Si cartridge (1 Og) eluting with cHex/DCM 50/50. Collected fractions, after solvent evaporation afforded the title compound (D84) (87 mg)
MS: (ES/+) m/z: 468.2 [MH+] C21 H17F8N02 requires 467.1 1
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.78 - 7.36 (m, 8 H), 5.31 - 5.14 (m, 2 H), 4.07 (d, J = 13.4 Hz, 1 H), 3.77 - 3.59 (m, 2 H), 3.37 (q, J = 12.2 Hz, 1 H), 2.91 (td, J = 10.9, 16.4 Hz, 1 H), 2.75 - 2.43 (m, 2 H).
General procedure for i-Butyl carbamate (Boc) cleavage
To an ice cooled solution of Boc protected amine in DCM a 3:1 mixture TFA:DCM was added and the resulting mixture was stirred at RT 1 h prior evaporation of solvents. The residue was loaded onto SPE-SCX cartridge. The collected ammonia fractions after solvent evaporation afforded the title compounds. Description 85: methyl 4-((1 S)-1-(piperidine-2-carboxamido)ethyl) (diastereoisomers mixture) (
Figure imgf000088_0001
The title compound (D85) (1 .37 g) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 2-(((S)-1 - (4-(methoxycarbonyl)phenyl)ethyl)carbamoyl) piperidine-1 -carboxylate (D51 ) (1 .95 g)-
MS: (ES/+) m/z: 291 .3 [MH+] C16H22N203 requires 290.16
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.01 (d, 2 H) 7.38 (d, 2 H) 7.13 - 7.27 (m, 1 H) 5.08 - 5.24 (m, 1 H) 3.93 (s, 3 H) 3.22 - 3.38 (m, 1 H) 3.05 (d, 1 H) 2.72 (t, 1 H) 2.50 (br. s., 1 H) 1 .98 (d, 1 H) 1 .80 (d, 1 H) 1 .60 (br. s., 1 H) 1 .50 (d, 3 H) 1 .38 - 1 .48 (m, 3 H). Description 86: methyl 4-((S)-1-((fi)-piperidine-2-carboxamido)ethyl)benzoate (D86)
Figure imgf000089_0001
The title compound (D86) (286 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-buty\ 2-(((S)- 1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl) piperidine-1 -carboxylate (D52) (405 mg).
MS: (ES/+) m/z: 291 .3 [MH+] C16H22N203 requires 290.16
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% EtOH; DAD: 237nm]: Peak retention time: 15.93 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (d, 2 H) 7.39 (d, 2 H) 7.15 (d, 1 H) 5.17 (t, 1 H) 3.93 (s, 3 H) 3.17 - 3.33 (m, 1 H) 3.03 (d, 1 H) 2.71 (br. s., 1 H) 1 .89 - 2.08 (m, 1 H) 1 .72 - 1 .86 (m, 1 H) 1 .54 - 1 .67 (m, 2 H) 1 .50 (d, 3 H) 1 .30 - 1 .46 (m, 3 H).
Description 87: (fi)-methyl 4-(1-(piperidine-2- carboxamido)cyclopropyl)benzoate (D87)
Figure imgf000089_0002
The title compound (D87) (490 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-buty\ 2-((1 - (4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl) piperidine-1 -carboxylate (D53) (650 mg).
MS: (ES/+) m/z: 303.2 [MH+] C17H22N203 requires 302.16
Description 88: methyl 4-(1-(6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (racemic mixture) (D88)
Figure imgf000089_0003
The title compound (D88) (230 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 5-((1 -(4-
(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (racemic mixture) (D54) (290 mg).
MS: (ES/+) m/z: 329.3 [MH+] C19H24N203 requires 328.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.08 (br. s., 1 H), 7.92 (d, J = 8.2 Hz, 2 H),
7.19 (d, J = 8.1 Hz, 2 H), 3.91 (s, 3 H), 3.74 (d, J = 9.4 Hz, 1 H), 3.1 1 (d, J = 12.0
Hz, 1 H), 2.98 - 2.84 (m, 1 H), 2.02 - 1 .78 (m, 2 H), 1 .39 - 1 .24 (m, 5 H), 0.88 (d, J
= 13.5 Hz, 1 H), 0.51 - 0.32 (m, 3 H), 0.26 (d, J = 6.1 Hz, 1 H).
Description 89: methyl 4-(1-(6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (single unknown enantiomer) (D89)
Figure imgf000090_0001
terf-butyl 5-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylate (D55) (19.7 g) was dissolved in DCM (220 ml) before adding TFA (35 ml). The reaction was stirred at RT for 18 hrs. After solvent evaporation the title compound (D89) (27 g) was isolated.
MS: (ES/+) m/z: 329.3 [MH+] C19H24N203 requires 328.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 9.89 - 9.40 (m, 1 H), 7.94 (d, J = 7.9 Hz, 2 H), 7.79 - 7.51 (m, 1 H), 7.12 (d, J = 7.9 Hz, 2 H), 4.41 (br. s., 1 H), 3.94 (s, 3 H), 3.47 - 3.27 (m, J = 10.5 Hz, 1 H), 3.24 - 3.02 (m, 1 H), 2.16 (t, J = 12.6 Hz, 1 H), 2.12 - 2.06 (m, 1 H), 1 .44 - 1 .17 (m, 5 H), 0.93 (d, J = 14.2 Hz, 1 H), 0.67 - 0.31 (m, 4 H).
Description 90: methyl 4-(1-(6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D90)
Figure imgf000090_0002
The title compound (D90) (310 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 5-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (D55) (405 mg).
MS: (ES/+) m/z: 329.2 [MH+] C19H24N203 requires 328.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.95 (d, J = 8.2 Hz, 2 H), 7.80 - 7.61 (m, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 3.91 (s, 3 H), 3.61 - 3.47 (m, 1 H), 3.19 - 3.05 (m, 1 H), 2.99 - 2.81 (m, 1 H), 1 .98 - 1 .72 (m, 2 H), 1 .33 (d, J = 5.7 Hz, 5 H), 1 .03 - 0.88 (m, 1 H), 0.38 (d, J = 6.0 Hz, 3 H), 0.34 - 0.21 (m, 1 H).
Description 91 : methyl 4-((1 S)-1-(6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D91)
Figure imgf000091_0001
The title compound (D91) (96 mg) was prepared according to the general procedure for f-Butyl carbamate (Boc) cleavage starting from terf-butyl 5-(((S)-1 - (4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (D56) (130 mg).
MS: (ES/+) m/z: 317 [MH-Boc+] C18H24N203 requires 316.18
Chiral HPLC [Phenomens LUX-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% IPA; DAD: 248 nm]: Peak 1 retention time: 13.6 min, peak 2 retention time: 15.7 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (dd, 4 H) 7.40 (d, 4 H) 7.18 (t, 2 H) 5.17 (t, 2 H) 3.93 (s, 6 H) 3.36 (ddd, 2 H) 2.97 - 3.16 (m, 2 H) 2.74 - 2.93 (m, 2 H) 1 .64 - 1 .87 (m, 5 H) 1 .45 - 1 .55 (d, 7 H) 1 .34 (t, 2 H) 0.91 (d, 2 H) 0.17 - 0.49 (m, 8 H)
Description 92: methyl 4-((1 S)-1-(5-methyl-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D92)
Figure imgf000091_0002
The title compound (D92) (19 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 5-(((S)-1 - (4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-5-methyl-6-azaspiro[2.5]octane-6- carboxylate (D57) (25 mg)
MS: (ES/+) m/z: 331 .3 [MH+] C19H26N203 requires 330.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.07 - 7.94 (m, 2 H), 7.92 - 7.74 (m, 1 H), 7.49 - 7.33 (m, 2 H), 5.15 (t, J = 7.1 Hz, 1 H), 3.92 (s, 3 H), 3.25 - 2.72 (m, 3 H), 1 .94 (t, J = 12.7 Hz, 1 H), 1 .55 - 1 .46 (m, 3 H), 1 .37 - 1 .24 (m, 3 H), 1 .01 - 0.81 (m, 2 H), 0.62 - 0.18 (171 , 4 H).
Description 93: methyl 4-(1 -(4,4-dimethylpiperidine-2- carboxamido)cyclopropyl)benzoate (D93)
Figure imgf000092_0001
The title compound (D93) (150 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 2-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpiperidine-1 - carboxylate (D58) (250 mg)
MS: (ES/+) m/z: 331 .3 [MH+] C19H26N203 requires 330.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.95 (d, J = 8.2 Hz, 2 H), 7.47 (br. s., 1 H), 7.24 (d, J = 8.3 Hz, 2 H), 3.91 (s, 3 H), 3.39 (dd, J = 2.7, 1 1 .5 Hz, 1 H), 3.00 - 2.78 (m, 2 H), 1 .78 - 1 .67 (m, 3 H), 1 .33 (d, J = 6.7 Hz, 4 H), 1 .29 - 1 .20 (m, 1 H), 0.98 (d, J = 5.2 Hz, 6 H).
Description 94: methyl 4-((1 S)-1-(4,4-dimethylpiperidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D94)
Figure imgf000092_0002
The title compound (D94) (150 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 2-(((S)-1 - (4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4,4-dimethylpiperidine-1 -carboxylate (diastereoisomers mixture) (D59) (230 mg) MS: (ES/+) m/z: 319.3 [MH+] C18H26N203 requires 318.25
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.09 - 7.96 (m, 2 H), 7.40 (d, J = 7.0 Hz, 2 H), 5.15 (br. s., 1 H), 3.93 (s, 3 H), 3.48 (d, J = 12.1 Hz, 1 H), 2.95 (br. s., 2 H), 1 .82 - 1 .69 (m, 1 H under solvent), 1 .51 (d, J = 6.5 Hz, 3 H), 1 .44 - 1 .28 (m, 3 H), 1 .04 - 0.91 (m, 6 H).
Description 95: methyl 4-((1 S)-1-((2R)-4-fluoropiperidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D95)
Figure imgf000093_0001
The title compound (D95) (75 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (2F?)-terf-butyl 4- fluoro-2-(((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1 - carboxylate (D62) (89 mg).
MS: (ES/+) m/z: 309.2 [MH+] C16H21 FN203 requires 308.15
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 7.20 - 7.07 (m, 1 H), 5.22 - 5.12 (m, 1 H), 5.00 - 4.80 (m, 1 H), 3.93 (s, 3 H), 3.70 - 3.62 (m, 1 H), 3.13 - 3.01 (m, 1 H), 2.96 - 2.83 (m, 1 H), 2.28 - 2.14 (m, 1 H), 1 .88 - 1 .61 (m, 4 H), 1 .52 (d, J = 6.9 Hz, 3 H). Description 96: methyl 4-(1-((2R)-4-fluoropiperidine-2- carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D96)
Figure imgf000093_0002
The title compound (D96) (26 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (2f?)-tert-butyl 4- fluoro-2-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1 - carboxylate (D65) (39 mg).
MS: (ES/+) m/z: 321 .1 [MH+] C17H21 FN203 requires 320.15
1 H NMR (400 MHz, CHCI3-d) δ (ppm8.05 - 7.86 (m, J = 8.0 Hz, 2 H), 7.55 (br. s., 1
H), 7.33 - 7.17 (m, 2 H), 5.06 - 4.77 (m, 1 H), 3.90 (s, 3 H), 3.71 - 3.58 (m, 1 H), 3.06 (d, J = 1 1 .0 Hz, 1 H), 2.98 - 2.83 (m, 1 H), 2.19 (d, J = 9.9 Hz, 1 H), 1 .98 - 1 .43 (m, 3 H), 1 .40 - 1 .09 (m, J = 6.5 Hz, 4 H).
Description 97: methyl 4-((S)-1-((fi)-4,4-difluoropiperidine-2- carboxamido)ethyl)benzoate
Figure imgf000094_0001
The title compound (D97) (66 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (F?)-terf-butyl 4,4- difluoro-2-(((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1 - carboxylate (D66) (98 mg).
MS: (ES/+) m/z: 327.4 [MH+] C16H20F2N2O3 requires 326.14
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (d, J = 7.8 Hz, 2 H), 7.38 (d, J = 7.8 Hz, 2 H), 6.98 (d, J = 5.9 Hz, 1 H), 5.27 - 5.05 (m, 1 H), 3.93 (s, 3 H), 3.43 - 3.13 (m, 1 H), 2.93 - 2.78 (m, 1 H), 2.56 - 2.33 (m, 1 H), 2.15 - 1 .94 (m, 1 H), 1 .90 - 1 .66 (m, 2 H), 1 .63 - 1 .44 (m, 4 H).
Description 98: (fi)-methyl 4-(1-(4,4-difluoropiperidine-2- carboxamido)cyclopropyl)benzoate (D98)
Figure imgf000094_0002
The title compound (D98) (47 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (F?)-terf-butyl 4,4- difluoro-2-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1 - carboxylate (D67) (68 mg).
MS: (ES/+) m/z: 339.4 [MH+] C17H20F2N2O3requires 338.14
Description 99: methyl 4-(1-(4,4-difluoropiperidine-2- carboxamido)cyclopropyl)benzoate (racemic mixture) (D99)
Figure imgf000094_0003
The title compound (D99) (500 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 4,4- difluoro-2-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1 - carboxylate (D68) (685 mg)
MS: (ES/+) m/z: 339.2 [MH+] C17H20F2N2O3 requires 338.46
Chiral HPLC [Daicel IC; Mobile phase A: 70% n-heptane (+0.1 % DEA), B: 30% EtOH; DAD: 248 nm]: Peak 1 retention time: 12.71 min, peak 2 retention time: 16.05 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.24 (d, J = 8.3 Hz, 2 H), 3.84 (s, 3 H), 3.34 - 3.31 (m, 1 H), 3.09 (d, J = 12.2 Hz, 1 H), 2.70 - 2.57 (m, 1 H), 2.25 - 2.07 (m, 1 H), 1 .99 - 1 .70 (m, 3 H), 1 .35 - 1 .16 (m, 4 H).
Description 100: methyl 4-(1-(3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D100)
Figure imgf000095_0001
The title compound (D100) (155 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from terf-butyl 4-((1 -(4- (methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-3-azabicyclo[4.1 .0]heptane-3- carboxylate (D69) (260 mg).
MS: (ES/+) m/z: 314.7 [MH+] C18H22N203 requires 314.16
Chiral HPLC [Daicel AD-H; Mobile phase A: 60% n-heptane (+0.1 % DEA), 40%
IPA; DAD: 248 nm]: Peak 1 retention time: 13.36 min, peak 2 retention time: 19.18 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.46 (s, 1 H), 7.88 - 7.81 (m, 2 H), 7.26 - 7.19 (m, 2 H), 3.83 (s, 3 H), 3.33 - 3.31 (m, 1 H), 2.86 (dd, J = 4.9, 9.8 Hz, 1 H), 2.69 - 2.65 (m, 1 H), 1 .91 - 1 .83 (m, 1 H), 1 .83 - 1 .73 (m, 1 H), 1 .30 - 1 .24 (m, 2 H), 1 .24 - 1 .17 (m, 2 H), 1 .05 - 0.87 (m, 2 H), 0.59 (dt, J = 4.4, 8.6 Hz, 1 H), 0.27 (q, J = 4.9 Hz, 1 H). Description 101 : methyl 4-(1-((3fi)-2-azabicyclo[4.1.0]heptane-3- carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D101)
Figure imgf000096_0001
The title compound (D101) (20 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3R)-tert-buty\ 3-((1 - (4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2-azabicyclo[4.1 .0]heptane-2- carboxylate (D70) (28 mg).
MS: (ES/+) m/z: 315.2 [MH+] C18H22N203 requires 314.16 Description 102: methyl 4-((1 S)-1-((3fi)-2-azabicyclo[4.1.0]heptane-3- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D102)
Figure imgf000096_0002
The title compound (D102) (17.5 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3F?)-terf-butyl 3- (((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[4.1 .0]heptane- 2-carboxylate (diastereoisomers mixture) (D71 ) (46 mg).
MS: (ES/+) m/z: 303.1 [MH+] C17H22N203 requires 302.16
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.13 - 7.93 (m, 2 H), 7.57 - 7.33 (m, 2 H), 5.29 - 5.04 (m, 1 H), 3.92 (s, 3 H), 3.35 - 3.19 (m, 1 H), 2.41 (m, 1 H), 2.21 - 0.83 (m, 8 H), 0.77 - 0.61 (m, 1 H), 0.38 (m, 1 H).
Description 103: methyl 4-((S)-1-((fi)-pyrrolidine-2- carboxamido)ethyl)benzoate
Figure imgf000096_0003
The title compound (D103) (550 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (F?)-terf-butyl 2-(((S)- 1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl) pyrrolidine-1 -carboxylate (D72) (815 mg). MS: (ES/+) m/z: 277.6 [MH+] C15H20N2O3 requires 276.15
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 70% n-hexane (+0.1 % DEA), 30% EtOH; DAD: 240 nm]: Peak retention time: 8.65 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.00 (d, J = 7.3 Hz, 2 H), 7.80 - 7.53 (m, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 5.15 (br. s., 1 H), 4.35 (br. s., 1 H), 3.93 (s, 3 H), 3.37 (br. s., 2 H), 2.07 (s, 4 H), 1 .50 (s, 12 H).
Description 104: methyl 4-(1-((1 fl,3fl,5fi)-2-azabicyclo[3.1.0]hexane-3- carboxamido)cyclopropyl)benzoate (syn diastereoisomer) (D104)
Figure imgf000097_0001
The title compound (D104) (1 .8 g) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (1 R,3R,5R)-tert-butyl 3-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[3.1 .0]hexane-2-carboxylate (syn diastereoisomer) (D73a) (2.6 g).
MS: (ES/+) m/z: 301 [MH+] C17H20N2O3 requires 300.15
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51 (s, 1 H), 7.88 - 7.81 (m, 2 H), 7.23 (d, J = 8.3 Hz, 2 H), 4.08 (s,1 H), 3.87 - 3.78 (m, 4 H), 2.77 (dt, J = 2.7, 6.2 Hz, 1 H), 2.15 - 1 .99 (m, 2 H), 1 .34 - 1 .23 (m, 3 H), 1 .21 - 1 .13 (m, 2 H), 0.47 - 0.37 (m, 1 H), -0.06 (ddd, J = 2.9, 4.3, 5.5 Hz, 1 H)
Description 105: methyl 4-(1-((1 S,3fl,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamido)cyclopropyl)benzoate (anti diastereoisomer) (D105)
Figure imgf000097_0002
The title compound (D106) (71 .9 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (1 S,3f?,5S)-tert-butyl 3-((1 -(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2- azabicyclo[3.1 .0]hexane-2-carboxylate (anti diastereoisomer) (D73b) (D76) (96 mg)
MS: (ES/+) m/z: 301 .3 [MH+] C17H20N2O3 requires 300.15 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (br. s., 1 H), 7.95 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 8.3 Hz, 2 H), 3.91 (s, 3 H), 3.62 - 3.41 (m, 1 H), 3.01 - 2.79 (m, J = 2.3 Hz, 1 H), 2.44 (dd, J = 8.4, 12.7 Hz, 1 H), 2.04 - 1 .90 (m, 1 H), 1 .54 - 1 .40 (m, 1 H), 1 .40 - 1 .25 (m, 4 H), 0.60 - 0.34 (m, 2 H).
Description 106: methyl 4-((1 S)-1-((3fi)-2-azabicyclo[3.1.0]hexane-3- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D106)
Figure imgf000098_0001
The title compounds (D106) (1 1 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3F?)-terf-butyl 3-
(((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexane-2- carboxylate (diastereoisomers mixture) (D74a) (15 mg)
MS: (ES/+) m/z: 289.3 [MH+] C16H20N2O3 requires 288.15
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.06 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 7.1 Hz, 4 H), 7.93 - 7.85 (m, 1 H), 7.37 (dd, J = 4.2, 7.7 Hz, 4 H), 5.08 (t, J = 7.2 Hz, 2
H), 4.1 1 (d, J = 7.2 Hz, 1 H), 3.92 (s, 6 H), 3.64 (s, 1 H), 2.93 - 2.87 (m, 2 H), 2.44
- 2.34 (m, 1 H), 2.28 (m, 1 H), 1 .99 - 1 .87 (m, 1 H), 1 .61 - 1 .35 (m, 9 H), 0.56 -
0.44 (m, 3 H), 0.05 (br. s., 1 H). Description 107: methyl 4-((1 S)-1-((3fi)-2-azabicyclo[3.1.0]hexane-3- carboxamido)ethyl)benzoate (single diastereoisomer) (D107)
Figure imgf000098_0002
The title compounds (D107) (48 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3F?)-terf-butyl 3- (((S)-1 -(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexane-2- carboxylate (single diastereoisomer) (D74b) (65 mg)
MS: (ES/+) m/z: 289.3 [MH+] C16H20N2O3 requires 288.15
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.99 (d, J = 8.1 Hz, 2 H), 7.89 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 2 H), 5.07 (t, J = 7.3 Hz, 1 H), 3.90 (s, 3 H), 3.60 (t, J = 8.7 Hz, 1 H), 2.90 - 2.80 (m, J = 2.5 Hz, 1 H), 2.36 (dd, J = 8.3, 12.7 Hz, 1 H), 1 .97 - 1 .81 (m, J = 4.1 , 4.1 , 8.3 Hz, 1 H), 1 .48 (d, J = 7.0 Hz, 3 H), 1 .45 - 1 .39 (m, J = 7.0 Hz, 1 H), 0.53 - 0.39 (m, 2 H).
Description 108: (fi)-methyl 4-(1-(4,4-dimethylpyrrolidine-2- carboxamido)cyclopropyl)benzoate (D108)
Figure imgf000099_0001
The title compound (D108) (70 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (F?)-terf-butyl 2-((1 - (4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpyrrolidine-1 - carboxylate (D75) (94 mg).
MS: (ES/+) m/z: 317.3 [MH+] C18H24N203 requires 316.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.51 (br. s., 1 H), 7.96 (d, J = 8.0 Hz, 2 H), 7.25 (br. d, J = 1 .0 Hz, 2 H), 4.13 - 4.00 (m, 1 H), 3.91 (s, 3 H), 2.86 (d, J = 10.7 Hz, 1 H), 2.72 (d, J = 10.6 Hz, 1 H), 2.22 - 2.07 (m, 1 H), 1 .66 (dd, J = 7.9, 12.8 Hz, 1 H), 1 .35 (s, 4 H), 1 .09 (d, J = 8.8 Hz, 6 H).
Description 109: methyl 4-((1 S)-1-(azetidine-2-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D
Figure imgf000099_0002
To a solution of methyl 4-((1 S)-1 -(1 -benzylazetidine-2- carboxamido)ethyl)benzoate (D76) (98 mg, 0.278 mmol in EtOH (20ml) Pd/C 10% (90 mg, 0.083 mmol) and ammonium formate (52 mg, 0.83 mmol) were added and the heterogeneous solution was left stirring at RT for 20 hrs. Further addition of Pd/C 10% (90 mg, 0.083 mmol) and ammonium formate (52 mg, 0.83 mmol) was done and the resulting mixture was stirred at RT for 5 hrs. Catalyst was filtered off and the solvent evaporated to afford the title compound (D109) (60 mg).
MS: (ES/+) m/z: 263.2 [MH+] C14H18N2O3 requires 262.13
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.24 (s, 1 H), 8.09 - 7.96 (m, 2 H), 7.46 - 7.33 (m, 2 H), 5.39 - 5.22 (m, 1 H), 5.22 - 5.05 (m, 1 H), 3.93 (d, J = 2.8 Hz, 3 H), 3.89 - 3.70 (m, 1 H), 2.78 (dd, J = 5.9, 9.2 Hz, 1 H), 2.65 - 2.34 (m, 1 H), 1 .51 (q, J = 6.8 Hz, 3 H), 1 .43 - 1 .34 (m, 1 H).
General procedure for esters hydrolysis
Method A
To a solution of the selected ester (1 eq) in dioxane/water (1 :1 ), LiOH H2O (1 .2-4 eq) was added and the resulting mixture was stirred at RT. Organic solvent was evaporated off and the aqueous solution was washed with DCM and evaporated in vacuo. The residue was loaded on a C18 cartridge eluting with H2O/MeOH 9/1 then MeOH. Collected methanolic phases were evaporated off affording the title compound as lithium salt.
Method B
To a solution of the selected ester (1 eq) in dioxane/water (1 :1 ), LiOH H2O (1 .2-4 eq) was added and the resulting mixture was stirred at RT. Dioxane was evaporated off and the aqueous solution was loaded onto a reverse phase Biotage SNAP-C18 column eluting with a mixture H2O/MeCN containing 0.1 % of CH3CO2H from 90/10 to 80/20. Collected fractions after solvent evaporation afforded the title compound
Method C
To a solution of the selected ester (1 eq) in dioxane/water (1 :1 ), LiOH H2O (1 .5 eq) was added and the resulting mixture was stirred at RT for 18 hrs or heated under microwave irradiation. Organic solvent was evaporated off and the aqueous solution was acidified with acetic acid and loaded onto a reverse phase Biotage SNAP-C18 column eluting first with H2O then MeOH. The methanolic phase was evaporated in vacuo to afford the title compound.
Method D
To a solution of the selected ester (1 eq) in dioxane/water (1 :1 ), LiOH H2O (1 .5-4 eq) was added and the resulting mixture was stirred at RT or heated under microwave irradiation. Organic solvent was evaporated off and the aqueous solution was washed with DCM prior addition of acetic acid until the solution reached the value of pH=4. The aqueous solution was extracted with EtOAc. The organic phases were collected and washed with NaCI sat sol, dried over Na2S04 and evaporated to afford the title compound.
Method E
To a solution of the selected ester (1 eq) in dioxane/water (1 :1 ), LiOH H2O (1 .5-4 eq) was added and the resulting mixture was stirred at RT or heated under microwave irradiation. Organic solvent was evaporated off and the aqueous solution was washed with DCM prior addition of acetic acid until the solution reached the value of pH=4. The dolid precipitated was extracted with EtOAc. The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford the title compound.
Description 110: 3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (syn relative stereochemistry) (D110)
Figure imgf000101_0001
The title compound (D110) (1 10 mg) was prepared according to the general procedure for for esters hydrolysis (Method C) starting from methyl 3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2-carboxylate (D77) (180 mg). (LiOH: 1 .5 eq; reaction temperature: 150°C under microwave irradiation, reaction time: 5 min).
MS: (ES/+) m/z: 286.3 [MH+] C14H14F3NO2 requires 285.10
1 H NMR (400 MHz, METHANOL-d4) δ (ppm): 7.77 - 7.72 (m, 2 H), 7.72 - 7.66 (m, 2 H), 4.42 (d, J = 1 .0 Hz, 1 H), 4.17 (d, J = 1 .0 Hz, 1 H), 4.05 (d, J = 4.0 Hz, 1 H), 3.38 (br. s., 2 H), 2.14 - 2.04 (m, 1 H), 1 .81 - 1 .70 (m, 1 H), 0.96 - 0.84 (m, 1 H), 0.73 - 0.59 (m, 1 H).
Description 111 : 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3- carboxylic acid (D111)
Figure imgf000102_0001
The title compound (D111 ) (45 mg) was prepared according to the general procedure for for esters hydrolysis (Method C) starting from ethyl 2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylate (D78) (420 mg). (LiOH : 2 eq; reaction time: 1 8hrs; RT).
MS: (ES/+) m/z: 314.3 [MH+] C1 6H1 8F3NO2 requires 31 3.1 3
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.85 - 7.79 (m, 2 H), 7.77 - 7.72 (m, 2 H), 4.48 - 4.36 (m, 2 H), 3.56 - 3.47 (m, 2 H), 2.41 - 2.28 (m, 2 H), 2.1 9 - 2.03 (m, 1 H), 1 .98 - 1 .88 (m, 2 H), 1 .88 - 1 .77 (m, 2 H), 1 .71 - 1 .56 (m, 2 H).
Description 112: lithium (H)-2-methyl-1 -(4-(trifluoromethyl)benzyl)piperidine- 2-carboxylate (D112)
Figure imgf000102_0002
The title compound (D112) (1 0 mg) was prepared according to the general procedure for for esters hydrolysis (Method A) starting from (R)-4-
(trifluoromethyl)benzyl 2-methyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxylate (D79) (70 mg). (LiOH : 3 eq; Reaction time: 48 hrs; RT then 140 °C under microwave irradiation for 2hrs).
MS: (ES/+) m/z: 302.2 [M-Li+2H+] C1 5H1 7F3UNO2 requires 307.14
Description 113: lithium (H)-2-methyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine- 2-carboxylate (D113)
Figure imgf000102_0003
The title compound (D113) (42 mg) was prepared according to the general procedure for for esters hydrolysis (Method A) starting from (F?)-methyl 2-methyl-1 - (4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D80) (50 mg). (LiOH : 3 eq; Reaction time: 1 8 hrs; RT)
MS: (ES/+) m/z: 288.2 [M-Li+2H+] C14H1 5F3UN02 requires 293.1 2
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.72 (s, 4 H), 4.35 (d, J = 1 2.7 Hz, 1 H), 4.02 (d, J = 1 2.7 Hz, 1 H), 3.25 - 2.96 (m, 2 H), 2.31 (d, J = 1 0.3 Hz, 1 H), 2.1 3 - 1 .80 (m, 3 H), 1 .54 (s, 3 H) Description 114: lithium (2fl,4S)-4-fluoro-1 -(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D114)
Figure imgf000103_0001
The title compound (D114) (60 mg) was prepared according to the general procedure for for esters hydrolysis (Method A) starting (2f?,4S)-3- (trifluoromethyl)benzyl 4-fluoro-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxylate (D82) (1 1 0 mg). (LiOH : 2 eq; Reaction time: 1 8 hrs)
MS: (ES/+) m/z: 292.2 [M-Li+2H+] C1 3H1 2F4UN02 requires 297.1 0
Description 115: lithium (fi)-4,4-difluoro-1 -(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D115)
Figure imgf000103_0002
The title compound (D115) (51 mg) was prepared according to the general procedure for for esters hydrolysis (Method A) starting (R)-4- (trifluoromethyl)benzyl 4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxylate (D84) (81 mg). Reaction time: 1 8 hrs; RT.
MS: (ES/+) m/z: 31 0.1 [M-Li+2H+] C1 3H1 1 F5UN02 requires 31 5.09 Description 116: methyl 4-((1 S)-1-(1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D116)
Figure imgf000104_0001
To a mixture of methyl 4-((1 S)-1 -(piperidine-2-carboxamido)ethyl) (diastereoisomers mixture) (D85) (50,0 mg, 0,172 mmol) and 4- (trifluoromethyl)benzaldehyde (0,028 ml, 0,207 mmol) in DCE (1 ,7 ml), catalytic AcOH was added and the mixture stirred 1 h at RT. NaBH(OAc)3 (43,8 mg, 0,207 mmol) was added and the resulting mixture stirred at RT overnight. Solvents were evaporated in vacuo and the residue was purified by SPE-Si (2g) eluting with a mixture DCM/MeOH 98/2. Collected fractions after solvent evaporation afforded the title compound (D116) (75 mg).
MS: (ES/+) m/z: 449 [MH+] C16H22N2O3 requires 290.16
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 90% n-hexane (+0.1 % DEA), B: 10% IPA; DAD: 237 nm]: Peak 1 retention time: 16.08 min, peak 2 retention time: 17.5 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.04 (d, 2 H) 7.84 (d, 2 H) 7.63 (d, 2 H) 7.50 (d, 2 H) 7.45 (d, 2 H) 7.39 (s, 2 H) 7.25 (d, 2 H) 7.20 (s, 2 H) 7.00 (d, 1 H) 6.95 (d, 1 H) 5.13 - 5.25 (m, 2 H) 3.88 - 4.01 (m, 7 H) 3.69 (d, 1 H) 3.32 (d, 1 H) 3.19 (d, 1 H) 2.81 - 2.95 (m, 4 H) 1 .95 - 2.14 (m, 4 H) 1 .78 (br. s., 2 H) 1 .47 - 1 .67 (m, 9 H) 1 .43 (d, 3 H) 1 .27 - 1 .40 (m, 2 H).
Description 117: methyl 4-((S)-1-((fi)-1-(4-fluorobenzyl)piperidine-2- carboxamido)ethyl)benzoate (D117)
Figure imgf000104_0002
The title compound (D117) (20 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1 - ((f?)-piperidine-2-carboxamido)ethyl)benzoate (D86) (50 mg) and 4-fluorobenzyl bromide (0.043 ml, 0.34 mmol). (Na2C03: 2.5 eq; reaction time: 4 hrs; 60 °C) MS: (ES/+) m/z: 399.3 [MH+] C23H27FN203 requires 398.20
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 80% n-hexane (+0.1 % DEA), B: 20% EtOH; DAD: 237 nm]: Peak retention time: 8.98 min.
Description 118: methyl 4-((S)-1-((/7)-1-(4-(trifluoromethyl)benzyl)piperidine- 2-carboxamido)ethyl)benzoat (D118)
Figure imgf000105_0001
The title compound (D118) (24 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1 - ((f?)-piperidine-2-carboxamido)ethyl)benzoate (D86) (40 mg) and 4- (trifluoromethyl)benzylbromide (0.032 ml). (Na2C03: 2.5 eq; reaction time: 4 hrs; 60 °C)
MS: (ES/+) m/z: 449.3 [MH+] C24H27F3N203 requires 448.20
Description 119: (fi)-methyl 4-(1-(1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (D119)
Figure imgf000105_0002
The title compound (D119) (74 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (F?)-methyl 4-(1 - (piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (50 mg) and 4- (trifluoromethyl)benzylbromide (0.039 ml). (Na2C03: 2.5 eq; reaction time: 6 hrs; 60 °C) MS: (ES/+) m/z: 461 .3 [MH+] C25H27F3N203 requires 460.20
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 7.8 Hz, 2 H), 7.48 - 7.34 (m, 3 H), 7.25 (d, J = 8.2 Hz, 2 H), 3.90 (s, 3 H), 3.79 (d, J = 14.4 Hz, 1 H), 3.27 (d, J = 14.5 Hz, 1 H), 2.97 - 2.82 (m, 2 H), 2.16 - 1 .97 (m, 2 H), 1 .80 (d, J = 12.7 Hz, 1 H), 1 .64 (t, J = 12.3 Hz, 2 H), 1 .49 (d, J = 12.2 Hz, 1 H), 1 .43 - 1 .26 (m, 4 H), 1 .13 (t, J= 7.2 Hz, 1 H)
Description 120: (fi)-methyl 4-(1-(1-(4-chlorobenzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (D120)
Figure imgf000106_0001
The title compound (D120) (45 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (F?)-methyl 4-(1 - (piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4- (Chloro)benzylbromide (35 mg). (Na2C03: 4 eq; reaction time: 18 hrs; 68 °C) MS: (ES/+) m/z: 427.3[MH+] C24H27CIN203 requires 426.17
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.93 (d, J = 8.1 Hz, 2 H), 7.40 (br. s., 1 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.27 - 7.17 (m, 4 H), 3.91 (s, 3 H), 3.72 (d, J = 14.1 Hz, 1 H), 3.18 (d, J = 14.1 Hz, 1 H), 2.94 - 2.82 (m, 2 H), 2.13 - 1 .96 (m, 2 H), 1 .85 - 1 .73 (m, 1 H), 1 .63 (br. s., 2 H), 1 .50 - 1 .44 (m, 1 H), 1 .43 - 1 .27 (m, 4 H), 1 .15 (br. s., 1 H).
Description 121 : (H)-methyl 4-(1-(1-(4-cyanobenzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (D121 )
Figure imgf000106_0002
The title compound (D121) (35 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from (F?)-methyl 4- (1 -(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4- Cyanobenzylbromide (33 mg). (Na2C03: 4 eq; reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 418.3 [MH+] C25H27N303 requires 417.21 Descriptions 122a and 122b
methyl 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (enantiomer 1) (D122a) and
methyl 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D122b)
Figure imgf000107_0001
To a solution of methyl 4-(1 -(6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (racemic mixture) (D88) (230 mg, 0.70 mmol) in dry MeCN (10 ml), Na2C03 (223 mg, 2.1 mmol) and 4-(trifluoromethyl)- benzylbromide (200 mg, 0.84 mmol) were added in sequence,. The mixture was heated at 68 °C for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by SPE-Si cartridge (1 Og) eluting with a mixture DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded 250 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-hexane/EtOH/DEA 60%/40% 0.1 % v/v; Flow rate 10ml/min; DAD: 246 nm). Collected fractions, after solvent evaporation of separated fractions afforded the two enantiomer compounds (D122a) (83.1 mg) and (D122b) (98.9 mg).
(D122a) (enantiomer 1) retention time: 8.15 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.1 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.47 - 7.37 (m, 3 H), 7.25 (d, J = 8.2 Hz, 2 H), 3.90 (s, 3 H), 3.84 (d, J = 14.4 Hz, 1 H), 3.35 (d, J = 14.4 Hz, 1 H), 3.09 - 3.00 (m, 1 H), 2.88 (br. s., 1 H), 2.26 (br. s., 1 H), 2.02 (br. s., 1 H), 1 .89 - 1 .78 (m, 1 H), 1 .45 - 1 .29 (m, 4 H), 1 .13 (br. s., 1 H), 0.99 (br. s., 1 H), 0.49 - 0.35 (m, 3 H), 0.30 (d, J = 6.6 Hz, 1 H). (D122b) (enantiomer 2) retention time: 1 1 .12 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 7.8 Hz, 2 H), 7.48 - 7.39 (m, 3 H), 7.25 (d, J = 8.2 Hz, 2 H), 3.90 (s, 3 H), 3.84 (d, J = 14.4 Hz, 1 H), 3.35 (d, J = 14.4 Hz, 1 H), 3.05 (dd, J = 3.1 , 10.1 Hz, 1 H), 2.89 (d, J = 1 1 .5 Hz, 1 H), 2.26 (br. s., 1 H), 2.02 (t, J = 1 1 .7 Hz, 1 H), 1 .83 (br. s., 1 H), 1 .44 - 1 .27 (m, 4 H), 1 .13 (t, J = 7.0 Hz, 1 H), 0.97 (d, J = 13.0 Hz, 1 H), 0.49 - 0.35 (m, 3 H), 0.30 (d, J = 6.7 Hz, 1 H).
Description 123: methyl 4-(1-(6-(4-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D123)
To a solution of methyl 4-(1 -(6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (D89) (27g, 61 .03 mmol) in dry MeCN (900 ml) Cs2C03 (39.7 g, 122.05 mmol) and a solution of 4- (trifluoromethyl)-benzylbromide (14.6 g, 61 .03 mmol) in MeCN (50ml) were added in sequence. The mixture was stirred at RT for 18 hrs. The solid was filtered off and solvents were evaporated. The residue was ri-dissolved in DCM (200 ml) and washed with H20 (3x100 ml) and NaCI sat. sol (50 ml). The organic phases were dried over Na2S04 and evaporated to afford a white solid, which was triturated in cyclohexane to afford the title compound (D123) (19.7 g).
MS: (ES/+) m/z: 488.2 [MH+] C27H29F3N203 requires 486.21
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.79 - 8.69 (m, 1 H), 7.87 - 7.76 (m, 2 H), 7.68 (s, 2 H), 7.64 (s, 2 H), 7.28 - 7.17 (m, 2 H), 3.89 - 3.71 (m, 4 H), 3.28 - 3.22 (m, 1 H), 2.98 - 2.88 (m, 1 H), 2.79 - 2.69 (m, 1 H), 2.16 - 1 .99 (m, 2 H), 1 .85 - 1 .71 (m, 1 H), 1 .35 - 1 .09 (m, 5 H), 0.92 - 0.83 (m, 1 H), 0.43 - 0.20 (m, 4 H). Description 124: methyl 4-(1-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D124)
Figure imgf000109_0001
The title compound (D124) (47 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4-(1 - (6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (D90) (50 mg) and 3-chloromethyl-6- (trifluoromethyl)piridine (38 mg). (Cs2C03: 1 .3 eq; reaction time: 18 hrs; RT) MS: (ES/+) m/z: 488.2 [MH+] C26H28F3N303 requires 487.21
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.68 (s, 1 H), 7.91 (d, J = 8.1 Hz, 2 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.33 (br. s., 1 H), 7.29 - 7.24 (m, 2 H), 3.89 (s, 3 H), 3.84 (d, J = 14.5 Hz, 1 H), 3.38 (d, J = 14.4 Hz, 1 H), 3.05 (dd, J = 2.8, 10.0 Hz, 1 H), 2.84 (d, J = 1 1 .4 Hz, 1 H), 2.26 (t, J = 10.5 Hz, 1 H), 2.05 - 1 .95 (m, 1 H), 1 .81 (t, J = 10.9 Hz, 1 H), 1 .45 - 1 .24 (m, 4 H), 1 .22 - 1 .13 (m, 1 H), 0.97 (d, J = 13.1 Hz, 1 H), 0.51 - 0.33 (m, 3 H), 0.30 (d, J = 5.1 Hz, 1 H).
Description 125: methyl 4-(1-(6-(3-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D125)
Figure imgf000109_0002
The title compound (D125) (60.7 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1 -(6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (single unknown enantiomer) (D90) (50 mg, 0.1 1 mmol) and 3- (Trifluoromethyl)benzyl bromide (0.020 ml, 0.12 mmol). (Cs2C03 :2 eq; reaction time: 4 hrs; reaction temperature: RT.
MS: (ES/+) m/z: 487.6 [MH+] C27H29F3N203 requires 486.21
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 - 8.70 (m, 1 H), 7.86 - 7.78 (m, 2 H), 7.77 - 7.68 (m, 2 H), 7.65 - 7.56 (m, 2 H), 7.29 - 7.19 (m, 2 H), 3.82 (s, 3 H), 3.81 - 3.75 (m, 1 H), 3.29 - 3.24 (m, 1 H), 2.96 - 2.88 (m, 1 H), 2.79 - 2.70 (m, 1 H), 2.18 - 1 .97 (m, 2 H), 1 .82 - 1 .69 (m, 1 H), 1 .33 - 1 .22 (m, 2 H), 1 .22 - 1 .08 (m, 3 H), 0.94 - 0.84 (m, 1 H), 0.44 - 0.19 (m, 4 H). Description 126: methyl 4-((1 S)-1-(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D126)
Figure imgf000110_0001
The title compound (D126) (30 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((1 S)-1 -(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D91 ) (60 mg) and 4-Fluorobenzylbromide (0.074 ml). (Na2C03: 2.5 eq; reaction time: 4hrs; 60 °C) MS: (ES/+) m/z: 425.3 [MKT] C25H29FN203 requires 424.22
Chiral HPLC [Phenomenex Lux Cellulose-2; Mobile phase A: 80% n-hexane (+0.1 % DEA), B: 20% IPA; DAD: 237 nm]: Peak 1 retention time 19.73 min, peak 2 retention time 21 .35 min.
Descriptions 127a and 127b:
4-((1 S)-1 -(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid (diastereoisomer 1) (D127a) and
4-((1 S)-1 -(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid (diastereoisomer 2) (D127b)
Figure imgf000111_0001
To a solution of methyl 4-((1 S)-1 -(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoate (D126) (80mg, 0.19 mmol) in a mixture of H20/Dioxane (1 /2 ml) LiOH H20 (1 1 .8 mg, 0.28 mmol) were added and the resulting mixture was stirred for 8 hrs before evaporating off the dioxane. The aqueous solution was loaded on a C18 column (1 Og). Collected methanolic fractions after solvent evaporation afforded of 80 mg of diastereoisomers mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: Phenomenex Lux-1 ; Mobile phase: n-hexane/EtOH/TFA 65%/35%/0.5% v/v; Flow rate 10ml/min; DAD: 235 nm). Collected fractions, after solvent evaporation afforded two separated peaks, each one of them was evaporated in vacuo, redissolved in H20/MeOH (5/1 ml), basified to pH ~ 8 with NaHC03 and loaded on a SPE- C18 column (1 Og). The methanolic phases were evaporated and the resulting residues were filtered on SPE-Si column (1 g) eluting with DCM/MeOH 90/10. Collected fractions after solvent evaporation of the separated fractions afforded the two diastereoisomers (D127a) (23 mg) and (D127b) (13 mg).
(D127a) (diastereoisomer 1): retention time: 6.7 min
MS: (ES/+) m/z: 41 1 .3 [MKT] C24H27FN203 requires 410.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.99 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.40 - 7.31 (m, 2 H), 7.05 (t, J = 8.5 Hz, 2 H), 5.16 - 5.05 (m, 1 H), 3.87 (d, J = 13.1 Hz, 1 H), 3.37 (m, 1 H), 3.16 - 3.07 (m, 1 H), 3.01 - 2.91 (m, 1 H), 2.40 - 2.28 (m, 1 H), 2.22 - 2.09 (m, 1 H), 2.03 - 1 .90 (m, 1 H), 1 .49 (d, J = 7.0 Hz, 3 H), 1 .19 - 1 .13 (m, 1 H), 0.97 - 0.87 (m, 1 H), 0.39 (d, J = 5.1 Hz, 4 H).
(D127b) (diastereoisomer 2): retention time 14.42 min
MS: (ES/+) m/z: 41 1 .3 [MH+] C24H27FN203 requires 410.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.92 (d, J = 8.0 Hz, 2 H), 7.48 - 7.28 (m, 4 H), 7.05 (t, J = 8.5 Hz, 2 H), 5.15 (m, 1 H), 3.86 (d, J = 13.2 Hz, 1 H), 3.37 (1 H, under solvent), 3.20 - 3.07 (d, J = 8.6 Hz, 1 H), 2.96 (d, J = 1 1 .4 Hz, 1 H), 2.33 (m, 1 H), 2.1 1 (m, 1 H), 1 .96 (br. s., 1 H), 1 .53 (d, J = 6.9 Hz, 3 H), 1 .20 - 1 .10 (m, 1 H), 0.91 (d, J = 12.8 Hz, 1 H), 0.48 - 0.24 (m, 4 H).
Descriptions 128: 4-((1 S)-1 -(6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid (single unknown diastereoisomer) (D128)
Figure imgf000112_0001
4-((1 S)-1 -(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (single unknown enantiomer) (D127a) (14 mg, 0.034 mmol) was dissolved in EtOH (3 ml) prior addition of Pd/C 10% (18 mg, 0.017 mmol) and ammonium formate (6.5 mg, 0.102 mmol). The heterogeneous solution was left stirring at RT for 24 hrs then catalyst was filtered off and the solvent evaporated in vacuo to afford the title compound (D128) (10 mg).
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.87 (d, J = 7.9 Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 5.12 - 4.99 (m, 1 H), 4.00 - 3.89 (m, 1 H), 3.45 - 3.35 (m, 1 H), 3.26 - 3.04 (m, 1 H), 2.26 - 2.08 (m, 2 H), 1 .55 - 1 .40 (m, J = 6.7 Hz, 4 H), 1 .32 (d, J = 6.8 Hz, 1 H), 1 .16 - 1 .04 (m, 1 H), 0.69 - 0.22 (m, 4 H).
Descriptions 129: 4-(trifluoromethyl)benzyl 4-((1 S)-1-(6-(4-
(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (single unknown diastereoisomer) (D129)
Figure imgf000112_0002
To a solution of 4-((1 S)-1 -(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (D128) (10 mg, 33.1 μιτιοΙ) in dry MeCN, Na2C03 (17.5 mg, 165.4 μιηοΙ) and 4-(trifluoromethyl)-benzylbromide (24 mg, 99.2 μιηοΙ) were added in sequence. The mixture was heated at 68 °C for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by Biotage SNAP-Si column (1 Og) eluting with a mixture DCM/EtOAc from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compounds (D129) (14.8 mg). 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.08 (d, J = 8.0 Hz, 2 H), 7.66 (dd, J = 8.0, 14.4 Hz, 4 H), 7.58 (d, J = 7.9 Hz, 2 H), 7.47 (d, J = 7.8 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 7.05 (d, J = 7.7 Hz, 1 H), 5.23 - 5.1 1 (m, 1 H), 4.00 (d, J = 14.4 Hz, 1 H), 3.37 (d, J = 14.4 Hz, 1 H), 3.06 (dd, J = 3.1 , 10.6 Hz, 1 H), 2.89 (d, J = 1 1 .4 Hz, 1 H), 2.31 - 2.18 (m, 1 H), 2.01 - 1 .80 (m, 2 H), 1 .59 - 1 .54 (m, 1 H), 1 .43 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 12.9 Hz, 1 H), 0.44 - 0.33 (m, 3 H), 0.28 (d, J = 6.8 Hz, 1 H).
Description 130: methyl 4-((1 S)-1-(5-methyl-6-(4-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D130)
Figure imgf000113_0001
The title compound (D130) (19 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((1 S)-1 -(5-methyl-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D92) (16 mg) and 4-(Trifluoromethyl)benzylbromide (0.01 1 ml). (Na2C03: 3 eq; reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 489 [MH+] C27H31 F3N203 requires 488.23
Descriptions 131a and 131 b:
methyl 4-(1 -(4,4-dimethyl-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 1) (D131a) and
methyl 4-(1 -(4,4-dimethyl-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D131 b)
Figure imgf000113_0002
To a solution of methyl 4-(1 -(4,4-dimethylpiperidine-2- carboxamido)cyclopropyl)benzoate (racemic mixture) (D93) (190 mg, 057 mmol) in dry MeCN (5 ml), Cs2C03 (606 mg, 1 .8 mmol) and 4-(trifluoromethyl)- benzylbromide (0.1 15 ml, 0.74 mmol) were added in sequence and the mixture was stirred at RT for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by SPE-Si cartridge (1 Og) eluting with a mixture DCM/EtOAc from 100/0 to 95/5. Collected fractions after solvent evaporation afforded 236 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-hexane/EtOH/DEA 80%/20% 0.1 % v/v; Flow rate 10ml/min; DAD: 246 nm). Collected fractions, after solvent evaporation afforded the two enantiomer compounds (D131a) (147 mg) and (D131 b) (141 mg).
(D131a) (enantiomer 1): retention time: 1 1 .43 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.2 Hz, 2 H), 7.61 (d, J = 7.9 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.34 (br. s., 1 H), 7.25 (d, J = 8.3 Hz, 2 H), 3.90 (s, 3 H), 3.80 (d, J = 14.4 Hz, 1 H), 3.26 (d, J = 14.4 Hz, 1 H), 3.07 (d, J = 9.2 Hz, 1 H), 2.71 (d, J = 1 1 .8 Hz, 1 H), 2.21 t, 1 H), 1 .79 (d, J = 13.1 Hz, 1 H), 1 .46 (t, J = 12.5 Hz, 2 H), 1 .40 - 1 .24 (m, 4 H), 1 .12 (d, J = 7.0 Hz, 1 H), 0.99 (d, J = 10.0 Hz, 6 H).
(D131 b) (enantiomer 2): retention time: 16.66 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.1 Hz, 2 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.34 (br. s., 1 H), 7.25 (d, J = 8.4 Hz, 2 H), 3.90 (s, 3 H), 3.80 (d, J = 14.5 Hz, 1 H), 3.26 (d, J = 14.5 Hz, 1 H), 3.07 (d, J = 9.1 Hz, 1 H), 2.70 (br. d, J = 1 .0 Hz, 1 H), 2.21 (t, J = 1 .0 Hz, 1 H), 1 .78 (d, J = 1 .0 Hz, 1 H), 1 .46 (t, J = 12.5 Hz, 2 H), 1 .40 - 1 .24 (m, 4 H), 1 .17 - 1 .08 (m, 1 H), 0.99 (d, J = 9.9 Hz, 6 H).
Descriptions 132a, 132b:
methyl 4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate (diastereoisomer 1) (D132a) and
methyl 4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate (diastereoisomer 2) (D132b)
Figure imgf000115_0001
To a solution of methyl 4-((1 S)-1 -(4,4-dimethylpiperidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D94) (150 mg, 047 mmol) in dry MeCN (5 ml), Cs2C03 (462 mg, 1 .4 mmol) and 4-(trifluoromethyl)- benzylbromide (0.08 ml, 0.56 mmol) were added in sequence and the mixture was stirred at RT for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by SPE-Si cartridge (1 Og) eluting with a mixture DCM/EtOAc from 100/0 to 95/5. Collected fractions after solvent evaporation afforded 140 mg of diastereoisomeric mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-hexane/EtOH/DEA 80%/20% 0.1 % v/v; Flow rate 10ml/min; DAD: 246 nm). Collected fractions, after solvent evaporation of the separated fractions afforded the two diastereoisomer compounds (D132a) (71 mg) and (D132b) (68 mg).
(D132a) (diastereoisomer 1): retention time: 8.95 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.83 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 7.9 Hz, 2 H), 7.25 (d, J = 8.1 Hz, 2 H), 7.16 (d, J = 7.8 Hz, 2 H), 6.97 - 6.87 (m, 1 H), 5.26 - 5.13 (m, 1 H), 3.90 (s, 3 H), 3.75 - 3.65 (m, 1 H), 3.23 - 3.12 (m, 1 H), 3.09 - 3.01 (m, 1 H), 2.74 - 2.63 (m, 1 H), 2.25 - 2.12 (m, 1 H), 1 .85 - 1 .74 (m, 1 H), 1 .54 - 1 .38 (m, 5 H), 1 .37 - 1 .28 (m, 1 H), 0.98 (d, J = 9.8 Hz, 6 H).
(D132b) (diastereoisomer 2): retention time: 17.94 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.05 (d, J = 8.1 Hz, 2 H), 7.63 (d, J = 7.9 Hz, 2 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 6.98 (d, J = 7.9 Hz, 1 H), 5.17 (t, J = 7.2 Hz, 1 H), 4.07 - 3.81 (m, 4 H), 3.31 (d, J = 14.4 Hz, 1 H), 3.09 (dd, J = 2.7, 1 1 .7 Hz, 1 H), 2.72 (d, J = 1 1 .8 Hz, 1 H), 2.23 (br. s., 1 H), 1 .72 (d, J = 13.1 Hz, 1 H), 1 .51 - 1 .25 (m, 6 H), 0.96 (s, 6 H).
Description 133: methyl 4-((1 S)-1-((2fi)-4-fluoro-1-(4-
(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate
(diastereoisomers mixture) (D133)
Figure imgf000116_0001
The title compound (D133) (62 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1 S)- 1 -((2f?)-4-fluoropiperidine-2-carboxamido)ethyl)benzoate (D95) (75 mg) and 4- (trifluoromethyl)-benzylbromide (0.045 ml). (Cs2C03: 1 .3 eq; reaction time: 18 hrs; RT).
MS: (ES/+) m/z: 467.0 [MH+] C24H26F4N203 requires 466.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (d, J = 7.4 Hz, 2 H), 7.63 (d, J = 7.3 Hz, 2 H), 7.44 (d, J = 7.7 Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 6.98 (d, J = 6.2 Hz, 1 H), 5.17 (t, J = 7.1 Hz, 1 H), 4.99 - 4.72 (m, 1 H), 4.03 - 3.86 (m, 4 H), 3.41 (d, J = 14.1 Hz, 1 H), 3.30 (d, J = 8.0 Hz, 1 H), 2.71 (d, J = 12.2 Hz, 1 H), 2.50 (t, J = 1 1 .3 Hz, 1 H), 2.22 (br. s., 1 H), 1 .97 - 1 .63 (m, 3 H), 1 .45 (d, J = 6.7 Hz, 3 H).
Description 134: methyl 4-(1-((2fi)-4-fluorc-1-(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (
Figure imgf000116_0002
The title compound (D134) (26 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1 - ((2f?)-4-fluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D96) (39 mg) and 4-(trifluoromethyl)-benzylbromide (0.015 ml). (Cs2C03: 1 .3 eq; reaction time: 18 hrs; RT).
MS: (ES/+) m/z: 479.2 [MH+] C25H26F4N203 requires 478.19
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.93 (d, J = 8.1 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.42 (d, J = 7.8 Hz, 2 H), 7.33 (br. s., 1 H), 7.25 (br. s., 2 H), 5.03 - 4.75 (m, 1 H), 3.91 (s, 3 H), 3.82 (d, J = 14.2 Hz, 1 H), 3.39 (d, J = 14.2 Hz, 1 H), 3.29 (dd, J = 3.1 , 9.8 Hz, 1 H), 2.78 - 2.66 (m, 1 H), 2.57 - 2.45 (m, 1 H), 2.27 (br. s., 1 H), 2.01 - 1 .68 (m, 3 H), 1 .41 - 1 .27 (m, 3 H), 1 .22 - 1 .12 (m, 1 H).
Description 135: methyl 4-((S)-1-((fi)-4,4-difluoro-1-(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (single diastereoisomer) (D135)
Figure imgf000117_0001
To a solution of methyl 4-((S)-1 -((/:?)-4,4-difluoropiperidine-2- carboxamido)ethyl)benzoate (D97) (66 mg, 0.20 mmol) in dry MeCN (4 ml), Cs2C03 (198 mg, 0.60 mmol) and the 4-(Trifluoromethyl)benzylbromide (0.037 ml, 0.24 mmol) were added in sequence and the resulting mixture was stirred at RT for 18 hrs. The solid was filtered off, the acetonitrile was evaporated and the crude was purified by flash chromatography SNAP HP_Si02 (10 g) eluting with a gradient DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation were purified onto reverse phase column GOLD-C18 (15 g) eluting with a gradient of H20/MeCN (containing 0.1 % Acetic acid) from 10/90 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D135) (20 mg).
MS: (ES/+) m/z: 485.5 [MH+] C24H25F5N203 requires 484.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm ): 8.03 (d, J = 8.1 Hz, 2 H), 7.64 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 7.8 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 6.85 (d, J = 7.9 Hz, 1 H), 5.19 (t, J = 7.2 Hz, 1 H), 3.98 (d, J = 14.4 Hz, 1 H), 3.95 - 3.89 (m, 3 H), 3.39 (d, J = 14.2 Hz, 1 H), 3.27 (dd, J = 3.3, 10.6 Hz, 1 H), 2.94 (d, J = 1 1 .1 Hz, 1 H), 2.51 - 2.30 (m, 2 H), 2.05 - 1 .86 (m, 3 H), 1 .57 - 1 .52 (m, J = 6.8 Hz, 1 H), 1 .48 (d, J = 6.8 Hz, 3 H).
Description 136: (fi)-methyl 4-(1-(4,4-difluoro-1-(4-
(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (single enantiomer) (D136)
Figure imgf000118_0001
The title compound (D136) (30 mg) was prepared according to the general procedure described in Description 135 starting from (F?)-methyl 4-(1 -(4,4- difluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D98) (47 mg) and 4- (trifluoromethyl)-benzylbromide (0.027 ml).
MS: (ES/+) m/z: 497.4 [MH+] C25H25F5N203 requires 496.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.92 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 2 H), 7.44 - 7.37 (m, 2 H), 7.26 (d, J = 8.6 Hz, 2 H), 3.91 (s, 3 H), 3.84 (d, J = 14.2 Hz, 1 H), 3.38 (d, J = 14.2 Hz, 1 H), 3.31 - 3.19 (m, 1 H), 2.96 (d, J = 1 1 .4 Hz, 1 H), 2.54 - 2.33 (m, 2 H), 2.25 - 2.1 1 (m, 1 H), 2.02 (br. s., 1 H), 1 .98 - 1 .85 (m, 1 H), 1 .43 - 1 .31 (m, 3 H), 1 .24 - 1 .14 (m, 1 H).
Descriptions 137a and 137b:
methyl 4-(1 -(4,4-dif luoro-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 1 ) (D137a) and
methyl 4-(1 -(4,4-dif luoro-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D137b)
Figure imgf000118_0002
To a solution of methyl 4-(1 -(4,4-difluoropiperidine-2- carboxamido)cyclopropyl)benzoate (D99) (500 mg, 1 .47 mmol) in dry MeCN (20 ml), Cs2C03 (1 .4 g, 4.43 mmol) and 4-(trifluoromethyl)-benzylbromide (0.27 ml, 1 .77 mmol) were added in sequence and the resulting mixture was stirred at RT for 12 hrs. The solid was filtered off and the solvent evaporated to afford a residue which was loaded on Biotage SNAP-Si cartridges (25 g) eluting with a mixture cHex/EtOAc from 90/10 to 70/30. Collected fractions after solvent evaporation afforded 490 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL IC; Mobile phase: n-heptane/IPA/DEA 60% 40%/0.1 % v/v Flow rate 10ml/min; DAD: 248 nm). Collected fractions, after solvent evaporation of the separated fractions afforded the two enantiomer compounds (D137a) (143 mg) and (D137b) (130 mg).
(D137a) (enantiomer 1): retention time: 10.86 min.
MS: (ES/+) m/z: 497.3 [MKT] C25H25F5N203 requires 496.18
1 H NMR (400MHz ,DMSO-d6) δ (ppm): 8.97 (s, 1 H), 7.86 - 7.77 (m, J = 8.3 Hz, 2 H), 7.74 - 7.67 (m, J = 7.8 Hz, 2 H), 7.65 - 7.55 (m, J = 7.8 Hz, 2 H), 7.27 - 7.17 (m, J = 8.8 Hz, 2 H), 3.87 - 3.77 (m, 4 H), 3.39 (d, J = 14.2 Hz, 1 H), 3.22 - 3.12 (m, 1 H), 2.86 - 2.76 (m, 1 H), 2.33 - 2.15 (m, J = 7.8 Hz, 3 H), 2.00 (br. s., 2 H), 1 .31 - 1 .13 (m, 4 H).
(D137b) (enantiomer 2): retention time: 13.81 min.
MS: (ES/+) m/z: 496.8 [MH+] C25H25F5N203 requires 496.18
1 H NMR (400MHz ,DMSO-d6) δ (ppm): 8.97 (s, 1 H), 7.81 (d, J = 8.3 Hz, 2 H), 7.76 - 7.66 (m, J = 8.3 Hz, 2 H), 7.66 - 7.56 (m, J = 8.3 Hz, 2 H), 7.23 (d, J = 8.3 Hz, 2 H), 3.86 - 3.74 (m, 4 H), 3.39 (d, J = 14.2 Hz, 1 H), 3.20 - 3.14 (m, 1 H), 2.82 (d, J = 12.2 Hz, 1 H), 2.35 - 2.16 (m, 3 H), 2.07 - 1 .81 (m, 2 H), 1 .34 - 1 .13 (m, 4 H) Descriptions 138a and 138b:
methyl 4-(1 -(4,4-dif luoro-1 -(3-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 1) (D138a) and
methyl 4-(1 -(4,4-dif luoro-1 -(3-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D138b)
Figure imgf000119_0001
To a solution of methyl 4-(1 -(4,4-difluoropiperidine-2- carboxamido)cyclopropyl)benzoate (D99) (50 mg, 0.15 mmol) in dry MeCN (5 ml), Cs2C03 (73 mg, 0.22 mmol) and 3-(trifluoromethyl)-benzylbromide (42 mg, 0.18 mmol) were added in sequence and the resulting mixture was stirred at RT for 12 hrs. The solid was filtered off and the solvent evaporated to afford a residue which was loaded on Biotage SNAP-Si cartridges (100 g) eluting with a mixture DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded 83 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL IC; Mobile phase: n-heptane/IPA/DEA 60% 40%/0.1 % v/v; Flow rate 10ml/min; DAD: 248 nm). Collected fractions, after solvent evaporation of the separated fractions afforded the two enantiomer compounds (D138a) (35 mg) and (D138b) (45 mg). (D138a) (enantiomer 1): retention time: 10.18 min
(D138b) (enantiomer 2): retention time: 15.06 min
Descriptions 139:
methyl 4-(1 -(3-(4-(trif luoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoate (racemic mixture) (D139)
Figure imgf000120_0001
To a solution of methyl 4-(1 -(3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (racemic mixture) (D100) (155 mg, 0.49 mmol) in dry MeCN (4 ml), Cs2C03 (241 mg, 0.74 mmol) and 4-(trifluoromethyl)- benzylbromide (0.09 ml, 0.59 mmol) were added in sequence and the resulting mixture was stirred at RT for 4 hrs. The residue obtained after solvent evaporation was loaded on Biotage SNAP-Si column (25 g) eluting with a mixture cHex/EtOAc from 65/35 to 40/60. Collected fractions after solvent evaporation afforded the title compound (D139) (racemic mixture) (215 mg).
MS: (ES/+) m/z: 472.7 [MKT] C26H27F3N203 requires 472.20
1 H NMR (400MHz ,DMSO-d6) δ (ppm): 8.64 (s, 1 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.72 - 7.65 (m, J = 7.8 Hz, 2 H), 7.59 (d, J = 7.8 Hz, 2 H), 7.22 - 7.15 (m, J = 8.3 Hz, 2 H), 3.82 (s, 3 H), 3.70 (d, J = 13.7 Hz, 1 H), 3.56 (d, J = 14.2 Hz, 1 H), 3.17 (dd, J = 7.1 , 12.5 Hz, 1 H), 2.99 (t, J = 6.1 Hz, 1 H), 2.32 (dd, J = 4.2, 12.5 Hz, 1 H), 2.18 (td, J = 6.7, 13.9 Hz, 1 H), 1 .68 (td, J = 4.3, 9.0 Hz, 1 H), 1 .30 - 1 .20 (m, 2 H), 1 .20 - 1 .08 (m, 2 H), 1 .08 - 0.90 (m, 2 H), 0.67 (dt, J = 4.2, 8.2 Hz, 1 H), 0.22 (q, J = 4.4 Hz, 1 H)
Descriptions 140a and 140b:
methyl 4-(1 -(3-(4-(trif luoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoate (enantiomer 1) (D140a) and
methyl 4-(1 -(3-(4-(trif luoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D140b)
Figure imgf000121_0001
Methyl 4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (racemic mixture) (189 mg) (D139) was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL IC; Mobile phase: n-heptane/IPA/DEA 60%/40%/0.1 % v/v Flow rate 10ml/min; DAD: 248 nm). Collected fractions, after solvent evaporation of separated fractions afforded the two diastereoisomer compounds (D140a) (78 mg) and (D140b) (82 mg).
(D140a) (enantiomer 1 with trans relative stereochemistry): retention time: 12.89 min.
MS: (ES/+) m/z: 472.7 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 70% n-heptane (+0.1 % DEA), B: 30% IPA; DAD: 248 nm]: Peak retention time: 12.9 min.
1 H NMR (400MHz ,DMSO-d6) δ (ppm): 8.65 (s, 1 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.72 - 7.65 (m, J = 7.8 Hz, 2 H), 7.62 - 7.56 (m, J = 7.8 Hz, 2 H), 7.19 (d, J = 8.3 Hz, 2 H), 3.82 (s, 3 H), 3.70 (d, J = 13.7 Hz, 1 H), 3.56 (d, J = 14.2 Hz, 1 H), 3.17 (dd, J = 7.1 , 12.5 Hz, 1 H), 2.99 (t, J = 6.1 Hz, 1 H), 2.32 (dd, J = 4.2, 12.5 Hz, 1 H), 2.23 - 2.14 (m, 1 H), 1 .69 (br. s., 1 H), 1 .30 - 1 .22 (m, 2 H), 1 .20 - 1 .13 (m, 1 H), 1 .1 1 (dd, J = 3.2, 6.1 Hz, 1 H), 1 .05 - 0.93 (m, 2 H), 0.70 - 0.64 (m, 1 H), 0.22 (d, J = 4.9 Hz, 1 H). (D140b) (enantiomer 2 with trans relative stereochemistry): retention time: 18.26 min.
MS: (ES/+) m/z: 473.6 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.1 % DEA), B: 40% IPA; DAD: 248 nm]: Peak retention time: 18.2 min
1 H NMR (400MHz ,DMSO-d6) δ (ppm): 8.65 (s, 1 H), 7.83 - 7.77 (m, J = 8.3 Hz, 2 H), 7.71 - 7.64 (m, J = 7.8 Hz, 2 H), 7.62 - 7.54 (m, J = 8.3 Hz, 2 H), 7.22 - 7.14 (m, J = 8.8 Hz, 2 H), 3.82 (s, 3 H), 3.70 (d, J = 1 3.7 Hz, 1 H), 3.56 (d, J = 14.2 Hz, 1 H), 3.17 (dd, J = 7.1 , 12.5 Hz, 1 H), 2.99 (t, J = 6.1 Hz, 1 H), 2.32 (dd, J = 4.2, 12.5 Hz, 1 H), 2.23 - 2.1 1 (m, 1 H), 1 .68 (d, J = 12.7 Hz, 1 H), 1 .30 - 1 .21 (m, 2 H), 1 .16 (dd, J = 4.2, 6.1 Hz, 1 H), 1 .1 1 (dd, J = 3.2, 6.1 Hz, 1 H), 1 .05 - 0.92 (m, 2 H), 0.68 (td, J = 4.3, 8.1 Hz, 1 H), 0.22 (d, J = 4.9 Hz, 1 H).
Description 141 : methyl 4-(1-(3-(3-(trifluoromethyl)benzyl)-3- azabicyclo[4.1.0]heptane-4-c rboxamido)cyclopropyl)benzoate (D141 )
Figure imgf000122_0001
The title compound (D141) (53 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1 -(3- azabicyclo[4.1 .0]heptane-4-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D100) (48 mg, 0.15 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.040 ml, 0.17 mmol). (Cs2C03 :2 eq; reaction time: 4 hrs; reaction temperature: RT. MS: (ES/+) m/z: 473 [MH+] C26H27F3N203 requires 472.20
Description 142: methyl 4-(1-((3fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoate
(diastereoisomers mixture) (D142)
Figure imgf000123_0001
The title compound (D142) (6.8 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4-(1 - ((3f?)-2-azabicyclo[4.1 .0]heptane-3-carboxamido)cyclopropyl)benzoate
(diastereoisomers mixture) (D101 ) (17.5 mg) and 4-(trifluoromethyl)- benzylbromide (0.01 ml). (Cs2C03: 1 .5 eq; Reaction time: 20 hrs; RT).
MS: (ES/+) m/z: 473.2 [MH+] C26H27F3N203 requires 472.20
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.01 - 7.84 (m, J = 8.3 Hz, 2 H), 7.66 - 7.60 (m, J = 8.8, 8.8 Hz, 2 H), 7.57 - 7.39 (m, 3 H), 7.28 - 7.09 (m, J = 8.1 Hz, 2 H), 4.03 - 3.65 (m, 5 H), 3.13 - 2.81 (m, 1 H), 2.06 (m, 2 H), 1 .80 - 0.98 (8 H, under residual solvent), 0.71 - 0.24 (m, 2 H).
Description 143: methyl 4-((1 S)-1-((3H)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D143)
Figure imgf000123_0002
The title compound (D143) (10 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((1 S)-1 -((3f?)-2-azabicyclo[4.1 .0]heptane-3-carboxamido)ethyl)benzoate
(diastereoisomers mixture) (D102) (20 mg) and 4-(trifluoromethyl)-benzylbromide (0.012 ml). (Cs2C03: 1 .5 eq; Reaction time: 20 hrs; RT).
MS: (ES/+) m/z: 461 .1 [MH+] C25H27F3N203 requires 460.20
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (d, J = 7.0 Hz, 2 H), 7.89 - 7.06 (m, 7 H), 5.24 - 5.04 (m, 1 H), 4.19 - 3.69 (m, 5 H), 3.13 - 2.76 (m, 1 H), 2.43 - 1 .81 (m, 2 H), 1 .81 - 1 .06 (7 H under residual solvent), 0.66 - 0.16 (m, 2 H). Description 144: methyl 4-((S)-1-((fi)-1-(4-(trifluoromethyl)benzyl)pyrrolidine- 2-carboxamido)ethyl)benzoat (D144)
Figure imgf000124_0001
The title compound (D144) (60 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((S)-1 -((f?)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and and 4- (trifluoromethyl)-benzylbromide (0.056 ml). (Na2C03; reaction time: 5 hrs; 70°C). MS: (ES/+) m/z: 434.8 [MH+] C23H25F3N203 requires 434.18
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 70% n-hexane (+0.1 % DEA), B: 30% IPA; DAD: 235 nm]: Peak retention time: 10.50 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.07 (d, J = 8.3 Hz, 1 H), 8.04 - 7.99 (m, J = 7.8 Hz, 2 H), 7.40 - 7.34 (m, J = 8.3 Hz, 2 H), 5.14 (quin, J = 7.3 Hz, 1 H), 3.93 (s, 3 H), 3.83 (dd, J = 5.1 , 9.0 Hz, 1 H), 3.06 (td, J = 6.8, 10.3 Hz, 1 H), 2.92 (td, J = 6.1 , 10.3 Hz, 1 H), 2.22 - 2.10 (m, 1 H), 1 .91 (qd, J = 6.4, 12.7 Hz, 1 H), 1 .77 - 1 .67 (m, 2 H), 1 .51 (d, J = 7.3 Hz, 3 H).
Description 145: methyl 4-((S)-1-((fi)-1-(4-fluorobenzyl)pyrrolidine-2- carboxamido)ethyl)benzoate
Figure imgf000124_0002
The title compound (D145) (22 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((S)-1 -((f?)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and and 4- Fluorobenzyl bromide (0.045 ml). (Na2C03; reaction time: 5 hrs; 70°C).
MS: (ES/+) m/z: 385 [MH+] C22H25FN203 requires 384.18
Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 80% n-hexane (+0.1 % DEA), B: 20% IPA; DAD: 235 nm]: Peak retention time 14.18 min. 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (d, J = 7.8 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2 H), 7.28 - 7.24 (m, 2 H), 7.10 - 7.02 (m, 2 H), 5.15 - 5.05 (m, 1 H), 3.93 (s, 3 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.58 (d, J = 12.7 Hz, 1 H), 3.25 (dd, J = 4.6, 10.5 Hz, 1 H), 3.08 (br. s., 1 H), 2.43 (d, J = 5.9 Hz, 1 H), 2.29 - 2.16 (m, 1 H), 1 .84 (d, J = 10.8 Hz, 2 H), 1 .74 - 1 .61 (m, 1 H), 1 .42 (d, J = 6.8 Hz, 3 H)
Description 146: methyl 4-(1-((3fi)-2-(3-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-car xamido)cyclopropyl)benzoate (D146)
Figure imgf000125_0001
The title compound (D146) (67 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl methyl 4- (1 -((3f?)-2-azabicyclo[3.1 .0]hexane-3-carboxamido)cyclopropyl)benzoate (D104) (37 mg, 0.12 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.029 ml, 0.19 mmol). (Cs2C03:2 eq; reaction time: 6hrs; reaction temperature: RT.
MS: (ES/+) m/z: 459 [MH+] C25H25F3N203 requires 458.18
Description 147: methyl 4-(1-((1 fl,3fl,5fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (syn diastereoisomer) (D147)
Figure imgf000125_0002
To a solution of methyl 4-(1 -((1 R,3R,5R)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoate (D104) (1 .7g, 5.7 mmol) in MeCN (80 ml) Cs2C03 (2.8g, 8.5 mmol) and 4-(trifloromethyl)benzylbromide (1 .6g, 6.8 mmol) were added and the resulting mixture was stirred at RT for 4 hrs. Solvent was evaporated and the residue was loaded on a SNAP-Si cartridge (100g), eluted with a mixture DCM/AcOEt from 10/0 to DCM/AcOEt 9/1 . Collected fractions after solvent evaporation afforded the title compound (D147) (2.41 g).
MS: (ES/+) m/z: 459 [MH+] C25H25F3N203 requires 458.18
1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.35 (s, 1 H), 7.81 - 7.74 (m, 4 H), 7.73 - 7.68 (m, 2 H), 7.03 (d, J = 8.3 Hz, 2 H), 4.04 - 3.97 (m, 1 H), 3.86 - 3.75 (m, 4 H), 3.54 (dd, J = 2.2, 10.0 Hz, 1 H), 2.77 - 2.69 (m, 1 H), 2.25 - 2.12 (m, 1 H), 2.05 - 1 .95 (m, 1 H), 1 .49 - 1 .26 (m, 2 H), 1 .22 - 1 .04 (m, 3 H), 0.47 (q, J = 7.0 Hz, 1 H), 0.22 - 0.14 (m, 1 H). Description 148: methyl 4-(1-((1 S,3R,5S)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (anti diastereoisomer) (D148)
Figure imgf000126_0001
The title compound (D148) (100.8 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4-(1 - ((1 S,3f?,5S)-2-azabicyclo[3.1 .0]hexane-3-carboxamido)cyclopropyl)benzoate (diastereoisomer trans) (D105) (71 .9 mg) and 4-(trifluoromethyl)-benzylbromide (0.047 ml). (Na2C03: 3 eq; Reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 459.4 [MH+] C25H25F3N203 requires 458.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.96 (d, J = 8.3 Hz, 2 H), 7.85 - 7.72 (m, 1 H), 7.65 (d, J = 7.8 Hz, 2 H), 7.48 (d, J = 7.5 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H), 3.91 (s, 3 H), 3.82 - 3.71 (m, 1 H), 3.62 - 3.47 (m, 1 H), 2.98 - 2.85 (m, 1 H), 2.76 - 2.64 (m, 1 H), 2.59 - 2.46 (m, 1 H), 2.06 - 1 .91 (m, 1 H), 1 .53 - 1 .44 (m, 1 H), 1 .38 (br. s., 1 H), 1 .34 - 1 .13 (m, 3 H), 0.64 (br. s., 1 H), 0.32 - 0.19 (m, 1 H).
Description 149: methyl 4-((1 S)-1-((3fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D149)
Figure imgf000127_0001
The title compounds (D149) (14 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((1 S)-1 -((3f?)-2-azabicyclo[3.1 .0]hexane-3-carboxamido)ethyl)benzoate (D106) (1 1 mg) and and 4-(trifluoromethyl)-benzylbromide (0.007 ml). (Na2C03: 3 eq; Reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 447.4 [MH+] C24H25F3N203 requires 446.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (d, J = 8.1 Hz, 4 H), 7.80 - 7.70 (m, 1
H), 7.69 - 7.58 (m, 4 H), 7.56 - 7.47 (m, 4 H), 7.47 - 7.41 (m, 1 H), 7.37 (d, J = 8.0 Hz, 4 H), 5.13 - 5.04 (m, 1 H), 5.04 - 4.95 (m, 1 H), 3.98 (d, J = 13.3 Hz, 1 H), 3.93 (s, 6 H), 3.87 - 3.79 (m, 1 H), 3.75 (d, J = 13.3 Hz, 1 H), 3.54 (d, J = 7.2 Hz, 2 H), 2.96 - 2.87 (m, 1 H), 2.73 - 2.60 (m, 2 H), 2.49 - 2.41 (m, 1 H), 2.26 - 2.20 (m, 2 H), 1 .95 - 1 .84 (m, 1 H), 1 .49 (d, J = 4.0 Hz, 1 H), 1 .45 (d, J = 7.0 Hz, 3 H), 1 .40 (d, J = 6.9 Hz, 4 H), 0.68 - 0.58 (m, 1 H), 0.42 (d, J = 7.6 Hz, 1 H), 0.30 - 0.19 (m, 1 H), 0.05 - -0.05 (m, 1 H).
Description 150: methyl 4-((1 S)-1-((3H)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (single diastereoisomer) (D150)
Figure imgf000127_0002
The title compounds (D150) (72 mg) was prepared according to the general procedure for for substituted benzyl amines preparation starting from methyl 4- ((1 S)-1 -((3f?)-2-azabicyclo[3.1 .0]hexane-3-carboxamido)ethyl)benzoate (D107) (48 mg) and 4-(trifluoromethyl)-benzylbromide (0.031 ml) (Na2C03: 3 eq; Reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 447.4 [MH+] C24H25F3N203 requires 446.18 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.04 (d, J = 8.1 Hz, 2 H), 7.66 (d, J = 7.7 Hz, 2 H), 7.51 (d, J = 7.3 Hz, 2 H), 7.46 - 7.41 (m, 1 H), 7.37 (d, J = 8.1 Hz, 2 H), 5.14 - 5.03 (m, 1 H), 3.94 (s, 3 H), 3.88 - 3.78 (m, 1 H), 3.64 - 3.51 (m, 1 H), 2.97 - 2.88 (m, 1 H), 2.74 - 2.65 (m, 1 H), 2.51 - 2.37 (m, 1 H), 1 .97 - 1 .84 (m, 1 H), 1 .56 - 1 .51 (m, 1 H), 1 .45 (d, J = 6.9 Hz, 3 H), 0.68 - 0.59 (m, 1 H), 0.31 - 0.20 (m, 1 H).
Description 151 : (fi)-methyl 4-(1-(4,4-dimethyl-1-(4-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoate
(D151)
Figure imgf000128_0001
The title compound (D151) (100 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (F?)-methyl 4-(1 - (4,4-dimethylpyrrolidine-2-carboxamido)cyclopropyl)benzoate (D108) (70 mg) and 4-(trifluoromethyl)-benzylbromide (0.041 ml). (Cs2C03: 1 .5 eq; reaction time: 20 hrs, RT)
MS: (ES/+) m/z: 475.4 [MH+] C26H29F3N203 requires 474.21
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.95 (d, J = 8.1 Hz, 2 H), 7.88 (br. s., 1 H), 7.63 (d, J = 7.7 Hz, 2 H), 7.41 (d, J = 7.6 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 3.91 (s, 4 H), 3.57 (d, J = 13.5 Hz, 1 H), 3.37 (dd, J = 6.5, 9.7 Hz, 1 H), 2.84 (d, J = 9.2 Hz, 1 H), 2.29 (d, J = 9.2 Hz, 1 H), 2.23 - 2.12 (m, 1 H), 1 .73 (dd, J = 6.2, 13.1 Hz, 1 H), 1 .43 - 1 .35 (m, 1 H), 1 .34 - 1 .28 (m, 2 H), 1 .25 - 1 .19 (m, 1 H), 1 .1 1 (d, J = 19.4 Hz, 6 H)
Description 152a and 152b:
methyl 4-((1 S)-1-(1-(4-(trifluoromethyl)benzyl)azetidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D152a) and methyl 4-((1 S)-1 -(1 -(4-(trif luoromethyl)benzyl)azetidine-2- carboxamido)ethyl)benzoate (single diastereoisomer) (D152b)
Figure imgf000129_0001
To a solution of methyl 4-((1 S)-1 -(azetidine-2-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D109) (60 mg, 0.23 mmol) in dry MeCN (5 ml), Cs2C03 (223.6 mg, 0.68 mmol) and the 4-(Trifluoromethyl)benzylbromide (0.042 ml, 0.27 mmol) were added in sequence and the resulting mixture was stirred at RT for 18 hrs. The solid was filtered off, solvent was evaporated and the residue was purified by Biotage SNAP HP-Si column (10 g) eluting with a gradient of DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded 23 mg of diasteroisomeric mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/DEA 70% 30%/0.1 % v/v Flow rate 10ml/min; DAD: 235 nm). Collected fractions, after solvent evaporation afforded the title compound (D152a) (diastereoisomers mixture) (6 mg) and (D152b) (diastereoisomer 2) (7 mg)
(D152b) (single diastereoisomer): retentiom time: 15.8 min
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.03 (d, J = 8.1 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.41 (d, J = 7.8 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.20 (d, J = 7.9 Hz, 1 H), 5.04 - 4.92 (m, 1 H), 3.94 (s, 3 H), 3.82 - 3.65 (m, 3 H), 3.44 (t, J = 6.6 Hz, 1 H), 3.1 1 (d, J = 8.0 Hz, 1 H), 2.45 (d, J = 8.6 Hz, 1 H), 2.14 - 1 .99 (m, 1 H), 1 .19 (d, J = 6.8 Hz, 3 H).
Description 153: methyl 4-((1 S)-1-(3-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)ethyl)benzoate (syn diastereoisomers mixture) (D
Figure imgf000129_0002
The title compound (D153) (85 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2-carboxylic acid (D1 10) (55 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (43.3 mg). (EDC.HCI: 1 .05 eq; reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 447.3 [MH+] C24H25F3N203 requires 446.18
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.04 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 7.7 Hz, 2 H), 7.49 (d, J = 7.8 Hz, 2 H), 7.44 - 7.31 (m, 6 H), 7.27 - 7.05 (m, 4 H), 5.30 - 5.09 (m, 2 H), 3.93 (d, J = 6.0 Hz, 7 H), 3.77 (d, J = 13.8 Hz, 1 H), 3.55 - 3.39 (m, 3 H), 3.34 (d, J = 13.6 Hz, 1 H), 3.05 (dd, J = 9.5, 13.1 Hz, 2 H), 2.56 (t, J = 9.4 Hz, 2 H), 1 .86 (d, J = 17.4 Hz, 2 H), 1 .57 (d, J = 6.8 Hz, 3 H), 1 .53 (d, J = 3.1 Hz, 2 H), 1 .44 (d, J = 6.8 Hz, 3 H), 0.76 - 0.59 (m, 2 H), 0.58 - 0.40 (m, 2 H). Descriptions 154a and 154b:
methyl 4-(1 -(3-(4-(trif luoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2- carboxamido)cyclopropyl)benzoate (enantiomer 1) (D154a) and
methyl 4-(1 -(3-(4-(trif luoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D154b)
Figure imgf000130_0001
To a solution of 3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2- carboxylic acid (D1 10) (55 mg, 0.19 mmol) in DCM (5 ml), HOBT.H20 (39 mg, 0.19 mmol), EDC HCI (35 mg, 0.20 mmol) were added and the mixture stirred 30 min to RT. Methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (43.3 mg, 0.19 mmol) were added and the resulting mixture stirred 18 hrs at RT. The mixture was then diluted with DCM, and washed with sat. sol. NaHC03 (2x10ml) then water (10 ml). Collected organic phases after drying over Na2S04 and solvent evaporation afforded a residue which was purified by SPE-Si cartridge (5g9 eluting with a mixture DCM/EtOAc 80/20. Collected fractions after solvent evaporation afforded the title compound 50 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/DEA 60% 40%/0.1 % v/v Flow rate 10ml/min; DAD: 249 nm). Collected fractions after solvent evaporation, afforded the two enantiomers (D154a) (10 mg) and (D154b) (15 mg).
(D154a) (enantiomer 1 with syn relative stereochemistry): retention time: 10.1 min
MS: (ES/+) m/z: 459 [MKT] C25H25F3N203 requires 458.18
1 H NMR (400MHz ,CHCI3-d) δ (ppm): 7.96 (d, J = 8.3 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.48 - 7.32 (m, 2 H), 7.26 (d, J = 8.8 Hz, 2 H), 3.91 (s, 4 H), 3.55 - 3.35 (m, 2 H), 3.19 - 3.00 (m, 1 H), 2.69 - 2.47 (m, 1 H), 2.03 - 1 .83 (m, 1 H), 1 .49 - 1 .37 (m, 1 H), 1 .36 - 1 .24 (m, 2 H), 1 .21 - 1 .14 (m, 1 H), 0.88 - 0.72 (m, 1 H), 0.68 - 0.50 (m, 1 H)
(D154b) (enantiomer 2 with syn relative stereochemistry): retention time: 18.1 min
MS: (ES/+) m/z: 459 [MH+] C25H25F3N203 requires 458.18
Description 155: methyl 4-((1 S)-1-(2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[2.2.2]octane-3-carboxamido)ethyl)benzoate (D155)
Figure imgf000131_0001
The title compound (D155) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D1 1 1 ) (22.5 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (17 mg). (Reaction time: 2 hrs; 60°C)
MS: (ES/+) m/z: 475.1 [MH+] C26H29F3N203 requires 474.21
Description 156: methyl 4-(1-(2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[2.2.2]octane-3-carboxamido)cyclopropyl)benzoate (D156)
Figure imgf000132_0001
The title compound (D156) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D1 1 1 ) (22.5 mg) and methyl 4-(1 -aminocyclopropyl)benzoate hydrochloride (18 mg). (Reaction time: 2 hrs; 60 °C)
MS: (ES/+) m/z: 487.4 [MH+] C27H29F3N203 requires 486.21
Description 157: (fi)-methyl 4-(1-(2-methyl-1-(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D157)
Figure imgf000132_0002
The title compound (D157) (5 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (F?)-2-methyl-1 - (4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D1 12) (20 mg) and methyl 4- (l -aminocyclopropyl)benzoate hydrochloride (17.2 mg).
MS: (ES/+) m/z: 475.4 [MH+] C26H29F3N203 requires 474.21
Description 158: methyl 4-((S)-1-((fi)-2-methyl-1-(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D158)
Figure imgf000132_0003
The title compound (D158) (10 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (F?)-2-methyl-1 - (4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D1 12) (20 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (16.32 mg).
MS: (ES/+) m/z: 463.4 [MH+] C25H29F3N203 requires 462.21
Description 159: (fi)-methyl 4-(1-(2-methyl-1-(4-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoate
(D159)
Figure imgf000133_0001
The title compound (D159) (13 mg) was prepared according to the general procedure for amides preparation (Method A) starting from lithium (F?)-2-methyl-1 - (4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D1 13) (21 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (16.3 mg).
MS: (ES/+) m/z: 461 .4 [MH+] C25H27F3N203 requires 460.20
Description 160: methyl 4-((S)-1-((2fl,4S)-4-fluoro-1-(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D160)
Figure imgf000133_0002
The title compound (D160) (67.3 mg) was prepared according to the general procedure for amides preparation (Method A) starting from lithium (2f?,4S)-4- fluoro-1 -(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D1 14) (60 mg) and (S)-methyl 4-(1 -aminoethyl)benzoate hydrochloride (43.5 mg). (Reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 475.2 [MH+Na+] C23H24F4N203 requires 452,17 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.01 (d, J = 8.1 Hz, 2 H), 7.75 - 7.46 (m, 5 H), 7.36 (d, J = 8.1 Hz, 2 H), 5.32 - 5.00 (m, 2 H), 4.01 (d, J = 13.2 Hz, 1 H), 3.92 (s, 3 H), 3.70 (d, J = 13.2 Hz, 1 H), 3.54 - 3.33 (m, 2 H), 2.73 - 2.41 (m, 2 H), 2.31 - 2.1 1 (m, 1 H), 1 .42 (d, J = 6.8 Hz, 3 H)
Description 161 : lithium 4-((S)-1-((2fl,4S)-4-fluoro-1-(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D161 )
Figure imgf000134_0001
The title compound (D161) (50 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1 -((2f?,4S)-
4-fluoro-1 -(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate
(D160) (67.3 mg). (LiOH H20: 4 eq; reaction time: 18 hrs).
MS: (ES/+) m/z: 439.2 [M-Li+2H+] C22H21 F4UN203 requires 444.16
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.90 (d, J = 7.9 Hz, 2 H), 7.71 (s, 4 H), 7.27 (d, J = 8.1 Hz, 2 H), 5.28 - 5.07 (m, 1 H), 4.95 - 4.88 (1 H under solvent), 4.00
- 3.90 (m, 1 H), 3.83 (s, 1 H), 3.43 - 3.35 (m, 2 H), 2.83 - 2.50 (m, 2 H), 2.16 - 1 .98
(m, 1 H), 1 .34 (d, J = 7.0 Hz, 3 H)
Description 162: 4-((S)-1-((2fl,4S)-4-fluoropyrrolidine-2- carboxamido)ethyl)benzoic acid (D162)
Figure imgf000134_0002
A suspension of lithium 4-((S)-1 -((2f?,4S)-4-fluoro-1 -(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D161 ) (47 mg) and 10%w Pd/C (5 mg) in MeOH (5 ml) and 1 M HCI (0.5 ml) was stirred under a constant current of H2 for 3 hrs. Catalyst was filtered off and solvent evaporated to afford a residue which was triturated with cHex and filtered to afford the title compound (D162) (22 mg).
MS: (ES/+) m/z: 281 .2 [MH+] C14H17FN4O3 requires 280.12 1 H NMR (400 MHz, MeOH-d4) δ (ppm): 8.99 - 8.87 (m, 1 H), 8.09 - 7.98 (m, 2 H), 7.52 - 7.46 (m, 2 H), 5.60 - 5.36 (m, 1 H), 5.20 - 5.06 (m, 1 H), 4.55 - 4.44 (m, 1 H), 3.86 - 3.72 (m, 1 H), 3.66 - 3.47 (m, 1 H), 2.94 - 2.72 (m, 1 H), 2.65 - 2.45 (m, 1 H), 1 .54 (d, J = 7.0 Hz, 3 H).
Description 163: 4-(trifluoromethyl)benzyl 4-((S)-1-((2fl,4S)-4-fluoro-1-(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D163)
Figure imgf000135_0001
The title compound (D163) (31 mg) was prepared according to the general procedure for substituted benzylamine preparation starting from 4-((S)-1 -((2f?,4S)- 4-fluoropyrrolidine-2-carboxamido)ethyl)benzoic acid (D162) (22 mg). (Na2C03: 4 eq; reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 597.4 [MH+] C30H27F7N2O3 requires 596.54
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.05 (d, J = 8.1 Hz, 2 H), 7.72 - 7.52 (m, 7 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 5.42 (s, 2 H), 5.27 - 4.99 (m, 2 H), 4.01 (d, J = 13.3 Hz, 1 H), 3.71 (d, J = 13.3 Hz, 1 H), 3.47 - 3.32 (m, 2 H), 2.72 - 2.45 (m, 2 H), 2.29 - 2.09 (m, 1 H), 1 .40 (d, J = 7.0 Hz, 3 H).
Description 164: methyl 4-((S)-1-((fi)-4,4-difluoro-1-(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D164)
Figure imgf000135_0002
The title compound (D164) (37 mg) was prepared according to the general procedure for amides preparation (Method A) starting from lithium (f?)-4,4-difluoro- 1 -(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D1 15) (51 mg) and (S)- methyl 4-(1 -aminoethyl)benzoate hydrochloride (35 mg). (Reaction time: 48 hrs;
RT). MS: (ES/+) m/z: 471 .2 [MH+] C23H23F5N203 requires 470,16
Description 165: methyl 4-((S)-1-((fi)-4,4-difluoropyrrolidine-2- carboxamido)ethyl)benzoate
Figure imgf000136_0001
A suspension of methyl 4-((S)-1 -((fl)-4,4-difluoro-1 -(3-
(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D164) (33 mg) and 10%w Pd/C (5 mg) in MeOH (5 ml) and 1 M HCI (0.5 ml) was stirred under a constant current of H2 for 3 hrs. Catalyst was filtered off and solvent evaporated to afford a residue which was triturated with cHex and filtered to afford the title compound (D165) (30 mg).
MS: (ES/+) m/z: 313.2 [MH+] C23H23F5N2O3 requires 312.13
Description 166: methyl 4-((S)-1-((fi)-4,4-difluoro-1-(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D166)
Figure imgf000136_0002
The title compound (D166) (16.5 mg) was prepared according to the general procedure for substituted benzylamine preparation starting from methyl 4-((S)-1 - ((f?)-4,4-difluoropyrrolidine-2-carboxamido)ethyl)benzoate (D165) (30 mg) and 4- (Trifluoromethyl) benzyl bromide (33 mg). (Na2CO3: 2.5 eq; reaction time: 18 hrs; 68 °C)
MS: (ES/+) m/z: 471 [MH+] C23H23F5N2O3 requires 470.16
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.04 (d, J = 7.8 Hz, 2 H), 7.67 (d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 3 H), 5.10 (t, J = 7.1 Hz, 1 H), 4.01 (d, J = 13.7 Hz, 1 H), 3.94 (s, 3 H), 3.68 (d, J = 13.2 Hz, 1 H), 3.61 - 3.54 (m, 1 H), 3.36 (d, J = 6.8 Hz, 1 H), 2.87 (d, J = 17.1 Hz, 2 H), 2.29 (br. s., 1 H), 1 .45 (d, J = 6.8 Hz, 3 H) EXAMPLES
Example 1 : lithium 4-((1 S)-1-(1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate (diastereoisomers mixture) (E1)
Figure imgf000137_0001
The title compound (E1) (70 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((1 S)-1 -(1 -(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D1 16) (75 mg). (LiOH: 1 .2 eq; reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 435 [M-Li+2H+] C23H24F3UN203 requires 440.19
Chiral HPLC: [Phenomenex Lux Cellulose-1 ; Mobile phase A: 70% n-hexane (+0.5% TFA), B: 30% EtOH; DAD: 230 nm]: Peak 1 retention time: 7.51 min; peak 2 retention time: 38.92 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.20 (br. s., 2 H) 7.81 (d, 2 H) 7.75 (d, 2 H) 7.66 (d, 4 H) 7.50 - 7.61 (m, 4 H) 7.10 - 7.31 (m, 4 H) 4.98 (br. s., 2 H) 3.73 (t, 2 H) 3.20 (d, 2 H) 2.83 (d, 2 H) 2.74 (d, 2 H) 1 .93 (br. s., 2 H) 1 .56 - 1 .82 (m, 6 H) 1 .46 (d, 3 H) 1 .41 (br. s., 1 H) 1 .35 (dd, 6 H) 1 .25 (br. s., 2 H).
Example 2: lithium 4-((S)-1-((fi)-1-(4-fluorobenzyl)piperidine-2- carboxamido)ethyl)benzoate (
Figure imgf000137_0002
The title compound (E2) (8 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1 -((f?)-1 -(4- fluorobenzyl)piperidine-2-carboxamido)ethyl)benzoate (D1 17) (10 mg).
(LiOH: 1 .5 eq; Reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 385.3 [M-Li+2H+] C22H24FUN203 requires 390.19 Chiral HPLC: [DAICEL OD-H; Mobile phase A: 60% n-hexane (+0.5% TFA), B: 40% EtOH; DAD: 235 nm]: Peak retention time: 5.68 min.
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.94 (d, J = 7.9 Hz, 2 H), 7.45 - 7.27 (m, 4 H), 7.03 (t, J = 8.5 Hz, 2 H), 5.1 1 (d, J = 6.9 Hz, 1 H), 3.75 (d, J = 13.1 Hz, 1 H), 3.17 (d, J = 13.2 Hz, 1 H), 2.81 (br. s., 2 H), 2.05 - 1 .94 (m, 1 H), 1 .91 - 1 .64 (m, 3 H), 1 .58 (br. s., 2 H), 1 .48 (d, J = 6.9 Hz, 3 H), 1 .40 - 1 .25 (m, 1 H)
Example 3: lithium 4-((S)-1-((R)-1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoate (
Figure imgf000138_0001
The title compound (E3) (21 .3 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1 -((f?)-1 -(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D1 18) (24 mg). (LiOH: 1 .5 eq; Reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 435.2 [M-Li+2H+] C23H24F3UN2O3 requires 440.19
Chiral HPLC [DAICEL OD-H; Mobile phase A: 60% n-hexane (+0.5% TFA), B: 40% EtOH; DAD: 235 nm]: Peak retention time: 6.09 min.
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.93 (d, J = 7.9 Hz, 2 H), 7.65 - 7.57 (m, 2 H), 7.57 - 7.49 (m, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 5.16 - 5.04 (m, 1 H), 3.88 - 3.78 (m, 1 H), 3.27 (s, 1 H), 2.86 (d, J = 10.3 Hz, 2 H), 2.09 - 1 .95 (m, 1 H), 1 .94 - 1 .65 (m, 3 H), 1 .59 (br. s., 2 H), 1 .46 (d, J = 6.9 Hz, 3 H), 1 .41 - 1 .26 (m, 1 H).
Example 4: lithium (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (E4)
Figure imgf000138_0002
The title compound (E4) (50 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from (F?)-methyl 4-(1 -(1 -(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D1 19) (74 mg). (LiOH: 3 eq; Reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 447.2 [M-Li+2H+] C24H24F3UN203 requires 452.19
Chiral HPLC: [DAICEL OD-H; Mobile phase A: 80% n-hexane (+0.2% TFA), B: 20% EtOH; DAD: 243 nm]: Peak retention time: 22.92 min.
Example 5: lithium (R)-4-(1-(1-(4-chlorobenzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (E5)
Figure imgf000139_0001
The title compound (E5) (31 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from (F?)-methyl 4-(1 -(1 -(4- chlorobenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D120) (45 mg). (LiOH: 3 eq; Reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 413 [M-Li+2H+] C23H24CIUN203 requires 418.16
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.85 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 4.9 Hz, 4 H), 7.23 (d, J = 8.1 Hz, 2 H), 4.90 - 4.82 (1 H under solvent peak), 3.79 - 3.65 (m, 1 H), 3.21 - 3.07 (m, 1 H), 2.93 - 2.75 (m, 2 H), 2.06 - 1 .86 (m, 2 H), 1 .86 - 1 .68 (m, 2 H), 1 .66 - 1 .50 (m, 2 H), 1 .41 - 1 .15 (m, 4 H).
Example 6: lithium (R)-4-(1-(1-(4-cyanobenzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (E6)
Figure imgf000139_0002
The title compound (E6) (34 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from (F?)-methyl 4-(1 -(1 -(4- cyanobenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D121 ) (35 mg). (LiOH: 3 eq; Reaction time: 3 hrs; RT)
MS: (ES/+) m/z: 404 [M-Li+2H+] C24H24UN303 requires 409.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.90 - 7.79 (m, 2 H), 7.74 - 7.65 (m, 2 H), 7.62 - 7.54 (m, 2 H), 7.28 - 7.17 (m, 2 H), 4.90 - 4.82 (1 H under solvent peak), 3.84 - 3.72 (m, 1 H), 3.28 - 3.19 (m, 1 H), 2.92 - 2.77 (m, 2 H), 2.07 - 1 .89 (m, 2 H), 1 .87 - 1 .68 (m, 2 H), 1 .65 - 1 .53 (m, 2 H), 1 .43 - 1 .10 (m, 4 H).
Example 7: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E7)
Figure imgf000140_0001
Procedure A:
The title compound (E7) (54 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-(1 -(6-(4- (trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (D122b) (100mg). (LiOH: 4 eq; Reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 18.97 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.0 Hz, 2 H), 7.74 - 7.35 (m, 5 H), 7.26 (br. s., 1 H), 3.86 (d, J = 14.1 Hz, 1 H), 3.38 (d, J = 14.1 Hz, 1 H), 3.08 (d, J = 7.8 Hz, 1 H), 2.91 (d, J = 9.8 Hz, 1 H), 2.27 (br. s., 1 H), 2.05 (t, J = 1 1 .2 Hz, 1 H), 1 .84 (br. s., 1 H), 1 .50 - 1 .24 (m, 4 H), 1 .14 (br. s., 1 H), 0.98 (d, J = 12.7 Hz, 1 H), 0.53 - 0.23 (m, 4 H)
Procedure B:
methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (D123)) (17.7 g, 36.38 mmol) was partitioned between dioxane (485 ml) and water (242 ml) prior addition of LiOH H2O (6.1 g, 145.5 mmol). The mixture was stirred at RT for 10 hrs. Water (200 ml) was added followed by addition of acetic acid (5.27 ml). Dioxane was evaporated off and acetic acid was added until the pH of the aqueous solution reached the value of ~ 4. The white solid was filtered from the reaction and dried under vacuum overnight then 24 hrs under vacuum at 40 °C affording the title compound (E7) (16.7g).
MS: (ES/+) m/z: 473.3 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 19.07 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.92 - 12.51 (m, 1 H), 8.83 - 8.62 (m, 1 H), 7.85 - 7.75 (m, 2 H), 7.74 - 7.57 (m, 4 H), 7.26 - 7.14 (m, 2 H), 3.87 - 3.72 (m, 1 H), 3.27 - 3.20 (m, 1 H), 2.99 - 2.86 (m, 1 H), 2.79 - 2.69 (m, 1 H), 2.19 - 1 .98 (m, 2 H), 1 .86 - 1 .70 (m, 1 H), 1 .32 - 1 .07 (m, 5 H), 0.94 - 0.82 (m, 1 H), 0.46 - 0.17 (m, 4 H). Example 8: 4-(1-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-6- azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E8)
Figure imgf000141_0001
The title compound (E8) (35 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -(6-((6- (trifluoromethyl)pyridin-3-yl)methyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl) benzoate (D124) (47 mg). (LiOH: 4 eq; Reaction time: 5 hrs; RT)
MS: (ES/+) m/z: 474.2 [MKT] C25H26F3N303 requires 473.19
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 8.74 (s, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 2 H), 3.88 (d, J = 14.2 Hz, 1 H), 3.39 (d, J = 14.2 Hz, 2 H), 3.06 (dd, J = 2.7, 10.5 Hz, 1 H), 2.84 (d, J = 1 1 .2 Hz, 1 H), 2.37 - 2.12 (m, 2 H), 2.04 - 1 .88 (m, 1 H), 1 .45 - 1 .14 (m, 6 H), 0.94 (d, J = 1 1 .2 Hz, 1 H), 0.51 - 0.28 (m, 4 H). Example 9: 4-(1-(6-(3-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benz ic acid (single unknown enantiomer) (E9)
Figure imgf000142_0001
The title compound (E9) (39 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -(6-(3- (trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D125) (60.7 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 473.2 [MH+] C26H27F3N2O3 requires 472.20
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.90 - 12.63 (m, 1 H), 8.71 - 8.64 (m, 1 H), 7.81 - 7.74 (m, 2 H), 7.72 - 7.66 (m, 2 H), 7.64 - 7.55 (m, 2 H), 7.22 - 7.1 1 (m, 2 H), 3.77 - 3.66 (m, 1 H), 3.60 - 3.47 (m, 1 H), 3.22 - 3.1 1 (m, 1 H), 3.03 - 2.95 (m, 1 H), 2.39 - 2.29 (m, 1 H), 2.25 - 2.1 1 (m, 1 H), 1 .76 - 1 .64 (m, 1 H), 1 .31 - 1 .19 (m, 3 H), 1 .19 - 1 .07 (m, 3 H), 1 .07 - 0.91 (m, 2 H), 0.73 - 0.59 (m, 1 H), 0.26 - 0.17 (m, 1 H).
Example 10: 4-((1 S)-1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoic acid (single unknown diastereoisomer) (E10)
Figure imgf000142_0002
The title compound (E10) (6.4 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from starting from 4-
(trifluoromethyl)benzyl 4-((1 S)-1 -(6-(4-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D129) (15 mg). (LiOH H2O: 4 eq; Reaction time: 18 hrs)
MS: (ES/+) m/z: 461 [MH+] C25H27F3N2O3 requires 460.20 1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.98 (d, J = 7.8 Hz, 2 H), 7.71 - 7.51 (m, 4 H), 7.44 (d, J = 7.6 Hz, 2 H), 5.21 - 5.02 (m, 1 H), 4.00 - 3.79 (m, 1 H), 3.1 1 - 2.96 (m, 1 H), 2.95 - 2.79 (m, 1 H), 2.34 - 2.06 (m, 2 H), 2.04 - 1 .87 (m, 1 H), 1 .47 (d, J = 6.9 Hz, 3 H), 1 .38 - 1 .23 (m, 1 H), 1 .23 - 1 .08 (m, 1 H), 1 .00 - 0.81 (m, 2 H), 0.48 - 0.24 (m, 4 H)
Example 11 : 4-((1 S)-1 -(5-methyl-6-(4-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (diastereoisomers mixture) (E11)
Figure imgf000143_0001
The title compound (E11) (4.5 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-((1 S)-1 -(5- methyl-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)benzoate (D130) (19 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 475.4 [MH+] C26H29F3N2O3 requires 474.21
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.96 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.68 (s, 2 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.47 - 7.31 (m, 2 H), 7.15 (d, J = 7.8 Hz, 1 H), 5.1 1 - 4.94 (m, 1 H), 3.51 (t, J = 13.4 Hz, 1 H), 2.73 (dd, J = 12.0, 19.8 Hz, 1 H), 2.65 - 2.46 (m, 1 H), 2.37 - 2.18 (m, 1 H), 2.05 (t, J = 12.0 Hz, 1 H), 1 .58 - 1 .24 (m, 7 H), 1 .18 - 1 .00 (m, 1 H), 0.94 (d, J = 1 1 .2 Hz, 1 H), 0.49 (br. s., 2 H), 0.27 (d, J = 6.8 Hz, 2 H).
Example 12: 4-(1 -(4,4-dimethyl-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E12)
Figure imgf000143_0002
The title compound (E12) (88.4 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1 -(4,4-dimethyl- 1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate
(enantiomer 2) (D131 b) (141 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 475.4 [MH+] C26H29F3N203 requires 474.21
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 70% n-heptane (+0.1 % AcOH), B: 30% EtOH; DAD: 245 nm]: Peak retention time: 1 1 .4 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 7.8 Hz, 2 H), 7.41 (d, J = 7.4 Hz, 3 H), 7.27 (br. s., 2 H), 3.82 (d, J = 14.0 Hz, 1 H), 3.29 (d, J = 13.5 Hz, 1 H), 3.10 (d, J = 7.7 Hz, 1 H), 2.73 (d, J = 10.0 Hz, 1 H), 2.23 (br. s., 1 H), 1 .81 (d, J = 13.1 Hz, 1 H), 1 .49 (t, J = 12.1 Hz, 2 H), 1 .42 - 1 .27 (m, 4 H), 1 .13 (br. s., 1 H), 1 .05 - 0.92 (m, 6 H)
Example 13: 4-((1 S)-1-(4,4-dimethyl-1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid (single unknown diastereoisomer) (E13)
Figure imgf000144_0001
The title compound (E13) (54.6 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -(4,4- dimethyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (diastereoisomer 2) (D132b) (69 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs) MS: (ES/+) m/z: 463.4 [MH+] C25H29F3N2O3 requires 462.21
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 70% n-heptane (+0.1 % DEA), B: 30% EtOH; DAD: 235 nm]: Peak retention time: 10.4 min. Example 14: 4-((1 S)-1-((2H)-4-fluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid (diastereoisomers mixture) (E14)
Figure imgf000145_0001
The title compound (E14) (42 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((1 S)-1 -((2f?)-4- fluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate
(D133) (62 mg). (LiOH H20: 4 eq; reaction time: 5 hrs)
MS: (ES/+) m/z: 471 .3 [MH+] C23H24F4N203 requires 452.17
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.99 (d, J = 8.1 Hz, 2 H), 7.66 - 7.36 (m, 6 H), 5.18 - 5.04 (m, 1 H), 3.88 - 3.76 (m, 1 H), 2.80 - 2.67 (m, 1 H), 2.55 - 2.35 (m, 1 H), 2.19 - 1 .75 (m, 4 H), 1 .49 (d, J = 7.0 Hz, 3 H), 1 .14 (d, J = 6.1 Hz, 3 H).
Example 15: 4-(1 -((2fi)-4-f luoro-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid (diastereoisomers mixture) (E15)
Figure imgf000145_0002
The title compound (E15) (15.8 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -((2f?)-4- fluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate
(D134) (25 mg). (LiOH H2O: 4 eq; reaction time: 5 hrs)
MS: (ES/+) m/z: 471 .3 [MH+] C23H24F4N2O3 requires 452.17
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.91 (d, J = 8.1 Hz, 2 H), 7.69 - 7.53 (m, 4 H), 7.31 (d, J = 8.1 Hz, 2 H), 5.06 - 4.91 (m, 1 H), 3.84 (d, J = 13.7 Hz, 1 H), 3.24
(br. s., 1 H), 2.72 (d, J = 1 1 .8 Hz, 1 H), 2.42 (br. s., 1 H), 2.22 - 1 .77 (m, 3 H), 1 .47
- 1 .16 (m, 6 H).
Example 16: 4-((S)-1-((/?)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine- 2-carboxamido)ethyl)benzoic acid (E16)
Figure imgf000146_0001
The title compound (E16) (15 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((S)-1 -((F?)-4,4- difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D135) (20 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 471 .3 [MH+] C23H23F5N203 requires 470.16
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.63 - 8.54 (m, 1 H), 7.87 - 7.77 (m, 2 H), 7.74 - 7.63 (m, 2 H), 7.60 - 7.51 (m, 2 H), 7.40 - 7.27 (m, 2 H), 5.06 - 4.92 (m, 1 H), 3.76 (d, J = 13.8 Hz, 1 H), 3.37 - 3.32 (1 H under residual solvent), 3.23 - 3.10 (m, J = 7.1 Hz, 1 H), 2.85 - 2.74 (m, J = 1 1 .7 Hz, 1 H), 2.32 - 2.04 (m, 3 H), 2.05 - 1 .83 (m, 2 H), 1 .37 (d, J = 6.8 Hz, 3 H).
Example 17: (H)-4-(1 -(4,4-dif luoro-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid (E17)
Figure imgf000146_0002
Procedure A: (F?)-methyl 4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (D136) (30 mg, 60.4 mmol) was partitioned between dioxane (2 ml) and water (2 ml) prior addition of LiOH H2O (10 mg, 242 mmol). The mixture was stirred at RT for 18 hrs then dioxane was evaporated off. The aqueous solution was loaded onto a reverse phase Porapak cartridge (5g) eluting with H2O (with 0.1 % CH3CO2H) then with MeCN (with 0.1 % CH3CO2H). Collected fractions after solvent evaporation afforded a 19 mg of racemic mixture which was submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/TFA 60%/40% 0.1 % v/v Flow rate 10ml/min; DAD: 245 nm). Collected fractions, after solvent evaporation afforded the title compound (E17) (1 1 mg).
MS: (ES/+) m/z: 483.3 [MKT] C24H23F5N203 requires 482.16
Chiral HPLC [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.2% TFA), B: 40% IPA; DAD: 245 nm]: Peak retention time: 15.6 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 13.00 - 12.49 (m, 1 H), 9.18 - 8.93 (m, 1 H), 7.81 (d, J = 8.1 Hz, 2 H), 7.72 (br. s., 2 H), 7.64 (br. s., 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 3.99 - 3.84 (m, 1 H), 3.38 - 3.23 (m, 2 H), 2.97 - 2.80 (m, 1 H), 2.44 - 2.12 (m, 3 H), 2.10 - 1 .89 (m, 2 H), 1 .38 - 1 .13 (m, 4 H)
Procedure B:
To a solution of methyl 4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 2) (D137b) (127 mg, 0.25 mmol) in dioxane (3 ml) and water (3 ml) LiOH H20 (43 mg, 1 .02 mmol) was added and the mixture was left stirring at RT for 16 hrs. Dioxane was evaporated off then acetic acid was added to the aqueous layer until the solution reached the value of pH=4. The solid was filtered off and dissolved in DMF/DMSO.The mixture was loaded on SNAP-C18 gold cartridge (15g) and eluted with a mixture H2O containing AcOH (0.1 %)/CH3CN containing AcOH (0.1 %) from 10/90 to 0/100. Collected fractions were evaporated in vacuo to afford a residue which was taken up in a mixture sat. sol. NH4CI/EtOAc (15/15ml) and extracted with AcOEt (2x20ml). The combined organic layers were evaporated in vacuo to afford the title compound (E17) (85 mg).
MS: (ES/+) m/z: 483 [MH+] C24H23F5N2O3 requires 482.16
Chiral HPLC [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.2% TFA), B: 40% IPA; DAD: 245 nm]: Peak retention time: 15.6 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.74 (br. s., 1 H), 8.96 (s, 1 H), 7.82 - 7.75 (m, J = 8.8 Hz, 2 H), 7.74 - 7.66 (m, J = 7.8 Hz, 2 H), 7.66 - 7.58 (m, J = 7.8 Hz, 2 H), 7.26 - 7.15 (m, J = 8.8 Hz, 2 H), 3.82 (d, J = 14.2 Hz, 1 H), 3.39 (d, J = 14.2 Hz, 1 H), 3.20 - 3.09 (m, 1 H), 2.82 (m, 1 H), 2.36 - 2.15 (m, 3 H), 1 .96 (m, 2 H), 1 .30 - 1 .1 1 (m, 4 H). Example 18: 4-(1 -(4,4-dif luoro-1 -(4-(trif luoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid (single enantiomer) (E18)
Figure imgf000148_0001
To a solution of methyl 4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 1 ) (D1 37a) (140 mg, 0.28 mmol) in dioxane (3 ml) and water (3 ml) LiOH H2O (47 mg, 1 .12 mmol) was added and the mixture was left stirring at RT for 16 hrs. Dioxane was evaporated off then acetic acid was added to the aqueous layer until the solution reached the value of pH=4. The solid was filtered off and dried under vacuum to afford the title compound (E18) (90 mg)
MS: (ES/+) m/z: 482.8 [MH+] C24H23F5N2O3 requires 482.16
Chiral HPLC [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.2% TFA), B:
40% IPA; DAD: 245 nm]: Peak retention time: 9.1 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (s, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.74 - 7.67 (m, J = 8.3 Hz, 2 H), 7.67 - 7.58 (m, J = 7.8 Hz, 2 H), 7.17 (d, J = 7.8 Hz, 2 H), 3.82 (d, J = 13.7 Hz, 1 H), 3.38 (d, J = 14.2 Hz, 1 H), 3.16 (dd, J = 5.4, 8.8 Hz, 1 H), 2.82 (d, J = 12.2 Hz, 1 H), 2.36 - 2.14 (m, 3 H), 2.03 - 1 .88 (m, 2 H), 1 .30 - 1 .21 (m, 2 H), 1 .21 - 1 .07 (m, 2 H) Example 19: 4-(1 -(4,4-dif luoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benz ic acid (single enantiomer) (E19)
Figure imgf000148_0002
To a solution of methyl 4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (enantiomer 1 ) (D138a) (35 mg, 0.07 mmol) in dioxane (3 ml) and water (1 ml) LiOH H2O (12 mg, 0.28 mmol) was added and the mixture was left stirring at RT for 4 hrs. Dioxane was evaporated off then HCI 2M was added to the aqueous layer until the solution reached the value of pH=4. The acqueous phase was extracted with AcOEt (40 ml), the organics washed with water (10 ml), dried over Na2S04 and evaporated to the title compound (E19) (34 mg)
MS: (ES/+) m/z: 483 [MH+] C24H23F5N203 requires 482.16
Chiral HPLC [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.2% TFA), B: 40% IPA; DAD: 245 nm]: Peak retention time: 9.0 min.
1 H NMR (400MHz ,CDCI3) δ (ppm): 7.98 (d, J = 8.8 Hz, 2 H), 7.60 (s, 1 H), 7.57 - 7.44 (m, 3 H), 7.36 (s, 1 H), 7.31 (s, 1 H), 3.83 (s, 1 H), 3.43 (s, 1 H), 3.32 - 3.24 (m, 1 H), 3.04 - 2.95 (m, 1 H), 2.52 (t, J = 10.3 Hz, 1 H), 2.45 - 2.33 (m, 1 H), 2.31 - 2.14 (m, 1 H), 2.06 - 1 .90 (m, 2 H), 1 .41 - 1 .35 (m, 2 H), 1 .33 - 1 .21 (m, 3 H)
Example 20: 4-(1-(4,4-difluoro-1-(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benz ic acid (single enantiomer) (E20)
Figure imgf000149_0001
The title compound (E20) (37 mg) was prepared following the same procedure reported in Example 19 starting from methyl 4-(1 -(4,4-difluoro-1 -(3- (trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate
(enantiomer 2) (D138b) (45 mg).
MS: (ES/+) m/z: 483 [MH+] C24H23F5N203 requires 482.16
Chiral HPLC [DAICEL AD-H; Mobile phase A: 70% n-heptane (+0.2% TFA), B: 30% IPA; DAD: 245 nm]: Peak retention time: 10.2 min.
1 H NMR (400MHz ,CDCI3) δ (ppm): 7.98 (d, J = 8.3 Hz, 2 H), 7.63 - 7.58 (m, 1 H), 7.56 - 7.44 (m, 3 H), 7.36 (s, 1 H), 7.31 (s, 1 H), 3.88 - 3.80 (m, 1 H), 3.45 - 3.37 (m, 1 H), 3.31 - 3.22 (m, 1 H), 3.04 - 2.93 (m, 1 H), 2.57 - 2.47 (m, 1 H), 2.44 - 2.32 (m, 1 H), 2.31 - 2.17 (m, 1 H), 2.05 - 1 .90 (m, 2 H), 1 .42 - 1 .34 (m, 2 H), 1 .33 - 1 .20 (m, 4 H) Example 21 : 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoic acid (racemic mixture) (E21)
Figure imgf000150_0001
The title compound (E21) (19 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -(3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (D139) (25 mg). (LiOH H20: 4 eq; reaction time: 10 hrs)
MS: (ES/+) m/z: 457.1 [MhT] C25H25F3N203 requires 458.18
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.74 (br. s., 1 H), 8.63 (s, 1 H), 7.78 (dd, J = 1 .5, 8.3 Hz, 2 H), 7.68 (d, J = 7.8 Hz, 2 H), 7.59 (d, J = 7.8 Hz, 2 H), 7.20 - 7.04 (m, 2 H), 3.70 (d, J = 13.7 Hz, 1 H), 3.56 (d, J = 13.7 Hz, 1 H), 3.16 (dd, J = 5.6, 12.5 Hz, 1 H), 2.98 (t, J = 5.4 Hz, 1 H), 2.35 - 2.29 (m, 1 H), 2.18 (td, J = 6.8, 13.3 Hz, 1 H), 1 .68 (d, J = 14.2 Hz, 1 H), 1 .27 - 1 .22 (m, 2 H), 1 .19 - 1 .06 (m, 2 H), 0.98 (d, J = 18.6 Hz, 2 H), 0.67 (dt, J = 4.4, 7.6 Hz, 1 H), 0.22 (d, J = 4.4 Hz, 1 H).
Example 22: 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoic acid (single unknown diastereoisomer with anti relative stereochemistry) (E22)
Figure imgf000150_0002
The title compound (E22) (65 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -(3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (D140a) (72 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
MS: (ES/+) m/z: 457.1 [MH"] C25H25F3N2O3 requires 458.18 Chiral HPLC: [Regis Welk 01 (SS); Mobile phase A: 70% n-heptane (+0.1 % AcOH), B: 30% IPA; DAD: 254 nm]: Peak retention time: 30 min
1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.31 - 12.10 (m, 1 H), 8.69 - 8.59 (m, 1 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.74 - 7.65 (m, J = 7.8 Hz, 2 H), 7.65 - 7.55 (m, J = 8.3 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 2 H), 3.70 (d, J = 14.2 Hz, 1 H), 3.56 (d, J = 14.2 Hz, 1 H), 3.16 (dd, J = 6.8, 12.2 Hz, 1 H), 2.98 (t, J = 6.1 Hz, 1 H), 2.31 (dd, J = 3.9, 12.2 Hz, 1 H), 2.18 (td, J = 6.7, 13.9 Hz, 1 H), 1 .73 - 1 .64 (m, 1 H), 1 .28 - 1 .20 (m, 2 H), 1 .19 - 1 .12 (m, 1 H), 1 .09 (dt, J = 3.2, 6.2 Hz, 1 H), 1 .06 - 0.92 (m, 2 H), 0.67 (dt, J = 4.4, 8.3 Hz, 1 H), 0.22 (q, J = 4.4 Hz, 1 H)
Example 23: 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benzoic acid (single unknown diastereoisomer with anti relative stereochemistry) (E23)
Figure imgf000151_0001
The title compound (E23) (56 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -(3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (D140b) (74 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
MS: (ES/+) m/z: 457.1 [MH"] C25H25F3N2O3 requires 458.18
Chiral HPLC: [Regis Welk 01 (SS); Mobile phase A: 70% n-heptane (+0.1 % AcOH), B: 30% IPA; DAD: 254 nm]: Peak retention time: 30.3 min
1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.64 (br. s., 1 H), 8.63 (s, 1 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.72 - 7.65 (m, J = 8.3 Hz, 2 H), 7.63 - 7.55 (m, J = 8.3 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 2 H), 3.74 - 3.66 (m, 1 H), 3.61 - 3.53 (m, 1 H), 3.16 (dd, J = 6.8, 12.2 Hz, 1 H), 2.98 (t, J = 6.1 Hz, 1 H), 2.31 (dd, J = 4.2, 12.5 Hz, 1 H), 2.18 (td, J = 6.7, 13.9 Hz, 1 H), 1 .73 - 1 .64 (m, 1 H), 1 .28 - 1 .21 (m, 2 H), 1 .19 - 1 .13 (m, 1 H), 1 .12 - 1 .06 (m, 1 H), 1 .06 - 0.92 (m, 2 H), 0.67 (dt, J = 4.2, 8.2 Hz, 1 H), 0.22 (q, J = 4.6 Hz, 1 H). Example 24: 4-(1-(3-(3-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4- carboxamido)cyclopropyl)benz ic acid (racemic mixture) (E24)
Figure imgf000152_0001
The title compound (E24) (32 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from (methyl 4-(1 -(3-(3- (trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4- carboxamido)cyclopropyl)benzoate (D141 ) (53 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 459.2 [MH+] C25H25F3N203 requires 458.18
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.81 - 12.62 (m, 1 H), 8.77 - 8.56 (m, 1 H), 7.99 - 7.45 (m, 5 H), 7.27 - 7.08 (m, 2 H), 3.80 - 3.66 (m, 1 H), 3.61 - 3.49 (m, 1 H), 3.24 - 3.1 1 (m, 1 H), 3.03 - 2.94 (m, 1 H), 2.39 - 2.29 (m, 1 H), 2.26 - 2.10 (m, 1 H), 1 .75 - 1 .58 (m, 1 H), 1 .33 - 1 .21 (m, 2 H), 1 .19 - 1 .07 (m, 2 H), 1 .05 - 0.90 (m, 2 H), 0.73 - 0.61 (m, 1 H), 0.26 - 0.17 (m, 1 H).
Example 25: 4-(1-((3fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoic acid (diastereoisomers mixture) (E
Figure imgf000152_0002
The title compound (E25 (4.9 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -((3f?)-2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D142) (6.8 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
MS: (ES/+) m/z: 459.1 [MH+] C25H25F3N2O3 requires 458.18 1 H NMR (400 MHz, MeOH-d4) δ (ppm): 8.02 - 7.84 (m, 2 H), 7.67 (m, 5 H), 7.31 - 7.16 (m, 2 H), 3.92 (s, 1 H), 3.85 (s, 1 H), 3.15 - 2.91 (m, 1 H), 2.66 - 0.82 (m, 10 H under residual solvent), 0.64 - 0.39 (m, 2 H). Example 26: 4-((1 S)-1-((3H)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoic acid (diastereoisomers mixture) (E
Figure imgf000153_0001
Te title compound (E26) (7.2 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((1 S)-1 -((3f?)-2- (4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)ethyl)benzoate (diastereoisomers mixture) (D143) (10 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
MS: (ES/+) m/z: 447.2 [MH+] C24H25F3N2O3 requires 446.18
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.99 (t, J = 9.2 Hz, 2 H), 7.74 - 7.29 (m, 7 H), 5.06 (m, 1 H), 4.03 - 3.69 (m, 2 H), 3.1 1 - 2.93 (m, 1 H), 2.58 - 0.77 (9 H under residual solvent), 0.52 (m, 2 H).
Example 27: lithium 4-((S)-1-((/?)-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoate (
Figure imgf000153_0002
The title compound (E27) (47 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1 -((f?)-1 -(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D144) (50 mg). (LiOH H2O: 1 .2 eq; reaction time: 5 hrs; 70°C)
MS: (ES/+) m/z: 421 .2 [M-Li+2H+] C22H22F3UN2O3 requires 426.17 Chiral HPLC [Phenomenex Lux Cellulose-1 ; Mobile phase A: 70% n-hexane (+0.5% TFA), B: 30% EtOH; DAD: 230 nm]: Peak retention time: 8.15 min.
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.95 - 7.90 (m, J = 8.3 Hz, 2 H), 7.69 - 7.63 (m, J = 7.8 Hz, 2 H), 7.60 - 7.55 (m, J = 8.3 Hz, 2 H), 7.33 - 7.27 (m, J = 7.8 Hz, 2 H), 4.97 - 4.90 (m, 1 H), 3.88 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 12.7 Hz, 1 H), 3.22 (dd, J = 4.4, 9.8 Hz, 1 H), 3.18 - 3.1 1 (m, 1 H), 2.49 (d, J = 6.8 Hz, 1 H), 2.21 (br. s., 1 H), 1 .87 - 1 .76 (m, 3 H), 1 .36 (d, J = 6.8 Hz, 3 H)
Example 28: lithium 4-((S)-1-((fi)-1-(4-fluorobenzyl)pyrrolidine-2- carboxamido)ethyl)benzoate (
Figure imgf000154_0001
The title compound (E28) (13 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1 -((f?)-1 -(4- fluorobenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D145) (22 mg). (LiOH H20: 1 .2 eq; reaction time: 5 hrs; 70 °C)
MS: (ES/+) m/z: 370.9 [M-Li+2H+] C21 H22FUN203 requires 376.18
Chiral HPLC [DAICEL OD-H; Mobile phase A: 70% n-hexane (+0.5% TFA), B:
30% EtOH; DAD: 230 nm]: Peak retention time: 8.7 min.
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.97 - 7.89 (m, J = 7.8 Hz, 2 H), 7.37 (dd, J = 5.9, 8.3 Hz, 2 H), 7.32 - 7.26 (m, J = 8.3 Hz, 2 H), 7.07 (t, J = 8.8 Hz, 2 H), 4.96 - 4.90 (m, 1 H), 3.77 (d, J = 12.7 Hz, 1 H), 3.66 (d, J = 12.7 Hz, 1 H), 3.23 - 3.06 (m, 2 H), 2.57 - 2.37 (m, 1 H), 2.27 - 2.10 (m, 1 H), 1 .89 - 1 .68 (m, 3 H), 1 .39 (d, J = 6.8 Hz, 3 H) Example 29: 4-(1-((1 R,3R,5H)-2-(3-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoic acid (syn diastereoisomer) (E29)
Figure imgf000155_0001
The title compound (E29) (52 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -((3f?)-2-(3- (trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoate (D146) (60 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 445.2 [MH+] C24H23F3N203 requires 444.17
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.85 - 12.69 (m, 1 H), 8.41 - 8.32 (m, 1 H), 7.91 - 7.81 (m, 2 H), 7.80 - 7.71 (m, 2 H), 7.70 - 7.54 (m, 2 H), 7.06 - 6.96 (m, 2 H), 4.08 - 3.95 (m, 1 H), 3.87 - 3.75 (m, 1 H), 3.59 - 3.48 (m, 1 H), 2.80 - 2.70 (m, 1 H), 2.20 - 2.08 (m, 1 H), 2.04 - 1 .94 (m, 1 H), 1 .48 - 1 .38 (m, 1 H), 1 .32 - 1 .23 (m, 1 H), 1 .22 - 1 .13 (m, 1 H), 1 .12 - 1 .01 (m, 2 H), 0.53 - 0.41 (m, 1 H), 0.25 - 0.12 (m, 1 H). Example 30: 4-(1-((1 R,3R,5R)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoic acid (E30)
Figure imgf000155_0002
The title compound (E30) (2.25 g) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1 -((1 R,3R,5R)- 2-azabicyclo[3.1 .0]hexane-3-carboxamido)cyclopropyl)benzoate (D147) (2.4 g) MS: (ES/+) m/z: 445 [MH+] C23H23F3N203 requires 444.17
Chiral HPLC [Regis Welk 01 (SS); Mobile phase A: 70% n-heptane (+0.1 % AcOH), B: 30% IPA; DAD: 245 nm]: Peak retention time: 32.8 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.73 (br. s., 1 H), 8.34 (s, 1 H), 7.92 - 7.62 (m, 6 H), 7.01 (d, J = 8.2 Hz, 2 H), 4.01 (d, J = 13.8 Hz, 1 H), 3.79 (d, J = 13.3 Hz, 1 H), 3.54 (d, J = 9.5 Hz, 1 H), 2.82 - 2.65 (m, 1 H), 2.28 - 2.1 1 (m, 1 H), 2.09 - 1 .92 (m, 1 H), 1 .50 - 1 .37 (m, J = 3.5 Hz, 1 H), 1 .35 - 1 .24 (m, J = 5.9 Hz, 1 H), 1 .23 - 0.99 (m, 3 H), 0.55 - 0.38 (m, J = 7.0 Hz, 1 H), 0.28 - 0.09 (m, 1 H)
Example 31 : 4-(1-((3fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoic acid (single unknown diastereoisomer) (E
Figure imgf000156_0001
The title compound (E31) (46 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1 -((3f?)-2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoate (diastereoisomer 2) (D148) (100 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 445.3 [MH+] C24H23F3N2O3 requires 444.17
Chiral HPLC [DAICEL AD-H; Mobile phase A: 60% n-heptane (+0.1 % TFA), B: 40% IPA; DAD: 245 nm]: Peak retention time: 12.91 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.50 - 8.09 (br. s., 1 H), 7.98 (d, J = 8.1 Hz, 2 H), 7.91 - 7.78 (m, 1 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.48 (d, J = 7.7 Hz, 2 H), 7.31 - 7.14 (m, 2 H), 3.77 (d, J = 13.0 Hz, 1 H), 3.66 - 3.41 (m, 1 H), 2.97 (t, J = 8.7 Hz, 1 H), 2.70 (br. s., 1 H), 2.54 (dd, J = 8.1 , 12.5 Hz, 1 H), 2.09 - 1 .93 (m, 1 H), 1 .54 - 1 .35 (m, 2 H), 1 .36 - 1 .21 (m, 2 H), 1 .21 - 1 .1 1 (m, 1 H), 0.63 (br. s., 1 H), 0.36 - 0.20 (m, 1 H)
Example 32: 4-((1 S)-1-((3fi)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoic acid (diastereoisomers mixture) (E
Figure imgf000156_0002
The title compound (E32) (12.3 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -((3f?)-2- (4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)ethyl)benzoate (D149) (14 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 433.4 [MH+] C23H23F3N2O3 requires 432.17
Chiral HPLC [DAICEL AD-H; Mobile phase A: 70% n-heptane 0.2% (+TFA), B: 30% EtOH; DAD: 245 nm]: Peak 1 retention time: 10.28 min; peak 2 retention time: 1 1 .35 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.09 (d, J = 7.8 Hz, 4 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.71 - 7.61 (m, 4 H), 7.57 - 7.46 (m, 5 H), 7.44 - 7.36 (m, 4 H), 5.17 - 4.93 (m, 2 H), 3.99 (d, J = 13.3 Hz, 1 H), 3.83 (d, J = 13.0 Hz, 1 H), 3.76 (d, J = 13.3 Hz, 1 H), 3.64 - 3.47 (m, 2 H), 2.97 (t, J = 8.8 Hz, 1 H), 2.75 - 2.60 (m, 2 H), 2.48 (dd, J = 8.0, 12.6 Hz, 1 H), 2.33 - 2.15 (m, 2 H), 1 .99 - 1 .85 (m, 1 H), 1 .54 - 1 .48 (m, J = 4.3 Hz, 1 H), 1 .45 (d, J = 6.7 Hz, 4 H), 1 .41 (d, J = 6.9 Hz, 3 H), 0.64 (br. s., 1 H), 0.44 (q, J = 7.3 Hz, 1 H), 0.33 - 0.16 (m, 1 H), 0.02 (br. s., 1 H).
Example 33: 4-((1 S)-1-((3H)-2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoic acid (single unknown diastereoisomer) (E33)
Figure imgf000157_0001
The title compound (E33) (62 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -((3f?)-2- (4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)ethyl)benzoate (single diastereoisomer 1 ) (D150) (72 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 433.4 [MH+] C23H23F3N2O3 requires 432.17
Chiral HPLC [DAICEL AD-H; Mobile phase A: 70% n-heptane (+0.2% TFA), B:
30% EtOH; DAD: 245 nm]: Peak retention time: 10.77 min. 1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.08 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 7.7 Hz, 2 H), 7.57 - 7.34 (m, 5 H), 5.18 - 4.97 (m, 1 H), 3.95 - 3.74 (m, 1 H), 3.70 - 3.46 (m, 1 H), 3.04 - 2.87 (m, 1 H), 2.83 - 2.61 (m, 1 H), 2.58 - 2.37 (m, 1 H), 1 .98 - 1 .87 (m, 1 H), 1 .66 - 1 .60 (m, 1 H), 1 .46 (d, J = 6.9 Hz, 3 H), 0.73 - 0.54 (m, 1 H), 0.34 - 0.18 (m, 1 H)
Example 34: (R)-4-(1-(4,4-dimethyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoic acid (E34)
Figure imgf000158_0001
(F?)-methyl 4-(1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoate (D151 ) (100 mg, 0.21 mmol) was partitioned between dioxane (2 ml) and water (2 ml) prior addition of LiOH H2O (35 mg, 0.84 mmol) and the resulting mixture was stirred at RT for 18 hrs. Dioxane was evaporated off and the aqueous solution acidified with acetic acid to pH~4 -5. A white solid precipitated which was filtered, dried under vacuum, then re-dissolved in dioxane (2 ml) and water (2 ml) and hydrolysed for additional 5 hrs after addition of LiOH H2O (18 mg, 0.42 mmol). Dioxane was evaporated off and the aqueous solution acidified with acetic acid to pH~4 -5. A white solid precipitated which was filtered and dried under vacuum, to afford the title compound (E34) (35.5 mg). MS: (ES/+) m/z: 461 .3 [MH+] C25H27F3N2O3 requires 460.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.91 (d, J = 8.3 Hz, 2 H), 7.70 - 7.54 (m, 4 H), 7.22 (d, J = 7.8 Hz, 2 H), 4.92 -4.74 (m, 1 H ), 3.97 - 3.84 (m, 1 H), 3.83 - 3.71 (m, 1 H), 3.00 - 2.89 (m, 1 H), 2.48 - 2.37 (m, 1 H), 2.22 - 2.06 (m, 1 H), 1 .82 - 1 .66 (m, 1 H), 1 .38 - 1 .24 (m, 2 H), 1 .19 (s, 3 H), 1 .1 1 (s, 5 H)
Example 35: 4-((1 S)-1-(1-(4-(trifluoromethyl)benzyl)azetidine-2- carboxamido)ethyl)benzoic acid (diastereoisomers mixture) (E35)
Figure imgf000159_0001
The title compound (E35) (1 .6 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -(1 -(4- (trifluoromethyl)benzyl)azetidine-2-carboxamido)ethyl)benzoate (D152a) (6 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 407.3 [MH+] C21 H21 F3N203 requires 406.15
Example 36: 4-((1 S)-1-(1-(4-(trifluoromethyl)benzyl)azetidine-2- carboxamido)ethyl)benzoic acid (single unknown diastereoisomer) (E36)
Figure imgf000159_0002
The title compound (E36) (2 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -(1 -(4- (trifluoromethyl)benzyl)azetidine-2-carboxamido)ethyl)benzoate (diastereoisomer 2) (D152b) (7 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 407.3 [MH+] C21 H21 F3N2O3 requires 406.15
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 8.02 (br. s., 2 H), 7.61 (br. s., 2 H), 7.41 (d, J = 5.4 Hz, 3 H), 7.21 (br. s., 2 H), 4.96 (br. s., 1 H), 3.86 - 3.71 (m, 3 H), 3.43 (br. s., 1 H), 3.1 1 (br. s., 1 H), 2.43 (br. s., 1 H), 2.07 (br. s., 1 H), 1 .16 (br. s., 3 H) Example 37: 4-((1 S)-1-(3-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)ethyl)benzoic acid (diastereoisomer 2 with syn relative stereochemistry)
Figure imgf000160_0001
To a mixture of methyl 4-((1 S)-1 -(3-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1 .0]hexane-2-carboxamido)ethyl)benzoate (D153) (84 mg, 0.19 mmol) in a 1 :1 mixture dioxane/water, LiOH H20 (12 mg, 0.28 mmol) was added and the reaction heated at 150°C under microwave irradiation for 5 min. Dioxane was evaporated off and the aqueous phase was acidified with CH3C02H. The precipitate (58 mg) was filtered off and submitted for chiral HPLC separation (Preparative chromatographic conditions: Column: DAICEL AD-H; Mobile phase: n-heptane/EtOH/TFA 60%/40%/0.2% v/v; DAD: 235 nm). Solvent evaporation od second eluted peak from chiral column, afforded the title compound (E37) (30 mg) (E37) (diastereoisomer 2 with syn relative stereochemistry): retention time: 9.28min
MS: (ES/+) m/z: 433 [MH+] C23H23F3N203 requires 432.17
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 8.03 (s, 2 H), 7.66 - 7.55 (m, 4 H), 7.38 (s, 2 H), 5.00 - 4.92 (m, 1 H), 4.55 - 4.47 (m, 1 H), 4.45 - 4.38 (m, 1 H), 4.37 - 4.30 (m, 1 H), 3.68 (br. s., 2 H), 2.31 - 2.21 (m, 1 H), 2.02 - 1 .90 (m, 1 H), 1 .47 (d, J = 6.9 Hz, 3 H), 0.96 - 0.88 (m, 1 H), 0.88 - 0.79 (m, 1 H).
Example 38: 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2- carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer with syn relative stereochemistry)
Figure imgf000160_0002
The title compound (E38) (4.8 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1 -(3-(4- (trifluoromethyl)benzyl)-3-azabicyclo[3.1 .0]hexane-2- carboxamido)cyclopropyl)benzoate (diastereoisomer 1 ) (D154a) (5 mg). (LiOH H20: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 445 [MH+] C24H23F3N203 requires 444.17
Chiral HPLC: [ADH- Mobile phase A: 70% n-heptane (+0.2% TFA), B: 30% IPA; DAD: 235 nm]: Peak retention time: 10.5 min
1 H NMR (400MHz ,METHANOL-d4) δ (ppm): 7.88 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 7.8 Hz, 2 H), 7.24 (d, J = 8.3 Hz, 2 H), 3.82 (d, J = 13.2 Hz, 1 H), 3.51 (d, J = 13.7 Hz, 1 H), 3.09 (d, J = 8.8 Hz, 1 H), 2.59 (dd, J = 4.4, 8.8 Hz, 1 H), 1 .82 (tt, J = 3.9, 7.4 Hz, 1 H), 1 .62 - 1 .53 (m, 1 H), 1 .41 - 1 .22 (m, 4 H), 1 .20 - 1 .12 (m, 2 H), 1 .10 - 1 .04 (m, 1 H), 0.55 (dt, J = 4.9, 7.8 Hz, 1 H)
Example 39: 4-((1 S)-1-(2-(4-(trifluoromethyl)benzyl)-2- azabicyclo[2.2.2]octane-3-carboxamido)ethyl)benzoic acid (diasteroisomers mixture) (E39)
Figure imgf000161_0001
The title compound (E39) (1 1 .04 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1 S)-1 -(2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxamido)ethyl)benzoate (D155) (1 1 .3 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 461 .4 [MH+] C25H27F3N2O3 requires 460.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.98 (d, J = 7.5 Hz, 2 H), 7.69 (d, J = 7.5 Hz, 2 H), 7.64 - 7.58 (m, 2 H), 7.37 (d, J = 7.6 Hz, 2 H), 4.89 (d, J = 7.2 Hz, 1 H), 3.96 (d, J = 1 .0 Hz, 1 H), 3.73 (d, J = 1 .0 Hz, 1 H), 3.13 (br. s., 1 H), 2.83 (br. s., 1 H), 2.24 - 2.09 (m, 1 H), 1 .89 - 1 .56 (m, 5 H), 1 .54 - 1 .34 (m, 3 H), 1 .27 (d, J = 6.7 Hz, 3 H).
Example 40: 4-(1-(2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3- carboxamido)cyclopropyl)benzoic acid (diasteroisomers mixture) (E40)
Figure imgf000162_0001
The title compound (E40) (8.03 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1 -(2-(4- (trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3- carboxamido)cyclopropyl)benzoate (D156) (7.6 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.91 - 7.82 (m, J = 1 .0 Hz, 2 H), 7.71 - 7.57 (m, 4 H), 7.19 - 7.10 (m, 2 H), 3.94 (d, J = 1 .0 Hz, 1 H), 3.73 (d, J = 1 .0 Hz, 1 H), 3.13 - 3.08 (m, 1 H), 2.90 - 2.82 (m, 1 H), 2.24 - 2.13 (m, 1 H), 2.02 - 1 .91 (m, 1 H), 1 .90 - 1 .56 (m, 4 H), 1 .55 - 1 .45 (m, 3 H), 1 .23 - 1 .1 1 (m, 2 H), 1 .06 - 0.97 (m, 1 H), 0.96 - 0.91 (m, 1 H).
Example 41 : (H)-4-(1-(2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoic acid (E41)
Figure imgf000162_0002
The title compound (E41) (3.9 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from (F?)-methyl 4-(1 -(2- methyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)benzoate (D157) (5 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs).
MS: (ES/+) m/z: 461 [MH+] C25H27F3N2O3 requires 460.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.87 - 7.78 (m, 2 H), 7.64 (s, 4 H), 7.22 - 7.07 (m, 2 H), 3.62 - 3.55 (m, 1 H), 3.43 - 3.37 (m, 1 H), 2.75 - 2.63 (m, 1 H), 2.43 - 2.31 (m, 1 H), 2.08 - 1 .91 (m, 1 H), 1 .80 - 1 .54 (m, 5 H), 1 .31 (s, 3 H), 1 .25 - 0.85 (m, 4 H). Example 42: 4-((S)-1-((R)-2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)benzoic acid (E42)
Figure imgf000163_0001
The title compound (E42) (4 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-((S)-1 -((f?)-2-methyl-1 -(4- (trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D158) (10 mg). (LiOH H20: 4 eq; reaction time: 18 hrs).
MS: (ES/+) m/z: 449.4 [MH+] C24H27F3N203 requires 448.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.76 (d, J = 7.8 Hz, 2 H), 7.54 (br. s., 2 H), 7.40 (br. s., 2 H), 7.16 (d, J = 7.8 Hz, 2 H), 5.1 1 - 5.00 (m, 1 H), 3.55 - 3.42 (m, 1 H), 2.77 - 2.62 (m, 1 H), 2.40 - 2.26 (m, 1 H), 1 .95 - 1 .83 (m, 1 H), 1 .78 - 1 .70 (m, 1 H), 1 .65 (br. s., 4 H), 1 .50 (d, J = 6.8 Hz, 3 H), 1 .30 (s, 3 H), 0.97 - 0.85 (m, 1 H) Example 43: (R)-4-(1-(2-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoic acid (E43)
Figure imgf000163_0002
The title compound (E43) (1 1 .2 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from (F?)-methyl 4-(1 -(2- methyl-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)cyclopropyl)benzoate (D159) (13 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs).
MS: (ES/+) m/z: 449.4 [MH+] C24H27F3N2O3 requires 448.20
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.90 (d, J = 7.8 Hz, 2 H), 7.71 - 7.63 (m, 2 H), 7.62 - 7.57 (m, 2 H), 7.25 (d, J = 7.8 Hz, 2 H), 3.90 (d, J = 14.2 Hz, 1 H), 3.58 (d, J = 13.7 Hz, 1 H), 3.05 (d, J = 4.4 Hz, 1 H), 2.54 (d, J = 8.3 Hz, 1 H), 2.27 - 2.14 (m, 1 H), 1 .96 - 1 .82 (m, 3 H), 1 .45 - 1 .17 (m, 8 H)
Example 44: lithium 4-((S)-1 -((2fl,4S)-4-f luoro-1 -(3- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (E44)
Figure imgf000164_0001
The title compound (E44) (50 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from 4-(trifluoromethyl)benzyl 4-((S)-1 -((2f?,4S)-4-fluoro-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)benzoate (D163) (67.3 mg). (LiOH H2O: 3 eq; reaction time: 18 hrs).
MS: (ES/+) m/z: 439.3 [M-Li+2H+] C22H21 F4UN2O3 requires 444.16
1 H NMR (400 MHz, MeOH-d4) δ (ppm): 7.91 (d, J = 8.1 Hz, 2 H), 7.67 (s, 2 H), 7.60 (s, 2 H), 7.29 (s, 2 H), 5.27 - 5.06 (m, 1 H), 4.93 - 4.89 (m, 1 H), 3.99 - 3.89 (m, 1 H), 3.87 - 3.77 (m, 1 H), 3.40 - 3.36 (m, 1 H), 2.84 - 2.50 (m, 2 H), 2.16 - 1 .98 (m, 1 H), 1 .33 (d, J = 7.0 Hz, 3 H).
Example 45: 4-((S)-1-((/?)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)pyrrolidine- 2-carboxamido)ethyl)benzoic acid (E45)
Figure imgf000164_0002
The title compound (E45) (12 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((S)-1 -((f?)-4,4- difluoro-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D166) (16.8 mg). (LiOH H2O: 3 eq; reaction time: 18 hrs)
MS: (ES/+) m/z: 457.3 [MH+] C22H21 F5N2O3 requires 456.15 1 H NMR (400MHz ,MeOH-d4) δ (ppm): 8.00 - 7.88 (m, 2 H), 7.71 - 7.48 (m, 6 H), 7.40 - 7.25 (m, 2 H), 5.07 - 4.92 (br. s., 1 H), 3.97 - 3.47 (m, 4 H), 2.98 - 2.58 (m, 2 H), 2.42 - 2.18 (m, 1 H), 1 .49 - 1 .25 (m, 3 H). Example 46: Determination of in vitro effects of the invention compounds
Stable expression of human EP4 receptors in the human embryonic kidney (HEK293) cell line
The cDNA clone of human EP4 receptor (NM_000958.2) was obtained from InvitrogenTM: Ultimate™ ORF Clone Collection - Clone ID IOH46525. The coding sequence was subcloned in expression vector pcDNATM6.2/V5-DEST by Gateway technology (InvitrogenTM).
Human embryonic kidney cells (HEK-293) were stably transfected with expression vector for human EP4 receptor in according to the method described in FuGENE®6 Transfection Reagent's manual (Roche Applied Science®).
Preparation of membrane fraction:
The EP4 transfected cells were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and 10 μg/ml Blasticidin S HCI (selection medium) at 37°C in a humidified atmosphere of 5% C02 in air.
For the membrane preparation, cells in flask were harvested by hypotonical/mechanical lysis with chilled (4°C) TE buffer (5mM TRIS, 5mM ethylenediamine tetra-acetic acid (EDTA), pH 7.4).
Cells were detached and lysed with 10ml of hypotonic lysis buffer and by scraping. The cell lysate was vortexed for 30 sec and centrifuged at 40000x g at 4°C for 22min.
a) Membrane binding assay[3H]-Prostaglandin E2
The membrane pellet was resuspended in the same buffer (5mM TRIS, 5mM ethylenediamine tetra-acetic acid (EDTA), pH 7.4), and protein concentration was determined by Bradford method (Bio-Bad® assay).
This membrane preparation was stored at -80 °C freezer until use for binding assay.
([3H]-PGE2) membranes binding assays toward hEP4 receptors (human EP4/HEK293 transfectant, see above) and hEP2 receptors (human EP2/HEK293 transfectant, purchased from PerkinElmer Inc) were performed in 10 mM MES- KOH buffer pH6, containing 10 mM MgCI2 and 1 mM CaCI2 for EP4 binding assay or 50 mM Tris-CI, BSA 0.5% for EP2 binding assay (according to supplier indication) .
Ten microgram of protein from membrane fractions were incubated in a total volume of 0.1 ml (EP4) or 0.2ml (EP2) with 1 nM (EP4) or 3nM (EP2) [3H]-PGE2 (PerkinElmer Inc, 171 Ci/mmol). In both assays to determine the total binding or non specific binding, 1 % DMSO or 1 μΜ prostaglandin E2 (EP4) or 100 μΜ (EP2) were added to reaction mixtures, respectively. Incubation was conducted in a polypropylene 96 multiwell for 90 min (EP4) or 60 min (EP2) at room temperature prior to separation of the bound and free radioligand by vacuum manifold rapid filtration on glass fiber filters (Unifilter GFB96, PerkinElmer Inc) pre-soaked in 0.3% polyethyleneimine. Filters were washed with ice cold buffer pH 7.4 (50mM HEPES, NaCI 500mM, BSA 0.1 % for EP4 binding assay or 50mM Tris-CI for EP2 binding assays) and the residual [3H]-PGE2 binding determined by solid scintillation counter (TopCount , PerkinElmer Inc).
In standard competition experiments the compounds were tested in a concentration range from 1 nM to 1 μΜ, and IC5o determined. The affinity (Ki) of each compound was calculated according to the Cheng-Prousoff equation: Ki = IC50/(1 +([C]/Kd)). Results were expressed as pKi (- logl 0 Ki (M)
Compounds of example 1 to 45 were tested according to method of example 41 a in a final concentration range range from 1 nM to 1 μΜ. All compounds showed good to excellent EP4 affinities having pKi values from 6 to 8.9 at EP4 receptor.
b) cAMP assay on human EP4 membrane of transfected cells.
The assay is based on the competition between endogenous cAMP and exogenously added biotinylated cAMP. The capture of cAMP is achieved by using a specific antibody conjugated to Donor beads.
Cell membranes prepared as described above, were resuspended in 1 ml stimulation buffer (HBSS 1 X + BSA 0.1 % + IBMX 0.5mM + HEPES 5mM + MgCI2 10mM + GTP 1 nM + GDP 10μΜ + ATP 100μΜ - pH 7.4). Cell membranes were dispensed into white 384-well microplates at final concentration of 1 μg/well and used for the determination of cAMP with the alphascreen cAMP functional assay (EnVision - PerkinElmer). Cell membrane/anti-cAMP Acceptor beads mix (5 μΙ) and a mixture of analysed compounds (dissolved in 1 00% DMSO to a final maximal concentration of 0.01 % DMSO)/PGE2 (5 μΙ) were incubated at room temperature (22-23°C) for 30 min in the dark. The Biotinylated-cAMP and donor beads (15 μΙ) were dispensed into each well to start the competition reaction. After 1 h incubation RT (22-23 °C) in the dark the plate was read using EnVision platform to determine the cAMP level (excitation: 680nm; emission:520,620nm).
In each experiment:
cAMP standard curve (concentration range from 1 x10-6 to 1 x10-1 1 M in log intervals) with a negative control (no cAMP)
a positive control: forskolin 10μΜ
Antagonism studies were performed stimulating HEK293 cell membrane with
PGE2 3nM. The AlphaScreen signal is plotted as a function of log concentration of cAMP and functional IC50 is determined. IC50 value is calculated by linear regression.
Some compounds were tested according to method of example 41 b. All compounds showed good to excellent EP4 antagonism having functional IC50 values from 3 μΜ to 4 nM at EP4 receptor.
The results of membrane binding assay and cAMP assay on human EP4 membrane of transfected cells selection of preferred compounds are summarised in table 1 .
Table 1 :
Figure imgf000167_0001
E19 8.9 15
E20 9.2 23
E23 8 1 1 .5
E25 8.5 43
E26 8.8 42
E27 7.3 50
E29 8.6 16
E30 8.3 21
Example 47: Determination of P of the invention compounds
The pharmacokinetics of compounds E7, E17 and E18, were studied in male Han Wistar rats. The rats were treated intravenously and orally (n=3 for each dose route) with compounds formulated as solutions. The rats were fitted with a jugular cannula for serial sampling. A full profile was acquired from each rat. Plasma extracts were quantitatively analyzed using a specific and sensitive LC-MS/MS bioanalytical method. Inter-individual variations between the three rats in each group were limited (CV for pharmacokinetic parameters was below 50%).
After intravenous injection all compounds showed moderate volume of distribution (Vss) ranging between 400 and 2000 ml. A range of clearance values were obtained for the different structure, ranging from low to moderate values (from 43 to 250 ml/h).
After oral administration, absorption was quite fast with a clear maximum concentration reached by the first sampling time-point of 15 minutes for all compounds. The absolute oral bioavailability was good for all compounds with F% around or in excess of 80%.
Figure imgf000168_0001
* Clearance, volume, half-life and AUC inf expressions may automatically be taken from calculations extrapolated to infinity from unrevised regression, indicative only; clearance values and AUC will usually never be much affected by error, volumes of distribution and half-life may or may not be precisely assessable from the data collected.
In summary tables for preliminary communications volumes may be taken from data until tlast, in which case it will be approximated by default due to lack of terminal phase data.

Claims

1 . A cyclic amine compound of Formula (I):
Figure imgf000170_0001
(I)
or a pharmaceutically acceptable salt or derivative thereof, wherein:
A is sel
Figure imgf000170_0002
B C D E
wherein
n= 0, 1 or 2
m= 0 or 1
R-i and R2 are independently hydrogen, linear or branched Ci-3 alkyl or are joined together to form a cyclopropyl ring;
R3 is H or linear or branched Ci-3 alkyl
R4 and R5 are independently hydrogen, fluorine, linear or branched Ci-3 alkyl or are joined together to form a cyclopropyl ring,
Ar is
- phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that
ii.a. when A is B, both R4 and R5 are fluorine, linear or branched
C-i-3 alkyl or joined together they form a cyclopropyl ring, ii.b. A is C and m is 0
ii.c. A is D and m is 1 , - a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
2. A cyclic amine compound of formula (I) according to claim 1 wherein Ar is phenyl having in 4 position one substituent selected from fluorine, cyano or trifluorormethyl.
3. A cyclic amine compound of formula (I) according to claim 2 wherein R is hydrogen and R2 is methyl or both Ri and R2 are fused toghether to form a cyclopropyl ring.
4. A cyclic amine compound according to claim 1 wherein A is B and is of the formula IB
Figure imgf000171_0001
(IB)
and/or pharmaceutically acceptable derivatives or salts thereof, wherein n= 0, 1 or 2
Ri and R2 are independently hydrogen, linear o branched Ci-3 alkyl, or are joined together to form a cyclopropyl ring,
R3 is H or linear or branched Ci-3 alkyl,
R4 and R5 are independently hydrogen, fluorine, linear or branched Ci-3 alkyl or are joined together to form a cyclopropyl ring,
Ar is
- phenyl having:
i. in 4-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, or
ii. in 3-position one substituent selected from the group consisting of halogen, cyano, trifluoromethyl, provided that both R4 and R5 are fluorine, linear or branched Ci-3 alkyl or are joined together to form a cyclopropyl ring,
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said heteroatoms independently of each others are S, O or N ; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
5. A cyclic amine compound of formula (IB) according to claim 4 wherein Ar is phenyl having in 4-position selected from fluorine, cyano and trifluoromethyl.
6. A cyclic amine compound of formula (IB) according to claim 4 or 5 wherein R and R2 are methyl or are linked together to form a cyclopropyl ring.
7. A cyclic amine compound of formula (IB) according to anyone of claims 4
- 6 wherein R3 is hydrogen.
8. A cyclic amine compound of formula (IB) according to anyone of claims 4 -
7 wherein R4 and R5 are independently selected from hydrogen, fluorine, methyl or are fused together to form a cyclopropyl ring.
9. A cyclic amine compound of formula (IB) according to anyone of claims 4 -
8 wherein n is 1 and R4 and R5 are are independently selected from hydrogen, fluorine, methyl.
1 0. A cyclic amine compound of formula (IB) according to anyone of claims 4
- 8 wherein n is 2 and Ar is phenyl substituted in 4 position with one substituent selected from fluorine, cyano or trifluoromethyl.
1 1 . A cyclic amine compound of formula (IB) according to anyone of claims 4
- 8 or 1 0 wherein n is 2, both R4 and R5 are fluorine or are fused toghether to form a cyclopropyl ring.
12. A cyclic amine compound according to claim 1 wherein A is C and is of the formula IC
Figure imgf000173_0001
(IC)
and/or pharmaceutically acceptable salts or derivatives thereof wherein m= 0 or 1
Ri and R2 are independently hydrogen, linear o branched Ci-3 alkyl, or joined together they form a cyclopropyl ring,
R3 is H or linear or branched (C -3)alkyl,
Ar is
- phenyl having
i) in 4-position halogen, cyano or trifluoromethyl,or
ii) in 3-position halogen, cyano, trifluoromethyl, provided that m is 0,
- a 5-memebered heteroaromatic ring containing 1 to 3 heteroatoms wherein said
heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
13. A cyclic amine compound of formula (IC) according to claim 12 wherein Ar is phenyl having in 4-position one substituent selected from fluorine, cyano or trifluoromethyl.
14. A cyclic amine compound of formula (IC) according to claim 12 or 13 wherein Ri and R2 are linked together to form a cyclopropyl ring.
15. A cyclic amine compound of formula (IC) according to anyone of claims 12 - 14 wherein R3 is hydrogen or methyl.
16. A cyclic amine compound of formula (IC) according to anyone of claims 12 - 15 wherein m is 0 and Ar is phenyl substituted in 4 position with one substituent selected from fluorine, cyano or trifluoromethyl.
17. A cyclic amine compound according to claim 1 wherein A is D and is of the formula (ID)
Figure imgf000174_0001
(ID) and/or pharmaceutically acceptable salts or derivatives thereof wherein m= 0 or 1
Ri and R2 are independently hydrogen, linear o branched Ci-3 alkyl, or joined together they form a cyclopropyl ring,
R3 is H or linear or branched Ci-3 alkyl,
Ar is
- phenyl having
i) in 4-position halogen, cyano or trifluoromethyl, or
ii) in 3-position halogen, cyano or trifluoromethyl provided that m is 1 ,
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said
heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
18. A cyclic amine compound of formula (ID) according to claim 17 wherein Ar is phenyl having in 4-position fluorine, cyano or trifluoromethyl.
19. A cyclic amine compound of formula (ID) according to claim 17 or 18 wherein R and R2 are linked together to form a cyclopropyl ring.
20. A cyclic amine compound of formula (ID) according to anyone of claims 17 - 19 wherein R3 is hydrogen or methyl.
21 . A cyclic amine compound of formula (ID) according to anyone of claims 17 - 19 wherein m is 1 and Ar is phenyl substituted in 4 position with one substituent selected from the group consisting of fluorine, chlorine, cyano or trifluoromethyl.
22. A cyclic amine compound according to claim 1 wherein A is E and is of the formula (IE)
Figure imgf000175_0001
(IE) and/or pharmaceutically acceptable salts or derivatives thereof wherein
Ri and R2 are independently hydrogen, linear o branched Ci-3 alkyl, or joined together they form a cyclopropyl ring,
R3 is H or linear or branched Ci-3 alkyl,
Ar is
- phenyl having in 3 or 4-position halogen, cyano or trifluoromethyl,
- a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms wherein said
heteroatoms independently of each others are S, O or N; or
- a 6-membered heteroaromatic ring containing 1 to 3 N.
23. A cyclic amine compound of formula (IE) according to claim 22 wherein Ar is phenyl having in 4-position one substituent selected from fluorine, cyano or trifluoromethyl.
24. A cyclic amine compound of formula (IE) according to claim 22 or 23 wherein R is hydrogen and R2 is methyl or both R and R2 are linked together to form a cyclopropyl ring.
25. A cyclic amine compound of formula (IE) according to anyone of claims 22 - 24 wherein R3 is hydrogen or methyl.
26. A compound according to claim 1 selected from the group consisting of lithium (f?)-4-(1 -(1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)
benzoate
4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)
benzoic acid
carboxamido)cyclopropyl)benzoic acid
4-((1 S)-1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)ethyl)
benzoic acid
4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)
benzoic acid
4-((S)-1 -((/:?)-4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)ethyl)
benzoic acid
(f?)-4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido) cyclopropyl)benzoic acid
4-(1 -(4,4-difluoro-1 -(4-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)
benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl) benzoic acid
4-(1 -(4,4-difluoro-1 -(3-(trifluoromethyl)benzyl)piperidine-2- carboxamido)cyclopropyl)
benzoic acid
4-(1 -(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1 .0]heptane-4-carboxamido) cyclopropyl)benzoic acid
4-(1 -((3fl)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)
cyclopropyl)benzoic acid
4-((1 S)-1 -((3/=?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1 .0]heptane-3- carboxamido)ethyl)benzoic acid
lithium 4-((S)-1 -((fl)-1 -(4-(trifluoromethyl)benzyl)pyrrolidine-2- carboxamido)ethyl)
benzoate
4-(1 -((1 f?,3/:?!5/:?)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid
4-(1 -((1 f?,3/:?!5/:?)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1 .0]hexane-3- carboxamido)cyclopropyl)benzoic acid.
27. A pharmaceutical composition comprising a compound of formula (I) according to anyone of claims 1 -26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or excipient.
28. A compound of formula (I) according to anyone of claims 1 -26 for use as a medicament.
29. A compound of formula (I) according to anyone of claims 1 -26 for use in the treatment of disorders selected from acute and chronic pain, inflammatory pain, inflammation-associated disorders, osteoarthritis and rheumatoid artritis.
PCT/EP2011/061226 2011-07-04 2011-07-04 Cyclic amine derivatives as ep4 receptor antagonists WO2013004290A1 (en)

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CN201180072023.8A CN103702980B (en) 2011-07-04 2011-07-04 Cycloamine derivative is as EP4receptor antagonist
RU2014103587/04A RU2565596C2 (en) 2011-07-04 2011-07-04 Cyclic amine derivatives as ep4 receptor antagonists
ES11743035.5T ES2559513T3 (en) 2011-07-04 2011-07-04 Cyclic amine derivatives as EP4 receptor antagonists
JP2014517473A JP5813223B2 (en) 2011-07-04 2011-07-04 Cyclic amine derivatives as EP4 receptor antagonists
PL11743035T PL2729445T3 (en) 2011-07-04 2011-07-04 Cyclic amine derivatives as ep4 receptor antagonists
US14/130,451 US9181279B2 (en) 2011-07-04 2011-07-04 Cyclic amine derivatives as EP4 receptor antagonists
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