WO2012126922A1 - Heterocyclic amine derivatives - Google Patents

Heterocyclic amine derivatives Download PDF

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Publication number
WO2012126922A1
WO2012126922A1 PCT/EP2012/054939 EP2012054939W WO2012126922A1 WO 2012126922 A1 WO2012126922 A1 WO 2012126922A1 EP 2012054939 W EP2012054939 W EP 2012054939W WO 2012126922 A1 WO2012126922 A1 WO 2012126922A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
morpholin
amine
pyrimidin
chloro
Prior art date
Application number
PCT/EP2012/054939
Other languages
French (fr)
Inventor
Guido Galley
Roger Norcross
Philippe Pflieger
Original Assignee
F. Hoffmann-La Roche Ag
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=45855803&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2012126922(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CN201280014644.5A priority Critical patent/CN103443074B/en
Priority to KR1020137027851A priority patent/KR101518660B1/en
Priority to CA2828283A priority patent/CA2828283A1/en
Priority to EP12709643.6A priority patent/EP2688870B1/en
Priority to AU2012230378A priority patent/AU2012230378B2/en
Priority to NZ616150A priority patent/NZ616150B2/en
Priority to BR112013024312A priority patent/BR112013024312A2/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to JP2014500358A priority patent/JP5716128B2/en
Priority to MX2013010954A priority patent/MX351918B/en
Priority to MA36362A priority patent/MA35062B1/en
Priority to SG2013070776A priority patent/SG193556A1/en
Priority to UAA201312080A priority patent/UA113167C2/en
Priority to EA201391341A priority patent/EA023237B1/en
Publication of WO2012126922A1 publication Critical patent/WO2012126922A1/en
Priority to IL228246A priority patent/IL228246A/en
Priority to ZA2013/06757A priority patent/ZA201306757B/en
Priority to HK14103750.8A priority patent/HK1190703A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D211/26—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 nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds of formula
  • R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy,
  • -0-CH 2 -C 3 -6-cycloalkyl -0-(CH 2 ) 2 -0-lower alkyl, S(0) 2 CH 3 , SF 5 , -C(0)NH-lower alkyl, phenyl, -O-pyrimidinyl, optionally substituted by lower alkoxy substituted by halogen, or is benzyl, oxetanyl or furanyl;
  • m is 1 or 2;
  • Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl;
  • Y is a bond, -CH 2 -, -CH 2 CH 2 -, -CH(CF 3 )- or -CH(CH 3 )-;
  • R is hydrogen or lower alkyl; A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl;
  • R' is hydrogen or halogen; with the proviso that when R' is halogen, then A is CH;
  • B is CH or N; n is 0, 1 or 2;
  • X is a bond, -CH 2 - or -0-; or to pharmaceutical active acid addition salts thereof.
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
  • all tautomeric forms of compounds of formula I are also provided.
  • the compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders,
  • psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's
  • neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and
  • Some of the physiological effects i.e. cardiovascular effects, hypotension, induction of sedation
  • cardiovascular effects i.e. cardiovascular effects, hypotension, induction of sedation
  • adrenergic receptors WO02/076950, W097/12874 or EP 0717 037
  • Objects of the present invention show selectivity for TAARl receptor over adrenergic receptors, in particular good selectivity vs the human and rat alphal and alpha2 adrenergic receptors.
  • biogenic amines The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [1]. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions [2-5].
  • a second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlaps with the classical biogenic amines regarding structure, metabolism and subcellular localization.
  • the TAs include p-tyramine, ⁇ -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines [6].
  • TARs trace amine associated receptors
  • TAAR genes There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene). The TAAR genes do not contain introns (with one
  • TAAR2 contains 1 intron) and are located next to each other on the same
  • TAAR1 is in the first subclass of four genes (TAAR 1-4) highly conserved between
  • TAs activate TAAR1 via Gas. Dysregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention
  • TAAR1 ligands have a high potential for the treatment of these diseases.
  • Objects of the present invention are new compounds of formula I and their pharmaceutically acceptable salts, their use for the manufacture of medicaments for the treatment of diseases related to the biological function of the trace amine associated receptors, their manufacture and medicaments based on a compound in accordance with the invention in the control or prevention of illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
  • illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders such as eating disorders, diabetes, diabet
  • the preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, diabetes, anxiety and attention deficit hyperactivity disorder (ADHD).
  • lower alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n- butyl, i-butyl, 2-butyl, t-butyl and the like.
  • Preferred alkyl groups are groups with 1 - 4 carbon atoms.
  • lower alkoxy denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.
  • lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
  • lower alkoxy substituted by halogen denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom and wherein at least on hydrogen atom is replaced by halogen.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl is an alkylene ring, containing from 3 to 6 carbon ring atoms.
  • aryl relates to an aromatic carbon ring such as to the phenyl or naphthyl ring, preferably the phenyl ring.
  • heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulphur, such as pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8-tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl;
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like.
  • One embodiment of the present invention are compounds of formula wherein
  • R 1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, nitro, C 3 _6-cycloalkyl, S(0) 2 CH 3 or phenyl; m is 1 or 2;
  • Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl or 1,3,4-oxadiazolyl;
  • Y is a bond, -CH 2 -, -CH 2 CH 2 -, -CH(CF 3 )- or -CH(CH 3 )-;
  • R is hydrogen or lower alkyl
  • A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl;
  • B is CH or N; n is 0, 1 or 2;
  • X is a bond, -CH 2 - or -0-; or a pharmaceutical active acid addition salt thereof.
  • One further embodiment of the invention are compounds of formula I, wherein A is CR, and B is CH.
  • Ar is phenyl or naphthyl, for example the following compounds
  • a further embodiment of this group are further compounds of formula I, wherein Y is -CH 2 -, -CH 2 CH 2 -, -CH(CF 3 )- or -CH(CH 3 )- and Ar is furyl, pyridinyl, pyrimidinyl, pyrazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7, 8-tetrahydro-quinazolinyl or 1,3,4-oxadiazoly, for example the following compounds
  • One further embodiment of the invention are compounds of formula I, wherein A is N, B is CH, Y is a bond and Ar is pyridinyl, pyrimidinyl, for example the following compounds (RS)-5-Chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
  • One further embodiment of the invention are compounds of formula I, wherein A is CR, B is N, Y is a bond and Ar is pyridinyl, for example the following compound
  • PG is a N-protecting group selected from -C(0)0-tert-butyl
  • the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
  • Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in schemes 1 to 11, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
  • Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • Step A Addition of a trifluoromethyl group to aromatic aldehyde 2 can be accomplished by treatment with (trifluoromethyl)trimethylsilane in the presence of a source of fluoride ion such as tetrabutylammonium fluoride.
  • a source of fluoride ion such as tetrabutylammonium fluoride.
  • Preferred conditions are using THF as solvent at 0 °C for 30 minutes and then at room
  • Step B Conversion of alcohol 3 to the corresponding triflate ester 4 can be can be accomplished by deprotonation with a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA in non-protic organic solvents such as THF, dioxane, 1,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 2 hrs followed by treatment with trifluoromethanesulfonyl chloride.
  • a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA
  • non-protic organic solvents such as THF, dioxane, 1,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 2
  • Preferred conditions are deprotonation at room temperature for 30 min using sodium hydride as base and diethyl ether as solvent, followed by treatment with trifluoromethanesulfonyl chloride at room temperature for 15 min.
  • Step C C-N bond formation can be accomplished by treatment of triflate 4 with aryl amine 5 in the presence of a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA in non-protic organic solvents such as THF, dioxane, 1 ,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 24 hours.
  • a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA
  • non-protic organic solvents such as THF, dioxane, 1 ,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 24 hours.
  • Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1] or 5-d [Example 3(b)], piperidine derivatives such as 5-b [CAS 875798-79-1] or 5-e [Example 4], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
  • Preferred conditions are deprotonation of amine 5 at room temperature for 15 min using sodium hydride as base and THF as solvent, followed by treatment with triflate 4 at room temperature overnight.
  • Step D Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 4 hours.
  • Step A C-N bond formation can be accomplished by treatment of aryl halide 7 or heteroaryl halide 7 with aryl amine 5 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1], piperidine derivatives such as 5-b [CAS 875798-79-1], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C overnight according to a modification of the procedure of van Leeuwen and co-workers ⁇ Tetrahedron. Lett. 1999, 40, 3789-3790).
  • aryl halide 7 or heteroaryl halide 7 is activated towards undergoing nucleophilic substitution due to the presence of electron withdrawing substitutuents, preferably by the presence of a trifluoromethylgroup
  • coupling with the aryl amine 5 can be achieved by reacting these compounds in the presence of a base such as diisopropylethylamine, triethylamine, potassium carbonate or sodium hydride in a solvent such as isopropanol, dioxane,
  • dimethylacetamide or dimethylformamide at a temperature between 50 °C and 140°C for 1 hour to 24 hours.
  • Preferred conditions are heating the mixture of 5 and 7 with diisopropylethylamine in
  • Step B Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2 , CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2 , CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Y is -CH 2 - or -CH 2 CH 2 -.
  • Step A C-N bond formation can be accomplished by a reductive amination reaction involving treatment of aldehyde 9 with aryl amine 5 in the presence of a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2- dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HC1 or a carboxylic acid or an activating Lewis acid such as ZnCl 2 or Ti(OiPr) 4 at a temperature of -10 to 60 °C for 1-40 h.
  • a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3
  • a solvent such as MeOH, EtOH, dichloromethane, 1,2- dichloroethane, THF, dioxane or mixtures thereof
  • an activating protic acid
  • Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1], piperidine derivatives such as 5-b [CAS 875798-79-1], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
  • Step B Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Step A C-N bond formation can be accomplished by treatment of amine 11 with aryl halide 12 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • aryl halides 12 include N-protected pyrrolidine derivatives such as 12-a [CAS 328546-99-2], piperidine derivatives such as 12-b [CAS 769944-73-2], or morpholine derivatives such as 12-c [CAS 1131220-82-0].
  • Preferred conditions are catalytic tris(dibenzylideneacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane in a sealed tube heated at 120 °C overnight.
  • Step B Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • hal' CI or Br mixture of both
  • the reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 15 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Preferred conditions are NaBH 4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 16 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
  • Step D Selective protection of the amino group of amino alcohol 17 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are THF in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 18 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
  • Step F Reduction of the nitro group of 19 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
  • Step G C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 20 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 80 °C for 1 hour according to a modification of the procedure of van Leeuwen and co-workers ⁇ Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p- toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p- toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Alpha-halo ketones 23 can be obtained by a homologation reaction of acyl chloride 22 [CAS 58757-38-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 23 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Preferred conditions are NaBH 4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 24 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
  • Step D Selective protection of the amino group of amino alcohol 25 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are THF in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 26 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 2.5 hours at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 15 minutes at room temperature.
  • Step F C-N bond formation can be accomplished by treatment of 27 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 16 hours.
  • Step G Removal of the nitrogen protecting group of 28 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
  • Step H C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 29 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step I Removal of the BOC N-protecting group can be effected with mineral acids such as HC1, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HC1, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for
  • X being O
  • Y being a bond
  • A being C-alkyl
  • B being N
  • FT being hydrogen
  • n 0
  • trimethylsulfonium iodide in the presence of a base such as sodium hydride in a non-protic polar organic solvent such as DMSO or DMF.
  • Preferred conditions are sodium hydride in DMSO at 0 °C for 30 minutes and then at room temperature for 16 hours.
  • Step B Nucleophilic ring-opening can be accomplished by treatment of epoxide 32 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
  • Step C Selective protection of the amino group of amino alcohol 33 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as
  • dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are THF in the absence of a base at room temperature for 7 hours.
  • Step D Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 34 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 15 minutes at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 10 minutes at room temperature.
  • Step E C-N bond formation can be accomplished by treatment of 35 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 16 hours.
  • Step F Removal of the nitrogen protecting group of 36 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 80 °C for 2 hours.
  • Step G C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 37 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p- toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HOAc or p- toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Alpha-halo ketones 40 can be obtained by a homologation reaction of acyl chloride 39 [CAS 695188-21-7] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 40 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 41 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
  • Step D Selective protection of the amino group of amino alcohol 42 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 43 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature.
  • Step F C-N bond formation can be accomplished by treatment of 44 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 1 hour.
  • Step G Removal of the nitrogen protecting group of 45 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • a catalyst such as Pt0 2 , Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HOAc, EtOAc CH 2 C1 2 , CHC1 3 , DMF or mixtures thereof.
  • Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
  • Step H C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 46 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 2 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H' C-N bond formation to afford bi-aryl amine 47 can alternatively be accomplished directly from aryl bromide 44 by treatment of aryl bromide 44 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 120 °C for 16 hours.
  • Step I Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Alpha-halo ketones 49 can be obtained by a homologation reaction of acyl chloride 48 [CAS 21900-32-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 min at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 49 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Preferred conditions are NaBH 4 in ethanol at 5 °C to room temperature for 90 minutes followed by treatment with sodium methoxide at 50 °C for 4 hours.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 50 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 7 hours.
  • Step D Selective protection of the amino group of amino alcohol 51 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 52 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
  • Step F C-N bond formation can be accomplished by treatment of 53 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 16 hours.
  • Step G Removal of the nitrogen protecting group of 54 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • a base such as sodium acetate or sodium methoxide
  • solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 60 °C for 1 hour.
  • Step H C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 55 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H' C-N bond formation to afford bi-aryl amine 56 can alternatively be accomplished directly from aryl bromide 53 by treatment of aryl bromide 53 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 120 °C for 16 hours.
  • Step I Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • Alpha-halo ketones 58 can be obtained by a homologation reaction of acyl chloride 57 [CAS 151982-51-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 58 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Preferred conditions are NaBH 4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 59 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
  • Step D Selective protection of the amino group of amino alcohol 60 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 61 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 20 minutes at room temperature.
  • Step F C-N bond formation can be accomplished by treatment of 62 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 90 minutes.
  • Step G Removal of the nitrogen protecting group of 63 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • a base such as sodium acetate or sodium methoxide
  • solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 50 °C for 16 hours.
  • Step H C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 64 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 3 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H' C-N bond formation to afford bi-aryl amine 56 can alternatively be accomplished directly from aryl bromide 53 by treatment of aryl bromide 53 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 100 °C for 2 hours.
  • Step I Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 16 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
  • hal' CI, Br or a
  • Alpha-halo ketones 67 can be obtained by a homologation reaction of acyl chloride 66 [CAS 21900-55-0] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
  • Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 min at room temperature for the second step.
  • Step B Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 67 by treatment with a reducing agent such as NaBH 4 or LiBH 4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • a reducing agent such as NaBH 4 or LiBH 4
  • a solvent such as MeOH, EtOH, THF, dioxane
  • a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
  • Preferred conditions are NaBH 4 in ethanol at 5 °C to room temperature for 90 minutes followed by treatment with sodium methoxide at 50 °C for 4 hours.
  • Step C Nucleophilic ring-opening can be accomplished by treatment of epoxide 68 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine
  • a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
  • Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 7 hours.
  • Step D Selective protection of the amino group of amino alcohol 69 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
  • halogenated solvents such as dichloromethane or 1,2-dichloroethane
  • ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
  • Step E Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 70 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME
  • Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration.
  • Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
  • Step F C-N bond formation can be accomplished by treatment of 71 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 16 hours.
  • Step G Removal of the nitrogen protecting group of 72 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • a base such as sodium acetate or sodium methoxide
  • solvents such as MeOH, EtOH, H 2 0, dioxane, THF, HO Ac, EtOAc CH 2 C1 2 , CHCI 3 , DMF or mixtures thereof.
  • Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 60 °C for 1 hour.
  • Step H C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 73 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
  • a palladium or copper catalyst such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
  • Step H' C-N bond formation to afford bi-aryl amine 74 can alternatively be accomplished directly from aryl bromide 71 by treatment of aryl bromide 71 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
  • solvents such as dioxane, DME, THF, toluene, DMF and DMSO
  • Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 100 °C for 2 hours.
  • Step I Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H 2 S0 4 or H 3 P0 4 or organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • mineral acids such as HCl, H 2 S0 4 or H 3 P0 4
  • organic acids such as CF 3 COOH, CHCl 2 COOH, HO Ac or p-toluenesulfonic acid
  • solvents such as CH 2 C1 2, CHC1 3 , THF, MeOH, EtOH or H 2 0 at 0 to 80 °C.
  • Preferred conditions are CF 3 COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours. Isolation and purification of the compounds
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
  • the compounds of formula I are basic and may be converted to a corresponding acid addition salt.
  • the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid,
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
  • an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like.
  • the temperature is maintained between 0 °C and 50 °C.
  • the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
  • the acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • Trifluoromethanesulfonyl chloride (1.4 ml) was added and stirring was continued for a further 15 min at room temperature.
  • the reaction mixture was quenched by addition of 10% aq. sodium bicarbonate solution and the mixture was extracted with diethyl ether.
  • the phases were separated and the organic phase was washed with saturared brine.
  • the organic phase was separated, dried over sodium sulphate, and concentrated in vacuo.
  • Trifluoro-methanesulfonic acid l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (74 mg) was then added and the mixture was stirred overnight at room temperature.
  • the reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturared brine.
  • the organic phase was separated, dried over sodium sulphate, and concentrated in vacuo.
  • tetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1 N). The mixture was washed sequentially with water and with saturated brine, dried over Na 2 S0 4 and concentrated in vacuo.
  • reaction mixture was stirred at room temperature for a further 20 min and was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml).
  • the filtrate was cooled to 0-5 °C and potassium 2-methyl- 2-butoxide (17.0 ml, 1.7 M solution in toluene) was added.
  • the reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na 2 S0 4 and concentrated in vacuo.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to compounds of formula (I) wherein R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, nitro, C3-6-cycloalkyl, -CH2-C3-6-cycloalkyl, -O-CH2-C3-6-cycloalkyl, -O-(CH2)2-O-lower alkyl, S(O)2CH3, SF5, -C(O)NH-lower alkyl, phenyl, -O-pyrimidinyl, optionally substituted by lower alkoxy substituted by halogen, or is benzyl, oxetanyl or furanyl; m Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl; Y is a bond, -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)-; R2 is hydrogen or lower alkyl; A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl; R' is hydrogen or halogen; with the proviso that when R' is halogen, then A is CH; B is CH or N; n is 0, 1 or 2; X is a bond, -CH2- or -O-; pharmaceutical active acid addition salts thereof. It has now been found that the compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Description

HETEROCYCLIC AMINE DERIVATIVES
The present invention relates to compounds of formula
Figure imgf000002_0001
wherein
R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy,
lower alkoxy substituted by halogen, cyano, nitro, C3_6-cycloalkyl, -CH2-C3_6-cycloalkyl,
-0-CH2-C3-6-cycloalkyl, -0-(CH2)2-0-lower alkyl, S(0)2CH3 , SF5, -C(0)NH-lower alkyl, phenyl, -O-pyrimidinyl, optionally substituted by lower alkoxy substituted by halogen, or is benzyl, oxetanyl or furanyl; m is 1 or 2; Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl;
Y is a bond, -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)-;
R is hydrogen or lower alkyl; A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl;
R' is hydrogen or halogen; with the proviso that when R' is halogen, then A is CH;
B is CH or N; n is 0, 1 or 2;
X is a bond, -CH2- or -0-; or to pharmaceutical active acid addition salts thereof.
The invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. In addition, all tautomeric forms of compounds of formula I are also
encompassed by the present invention.
It has now been found that the compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAARl.
The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders,
psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's
disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and
assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
Some of the physiological effects (i.e. cardiovascular effects, hypotension, induction of sedation) which have been reported for compounds which may bind to adrenergic receptors (WO02/076950, W097/12874 or EP 0717 037) may be considered to be undesirable side effects in the case of medicaments aimed at treating diseases of the central nervous system as described above. Therefore it is desirable to obtain medicaments having selectivity for the TAARl receptor vs adrenergic receptors. Objects of the present invention show selectivity for TAARl receptor over adrenergic receptors, in particular good selectivity vs the human and rat alphal and alpha2 adrenergic receptors.
The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [1]. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions [2-5]. A second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlaps with the classical biogenic amines regarding structure, metabolism and subcellular localization. The TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines [6].
Their dysregulation has been linked to various psychiatric diseases like schizophrenia and depression [7] and for other conditions like attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse and eating disorders [8,9].
For a long time, TA- specific receptors had only been hypothesized based on
anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10,11]. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either
triggering their release, inhibiting their reuptake or by "crossreacting" with their receptor systems [9,12,13]. This view changed significantly with the identification of several
members of a novel family of GPCRs, the trace amine associated receptors (TAARs)
[7,14]. There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene). The TAAR genes do not contain introns (with one
exception, TAAR2 contains 1 intron) and are located next to each other on the same
chromosomal segment. The phylogenetic relationship of the receptor genes, in
agreement with an in-depth GPCR pharmacophore similarity comparison and
pharmacological data suggest that these receptors form three distinct subfamilies [7,14].
TAAR1 is in the first subclass of four genes (TAAR 1-4) highly conserved between
human and rodents. TAs activate TAAR1 via Gas. Dysregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention
deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.
Therefore, there is a broad interest to increase the knowledge about trace amine associated receptors.
References used:
1 Deutch, A.Y. and Roth, R.H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd edn) (Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L, and Squire, L.R., eds.), pp. 193-234, Academic Press;
2 Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat.
Rev. Neurosci. 2, 343-351;
3 Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GAB A in schizophrenia: new evidence. Anna. Rev. Pharmacol. Toxicol. 41, 237-260;
4 Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs 12, 1335-1352, 5 Castellanos, F.X. and Tannock, R. (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617-628;
6 Usdin, Earl; Sandler, Merton; Editors. Psychopharmacology Series, Vol. 1: Trace Amines and the Brain. [Proceedings of a Study Group at the 14th Annual Meeting of the American College of Neuropsychoparmacology, San Juan, Puerto Rico] (1976);
7 Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Sci. 26, 274-281;
8 Branchek, T.A. and Blackburn, T.P. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr. Opin. Pharmacol. 3, 90-97;
9 Premont, R.T. et al. (2001) Following the trace of elusive amines. Proc. Natl. Acad. Sci. U.
S. A. 98, 9474-9475;
10 Mousseau, D.D. and Butterworth, R.F. (1995) A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 106, 285-291;
11 McCormack, J.K. et al. (1986) Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. . Neurosci. 6, 94-101;
12 Dyck, L.E. (1989) Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor. Life Sci. 44, 1149-1156;
13 Parker, E.M. and Cubeddu, L.X. (1988) Comparative effects of amphetamine,
phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J. Pharmacol. Exp. Ther. 245, 199-210;
14 Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and
functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85, 372-385.
Objects of the present invention are new compounds of formula I and their pharmaceutically acceptable salts, their use for the manufacture of medicaments for the treatment of diseases related to the biological function of the trace amine associated receptors, their manufacture and medicaments based on a compound in accordance with the invention in the control or prevention of illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, diabetes, anxiety and attention deficit hyperactivity disorder (ADHD).
As used herein, the term "lower alkyl" denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n- butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1 - 4 carbon atoms.
As used herein, the term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.
As used herein, the term "lower alkyl substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF3, CHF2, CH2F, CH2CF3, CH2CH2CF3, CH2CF2CF3 and the like.
As used herein, the term "lower alkoxy substituted by halogen" denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom and wherein at least on hydrogen atom is replaced by halogen.
The term "halogen" denotes chlorine, iodine, fluorine and bromine.
The term "cycloalkyl" is an alkylene ring, containing from 3 to 6 carbon ring atoms. The term "aryl", relates to an aromatic carbon ring such as to the phenyl or naphthyl ring, preferably the phenyl ring.
The term "heteroaryl" refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulphur, such as pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8-tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl;
The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like.
One embodiment of the present invention are compounds of formula
Figure imgf000007_0001
wherein
R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, nitro, C3_6-cycloalkyl, S(0)2CH3 or phenyl; m is 1 or 2;
Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl or 1,3,4-oxadiazolyl;
Y is a bond, -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)-;
R is hydrogen or lower alkyl;
A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl;
B is CH or N; n is 0, 1 or 2;
X is a bond, -CH2- or -0-; or a pharmaceutical active acid addition salt thereof.
One further embodiment of the invention are compounds of formula I, wherein A is CR, and B is CH.
An embodiment of this group are compounds of formula I, wherein Y is a bond and Ar is phenyl or naphthyl, for example the following compounds
(RS)-(4-Chloro-phenyl)-(4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-naphthalen-2-yl-amine
(S)-4-Chloro-2-fluoro-N-(4-(morpholin-2-yl)phenyl)aniline
(4-Chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine (RS)-(4-Chloro-phenyl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine
[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine or
[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine An embodiment of this group are further compounds of formula I, wherein Y is a bond and Ar is pyridinyl, pyrimidinyl, pyrazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8-tetrahydro-quinazolinyl, pyrazinyl, pyridazinyl or 1,3,4- oxadiazolyl, for example the following compounds
(RS)-(4,6-Dimethyl-pyrimidin-2-yl)-(4-pyrrolidin-3-yl-phenyl)-amine; hydrochloride (RS)-(5-Chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(5-Chloro-pyrimidin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(5-Bromo-pyrimidin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
(5-Methoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Fluoro-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
2-((S)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carbonitrile
(5-Cyclopropyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5 -Methyl-pyrimidin-2- yl)-((S)-4 -morpholin-2- yl-phenyl) - amine
((S)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(6-Chloro-benzothiazol-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5 -Ethoxy-pyrimidin-2- yl)-((S)-4 -morpholin-2- yl-phenyl) - amine
(5-Chloro-pyridin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-4-Methoxy-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-6-Chloro-5-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-3-(trifluoromethyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine
(S)-5-Fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
((S)-4-Morpholin-2-yl-phenyl)-quinolin-2-yl-amine
(S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-2-Methyl-N-(4-(morpholin-2-yl)phenyl)quinolin-8-amine (S)-N-(4-(Morpholin-2-yl)phenyl)-2,8-bis(trifluoromethyl)quinolin-4-amine (S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinazolin-4-amine
(S)-8-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-4-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(2-Fluoro-pyridin-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-5-Bromo-3-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-5-Bromo-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-3,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-3,5-Dibromo-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-5-Bromo-4-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyridin-4-amine
(S)-4-Bromo-5-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)benzo[d][l,3]dioxol-5-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-8-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(R)-5-Ethyl-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-6-Chloro-5-ethoxy-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(5-Ethyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Isopropyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine ((S)-4-Morpholin-2-yl-phenyl)-(5,6,7,8-tetrahydro-quinazolin-2-yl)-amine ((S)-4-Morpholin-2-yl-phenyl)-(5-nitro-pyrimidin-2-yl)-amine
(RS)-5-Bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-5-Chloro-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(5-Methanesulfonyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine (RS)-(5-Chloro-pyridin-2-yl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine (RS)-(5-Chloro-pyrimidin-2-yl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine (S)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine (S)-5-Chloro-4-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(RS)-5-Chloro-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (RS)-5-Bromo-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (5-Cyclopropyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine (RS)-5-Cyclopropyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (RS)-5-Ethyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
((R)-4-Morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(5-Bromo-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
(RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Cyclopropyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyridin-2-amine
(RS)-(5-Ethoxy-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine (RS)-(5-Bromo-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(S)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(5-Ethoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine (5-Cyclopropyl-pyrimidin-2-yl)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine (5-Ethyl-pyrimidin-2-yl)-((S)-4-piperidin-3-yl-phenyl)-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-phenyl-lH-pyrazol-3-amine
(5 -Ethoxy-pyrimidin-2- yl)-((S)-4 -piperidin-3 - yl-phenyl) - amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-phenyl-l,3,4-oxadiazol-2-amine
(5-Ethyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine (5-Cyclopropyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine (RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (5-Isopropoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Isopropoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(S)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (R)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (5-Bromo-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine (5-Bromo-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(5-Chloro-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Chloro-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethoxy-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethoxy-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine ((S)-4-Morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
((R)-4-Morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
(RS)-(l-Methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(4-Bromo-l-methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine (RS)-(l-Cyclopropylmethyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
(5-Furan-2-yl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Furan-2-yl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(RS)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
(RS)-[l-(2,2-Difluoro-ethyl)-lH-pyrazol-3-yl]-(4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine ((S)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
(RS)-(4-Morpholin-2-yl-phenyl)-(lH-pyrazol-3-yl)-amine
(5-Methyl-pyrazin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Methyl-pyrazin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
2-((S)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide 2-((R)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide (6-Methyl-pyridazin-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine (l-Benzyl-lH-pyrazol-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(l-Benzyl-lH-pyrazol-3-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(5-oxetan-3-yl-pyridin-2-yl)-amine
((R)-2-Methyl-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-2-Methyl-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((R)-2-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-2-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
(R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
(S)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
((R)-4-Morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
(R)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine
(R)-5-(5-(Difluoromethoxy)pyrimidin-2-yloxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-am (R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-(5-(difluoromethoxy)pyrimidin-2- yloxy)pyrimidin-2-amine
(R) -N- (4 -(Morpholin-2- yl)phenyl)pyrimidin-2- amine
((R)-4-Morpholin-2-yl-phenyl)-quinazolin-2-yl-amine
(4-Methyl-6-trifluoromethyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(R)-5-(Difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(4-Chloro-6-methoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
2-((R)-4-Morpholin-2-yl-phenylamino)-pyrimidine-4-carbonitrile
(4,6-Dimethyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(4,6-Dimethoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((R)-2-Chloro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine (R)-3-Chloro-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
(S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine
((S)-4-Morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
[5-Fluoro-4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine (4-Cyclopropyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(4-Cyclopropyl-5-fluoro-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(4-Pentafluorosulfanyl-phenyl)-((R)-4-morpholin-2-yl-phenyl)-amine
(R)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine ((S)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine ((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine
(S)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrirnidin-2-amine
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine
(S)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine
(R)-N-(4-(Morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine
(R)-N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)pyrimidin-4-amine
(R)-N-(4-(Morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrazin-2-amine
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-chloro-pyrimidin-2-yl)-amine
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amm^ ((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrazin-2-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrazin-2-amine
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-amine (R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine (R)-5-Fluoro-N-(3-fluoro-4-(morpholin-2-yl)phenyl)-4-(2,2,2-trifluoroethoxy)pyrimidin-2-am (R)-5-Chloro-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine or
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amm^
An embodiment of this group are compounds of formula I, wherein Y is -CH2-,
-CH2CH2-, -CH(CF3)- or -CH(CH3)- and Ar is phenyl or naphthyl, for example the following compounds
[(RS)-l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2-pyrrolidin-3-yl-ethyl)-phenyl]- amine
(RS)-[l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2-piperidin-3-yl-ethyl)-phenyl]-amine (RS)-(4-Chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-phenethyl-amine
(4-Methoxy-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Methyl-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
4-[((S)-4-Morpholin-2-yl-phenylamino)-methyl]-benzonitrile
((S)-4-Morpholin-2-yl-phenyl)-(4-trifluoromethyl-benzyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(4-trifluoromethoxy-benzyl)-amine (3,4-Dichloro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
[2-(4-Chloro-phenyl)-ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Chloro-2-fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Ethyl-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Bromo-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine or
[(RS)-l-(4-Chloro-phenyl)-ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine.
A further embodiment of this group are further compounds of formula I, wherein Y is -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)- and Ar is furyl, pyridinyl, pyrimidinyl, pyrazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7, 8-tetrahydro-quinazolinyl or 1,3,4-oxadiazoly, for example the following compounds
[(RS)-l-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-((RS)-4-pyrrolidin-3-yl-phenyl)-amine (5-Bromo-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(6-Methoxy-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-N-((6-Chloropyridin-3-yl)methyl)-4-(morpholin-2-yl)aniline
(S)-4-(Morpholin-2-yl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)aniline
(5-Fluoro-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine or
(S)-N-((2-Chloroquinolin-3-yl)methyl)-4-(morpholin-2-yl)aniline.
One further embodiment of the invention are compounds of formula I, wherein A is N, B is CH, Y is a bond and Ar is pyridinyl, pyrimidinyl, for example the following compounds (RS)-5-Chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
(RS)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
(RS)-5-Cyclopropyl-N-(5-(morpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine
(R)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine or
(S)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine.
One further embodiment of the invention are compounds of formula I, wherein A is CR, B is N, Y is a bond and Ar is pyridinyl, for example the following compound
(RS)-N-(5-Bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) cleaving off the N-protecting group from compounds of formula
Figure imgf000015_0001
to a compound of formula
Figure imgf000015_0002
PG is a N-protecting group selected from -C(0)0-tert-butyl, and
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1-11 and in the description of 211 specific examples. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in schemes 1 to 11, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art. GENERAL PROCEDURE
Scheme 1
For Y being -CH(CF3)-
B
Figure imgf000016_0001
1-1
Figure imgf000016_0002
The substituents are as described above and Y is -CH(CF3)-.
Step A : Addition of a trifluoromethyl group to aromatic aldehyde 2 can be accomplished by treatment with (trifluoromethyl)trimethylsilane in the presence of a source of fluoride ion such as tetrabutylammonium fluoride.
Preferred conditions are using THF as solvent at 0 °C for 30 minutes and then at room
temperature for 2 hours.
Step B: Conversion of alcohol 3 to the corresponding triflate ester 4 can be can be accomplished by deprotonation with a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA in non-protic organic solvents such as THF, dioxane, 1,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 2 hrs followed by treatment with trifluoromethanesulfonyl chloride.
Preferred conditions are deprotonation at room temperature for 30 min using sodium hydride as base and diethyl ether as solvent, followed by treatment with trifluoromethanesulfonyl chloride at room temperature for 15 min.
Step C: C-N bond formation can be accomplished by treatment of triflate 4 with aryl amine 5 in the presence of a base such as NaH, KOtBu, n-BuLi, LiHMDS, NaHMDS, KHMDS or LDA in non-protic organic solvents such as THF, dioxane, 1 ,2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at temperatures from -78 °C to 80 °C for 15 min - 24 hours.
Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1] or 5-d [Example 3(b)], piperidine derivatives such as 5-b [CAS 875798-79-1] or 5-e [Example 4], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
Preferred conditions are deprotonation of amine 5 at room temperature for 15 min using sodium hydride as base and THF as solvent, followed by treatment with triflate 4 at room temperature overnight.
Step D: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 4 hours.
Scheme 2
For Y being a bond
Figure imgf000018_0001
8 B
hal = CI.
Cleavage of protecting group
Figure imgf000018_0002
1-2
for example using:
Figure imgf000018_0003
5-a 5-b 5-c
The substituents are as described above and Y is a bond.
Step A : C-N bond formation can be accomplished by treatment of aryl halide 7 or heteroaryl halide 7 with aryl amine 5 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1], piperidine derivatives such as 5-b [CAS 875798-79-1], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C overnight according to a modification of the procedure of van Leeuwen and co-workers {Tetrahedron. Lett. 1999, 40, 3789-3790). In case the aryl halide 7 or heteroaryl halide 7 is activated towards undergoing nucleophilic substitution due to the presence of electron withdrawing substitutuents, preferably by the presence of a trifluoromethylgroup, coupling with the aryl amine 5 can be achieved by reacting these compounds in the presence of a base such as diisopropylethylamine, triethylamine, potassium carbonate or sodium hydride in a solvent such as isopropanol, dioxane,
dimethylacetamide or dimethylformamide at a temperature between 50 °C and 140°C for 1 hour to 24 hours.
Preferred conditions are heating the mixture of 5 and 7 with diisopropylethylamine in
isopropanol or dimethylacetamide at 80 °C for 18 hours.
Step B: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 3
For Y being -CH - or -CH2CH2
Figure imgf000020_0001
Y' = a bond or -CH,
B
Cleavage of protecting group
Figure imgf000020_0002
The substituents are as described above and Y is -CH2- or -CH2CH2-.
Step A : C-N bond formation can be accomplished by a reductive amination reaction involving treatment of aldehyde 9 with aryl amine 5 in the presence of a reducing agent such as NaBH4, LiBH4, NaBH(OAc)3 or Na(CN)BH3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2- dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HC1 or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr)4 at a temperature of -10 to 60 °C for 1-40 h.
Examples of appropriate amines 5 include N-protected pyrrolidine derivatives such as 5-a [CAS 908334-28-1], piperidine derivatives such as 5-b [CAS 875798-79-1], or morpholine derivatives such as 5-c [CAS 1002726-96-6].
Preferred conditions are sodium triacetoxyborohydride in acetic acid and THF at 60 °C for 3 hours. Step B: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 4
For Y being a bond, -CH2-, -CH2CH2- or -CH(CH3)
Figure imgf000021_0001
hal = CI
B
Cleavage of protecting group
f
Figure imgf000021_0002
12-a 12-b 12-C The substituents are as described above and Y is a bond, -CH2-, -CH2CH2- or -CH(CH3)-.
Step A : C-N bond formation can be accomplished by treatment of amine 11 with aryl halide 12 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction. Examples of appropriate aryl halides 12 include N-protected pyrrolidine derivatives such as 12-a [CAS 328546-99-2], piperidine derivatives such as 12-b [CAS 769944-73-2], or morpholine derivatives such as 12-c [CAS 1131220-82-0].
Preferred conditions are catalytic tris(dibenzylideneacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane in a sealed tube heated at 120 °C overnight.
Step B: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 5
For X being O, Y being a bond, A being C-lower alkyl, B being CH, R' being hydrogen and n being 0
A
Nucleophilic
Figure imgf000023_0001
Ring-opening
hal" = CI, Br or a Reaction
hal' = CI or Br mixture of both
7
Figure imgf000023_0002
Reduction
Figure imgf000023_0003
hal = CI H
Cleavage of protecting group
Figure imgf000023_0004
I -4 The substituents are as described above and X is O, Y is a bond, A is C-lower alkyl, B is CH, R' is hydrogen and n is 0.
Step A : Alpha-halo ketones 15 can be obtained by a homologation reaction of an acyl halide 14 [e.g. hal' = chloro and alkyl = methyl, CAS 35675-46-8] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 15 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 16 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
Step D: Selective protection of the amino group of amino alcohol 17 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are THF in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 18 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME. Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
Step F: Reduction of the nitro group of 19 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt02, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H20, dioxane, THF, HOAc, EtOAc CH2C12, CHC13, DMF or mixtures thereof.
Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
Step G: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 20 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 80 °C for 1 hour according to a modification of the procedure of van Leeuwen and co-workers {Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p- toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours. Scheme 6
For X being O, Y being a bond, A being N, B being CH, R' being hydrogen and n being 0
B
Homologation
Reaction
Nucleophilic 2 Ring-opening
Reaction
Figure imgf000026_0001
m xture o ot
Figure imgf000026_0002
I
hal = CI, Br, I Cleavage of protecting group
Figure imgf000026_0003
I-5
The substituents are as described above and X is O, Y is a bond, A is N, B is CH, R' is hydrogen and n is 0. Step A : Alpha-halo ketones 23 can be obtained by a homologation reaction of acyl chloride 22 [CAS 58757-38-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 23 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 24 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
Step D: Selective protection of the amino group of amino alcohol 25 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are THF in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 26 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 2.5 hours at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 15 minutes at room temperature.
Step F: C-N bond formation can be accomplished by treatment of 27 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 16 hours.
Step G: Removal of the nitrogen protecting group of 28 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt02, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H20, dioxane, THF, HOAc, EtOAc CH2C12, CHC13, DMF or mixtures thereof.
Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
Step H: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 29 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step I: Removal of the BOC N-protecting group can be effected with mineral acids such as HC1, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C. Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 2 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 7
For X being O, Y being a bond, A being C-alkyl, B being N, FT being hydrogen and n being 0
Figure imgf000029_0001
hal = CI, Br, I H
Cleavage of protecting group
Figure imgf000029_0002
I-6 The substituents are as described above and X is O, Y is a bond, A is C-alkyl, B is N, R' is hydrogen and n is 0.
Step A : Epoxide formation can be accomplished by a Corey-Tchaikovsky reaction of aldehydes 31 [e.g. alkyl = methyl, CAS 885167-81-7] by treatment with trimethylsulfonium iodide in the presence of a base such as sodium hydride in a non-protic polar organic solvent such as DMSO or DMF.
Preferred conditions are sodium hydride in DMSO at 0 °C for 30 minutes and then at room temperature for 16 hours.
Step B : Nucleophilic ring-opening can be accomplished by treatment of epoxide 32 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
Step C: Selective protection of the amino group of amino alcohol 33 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as
dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are THF in the absence of a base at room temperature for 7 hours.
Step D: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 34 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 15 minutes at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 10 minutes at room temperature. Step E: C-N bond formation can be accomplished by treatment of 35 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 16 hours.
Step F: Removal of the nitrogen protecting group of 36 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt02, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H20, dioxane, THF, HOAc, EtOAc CH2C12, CHC13, DMF or mixtures thereof.
Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 80 °C for 2 hours.
Step G: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 37 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 100 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p- toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours. Scheme 8
For X being O, Y being a bond, A being C-F, B being CH, R' being hydrogen and n being 0
Figure imgf000032_0001
hal = CI.
I
Cleavage of protecting group
Figure imgf000032_0002
I -7
The substituents are as described above and X is O, Y is a bond, A is C-F, B is CH, R' is hydrogen and n is 0. Step A : Alpha-halo ketones 40 can be obtained by a homologation reaction of acyl chloride 39 [CAS 695188-21-7] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 40 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours amd then at 40 °C for 1 hour. Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 41 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
Step D: Selective protection of the amino group of amino alcohol 42 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 43 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature.
Step F: C-N bond formation can be accomplished by treatment of 44 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 100 °C for 1 hour.
Step G: Removal of the nitrogen protecting group of 45 can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as Pt02, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H20, dioxane, THF, HOAc, EtOAc CH2C12, CHC13, DMF or mixtures thereof.
Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 °C for 1 hour.
Step H: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 46 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 2 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H': C-N bond formation to afford bi-aryl amine 47 can alternatively be accomplished directly from aryl bromide 44 by treatment of aryl bromide 44 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 120 °C for 16 hours.
Step I: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 9
For X being O, Y being a bond, A being C-CI, B being CH, FT being hydrogen and n being 0
Figure imgf000036_0001
hal = CI,
I
Cleavage of protecting group
Figure imgf000036_0002
The substituents are as described above and X is O, Y is a bond, A is C-Cl, B is CH, R' is hydrogen and n is 0.
Step A : Alpha-halo ketones 49 can be obtained by a homologation reaction of acyl chloride 48 [CAS 21900-32-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 min at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 49 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 90 minutes followed by treatment with sodium methoxide at 50 °C for 4 hours.
Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 50 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 7 hours.
Step D: Selective protection of the amino group of amino alcohol 51 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 52 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME. Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
Step F: C-N bond formation can be accomplished by treatment of 53 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 16 hours.
Step G: Removal of the nitrogen protecting group of 54 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H20, dioxane, THF, HO Ac, EtOAc CH2C12, CHCI3, DMF or mixtures thereof.
Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 60 °C for 1 hour.
Step H: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 55 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H': C-N bond formation to afford bi-aryl amine 56 can alternatively be accomplished directly from aryl bromide 53 by treatment of aryl bromide 53 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction. Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 120 °C for 16 hours.
Step I: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 10
For X being O, Y being a bond, A being CH, FT being F, B being CH and n being 0
Homologation
Reaction
Nucleophilic
Ring-opening
Reaction
Figure imgf000040_0001
Figure imgf000040_0002
hal =
Br, I I
Cleavage of protecting group
Figure imgf000040_0003
I-9
The substituents are as described above and X is O, Y is a bond, A is CH, R' is F, B is CH and n is O.
Step A : Alpha-halo ketones 58 can be obtained by a homologation reaction of acyl chloride 57 [CAS 151982-51-3] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 1 hour at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 58 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 1 hour followed by treatment with sodium methoxide at room temperature for 16 hours.
Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 59 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 16 hours.
Step D: Selective protection of the amino group of amino alcohol 60 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 61 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME. Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 20 minutes at room temperature.
Step F: C-N bond formation can be accomplished by treatment of 62 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 90 minutes.
Step G: Removal of the nitrogen protecting group of 63 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H20, dioxane, THF, HO Ac, EtOAc CH2C12, CHCI3, DMF or mixtures thereof.
Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 50 °C for 16 hours.
Step H: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 64 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 3 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H': C-N bond formation to afford bi-aryl amine 56 can alternatively be accomplished directly from aryl bromide 53 by treatment of aryl bromide 53 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction. Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 100 °C for 2 hours.
Step I: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 16 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours.
Scheme 11
For X being O, Y being a bond, A being CH, FT being CI, B being CH and n being 0
B
Homologatio Epoxi UdeB
Reaction Formation
Nucleophilic
Figure imgf000044_0001
Ring-opening
Reaction
hal' = CI, Br or a
mixture of both
Figure imgf000044_0002
hal =
Br, I I
Cleavage of protecting group
Figure imgf000044_0003
1-10
The substituents are as described above and X is O, Y is a bond, A is CH, R' is CI, B is CH and n is 0.
Step A : Alpha-halo ketones 67 can be obtained by a homologation reaction of acyl chloride 66 [CAS 21900-55-0] involving sequential treatment first with (trimethylsilyl)diazomethane and then treatment with concentrated hydrobromic acid or hydrochloric acid. The reaction is carried out using a mixture of acetonitrile, THF and hexane as solvent at temperatures between 0 °C and room temperature.
Preferred conditions are mixing of reactants at 0-5 °C followed by allowing to react for 30 minutes at room temperature for the first step, and mixing of reactants at 0-5 °C followed by allowing to react for 30 min at room temperature for the second step.
Step B: Epoxide formation can be accomplished by a stepwise process involving reduction of alpha-halo ketones 67 by treatment with a reducing agent such as NaBH4 or LiBH4 in a solvent such as MeOH, EtOH, THF, dioxane, followed by cyclisation of the ensuing alpha-halo alcohol by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or caesium carbonate in the same solvent.
Preferred conditions are NaBH4 in ethanol at 5 °C to room temperature for 90 minutes followed by treatment with sodium methoxide at 50 °C for 4 hours.
Step C: Nucleophilic ring-opening can be accomplished by treatment of epoxide 68 with 2- aminoethanol, optionally in the presence of an organic base such as triethylamine, N,N- diisopropylethylamine or N-methylmorpholine in a non-protic polar organic solvent such as ether, THF, dioxane or TBME.
Preferred conditions are using excess 2-aminoethanol as base in THF at room temperature for 7 hours.
Step D: Selective protection of the amino group of amino alcohol 69 can be effected by treatment with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane, THF or TBME.
Preferred conditions are dichloromethane in the absence of a base at room temperature for 16 hours.
Step E: Cyclisation can be accomplished by a stepwise process involving sulphonate ester formation by treatment of diol 70 with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N- methylmorpholine in ethereal solvents such as diethyl ether, dioxane, THF or TBME, followed by cyclisation by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in ethereal solvents such as diethyl ether, dioxane, THF or TBME. Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 °C and then allowing to react for 1 hour at room temperature, then removal of the by-product triethylamine hydrochloride by filtration. Preferred conditions for the second step are potassium 2-methyl-2-butoxide in THF mixing the reactants at 0-5 °C and then allowing to react for 30 minutes at room temperature.
Step F: C-N bond formation can be accomplished by treatment of 71 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic (R)-(+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in dioxane at 90 °C for 16 hours.
Step G: Removal of the nitrogen protecting group of 72 can be effected by treatment with hydroxylamine hydrochloride in the presence of a base such as sodium acetate or sodium methoxide in solvents such as MeOH, EtOH, H20, dioxane, THF, HO Ac, EtOAc CH2C12, CHCI3, DMF or mixtures thereof.
Preferred conditions are hydroxylamine hydrochloride in the presence of sodium acetate in MeOH at 60 °C for 1 hour.
Step H: C-N bond formation can be accomplished by treatment of an aryl halide 7 with aryl amine 73 in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium chloroform complex, catalytic 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)and caesium carbonate in dioxane in a sealed tube heated at 120 °C for 16 hours according to a modification of the procedure of van Leeuwen and co-workers (Tetrahedron. Lett. 1999, 40, 3789-3790).
Step H': C-N bond formation to afford bi-aryl amine 74 can alternatively be accomplished directly from aryl bromide 71 by treatment of aryl bromide 71 with an aryl amine 11' in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene, DMF and DMSO at elevated temperatures, for instance using a palladium- catalysed Buchwald-Hartwig reaction. Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide in dioxane at 100 °C for 2 hours.
Step I: Removal of the BOC N-protecting group can be effected with mineral acids such as HCl, H2S04 or H3P04 or organic acids such as CF3COOH, CHCl2COOH, HO Ac or p-toluenesulfonic acid in solvents such as CH2C12, CHC13, THF, MeOH, EtOH or H20 at 0 to 80 °C.
Preferred conditions are CF3COOH in aqueous acetonitrile at 80 °C for 3 hours or 4 N HCl in dioxane and THF at 60 °C for 16 hours. Isolation and purification of the compounds
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
Salts of compounds of formula I
The compounds of formula I are basic and may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. Example 1
(RS)-(4,6-Dimethyl-pyrimidin-2- -(4-pyrrolidin-3-yl-phenyl)-amine; hydrochloride
Figure imgf000048_0001
The title compound was obtained in analogy to example 5 using (RS)- 3-(4-amino-phenyl)- pyrrolidine- 1-carboxylic acid tert-butyl ester (CAS 908334-28-1) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4,6-dimethylpyrimidine (CAS 4472-44-0) instead of 2,5-dichloropyridine in step (a). Light brown solid. MS (ISP): 271.3 ([{37C1}M+H]+), 269.4 ([{35C1}M+H]+).
Example 2
[(RS)-l-(5-Bromo^yridin-2-yl)-2,2,2-trifluoro-ethyl]-((RS)-4-pyrrolidin-3-yl-phenyl)-
Figure imgf000048_0002
a) (RS)-l-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol
To a cooled, stirred solution of 5-bromopyridine-2-carbaldehyde (3.72 g, CAS 31181-90-5) and (trifluoromethyl)trimethylsilane (3.56 ml) in THF (30 ml) at 0 °C was added dropwise tetrabutylammonium fluoride solution (1.0 ml, 1 M solution in THF). The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 hours. The mixture was then diluted with 1 N aq. HC1 (20 ml) and stirring was continued for a further 2 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Si02; gradient: heptane/EtOAc) to give (RS)-l-(5-bromo-pyridin-2-yl)-2,2,2- trifluoro-ethanol as a light yellow solid (3.35 g, 65%). MS (ISP): 258.0 ([{ 81Br}M+H]+), 256.1 ([{79Br}M+H]+). b) Trifluoro-methanesulfonic acid (RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester To a stirred suspension of sodium hydride (765 mg, 60% dispersion in mineral oil) in dry diethyl ether (20 ml) under an argon atmosphere at 0 °C was added dropwise a solution of (RS)-l-(5- bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol (3.06 g) in diethyl ether (10 ml) and the resulting mixture was stirred at room temperature for 30 min. Trifluoromethanesulfonyl chloride (1.4 ml) was added and stirring was continued for a further 15 min at room temperature. The reaction mixture was quenched by addition of 10% aq. sodium bicarbonate solution and the mixture was extracted with diethyl ether. The phases were separated and the organic phase was washed with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by Kugelrohr distillation (60 °C oven temperature, 0.3 mbar) to give trifluoro -methane sulfonic acid (RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (3.6 g, 78%) as a white solid. MS (EI): 389 ([{81Br}M]+), 387 ([{79Br}M]+), 320 ([{ 81Br}M- CF3]+), 318 ([{79Br}M-CF3]+), 256 ([{81Br}M-CF3-S02]+), 254 ([{79Br}M-CF3-S02]+), 240 ([{81Br}M-OS02CF3]+), 238 ([{79Br}M-OS02CF3]+). c) (RS )-3 - 14- IYRS )- 1 -( 5-Bromo-p yridin-2- yl)-2,2,2-trifluoro-ethylaminol -phenyl I -pyrrolidine- 1 - carboxylic acid tert-butyl ester
To a stirred solution of (RS)- 3-(4-amino-phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (50 mg, CAS 908334-28-1) in dry THF (0.1 ml) under an argon atmosphere was added sodium hydride (14 mg, 60% dispersion in mineral oil) and stirring was continued for 15 minutes.
Trifluoro-methanesulfonic acid l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (74 mg) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by flash column chromatography (silical gel; gradient: heptane/EtOAc) to give (RS)-3-{4-[(RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-pyrrolidine-l- carboxylic acid tert-butyl ester (34 mg, 36%) as a yellow oil. MS (ISP): 501.9 ([{ 81Br}M+H]+), 500.2 ([{79Br}M+H]+), 446.2 ([{ 81Br}M+H-C4H8]+), 444.1 ([{79Br}M+H-C4H8]+). d) r(RS)-l-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyll-((RS)-4-pyrrolidin-3-yl-phenyl)-amine To a stirred solution of (RS)-3-{4-[(RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]- phenyl} -pyrrolidine- 1 -carboxylic acid tert-butyl ester (27 mg) in THF (1 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.20 ml, 4 M solution) and the mixture was heated at 60 °C for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate/THF (1: 1), and washed sequentially with 2 N aq. sodium hydroxide solution and with saturated brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by flash column chromatography (silical gel; gradient:
heptane/dichloromethane/methanol) to give [(RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro- ethyl]-((RS)-4-pyrrolidin-3-yl-phenyl)-amine (12 mg, 56%) as a yellow amorphous solid. MS (ISP): 402.1 ([{ 81Br}M+H]+), 400.1 ([{79Br}M+H]+).
Example 3
[(RS)-l-(4-Chloro^henyl)-2,2,2 rifluo^^
amine
Figure imgf000050_0001
a) (RS)-3-r(E)-2-(4-Nitro-phenyl)-vinyll-pyrrolidine-l-carboxylic acid tert-butyl ester
To a stirred solution of N,N-diisopropylamine (3.36 ml) in tetrahydrofuran (20 ml) at
-78 °C was added dropwise a solution of n-butyllithium (14.9 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0 °C for 15 min. After re-cooling to -78°C, a solution of diethyl (4-nitrobenzyl) phosphonate (5.00 g, CAS 2609-49-6) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at -78 °C for 60 min and then a solution of (RS)-3- formyl-pyrrolidine-l-carboxylic acid tert-butyl ester (4.01 g, CAS 59379-02-1) in
tetrahydrofuran (10 ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1 N). The mixture was washed sequentially with water and with saturated brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, gradient: heptane/EtOAc) to yield (RS)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-pyrrolidine- 1-carboxylic acid tert-butyl ester (3.39 g, 58%) as a yellow oil. b) (RS)-3-r2-(4-Amino-phenyl)-ethyll-pyrrolidine-l-carboxylic acid tert-butyl ester
To a solution of (RS)-3-formyl-pyrrolidine-l-carboxylic acid tert-butyl ester (3.39 g) in methanol (250 ml) was added palladium on charcoal (10 %, 340 mg). The mixture was stirred vigorously under an atmosphere of hydogen for 7 hours. The catalyst was filtered off and the filtrate was evaporated. The crude product was purified by flash column chromatography (silica gel; gradient: heptane/EtOAc) to give (RS)-3-[2-(4-amino-phenyl)-ethyl]-pyrrolidine-l- carboxylic acid tert-butyl ester (2.44 g, 79%) as a yellow oil. MS (ISP): 291.2 ([M+H]+). c) (RS)-3-(2-{4-r(RS)-l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethylaminol-phenyl|-ethvD- pyrrolidine- 1-carboxylic acid tert-butyl ester
The title compound was obtained in analogy to example 2 step (c) using (RS)-3-[2-(4-amino- phenyl) -ethyl] -pyrrolidine- 1-carboxylic acid tert-butyl ester instead of (RS)-3-(4-amino-phenyl)- pyrrolidine- 1-carboxylic acid tert-butyl ester and trifluoro-methanesulfonic acid (RS)-l-(4- chloro-phenyl)-2,2,2-trifluoro-ethyl ester (CAS 1202576-95-1) instead of trifluoro- methanesulfonic acid (RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester. Yellow oil. MS (ISP): 429.2 ([{37C1}M+H-C4H8]+), 427.1 ([{35C1}M+H-C4H8]+). d) r(RS)-l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyll-r(RS)-4-(2-pyrrolidin-3-yl-ethyl)-phenyll- amine
The title compound was obtained in analogy to example 2 step (d) using (RS)-3-(2-{4-[(RS)-l- (4-chloro-phenyl)-2,2,2-trifluoro-ethylamino]-phenyl}-ethyl)-pyrrolidine- 1-carboxylic acid tert- butyl ester instead of (RS)-3-{4-[(RS)-l-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]- phenyl} -pyrrolidine- 1-carboxylic acid tert-butyl ester. Off-white solid. MS (ISP): 385.2
([{37C1}M+H]+), 383.2 ([{35C1}M+H]+).
Example 4
(RS)-[l-(4-Chloro^henyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2^iperidin-3-yl-ethyl)-phenyl]-
Figure imgf000051_0001
The title compound was obtained in analogy to example 3 using (RS)-3-formyl-piperidine- carboxylic acid tert-butyl ester (CAS 118156-93-7) instead of (RS)-3-formyl -pyrrolidine- 1 carboxylic acid tert-butyl ester in step (a). Colourless amorphous solid. MS (ISP): 399.1 ([{37C1}M+H]+), 397.1 ([{35C1}M+H]+).
Example 5
(RS)-(5-Chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000051_0002
a) (RS)-2-r4-(5-Chloro-pyridin-2-ylamino)-phenyll-morpholine-4-carboxylic acid tert-butyl ester (RS)-2-(4-Amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726- 96-6), 2,5-dichloropyridine (31.9 mg, CAS 16110-09-1) and cesium carbonate (105 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.48 mg) and
tris(dibenzylideneacetone)dipalladium chloroform complex (6.69 mg) were then added. The reaction mixture was then capped and stirred at 100 °C overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (52 mg, 62%) as a yellow amorphous solid. MS (ISP): 392.0 ([{37C1}M+H]+), 390.1 ([{35C1}M+H]+), 336.4 ([{37C1}M+H-C4H8]+), 334.3 ([{35C1}M+H-C4H8]+). b) (RS)-(5-Chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
To a stirred solution of (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (50 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.26 ml, 4 M solution) and the mixture was heated at 60 °C overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(5-chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine (19 mg, 51%) as a white solid. MS (ISP): 292.1 ([{37C1}M+H]+), 290.1 ([{35C1}M+H]+).
Example 6
(RS)-(5-Chloro-pyrimidin-2- l - 4-mor holin-2-yl-phenyl)-amine
Figure imgf000052_0001
The title compound was obtained in analogy to example 5 using 2,5-dichloropyrimidine (CAS 22536-67-0) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 293.1
([{37C1}M+H]+), 291.1 ([{35C1}M+H]+). Example 7
(RS)-(5-Bromo-pyrimidin-2-yl)-(4-morpholin-2-yl-phenyl)-
Figure imgf000053_0001
The title compound was obtained in analogy to example 5 using 2,5-dibromopyrimidine (CAS 32779-37-6) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 337.1
([{81Br}M+H]+), 335.1 ([{79Br}M+H]+).
Example 8
(RS)-(4-Chloro-phenyl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000053_0002
The title compound was obtained in analogy to example 5 using l-bromo-4-chlorobenzene (CAS 106-39-8) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 291.1
([{37C1}M+H]+), 289.1 ([{35C1}M+H]+).
Example 9
(RS)-(4-Chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000053_0003
a) (RS)-2-r4-(4-Chloro-benzylamino)-phenyll-morpholine-4-carboxylic acid tert-butyl ester To a mixture of (RS)-2-(4-amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 4-chlorobenzaldehyde (33.3 mg) and AcOH (123 μΐ) in THF (2 ml) was added sodium triacetoxyborohydride (68.5 mg). The reaction mixture was then capped and the mixture was shaken at 60 °C for 3 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 65% EtOAc in hexanes) to afford (RS)- 2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (68 mg, 78%) as a colourless oil. MS (ISP): 405.4
([{37C1}M+H]+), 403.4 ([{35C1}M+H]+). b) (RS)-(4-Chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine
To a stirred solution of (RS)- 2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.34 ml, 4 M solution) and the mixture was heated at 60 °C overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(4- chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine (36 mg, 70%) as a white solid. MS (ISP): 305.1 ([{37C1}M+H]+), 303.2 ([{35C1}M+H]+).
Example 10
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000054_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromopyridine (CAS 624-28-2) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 336.1 ([{ 81Br}M+H]+), 334.1 ([{79Br}M+H]+).
Example 11
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000054_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-bromo-5-(trifluoromethyl)pyridine (CAS 50488-42-1) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 324.1 ([M+H]+).
Example 12
(5-Methoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000055_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-methoxypyrimidine (CAS 22536-65-8) instead of 2,5-dichloropyridine in step (a). Light yellow solid. MS (ISP): 287.1 «M+H]+).
Example 13
((S)-4-Morpholin-2-yl-phenyl)-phenethyl-amine
Figure imgf000055_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and phenylacetaldehyde instead of 4- chlorobenzaldehyde in step (a). Light brown solid. MS (ISP): 283.2 ([M+H]+). Example 14
(5-Fluoro-pyrimidin- -yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000055_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-fluoropyrimidine (CAS 62802-42-0) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 275.3 «M+H]+).
Example 15
(5-Ethyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000056_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 285.3 ([M+H]+).
Example 16
2-((S)-4-Morpholin- -yl-phenylamino)-pyrimidine-5-carbonitrile
Figure imgf000056_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloropyrimidine-5-carbonitrile (CAS 1753-50-0) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 282.1 ([M+H]+).
Example 17
(5-Cyclopropyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000056_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-cyclopropylpyrimidine (CAS 166740-44-9) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 297.4 «M+H]+).
Example 18
(5-Methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000057_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- henyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-methylpyrimidine (CAS
Figure imgf000057_0002
a) (S)-2-r4-(5-Trifluoromethyl-pyrimidin-2-ylamino)-phenyll-morpholine-4-carboxylic acid tert- butyl ester
To a 10 ml glass vial was added (S)-2-(4-bromo-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, CAS 1131220-37-5) and 5-trifluoromethyl-pyrimidin-2-ylamine (66.7 mg, CAS 69034-08-8) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl (14.3 mg), tris(dibenzylideneacetone)dipalladium(0) (7.49 mg) and sodium tert-butoxide (21.6 mg) were then added. The vial was capped and heated at 120 °C for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (S)-2-[4-(5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (94 mg, quant.) as an off-white solid. MS (ISP): 425.2 ([M+H]+). b) ((S)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
To a stirred solution of (S)-2-[4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (87 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.77 ml, 4 M solution) and the mixture was heated at 60 °C overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford ((S)-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)- amine (41 mg, 62%) as a white solid. MS (ISP): 325.3 ([M+H]+).
Example 20
(4-Methoxy-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000058_0001
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-methoxy-benzaldehyde instead of 4- chlorobenzaldehyde in step (a). Yellow solid. MS (ISP): 299.4 ([M+H]+).
Example 21
((S)-4-Morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
Figure imgf000058_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-propylpyrimidine (CAS 219555-98-3) instead of 2,5-dichloropyridine in step (a). Off-white amorphous solid. MS (ISP): 299.4 ([M+H]+).
Example 22
(4-Methyl-benz l)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000058_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-methyl-benzaldehyde instead of 4- chlorobenzaldehyde in step (a). Light yellow solid. MS (ISP): 283.4 ([M+H]+).
Example 23
4-[((S)-4-Morph thyl]-benzonitrile
Figure imgf000059_0001
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-cyano-benzaldehyde instead of 4- chlorobenzaldehyde in step (a). White solid. MS (ISP): 294.2 ([M+H]+).
Example 24
((S)-4-Morpholin-2- -phenyl)-(4-trifluoromethyl-benzyl)-
Figure imgf000059_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-(trifluoromethyl)benzaldehyde instead of 4-chlorobenzaldehyde in step (a). Light yellow solid. MS (ISP): 337.4 ([M+H]+).
Example 25
((S)-4-Morpholin-2-yl-phenyl)-(4-trifluoromethoxy-benzyl)-amine
Figure imgf000059_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-(trifluoromethoxy)benzaldehyde instead of 4-chlorobenzaldehyde in step (a). Light yellow solid. MS (ISP): 353.3 ([M+H]+).
Example 26
(6-Chloro-benzothiaz -2-yl)-((S)-4-morpholin-2-yl-phenyl)-
Figure imgf000060_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,6-dichlorobenzo[d]thiazole (CAS 3622-23-9) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 348.2 ([{37C1}M+H]+), 346.0 ([{35C1}M+H]+).
Example 27
(5-Bromo-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000060_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-bromopicolinaldehyde instead of 4- chlorobenzaldehyde in step (a). Brown oil. MS (ISP): 350.1 ([{81Br}M+H]+), 348.2
([{79Br}M+H]+).
Example 28
(6-Methoxy-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000060_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 6-methoxypicolinaldehyde instead of 4-chlorobenzaldehyde in step (a). Colourless oil. MS (ISP): 300.2 ([M+H]+).
Example 29
(5-Ethoxy-pyrimidin-2- l - S -4-mor holin-2-yl-phenyl)-
Figure imgf000061_0001
The title compound was obtained in analogy to example 19 using 2-amino-5-ethoxypyrimidine (CAS 39268-74-1) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Yellow solid. MS (ISP): 301.3 ([M+H]+).
Example 30
(3,4-Dichloro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000061_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 3,4-dichlorobenzaldehyde instead of 4-chlorobenzaldehyde in step (a). Off-white solid. MS (ISP): 341.3 ([{37C1}M+H]+), 339.2 ([{37C135C1}M+H]+), 337.3 ([{35C1}M+H]+).
Example 31
(4-Fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000061_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-fluoro-benzaldehyde instead of 4- chlorobenzaldehyde in step (a). Off-white solid. MS (ISP): 287.2 ([M+H]+).
Example 32
(S)-N-((6-Chloropyridin-3-yl)methyl)-4-(morpholin-2-yl)aniline
Figure imgf000062_0001
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 6-chloronicotinaldehyde instead of 4- chlorobenzaldehyde in step (a). White solid. MS (ISP): 306.1 ([{37C1}M+H]+), 304.1
([{35C1}M+H]+).
Example 33
(S)-4-(Morpholin-2-yl)- -((6-(trifluoromethyl)pyridin-3-yl)methyl)aniline
Figure imgf000062_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 6-(trifluoromethyl)nicotinaldehyde instead of 4-chlorobenzaldehyde in step (a). White solid. MS (ISP): 338.1 ([M+H]+). Example 34
[2-(4-Chloro-pheny -ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000062_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-a phenyl)-morpholine-4-carboxylic acid tert-butyl ester and (4-chloro-phenyl)-acetaldehyde instead of 4-chlorobenzaldehyde in step (a). Off-white solid. MS (ISP): 319.2 ([{37C1}M+H]+), 317.2 ([{35C1}M+H]+).
Example 35
(4-Chloro-2-fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000063_0001
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-chloro-2-fluorobenzaldehyde instead of 4-chlorobenzaldehyde in step (a). Off-white solid. MS (ISP): 323.3 ([{37C1}M+H]+), 321.2 ([{35C1}M+H]+).
Example 36
(4-Ethyl-benz l)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000063_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-ethylbenzaldehyde instead of 4- chlorobenzaldehyde in step (a). Off-white solid. MS (ISP): 297.4 ([M+H]+).
Example 37
(5-Fluoro-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000063_0003
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-fluoropicolinaldehyde instead of 4- chlorobenzaldehyde in step (a). Yellow oil. MS (ISP): 288.2 ([M+H]+). Example 38
(5-Chloro-pyridin- -yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000064_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in step (a). Yellow solid. MS (ISP): 292.1 ([{37C1}M+H]+), 290.1 ([{35C1}M+H]+).
Example 39
(S)-4-Methoxy-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000064_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-methoxypyridine (CAS 17228-69-2) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 286.2 ([M+H]+).
Example 40
(S)-6-Chloro-5-fluoro- -(4-(morpholin-2-yl)phenyl)pyridin-3-amine
Figure imgf000064_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-bromo-2-chloro-3-fluoropyridine (CAS 831203-13-5) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 310.1 ([{37C1}M+H]+), 308.1 ([{35C1}M+H]+).
Example 41
(S)-N-(4-(Morpholin-2-yl)phenyl)-3-(trifluoromethyl)pyridin-2-amine
Figure imgf000065_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-3-(trifluoromethyl)pyridine (CAS 65753-47-1) instead of 2,5-dichloropyridine in step (a). Colourless oil. MS (ISP): 324.1 ([M+H]+).
Example 42
(S)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine
Figure imgf000065_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-(trifluoromethyl)pyridine (CAS 81565-18-6) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 324.1 ([M+H]+).
Example 43
(S)-5-Fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
Figure imgf000065_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 3-bromo-5-fluoropyridine (CAS 407- 20-5) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 274.1 ([M+H]+).
Example 44
((S)-4-Morpholin-2-yl-phenyl)-naphthalen-2-yl-amine
Figure imgf000066_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-bromonaphthalene (CAS 580-13-2) instead of 2,5-dichloropyridine in step (a). Orange gum. MS (ISP): 305.3 ([M+H]+).
Example 45
(4-Bromo-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000066_0002
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-bromo-benzaldehyde instead of 4- chlorobenzaldehyde in step (a). White solid. MS (ISP): 349.2 ([{81Br}M+H]+), 347.1
([{79Br}M+H]+).
Example 46
((S)-4-Morph olin-2-yl-amine
Figure imgf000066_0003
The title compound was obtained in analogy to example 19 using 2-aminoquinoline (CAS 580- 22-3) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Light yellow solid. MS (ISP): 306.3 ([M+H]+).
Example 47
(S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
Figure imgf000066_0004
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,6-dichloroquinoline (CAS 1810-72- 6) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 342.1 ([{37C1}M+H]+), 340.1 ([{35C1}M+H]+).
Example 48
(S)-2-Methyl-N-(4-(mor holin-2-yl)phenyl)quinolin-8-amine
Figure imgf000067_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 8-bromo-2-methylquinoline (CAS 61047-43-6) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 320.2 ([M+H]+).
Example 49
(S)-N-(4-(Morpholin-2-yl henyl)-2,8-bis(trifluoromethyl)quinolin-4-amine
Figure imgf000067_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-bromo-2,8- bis(trifluoromethyl)quinoline (CAS 35853-45-3) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 442.1 ([M+H]+).
Example 50
(S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinazolin-4-amine
Figure imgf000067_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4,6-dichloroquinazoline (CAS 7253- 22-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 343.1 ([{37C1}M+H]+), 341.1 ([{35C1}M+H]+).
Example 51
(S)-N-((2-Chloroquinolin-3- l)methyl)-4-(morpholin-2-yl)aniline
Figure imgf000068_0001
The title compound was obtained in analogy to example 9 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloroquinoline-3-carbaldehyde instead of 4-chlorobenzaldehyde in step (a). White solid. MS (ISP): 356.1 ([{37C1}M+H]+), 354.1 ([{35C1}M+H]+).
Example 52
(S)-8-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
Figure imgf000068_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,8-dichloroquinoline (CAS 4470-83- 1) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 342.1 ([{37C1}M+H]+), 340.1 ([{35C1}M+H]+).
Example 53
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
Figure imgf000068_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-bromo-2-chloroquinoline (CAS 99455-13-7) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 386.1
([{81Br}M+H]+), 384.1 ([{79Br}M+H]+).
Example 54
(S)-4-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
Figure imgf000069_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,4-dichloroquinoline (CAS 703-61-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 342.1 ([{37C1}M+H]+), 340.1 ([{35C1}M+H]+).
Example 55
(2-Fluoro-pyridin-3- -((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000069_0002
The title compound was obtained in analogy to example 19 using 3-amino-2-fluoropyridine (CAS 1597-33-7) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Orange gum. (ISP): 274.3 ([M+H]+).
Example 56
(S)-5-Bromo-3-methyl-N- 4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000069_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromo-3-methylpyridine (CAS 3430-18-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 350.1
([{81Br}M+H]+), 348.1 ([{79Br}M+H]+).
Example 57
(S)-5-Bromo-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000070_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromo-3-fluoropyridine (CAS 156772-60-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 354.0
([{81Br}M+H]+), 352.0 ([{79Br}M+H]+).
Example 58
(S)-3,5-Dichloro-N-( -(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000070_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,3,5-trichloropyridine (CAS 16063- 70-0) instead of 2,5-dichloropyridine in step (a). White amorphous solid. MS (ISP): 328.1 ([{37C1}M+H]+), 326.1 ([{37C135C1}M+H]+), 324.1 ([{35C1}M+H]+). Example 59
(S)-4-Chloro-2-fluoro-N-(4-(morpholin-2-yl)phenyl)aniline
Figure imgf000070_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-chloro-2-fluoro-l-iodobenzene (CAS 6797-79-1) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 309.1 ([{37C1}M+H]+), 307.1 ([{35C1}M+H]+).
Example 60
(4-Chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000071_0001
a) (S)-2-r4-(4-Chloro-phenylamino)-phenyll-morpholine-4-carboxylic acid tert-butyl ester
The title compound was obtained in analogy to example 5 step (a) using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and l-bromo-4-chlorobenzene (CAS 106- 39-8) instead of 2,5-dichloropyridine. Yellow viscous oil. MS (ISP): 391.3 ([{37C1}M+H]+), 389.3 ([{35C1}M+H]+). b) (S)-2-{4-r(4-Chloro-phenyl)-methyl-aminol-phenyl|-morpholine-4-carboxylic acid tert-butyl ester
To a stirred solution of (S)-2-[4-(4-chloro-phenylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (60 mg) in DMF (2 ml) was added sodium hydride (6.2 mg) and stirring was continued at room temperature for 15 min. lodomethane (24.3 mg) was then added dropwise. The reaction mixture was stirred at room temperature for 1 h. TLC at t = 1 h showed the reaction was incomplete with some starting material remaining. A second portion of sodium hydride (6.2 mg) was added. After stirring at room temperature for 15 min, iodomethane (24.3 mg) was added. Stirring was continued for a further hour. TLC then showed the reaction was complete. The reaction mixture was poured into sat. aq. NaCl and extracted twice with EtOAc. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert- butyl ester (49 mg, 79%) as a colourless gum. MS (ISP): 405.4 ([{37C1}M+H]+), 403.4
([{35C1}M+H]+). c) (4-Chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine
To a stirred solution of trifluoroacetic acid (51.3 μΐ) in water (4 ml) was added a solution of (S)- 2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (45 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 °C for 2 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: 0% to 100% EtOAc in heptane, then 0% to 10% MeOH in EtOAc) to afford (4-chloro-phenyl)-methyl-((S)-4-morpholin-2-yl- phenyl)-amine (9 mg, 27%) as a colourless gum. MS (ISP): 305.3 ([{37C1}M+H]+), 303.3 ([{35C1}M+H]+).
Example 61
(S)-3,5-Dibromo-N-( -(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000072_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,3,5-tribromopyridine (CAS 75806- 85-8) instead of 2,5-dichloropyridine in step (a). White amorphous solid. MS (ISP): 415.8 ([{81Br}M+H]+), 413.9 ([{ 81Br79Br}M+H]+), 412.0 ([{79Br}M+H]+).
Example 62
(S)-5-Bromo-4-methyl- -(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000072_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromo-4-methylpyridine (CAS 3430-26-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 350.2
([{81Br}M+H]+), 348.0 ([{79Br}M+H]+).
Example 63
(S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyridin-4-amine
Figure imgf000073_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-bromo-2,5-dichloropyridine (CAS 1184917-16-5) instead of 2,5-dichloropyridine in step (a). White amorphous solid. MS (ISP): 328.1 ([{37C1}M+H]+), 326.1 ([{37C135C1}M+H]+), 324.2 ([{35C1}M+H]+).
Example 64
(S)-4-Bromo-5-methyl- -(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000073_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 4-bromo-2-chloro-5-methylpyridine (CAS 867279-13-8) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 350.1 ([{81Br}M+H]+), 348.2 ([{79Br}M+H]+).
Example 65
(S)-N-(4-(Morpholi -2-yl)phenyl)benzo[d][l,3]dioxol-5-amine
Figure imgf000073_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-iodobenzo[d][l,3]dioxole (CAS 5876-51-7) instead of 2,5-dichloropyridine in step (a). Brown amorphous solid. MS (ISP): 299.1 ([M+H]+).
Example 66
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-8-amine
Figure imgf000074_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5,8-dibromoquinoline (CAS 81278- 86-6) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 386.1 ([{81Br}M+H]+), 384.1 ([{79Br}M+H]+).
Example 67
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
Figure imgf000074_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-bromo-2-chloropyridine (CAS 53939-30-3) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 292.1 ([{37C1}M+H]+), 290.1 ([{35C1}M+H]+).
Example 68
(R)-5-Ethyl-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000074_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 285.2
«M+H]+).
Example 69
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000075_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloropyridine (CAS 16110-09- 1) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 292.1 ([{37C1}M+H]+), 290.1 ([{35C1}M+H]+).
Example 70
[(RS)-l-(4-Chloro-phenyl)-ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000075_0002
The title compound was obtained in analogy to example 19 using (RS)-l-(4-chlorophenyl)- ethylamine (CAS 6299-02-1) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Colourless gum. MS (ISP): 319.2 ([{37C1}M+H]+), 317.2 ([{35C1}M+H]+).
Example 71
(S)-6-Chloro-5-ethoxy-N- 4-(morpholin-2-yl)phenyl)pyridin-3-amine
Figure imgf000075_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-bromo-2-chloro-3-ethoxypyridine (CAS 1241752-29-3) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 336.1 ([{37C1}M+H]+), 334.1 ([{35C1}M+H]+).
Example 72
(5-Ethyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000076_0001
The title compound was obtained in analogy to example 19 using 2-amino-5-ethyl-4-methyl- pyrimidine (CAS 861031-36-9) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Light yellow gum. MS (ISP): 299.4 ([M+H]+).
Example 73
(5-Isopropyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000076_0002
The title compound was obtained in analogy to example 19 using 4-methyl-5-(l-methylethyl)- pyrimidine (CAS 1071763-86-4) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Light yellow gum. MS (ISP): 313.3 ([M+H]+).
Example 74
((S)-4-Morpholin-2-yl-phenyl)-(5,6,7,8-tetrahydro-quinazolin-2-yl)-amine
Figure imgf000076_0003
The title compound was obtained in analogy to example 19 using 2-amino-5,6,7,8-tetrahydro- quinazoline (CAS 2305-85-3) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). White solid. MS (ISP): 311.4 ([M+H]+).
Example 75
((S)-4-Morpholin-2- -phenyl)-(5-nitro-pyrimidin-2-yl)-amine
Figure imgf000076_0004
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-nitro-pyrimidine (CAS 10320-42-0) instead of 2,5-dichloropyridine in step (a). Yellow solid. MS (ISP): 302.3
([M+H]+).
Example 76
(RS)-5-Bromo-N-(2-meth l-4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000077_0001
a) 2-Bromo-l-(3-methyl-4-nitrophenyl)ethanone & 2-Chloro-l-(3-methyl-4- nitrophenyPethanone
To a stirred solution of 3-methyl-4-nitrobenzoyl chloride (5.85 g, CAS 35675-46-8) in acetonitrile (70 ml) and THF (70ml) at 0-5 °C was added dropwise (trimethylsilyl)diazomethane (16.5 ml, 2 M solution in hexane). The reaction mixture was stirred at room temperature for 1 hour. TLC analysis showed the reaction was complete. Hydrobromic acid (9.29 g) was then added dropwise at 0-5 °C and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2C03 solution, water and saturated brine. The organic layer was then dried over Na2S04 and concentrated in vacuo to afford a ca 1: 1 mixture of 2-bromo-l-(3-methyl-4-nitrophenyl)ethanone and 2-chloro-l-(3-methyl-4-nitrophenyl)ethanone (6.23 g) as a brown solid which was used in the next step without further purification. MS (EI): 163.9 ([Mi-CH2C1]+ & [M2-CH2Br]+). b) (RS)-2-(3-Methyl-4-nitrophenyl)oxirane
To a stirred suspension of the mixture of 2-bromo-l-(3-methyl-4-nitrophenyl)ethanone and 2- chloro-l-(3-methyl-4-nitrophenyl)ethanone (6.23 g) in ethanol (100 ml) at 5 °C was added portionwise over 5 min NaBH4 (913 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a dark yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (652 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was then poured into EtOAc and extracted with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford (RS)-2-(3-methyl-4-nitrophenyl)oxirane (4.63 g, 94% over 2 steps) as a yellow oil. MS (EI): 179 (M+), 164 ([M-CH3]+), 162 [M-OH]+), 132 [M-OH-NO]+), 103, 77. c) (RS)-2-(2-Hydroxyethylamino)- 1 -(3-methyl-4-nitrophenyl)ethanol
To a stirred solution of (RS)-2-(3-methyl-4-nitrophenyl)oxirane (4.63 g) in THF (15 ml) was added 2-aminoethanol (15.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1: 1) and extracted with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford (RS)-2-(2- hydroxyethylamino)-l-(3-methyl-4-nitrophenyl)ethanol (6.84 g, quant.) as a brown oil which was used in the next step without further purification. MS (ISP): 241.1 ([M+H]+). d) tert-Butyl (RS)-2-hydroxy-2-(3-methyl-4-nitrophenyl)ethyl(2-hydroxyethyl)carbamate
To a stirred solution of (RS)-2-(2-hydroxyethylamino)-l-(3-methyl-4-nitrophenyl)ethanol (6.84 g) in THF (50 ml) was added Boc20 (6.52 g) and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: heptane/CH2Cl2/MeOH) to afford tert-butyl (RS)-2-hydroxy-2-(3-methyl-4-nitrophenyl)ethyl(2-hydroxyethyl)carbamate (6.55 g, 74% over 2 steps) as a yellow oil. MS (ISP): 385.2 ([M+HCOOJ). e) tert-Butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-hydroxy-2-(3-methyl-4-nitrophenyl)ethyl(2- hydroxyethyl)carbamate (6.55 g) and triethylamine (3.22 ml) in THF (50 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (1.65 ml). The reaction mixture was then stirred at room temperature for 30 min to afford a yellow suspension. TLC analysis showed a small amount of starting material remaining and so further aliquots of triethylamine (0.5 ml) and methanesulfonyl chloride (0.2 ml) were added. The reaction mixture was stirred at room temperature for a further 20 min and was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl- 2-butoxide (17.0 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4- carboxylate (2.21 g, 36%) as a yellow oil. MS (ISP): 223.1 ([M+H-C5H802]+). f) tert-Butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate To a stirred solution of tert-butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4-carboxylate (2.21 g) in methanol (100 ml) was added ammonium formate (6.48 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (219 mg) was then added and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was taken up in EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford tert-butyl (RS)-2-(4-amino-3- methylphenyl)morpholine-4-carboxylate (1.99 g, 99%) as a colourless oil. MS (EI): 292 (M+), 235 ([M-C4H9]+), 219 ([M-C4H90]+), 191, 136, 57 ([C4H9]+). g) tert-butyl (RS)-2-(4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate tert-butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (60 mg), 2,5- dibromopyridine (48.6 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.12 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.37 mg) were then added. The reaction mixture was then capped and stirred at 80 °C for 1 hour. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2- (4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate (40 mg, 44%) as a colourless amorphous solid. MS (ISP): 450.2 ([{81Br}M+H]+), 448.1 ([{79Br}M+H]+), 394.3 ([{81Br}M+H-C4H8]+), 392.1 ([{79Br}M+H-C4H8]+). h) (RS)-5-Bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine
To a stirred solution of trifluoroacetic acid (67.0 μΐ) in water (6 ml) was added a solution of tert- butyl (RS)-2-(4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate (39 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 °C for 2 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and
concentrated in vacuo. The crude material was purified by flash column chromatography
(Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-bromo-N- (2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (17 mg, 56%) as a light yellow amorphous solid. MS (ISP): 350.1 ([{81Br}M+H]+), 348.2 ([{79Br}M+H]+). Example 77
(S)-5-Chloro-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000080_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloro-3-fluoropyridine (CAS 103999-77-5) instead of 2,5-dichloropyridine in step (a). Yellow amorphous solid. MS (ISP): 310.2 ([{37C1}M+H]+), 308.2 ([{35C1}M+H]+).
Example 78
(5-Methanesulfonyl-pyrimidin-2- l - S -4-mo
Figure imgf000080_0002
a) (S)-2-r4-(5-Methylsulfanyl-pyrimidin-2-ylamino)-phenyll-morpholine-4-carboxylic acid tert- butyl ester
The title compound was obtained in analogy to example 5 step (a) using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-methylsulfanylpyrimidine (CAS 115581-36-7) instead of 2,5-dichloropyridine. Yellow solid. MS (ISP): 403.3 ([M+H]+), 347.1 ([M+H-C4H8]+). b) (S)-2-r4-(5-Methanesulfonyl-pyrimidin-2-ylamino)-phenyll-morpholine-4-carboxylic acid tert-butyl ester
To a stirred solution of (S)-2-[4-(5-methylsulfanyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (72 mg) in dichloromethane (5 ml) was added 3- chloroperoxybenzoic acid (77.2 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into saturated aq. Na2S03 solution and extracted twice with dichloromethane. The combined organic layers were dried over Na2S04 and concentrated in vacuo to afford (S)-2-[4-(5-methanesulfonyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (84 mg, quant.) as a light brown foam which was used in the next step without further purification. MS (ISP): 435.2 ([M+H]+), 379.2 ([M+H-C4H8]+). c) (5-Methanesulfonyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
The title compound was obtained in analogy to example 60 step (c) using (S)-2-[4-(5- methanesulfonyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester in place of (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert- butyl ester. Off-white solid. MS (ISP): 335.3 ([M+H]+).
Example 79
(RS)-(4-Chloro-phenyl -(2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000081_0001
The title compound was obtained in analogy to example 76 using l-bromo-4-chlorobenzene (CAS 106-39-8) instead of 2,5-dibromopyridine in step (g). Light yellow gum. MS (ISP): 305.3 ([{37C1}M+H]+), 303.3 ([{35C1}M+H]+).
Example 80
(RS)-(5-Chloro-pyridin-2- l)-(2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000081_0002
The title compound was obtained in analogy to example 76 using 2-bromo-5-chloropyridine (CAS 40473-01-6) instead of 2,5-dibromopyridine in step (g). Light yellow gum. MS (ISP): 306.2 ([{37C1}M+H]+), 304.2 ([{35C1}M+H]+).
Example 81
(RS)-(5-Chloro-pyrimidin-2- l)-(2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000081_0003
The title compound was obtained in analogy to example 76 using 2,5-dichloropyrimidine (CAS 22536-67-0) instead of 2,5-dibromopyridine in step (g). Colourless gum. MS (ISP): 307.2 ([{37C1}M+H]+), 305.2 ([{35C1}M+H]+).
Example 82
(S)-5-Chloro-N-(4-(morphol -2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine
Figure imgf000082_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloro-4- (trifluoromethyl)pyridine (CAS 89719-92-6) instead of 2,5-dichloropyridine in step (a). Light yellow solid. MS (ISP): 360.1 ([{37C1}M+H]+), 358.1 ([{35C1}M+H]+).
Example 83
(S)-5-Chloro-4-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000082_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloro-4-methylpyridine (CAS 886365-00-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 306.1
([{37C1}M+H]+), 304.1 ([{35C1}M+H]+).
Example 84
(RS)-5-Chloro-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000082_0003
The title compound was obtained in analogy to example 76 using 2,5-dichloro-4-methylpyridine (CAS 886365-00-0) instead of 2,5-dibromopyridine in step (g). Colourless amorphous solid. MS (ISP): 320.1 ([{37C1}M+H]+), 318.1 ([{35C1}M+H]+). Example 85
(RS)-5-Bromo-4-methyl-N-(2-meth l-4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000083_0001
The title compound was obtained in analogy to example 76 using 2,5-dibromo-4-methylpyridine (CAS 3430-26-0) instead of 2,5-dibromopyridine in step (g). Light yellow amorphous solid. MS (ISP): 364.1 ([{ 81Br}M+H]+), 362.1 ([{79Br}M+H]+).
Example 86
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000083_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-cyclopropylpyrimidine (CAS 166740-44-9) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 297.4 ([M+H]+).
Example 87
(RS)-5-Cyclopropyl-N-(2-meth l-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000083_0003
The title compound was obtained in analogy to example 76 using 2-chloro-5- cyclopropylpyrimidine (CAS 166740-44-9) instead of 2,5-dibromopyridine in step (g).
Colourless oil. MS (ISP): 311.2 ([M+H]+). Example 88
(RS)-5-Ethyl-N-(2-meth l-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000084_0001
The title compound was obtained in analogy to example 76 using 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dibromopyridine in step (g). Yellow oil. MS (ISP): 299.2 ([M+H]+).
Example 89
(RS)-5-Bromo-N-(2-meth l-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000084_0002
The title compound was obtained in analogy to example 76 using 2,5-dibromopyrimidine (CAS 32779-37-6) instead of 2,5-dibromopyridine in step (g). Off-white amorphous solid. MS (ISP): 351.1 ([{81Br}M+H]+), 349.2 ([{79Br}M+H]+).
Example 90
(RS)-5-Chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
Figure imgf000084_0003
a) 2-Bromo-l-(6-chloropyridin-3-yl)ethanone & 2-Chloro-l-(6-chloropyridin-3-yl)ethanone To a stirred solution of 6-chloronicotinoyl chloride (5.83 g, CAS 58757-38-3) in acetonitrile (70 ml) and THF (70ml) at 0-5 °C was added dropwise (trimethylsilyl)diazomethane (15.9 ml, 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 1 hour. TLC analysis showed the reaction was complete. Hydrobromic acid (5.98 ml) was then added dropwise at 0-5 °C and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2C03 solution, water and saturated brine. The organic layer was then dried over Na2S04 and concentrated in vacuo to afford a ca 1: 1 mixture of 2-bromo-l-(6-chloropyridin-3-yl)ethanone and 2-chloro-l-(6-chloropyridin-3-yl)ethanone (5.6 g) as a brown solid which was used in the next step without further purification. MS (EI): 142 ([{37Cl}Mi-CH2Cl]+ & [{37Cl}M2-CH2Br]+), 140 ([{35C1}M!-CH2C1]+ & [{35Cl}M2-CH2Br]+), 114 ([{37C1}M!-CH2C1-C0]+ & [{37C1}M2- CH2Br-CO]+), 112 ([{3¾1}Μ!^Η^1^0]+ & [{35Cl}M2-CH2Br-CO]+). b) (RS)-2-Chloro-5-(oxiran-2-yl)pyridine
To a stirred solution of the mixture of 2-bromo-l-(6-chloropyridin-3-yl)ethanone and 2-chloro-l- (6-chloropyridin-3-yl)ethanone (5.6 g) in ethanol (100 ml) at 5 °C was added portionwise over 5 min NaBH4 (904 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (645 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was then poured into EtOAc and washed with saturated brine. The organic phase was dried over Na2S04 and concentrated in vacuo to afford (RS)-2-chloro-5-(oxiran-2-yl)pyridine (4.04 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 158.0 ([{37C1}M+H]+), 156.0
([{35C1}M+H]+). c) (RS)-l-(6-Chloropyridin-3-yl)-2-(2-hvdroxyethylamino)ethanol
To a stirred solution of (RS)-2-chloro-5-(oxiran-2-yl)pyridine (4.0 g) in THF (15 ml) was added 2-aminoethanol (15.4 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1: 1) and the mixture was washed with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford (RS)-l-(6-chloropyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (5.05 g) as a yellow solid which was used in the next step without further purification. MS (ISP): 219.3 ([{37C1}M+H]+), 217.2 ([{35C1}M+H]+), 201.3 ([{37C1}M+H-H20]+), 199.1 ([{35C1}M+H-H20]+). d) tert-Butyl (RS)-2-(6-chloropyridin-3-yl)-2-hvdroxyethyl(2-hvdroxyethyl)carbamate
To a stirred solution of (RS)-l-(6-chloropyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (5.05 g) in THF (50 ml) was added Boc20 (5.34 g) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with dichloromethane. The organic layer was washed sequentially with 1 M aq. HC1, sat. aq. NaHC03 solution and saturated brine, then dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: MeOH/dichloromethane/heptane) to afford tert-butyl (RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (4.68 g, 45% over 4 steps) as a yellow oil. MS (ISP): MS (ISP): 319.1 ([{37C1}M+H]+), 317.1 ([{35C1}M+H]+),
263.1 ([{37C1}M+H-C4H8]+), 261.1 ([{35C1}M+H-C4H8]+). e) tert-Butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl(2- hydroxyethyl)carbamate (4.68 g) and triethylamine (3.5 ml) in THF (50 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (1.84 ml). The reaction mixture was then stirred at room temperature for 2.5 hours to afford a yellow suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl-2-butoxide (15.6 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 15 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2- (6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g, 26%) as a yellow solid. MS (ISP):
301.2 ([{37C1}M+H]+), 299.1 ([{35C1}M+H]+), 245.2 ([{37C1}M+H-C4H8]+), 243.2
([{35C1}M+H-C4H8]+). f) tert-Butyl (RS)-2-(6-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g) and benzophenone imine (977 μΐ) in toluene (35 ml) was added sodium tert-butoxide (597 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl (242 mg) and tris(dibenzylideneacetone)dipalladium(0) (107 mg) were added and the reaction mixture was heated at 100 °C overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford tert-butyl (RS)-2- (6-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-carboxylate (374 mg, 22%) as a yellow oil. MS (ISP): 444.2 ([M+H]+). g) tert-Butyl (RS)-2-(6-aminopyridin-3-yl)morpholine-4-carboxylate To a stirred solution of tert-butyl (RS)-2-(6-(diphenylmethyleneamino)pyridin-3-yl)morpholine- 4-carboxylate (370 mg) in methanol (20 ml) was added ammonium formate (789 mg). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (44 mg) was then added and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the mixture was washed sequentially with water and with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: heptane/dichloromethane/MeOH) to afford tert-butyl (RS)-2-(6-aminopyridin-3- yl)morpholine-4-carboxylate (171 mg, 73%) as a light yellow oil. MS (ISP): 280.2 ([M+H]+). h) tert-Butyl 2-(6-(5-chloropyridin-2-ylamino)pyridin-3-yl)morpholine-4-carboxylate
tert-Butyl (RS)-2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (55 mg), 2,5-dichloropyridine (29 mg, CAS 16110-09-1) and cesium carbonate (96 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (6.84 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.11 mg) were then added. The reaction mixture was then capped and stirred at 100 °C overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl 2-(6-(5-chloropyridin-2- ylamino)pyridin-3-yl)morpholine-4-carboxylate (22 mg, 29%) as a yellow solid. MS (ISP): 393.2 ([{37C1}M+H]+), 391.2 ([{35C1}M+H]+). i) (RS)-5-Chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
To a stirred solution of tert-butyl 2-(6-(5-chloropyridin-2-ylamino)pyridin-3-yl)morpholine-4- carboxylate (22 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (43 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-chloro-N-(5-(morpholin-2- yl)pyridin-2-yl)pyridin-2-amine (15 mg, 92%) as a colourless amorphous solid. MS (ISP): 293.1 ([{37C1}M+H]+), 291.1 ([{35C1}M+H]+). Example 91
(RS)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
Figure imgf000088_0001
The title compound was obtained in analogy to example 90 using 2,5-dibromopyridine (CAS 624-28-2) instead of 2,5-dichloropyridine in step (h). Light yellow solid. MS (ISP): 337.1 ([{81Br}M+H]+), 335.1 ([{79Br}M+H]+).
Example 92
(RS)-5-Cyclopropyl-N-(5-(morpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine
Figure imgf000088_0002
The title compound was obtained in analogy to example 90 using 2-chloro-5- cyclopropylpyrimidine (CAS 166740-44-9) instead of 2,5-dichloropyridine in step (h). White. MS (ISP): 298.2 ([M+H]+).
Example 93
((R)-4-Morpholin- -yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
Figure imgf000088_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-propylpyrimidine (CAS 219555-98-3) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 299.4 ([M+H]+).
Example 94
(5-Bromo-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000088_0004
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromopyrimidine (CAS 32779- 37-6) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 337.3 ([{ 81Br}M+H]+), 335.3 ([{79Br}M+H]+).
Example 95
((R)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000089_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4 carboxylic acid tert-butyl ester in step (a). White solid. MS (ISP): 325.3 ([M+H]+).
Example 96
(RS)-5-Chloro-N-(2-fluo -4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000089_0002
a) 2-Bromo-l-(4-bromo-3-fluoro-phenyl)-ethanone & 2-Chloro-l-(4-bromo-3-fluoro-phenyl)- ethanone
To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (5.4 g, CAS 695188-21-7) in acetonitrile (60 ml) and THF (60ml) at 0-5 °C was added dropwise (trimethylsilyl)diazomethane (13.6 ml, 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the reaction was complete. Hydrobromic acid (5.15 ml) was then added dropwise at 0-5 °C and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2C03 solution, water and saturated brine. The organic layer was then dried over Na2S04 and concentrated in vacuo to afford a ca 1: 1 mixture of 2-bromo-l-(4-bromo-3-fluoro-phenyl)- ethanone and 2-chloro-l-(4-bromo-3-fluoro-phenyl)-ethanone (6.16 g) as a light yellow solid which was used in the next step without further purification. MS (EI): 203.2 ([{81Br}Mi-CH2Cl]+ & [{ 81Br}M2-CH2Br]+), 201.2 ([{79Br}Mi-CH2Cl]+ & [{79Br}M2-CH2Br]+). b) (RS)-2-(4-Bromo-3-fluoro-phenyl)-oxirane
To a stirred solution of the mixture of 2-bromo-l-(4-bromo-3-fluoro-phenyl)-ethanone and 2- chloro-l-(4-bromo-3-fluoro-phenyl)-ethanone (6.16 g) in ethanol (100 ml) at 5 °C was added portionwise over 5 min NaBH4 (788 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (562 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2S04 and concentrated in vacuo to afford (RS)-2-(4-bromo-3- fluoro-phenyl)-oxirane (4.69 g) as a yellow oil which was used in the next step without further purification. c) (RS)-l-(4-Bromo-3-fluoro-phenyl)-2-(2-hvdroxy-ethylamino)-ethanol
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) in THF (11 ml) was added 2-aminoethanol (13.2 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers was dried over Na2S04 and concentrated in vacuo to afford (RS)-l-(4-bromo-3- fluoro-phenyl)-2-(2-hydroxy-ethylamino)-ethanol (5.37 g) as a yellow viscous oil which was used in the next step without further purification. MS (ISP): 280.2 ([{81Br}M+H]+), 278.1 ([{79Br}M+H]+). d) (RS)-r2-(4-Bromo-3-fluoro-phenyl)-2-hvdroxy-ethyll-(2-hvdroxy-ethyl)-carbamic acid tert- butyl ester
To a stirred solution of (RS)-l-(4-bromo-3-fluoro-phenyl)-2-(2-hydroxy-ethylamino)-ethanol (5.37 g) in dichloromethane (60 ml) was added Boc20 (4.00 g) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with dichloromethane. The organic layer was washed sequentially with 1 M aq. HC1, sat. aq. NaHC03 solution and saturated brine, then dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 10% MeOH in dichloromethane) to afford (RS)-[2-(4-bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy- ethyl)-carbamic acid tert-butyl ester (3.89 g, 45% over 4 steps) as a light yellow viscous oil. MS (ISP): 380.1 ([{ 81Br}M+H]+), 378.2 ([{79Br}M+H]+). e) (RS)-2-(4-Bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester
To a stirred solution of (RS)-[2-(4-bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)- carbamic acid tert-butyl ester (3.88 g) and triethylamine (1.71 ml) in THF (40 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (873 μΐ). The reaction mixture was then stirred at room temperature for 30 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (6 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl-2-butoxide (9.05 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 1 hour and then poured into water and extracted twice with EtOAc. The combined organic phases were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-bromo-3-fluoro-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (1.73 g, 47%) as an orange viscous oil. MS (ISP): 306.1 ([{81Br}M+H-C4H8]+), 304.1 ([{79Br}M+H-C4H8]+), 262.0 ([{81Br}M+H-C4H8-C02]+), 260.1 ([{79Br}M+H-C4H8-C02]+). f) (RS)-2-r4-(Benzhydrylidene-amino)-3-fluoro-phenyll-morpholine-4-carboxylic acid tert-butyl ester
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert- butyl ester (1.57 g) and benzophenone imine (1.15 ml) in toluene (40 ml) was added sodium tert- butoxide (691 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (280 mg) and tris(dibenzylideneacetone)dipalladium(0) (120 mg) were added and the reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-[4- (benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.215 g, quant.) as a yellow viscous oil. MS (ISP): 461.3 ([M+H]+), 405.4 ([M+H-C4H8]+), 361.3 ([M+H-C4H8-C02]+). g) (RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester
To a stirred solution of tert-butyl (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]- morpholine-4-carboxylic acid tert-butyl ester (2.21 g) in methanol (40 ml) was added ammonium formate (4.54 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (255 mg) was then added and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was then filtered through celite and the filtrate was poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.42 g, 74%) as a white solid. MS (ISP): 319.2 ([M+Na]+), 297.3 ([M+H]+), 241.2 ([M+H-C4H8]+), 197.2 ([M+H-C4H8-C02]+). h) tert-Butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3-fluorophenyl)morpholine-4- carboxylate
(RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg), 2,5- dichloropyrimidine (30.2 mg, CAS 22536-67-0) and cesium carbonate (99 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.03 mg) and
tris(dibenzylideneacetone)dipalladium chloroform complex (6.29 mg) were then added. The reaction mixture was then capped and stirred at 120 °C for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3- fluorophenyl)morpholine-4-carboxylate (26 mg, 31%) as a colourless amorphous solid. MS (ISP): 411.3 ([{37C1}M+H]+), 409.2 ([{35C1}M+H]+), 355.3 ([{37C1}M+H-C4H8]+), 353.3 ([{35C1}M+H-C4H8]+). i) (RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
To a stirred solution of tert-butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3- fluorophenyl)morpholine-4-carboxylate (26 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (49.0 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column
chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (14 mg, 71%) as a white solid. MS (ISP): 311.1 ([{37C1}M+H]+), 309.1 ([{35C1}M+H]+).
Example 97
(RS)-5-Ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000093_0001
The title compound was obtained in analogy to example 96 using 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dichloropyrimidine in step (h). White solid. MS (ISP): 303.2 ([M+H]+).
Example 98
(RS)-5-Cyclopropyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000093_0002
The title compound was obtained in analogy to example 96 using 2-chloro-5- cyclopropylpyrimidine (CAS 166740-44-9) instead of 2,5-dichloropyrimidine in step (h).
solid. MS (ISP): 315.2 ([M+H]+).
Example 99
(RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyridin-2-amine
Figure imgf000093_0003
The title compound was obtained in analogy to example 96 using 2,5-dichloropyridine (CAS 16110-09-1) instead of 2,5-dichloropyrimidine in step (h). Off-white solid. MS (ISP): 310.1 ([{37C1}M+H]+), 308.1 ([{35C1}M+H]+).
Example 100
(RS)-(5-Ethoxy-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000094_0001
a) (RS)-2-r4-(5-Ethoxy-pyrimidin-2-ylam acid tert-butyl ester
To a 10 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, Example 96(e)) and 5-ethoxy-2-pyrimidinamine (40.6 mg, CAS 39268-74-1) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl (13.6 mg), tris(dibenzylideneacetone)dipalladium(0) (7.12 mg) and sodium tert-butoxide (21.0 mg) were then added. The vial was capped and heated at 120 °C for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-[4-(5-ethoxy-pyrimidin-2-ylamino)-3- fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (15 mg, 18%) as a yellow gum. MS (ISP): 441.4 ([M+Na]+), 419.3 ([M+H]+). b) (RS)-(5-Ethoxy-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine
To a stirred solution of (RS)-2-[4-(5-ethoxy-pyrimidin-2-ylamino)-3-fluoro-phenyl]-morpholine- 4-carboxylic acid tert-butyl ester (12 mg) in acetonitrile (1.5 ml) and water (3 ml) was added trifluoroacetic acid (22.0 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 3.5 h. The reaction mixture was then cooled to room temperature and poured into EtOAc and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography
(Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-(5-ethoxy- pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (10 mg, quant.) as an off-white solid. MS (ISP): 319.2 ([ M+H]+).
Example 101
(RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
Figure imgf000094_0002
The title compound was obtained in analogy to example 96 using 2-chloro-5-propylpyrimidine (CAS 219555-98-3) instead of 2,5-dichloropyrimidine in step (h). Off-white solid. MS (ISP): 317.2 ([M+H]+).
Example 102
(RS)-(5-Bromo-pyrimidin- -yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000095_0001
The title compound was obtained in analogy to example 96 using 2,5-dibromopyrimidine (CAS 32779-37-6) instead of 2,5-dichloropyrimidine in step (h). Off-white solid. MS (ISP): 355.3 ([{81Br}M+H]+), 353.1 ([{79Br}M+H]+).
Example 103
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000095_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloropyrimidine (CAS 22536- 67-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 293.1 ([{37C1}M+H]+), 291.1 ([{35C1}M+H]+).
Example 104
(S)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000095_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloropyrimidine (CAS 22536- 67-0) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 293.0
([{37C1}M+H]+), 291.1 ([{35C1}M+H]+). Example 105
(5-Ethoxy-pyrimidi -2-yl)-((R)-4-morpholin-2-yl-phenyl)-
Figure imgf000096_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 5-ethoxy-2-pyrimidinamine (CAS 39268-74-1) instead of 5- trifluoromethyl-pyrimidin-2-ylamine in step (a). White solid. MS (ISP): 301.3 ([M+H]+).
Example 106
(5-Ethyl-pyrimidin-2-yl)- R)-2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000096_0002
a) (R)-tert-Butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylate & (S)-tert-Butyl 2-(4- amino-3-methylphenyl)morpholine-4-carboxylate
The enantiomers of tert-butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (1.18 g, Example 76(f)) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 5 % isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording:
(+)-(R)-tert-Butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (453 mg, yellow oil) Retention time = 120 min
(-)-(S)-tert-Butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (464 mg, yellow oil) Retention time = 152 min b) (5-Ethyl-pyrimidin-2-yl)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine
The title compound was obtained in analogy to example 76 (g)-(h) using (+)-(R)-tert-butyl 2-(4- amino-3-methylphenyl)morpholine-4-carboxylate in place of (RS)-tert-butyl 2-(4-amino-3- methylphenyl)morpholine-4-carboxylate and 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dibromopyridine in step (g). Light brown viscous oil. MS (ISP): 299.4 ([M+H]+).
Example 107
(5-Ethyl-pyrimidin-2-yl)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000097_0001
The title compound was obtained in analogy to example 106 using (-)-(S)-tert-butyl 2-(4-amino- 3-methylphenyl)morpholine-4-carboxylate in place of (+)-(R)-tert-butyl 2-(4-amino-3- methylphenyl)morpholine-4-carboxylate in step (b). Orange viscous oil. MS (ISP): 299.4 ([M+H]+).
Example 108
(R)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
Figure imgf000097_0002
a) (R)-tert-Butyl 2-(6-aminopyridin-3-yl)morpholine-4-carboxylate & (S)-tert-Butyl 2-(6- aminopyridin-3-yl)morpholine-4-carboxylate
The enantiomers of (RS)-tert-butyl 2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (430 mg, Example 90(g)) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 5 % isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording:
(+)-(R)-tert-Butyl 2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (157 mg, light yellow amorphous solid)
Retention time = 93 min
(-)-(S)-tert-Butyl 2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (157 mg, light yellow amorphous solid)
Retention time = 112 min b) (R)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
The title compound was obtained in analogy to example 90 (h)-(i) using (+)-(R)-tert-butyl 2-(6- aminopyridin-3-yl)morpholine-4-carboxylate in place of (RS)-tert-butyl 2-(6-aminopyridin-3- yl)morpholine-4-carboxylate and 2,5-dibromopyridine (CAS 32779-37-6) instead of 2,5- dichloropyridine in step (h). Yellow amorphous solid. MS (ISP): 337.0 ([{ 81Br}M+H]+), 335.1 ([{79Br}M+H]+).
Example 109
(S)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
Figure imgf000098_0001
The title compound was obtained in analogy to example 108 using (-)-(S)-tert-butyl 2-(6- aminopyridin-3-yl)morpholine-4-carboxylate in place of (+)-(R)-tert-butyl 2-(6-aminopyridin-3- yl)morpholine-4-carboxylate in step (b). Yellow amorphous solid. MS (ISP): 337.0
([{81Br}M+H]+), 335.1 ([{79Br}M+H]+).
Example 110
(5-Cyclopropyl-pyrimidin-2- l)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000098_0002
The title compound was obtained in analogy to example 106 using (+)-(R)-tert-butyl 2-(4-amino- 3-methylphenyl)morpholine-4-carboxylate and 2-chloro-5-cyclopropylpyrimidine (CAS 166740- 44-9) instead of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 311.4 ([M+H]+).
Example 111
(5-Cyclopropyl-pyrimidin-2- l)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine
Figure imgf000098_0003
The title compound was obtained in analogy to example 106 using (-)-(S)-tert-butyl 2-(4-amino- 3-methylphenyl)morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4-amino-3- methylphenyl)morpholine-4-carboxylate and 2-chloro-5-cyclopropylpyrimidine (CAS 166740- 44-9) instead of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 311.4 ([M+H]+).
Example 112
-pyrimidin-2-yl)-((S)-4-piperidin-3-yl-phenyl)-amine
Figure imgf000098_0004
The title compound was obtained in analogy to example 5 using (S)-4-(4-amino-phenyl)- piperidine-l-carboxylic acid tert-butyl ester (CAS 1171197-20-8) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 283.4 ([M+H]+).
Example 113
(S)-N-(4-(Morpholi -2-yl)phenyl)-5-phenyl-lH-pyrazol-3-amine
Figure imgf000099_0001
The title compound was obtained in analogy to example 19 using 5-phenyl-lH-pyrazol-3-amine (CAS 1572-10-7) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Orange solid. MS (ISP): 321.1 ([M+H]+).
Example 114
(5-Ethoxy-pyrimidin-2-yl)-((S)-4-piperidin-3-yl-phenyl)-amine
Figure imgf000099_0002
The title compound was obtained in analogy to example 5 using (S)-4-(4-amino-phenyl)- piperidine-l-carboxylic acid tert-butyl ester (CAS 1171197-20-8) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethoxypyrimidine (CAS 82153-68-2) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 299.3 ([M+H]+).
Example 115
(S)-N-(4-(Morpholin-2- l)phenyl)-5-phenyl-l,3,4-oxadiazol-2-amine
Figure imgf000099_0003
The title compound was obtained in analogy to example 19 using 5-phenyl-l,3,4-oxadiazol-2- amine (CAS 1612-76-6) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 323.3 ([M+H]+). Example 116
-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-
Figure imgf000100_0001
a) (+)-(R)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester & (-)-(S)- 2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester
The enantiomers of (RS)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (520 mg, Example 96(g)) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 10 % isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording: (+)-(R)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (146 mg, light yellow solid)
Retention time = 62 min
(-)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (153 mg, off- white solid)
Retention time = 74 min b) (5-Ethyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
The title compound was obtained in analogy to example 96 (h)-(i) using (+)-(R)-2-(4-amino-3- fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (RS)-2-(4-amino-3- fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine (CAS 111196-81-7) instead of 2,5-dichloropyrimidine in step (h). White solid. MS (ISP): 303.3 ([M+H]+).
Example 117
(5-Ethyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000100_0002
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in step (b). Off-white solid. MS (ISP): 303.3 ([M+H]+). Example 118
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000101_0001
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-cyclopropylpyrimidine (CAS 166740-44-9) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 315.1 ([M+H]+).
Example 119
(5-Cyclopropyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000101_0002
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-cyclopropylpyrimidine (CAS 166740-44-9) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 315.1 ([M+H]+).
Example 120
(RS)-N-(5-Bromopyridin-2- l)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine
Figure imgf000101_0003
a) (RS)-2-Bromo-3-methyl-5-(oxiran-2-yl)pyridine
To a stirred suspension of sodium hydride (1.01 g) in THF (20 ml) was added dropwise over 5 min a solution of trimethylsulfonium iodide (4.69 g) in DMSO (20 ml). The reaction mixture was stirred for 5 minand then cooled to 0 °C. A solution of 6-bromo-5-methylnicotinaldehyde (4.6 g, CAS 885167-81-7) in THF (15 ml) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature overnight. The mixture was then poured into EtOAc/Et20 (1: 1) and washed with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-bromo-3-methyl-5-(oxiran-2- yl)pyridine (1.26 g, 26%) as a colourless oil. MS (ISP): 216.1 ([{ 81Br}M+H]+), 214.1
([{79Br}M+H]+). b) (RS)-l-(6-Bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol
To a stirred solution of (RS)-2-bromo-3-methyl-5-(oxiran-2-yl)pyridine (1.4 g) in THF (6 ml) was added 2-aminoethanol (3.92 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1: 1) and the mixture was washed with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford (RS)-l-(6-bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (1.76 g) as an off- white solid which was used in the next step without further purification. MS (ISP): 277.0 ([{81Br}M+H]+), 275.0 ([{79Br}M+H]+), 258.9 ([{81Br}M+H-H20]+), 257.0 ([{79Br}M+H- H20]+). c) tert-Butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)-2-hvdroxyethyl(2-hvdroxyethyl)carbamate To a stirred solution of (RS)-l-(6-bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (1.76 g) in THF (20 ml) was added Boc20 (1.54 g) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into EtOAc and the mixture was washed sequentially with dilute aq. NaOH and saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)-2- hydroxyethyl(2-hydroxyethyl)carbamate (2.57 g) as a colourless oil which was used in the next step without further purification. MS (ISP): MS (ISP): 377.2 ([{81Br}M+H]+), 375.2
([{79Br}M+H]+), 321.0 ([{ 81Br}M+H-C4H8]+), 319.0 ([{79Br}M+H-C4H8]+). d) tert-Butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)-2-hydroxyethyl(2- hydroxyethyl)carbamate (2.57 g) and triethylamine (1.51 ml) in THF (30 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (546 1). The reaction mixture was then stirred at room temperature for 15 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl-2-butoxide (5.62 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 10 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2- (6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.7 g, 73% over 3 steps) as a colourless oil. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H- C4H8]+), 301.0 ([{79Br}M+H-C4H8]+). e) tert-Butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3-yl)morpholine-4- carboxylate
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4- carboxylate (1.7 g) and benzophenone imine (1.2 ml) in toluene (20 ml) was added sodium tert- butoxide (732 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (296 mg) and tris(dibenzylideneacetone)dipalladium(0) (131 mg) were added and the reaction mixture was heated at 100 °C overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.01 g, 46%) as a yellow foam. MS (ISP): 458.3 ([M+H]+). f) tert-Butyl (RS)-2-(6-amino-5-methylpyridin-3-yl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3- yl)morpholine-4 -carboxylate (1.0 g) in ethanol (100 ml) was added ammonium formate (14 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (2.56 mg) was then added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the mixture was washed sequentially with water and with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: heptane/dichloromethane/MeOH) to afford tert-butyl (RS)-2-(6-amino-5- methylpyridin-3-yl)morpholine-4-carboxylate (246 mg, 38%) as a colourless oil. MS (ISP):
294.2 ([M+H]+). g) tert-Butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3-yl)morpholine-4- carboxylate
tert-Butyl (RS)-2-(6-amino-5-methylpyridin-3-yl)morpholine-4-carboxylate (60 mg), 2,5- dibromopyridine (72.7 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (14.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (12.6 mg) were then added. The reaction mixture was then capped and stirred at 100 °C overnight and then at 120 °C for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 100% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3- yl)morpholine-4-carboxylate (26 mg, 28%) as a yellow amorphous solid. MS (ISP): 451.1 ([{81Br}M+H]+), 449.1 ([{79Br}M+H]+). h) (RS)-N-(5-Bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine
To a stirred solution of tert-butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3- yl)morpholine-4-carboxylate (26 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (45 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-N-(5- bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine (11 mg, 54%) as a colourless amorphous solid. MS (ISP): 351.1 ([{81Br}M+H]+), 349.1 ([{79Br}M+H]+).
Example 121
(RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000104_0001
a) (RS)-2-r3-Fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyll-morpholine-4- carboxylic acid tert-butyl ester To a 20 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (200 mg, example 96(e)) and 5-trifluoromethyl-pyrimidin-2-ylamine (145 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (38.9 mg),
tris(dibenzylideneacetone)dipalladium(0) (20.3 mg) and sodium tert-butoxide (59.9 mg) were then added. The vial was capped and heated at 120 °C for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (115 mg, 47%) as a yellow gum. MS (ISP): 441.4 ([M-H]"). b) (RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
To a stirred solution of (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholine-4-carboxylic acid tert-butyl ester (110 mg) in acetonitrile (2 ml) and water (4 ml) was added trifluoroacetic acid (190 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc) to (RS)-(2-fluoro- 4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (23 mg, 27%) as a white solid. MS (ISP): 343.1 ([M+H]+).
Example 122
(5-Isopropoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000105_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(l-methylethoxy)- pyrimidine (CAS 169677-67-2) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 315.1 ([M+H]+).
Example 123
(5-Isopropoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000106_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(l-methylethoxy)- pyrimidine (CAS 169677-67-2) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 315.1 ([M+H]+).
Example 124
(S)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000106_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(cyclopropylmethoxy)- pyrimidine (CAS 169677-66-1) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 327.2 ([M+H]+).
Example 125
(R)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000106_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(cyclopropylmethoxy)- pyrimidine (CAS 169677-66-1) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 327.2 ([M+H]+).
Example 126
(5-Bromo-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000107_0001
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromopyrimidine (CAS 32779- 37-6) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 355.0
([{81Br}M+H]+), 353.0 ([{79Br}M+H]+).
Example 127
(5-Bromo-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000107_0002
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dibromopyrimidine (CAS 32779- 37-6) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 355.0
([{81Br}M+H]+), 353.0 ([{79Br}M+H]+). Example 128
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
Figure imgf000107_0003
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-n-propylpyrimidine (CAS 219555-98-3) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 317.2 ([M+H]+).
Example 129
((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
Figure imgf000108_0001
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-n-propylpyrimidine (CAS 219555-98-3) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 317.3 ([M+H]+).
Example 130
(5-Chloro-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000108_0002
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloropyrimidine (CAS 22536- 67-0) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 309.3 ([M+H]+)
Example 131
(5-Chloro-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000108_0003
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloropyrimidine (CAS 22536- 67-0) in place of 2-chloro-5-ethylpyrimidine in step (b). Off-white solid. MS (ISP): 309.3 «M+H]+).
Example 132
(5-Ethoxy-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000109_0001
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethoxypyrimidine (CAS 82153-68-2) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 319.2 ([M+H]+).
Example 133
(5-Ethoxy-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
Figure imgf000109_0002
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-ethoxypyrimidine (CAS 82153-68-2) in place of 2-chloro-5-ethylpyrimidine in step (b). Off-white solid. MS (ISP): 319.2 «M+H]+).
Example 134
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000109_0003
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(trifluoromethyl)- pyrimidine (CAS 69034-12-4) in place of 2-chloro-5-ethylpyrimidine in step (b). Yellow solid. MS (ISP): 343.1 ([M+H]+).
Example 135
((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000110_0001
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(trifluoromethyl)- pyrimidine (CAS 69034-12-4) in place of 2-chloro-5-ethylpyrimidine in step (b). Yellow solid. MS (ISP): 343.1 ([M+H]+).
Example 136
((S)-4-Morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000110_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 145948-01-2) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 355.2 ([M+H]+).
Example 137
((R)-4-Morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000110_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 145948-01-2) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 355.2 ([M+H]+).
Example 138
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000111_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2- methoxyethoxy)pyrimidine (CAS 61533-68-4) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 331.2 ([M+H]+).
Example 139
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000111_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2- methoxyethoxy)pyrimidine (CAS 61533-68-4) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 331.2 ([M+H]+).
Example 140
(RS)-(l-Methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000111_0003
The title compound was obtained in analogy to example 19 using (RS)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4 carboxylic acid tert-butyl ester and 3-amino-l-methylpyrazole (CAS 1904-31-0) instead of 5- trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 259.2 ([M+H]+).
Example 141
[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000112_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(3,4- dimethoxyphenyl)pyrimidine (CAS 76972-10-6) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 393.2 ([M+H]+).
Example 142
[5-(3,4-Dimethoxy-pheny -pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-
Figure imgf000112_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(3,4- dimethoxyphenyl)pyrimidine (CAS 76972-10-6) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 393.2 ([M+H]+).
Example 143
(RS)-(4-Bromo-l-methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000112_0003
The title compound was obtained in analogy to example 19 using (RS)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 3-amino-4-bromo-l-methylpyrazole (CAS 146941-72-2) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 339.1 ([{81Br}M+H]+), 337.2 ([{ 81Br}M+H]+). Example 144
((R)-2-Fluoro-4-morpholin-2- -phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000113_0001
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 145948-01-2) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 373.1 ([M+H]+).
Example 145
((S)-2-Fluoro-4-morpholin-2- -phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000113_0002
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 145948-01-2) in place of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 373.1 ([M+H]+).
Example 146
(RS)-(l-Cyclopropylmethyl- -pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000113_0003
The title compound was obtained in analogy to example 19 using (RS)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and [l-(cyclopropylmethyl)-lH-pyrazol-3-yl]amine (CAS 899899-07-1) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 299.3 ([M+H]+). Example 147
(5-Furan-2-yl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000114_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2-furanyl)-pyrimidine (CAS 63558-66-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 323.2 «M+H]+).
Example 148
(5-Furan-2-yl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000114_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2-furanyl)-pyrimidine (CAS 63558-66-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 323.2 ([M+H]+).
Example 149
(RS)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
Figure imgf000114_0003
a) 2-Bromo-l-(4-bromo-3-chlorophenyl)ethanone & 2-Chloro-l-(4-bromo-3- chlorophenvPethanone
To a stirred solution of 4-bromo-3-chlorobenzoyl chloride (16.4 g, CAS 21900-32-3) in acetonitrile (80 ml) and THF (120ml) at 0-5 °C was added dropwise
(trimethylsilyl)diazomethane (38.8 ml, 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the reaction was complete. Hydrobromic acid (14.6 ml) was then added dropwise at 0-5 °C and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2C03 solution, water and saturated brine. The organic layer was then dried over Na2S04 and concentrated in vacuo to afford a ca 1: 1 mixture of 2-bromo-l- (4-bromo-3-chlorophenyl)ethanone and 2-chloro-l-(4-bromo-3-chlorophenyl)ethanone (18.4 g) as a brown solid which was used in the next step without further purification. b) (RS)-2-(4-Bromo-3-chloro-phenyl)-oxirane
To a stirred solution of the mixture of 2-bromo-l-(4-bromo-3-chlorophenyl)ethanone and 2- chloro-l-(4-bromo-3-chlorophenyl)ethanone (18.4 g) in ethanol (200 ml) at 5 °C was added portionwise over 5 min NaBH4 (2.23 g). The reaction mixture was then stirred at room temperature for 90 min to afford a yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (1.59 g) was then added and the reaction mixture was stirred at 50 °C for 4 h. TLC analysis showed the reaction was complete. The reaction mixture was then poured into TBME and washed with saturated brine. The organic layer was separated, then dried over Na2S04 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-chloro-phenyl)-oxirane (15.2 g) as a brown oil which was used in the next step without further purification. c) (RS)-l-(4-bromo-3-chlorophenyl)-2-(2-hvdroxyethylamino)ethanol
To a stirred solution of (RS)-2-(4-bromo-3-chloro-phenyl)-oxirane (15.2 g) in THF (40 ml) was added 2-aminoethanol (35.1 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into EtOAc/THF (1: 1) and washed with saturated brine. The organic layer was separated and was then dried over Na2S04 and concentrated in vacuo to afford (RS)-l-(4-bromo-3-chlorophenyl)-2-(2-hydroxyethylamino)ethanol (19.0 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 298.1
([{81Br37Cl}M+H]+), 296.0 ([{81Br35Cl or 79Br37Cl }M+H]+), 293.9 ([{79Br35Cl}M+H]+). d) tert-Butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hvdroxyethyl(2-hvdroxyethyl)carbamate
To a stirred solution of (RS)-l-(4-bromo-3-chlorophenyl)-2-(2-hydroxyethylamino)ethanol (19.0 g) in dichloromethane (200 ml) at 0 °C was added Boc20 (14.1 g) and the mixture was then stirred at room temperature overnight. The reaction mixture was then poured into EtOAc and the mixture was washed sequentially with dilute aq. sodium hydroxide and with saturated brine. The organic phase was separated and then dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: MeOH/dichloromethane 20/1) to afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (12.7 g, 50% over 4 steps) as a yellow oil. MS (ISP): 398.0 ([{81Br37Cl}M+H]+), 395.9
([{81Br35Cl or 79Br37Cl }M+H]+), 393.9 ([{79Br35Cl}M+H]+). e) tert-Butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hydroxyethyl(2- hydroxyethyl)carbamate (12.7 g) and triethylamine (6.72 ml) in THF (150 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (2.76 ml). The reaction mixture was then stirred at room temperature for 60 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl-2-butoxide (28.4 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and washed sequentially with dilute aq. HC1, water and saturated brine. The organic phase was separated and was then dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (9.32 g, 77%) as a yellow oil. MS (ISP): 324.0 ([{81Br37Cl}M+H-C4H8]+), 321.9 ([{81Br35Cl or 79Br37Cl}M+H- C4H8]+), 319.9 ([{79Br35Cl}M+H-C4H8]+), 279.9 ([{ 81Br37Cl}M+H-C4H8-C02]+), 277.9
([{81Br35Cl or 79Br37Cl}M+H-C4H8-C02]+), 276.0 ([{79Br35Cl}M+H-C4H8-C02]+). f) tert-Butyl (RS)-2-(3-chloro-4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate To a stirred solution of afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4- carboxylate (0.50 g) and benzophenone imine (253 mg) in toluene (5 ml) was added sodium tert- butoxide (204 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (82.7 mg) and tris(dibenzylideneacetone)dipalladium(0) (36.5 mg) were added and the reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was poured into EtOAc and washed sequentially with dilute aq. HC1, water and saturated brine. The organic phase was separated and was then dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4- (diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (639 mg, quant.) as a yellow oil. MS (ISP): 479.1 ([{37C1}M+H]+), 477.1 ([{35C1}M+H]+). g) tert-Butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate
To a stirred solution of tert-butyl (RS)-2-(3-chloro-4-
(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (0.63 g) in methanol (8 ml) were added sodium acetate (325 mg) and hydroxylamine hydrochloride (202 mg). The reaction mixture was stirred at room tempearture for 16 hours and then at 60 °C for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (345 mg, 84%) as a white solid. MS (ISP): 337.2 ([{37C1}M+Na]+), 335.1 ([{35C1}M+Na]+), 314.9 ([{37C1}M+H]+), 313.0 ([{35C1}M+H]+), 259.1 ([{37C1}M+H-C4H8]+), 257.1 ([{35C1}M+H-C4H8]+), 215.3 ([{37C1}M+H-C4H8-C02]+), 213.0 ([{35C1}M+H-C4H8-C02]+). h) tert-Butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2-ylamino)phenyl)morpholine-4- carboxylate
tert-Butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (70 mg), 2-chloro-5- cyclopropylpyrimidine (45.0 mg, CAS 166740-44-9) and cesium carbonate (109 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.77 mg) and
tris(dibenzylideneacetone)dipalladium chloroform complex (6.95 mg) were then added. The reaction mixture was then capped and stirred at 120 °C for 16 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2- ylamino)phenyl)morpholine-4-carboxylate (48 mg, 50%) as a colourless amorphous solid. MS (ISP): 433.2 ([{37C1}M+H]+), 431.2 ([{35C1}M+H]+). i) (RS)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cvclopropylpyrimidin-2-amine
To a stirred solution of tert-butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2- ylamino)phenyl)morpholine-4-carboxylate (35 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (77.3 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-N-(2-chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine (28 mg, 76%) as a white solid. MS (ISP): 333.1 ([{37C1}M+H]+), 331.1 ([{35C1}M+H]+).
Example 150
(RS)-[l-(2,2-Difluoro-ethyl -lH-pyrazol-3-yl]-(4-morpholin-2-yl-phenyl)-amine
Figure imgf000118_0001
The title compound was obtained in analogy to example 19 using (RS)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and l-(2,2-difluoro-ethyl)-lH-pyrazol-3-ylamine (CAS 1006462- 38-9) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 309.4 ([M+H]+).
Example 151
((R)-2-Fluoro-4-morpholin- -yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000118_0002
The title compound was obtained in analogy to example 116 using (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2- methoxyethoxy)pyrimidine (CAS 61533-68-4) in place of 2-chloro-5-ethylpyrimidine in step (b). Colourless gum. MS (ISP): 349.2 ([M+H]+).
Example 152
((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000118_0003
The title compound was obtained in analogy to example 116 using (-)-(S)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-(4-amino-3-fluoro- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(2- methoxyethoxy)pyrimidine (CAS 61533-68-4) in place of 2-chloro-5-ethylpyrimidine in step (b). Colourless gum. MS (ISP): 349.2 ([M+H]+). Example 153
((S)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
Figure imgf000119_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-chloro-2-trifluoromethylpyrimidine (CAS 845618-08-8) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 325.3 «M+H]+).
Example 154
((R)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
Figure imgf000119_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 5-chloro-2-trifluoromethylpyrimidine (CAS 845618-08-8) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 325.3 ([M+H]+).
Example 155
(RS)-(4-Morpholin- -yl-phenyl)-(lH-pyrazol-3-yl)-amine
Figure imgf000119_0003
The title compound was obtained in analogy to example 19 using (RS)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 3-aminopyrazole-l-carboxylic acid tert-butyl ester (CAS 863504-84-1) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Orange gum. MS (ISP): 245.3 ([M+H]+).
Example 156
(5-Methyl-pyrazin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000120_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-methylpyrazine (CAS 59303-10-5) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 271.4 ([M+H]+).
Example 157
(5-Methyl-pyrazin- -yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000120_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-methylpyrazine (CAS 59303-10-5) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 271.4 ([M+H]+).
Example 158
2-((S)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide
Figure imgf000120_0003
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-N-methylpyrimidine-5- carboxamide instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 314.2 ([M+H]+). Example 159
2-((R)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide
Figure imgf000121_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-N-methylpyrimidine-5- carboxamide instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 314.2 ([M+H]+).
Example 160
(6-Methyl-pyridazin- -yl)-((S)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000121_0002
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 3-chloro-6-methylpyridazine (CAS 1121-79-5) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 271.4
([M+H]+).
Example 161
(l-Benzyl-lH-pyrazol-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
The title compound was obtained in analogy to example 19 using 1 -benzyl- lH-pyrazol-3- ylamine (CAS 21377-09-3) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off- white solid. MS (ISP): 335.4 ([M+H]+).
Example 162
(l-Benzyl-lH-pyrazol-3-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000122_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and l-benzyl-lH-pyrazol-3-ylamine (CAS 21377-09-3) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off-white solid. MS (ISP): 335.4 ([M+H]+).
Example 163
((S)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
Figure imgf000122_0002
The title compound was obtained in analogy to example 19 using 1 -phenyl- lH-pyrazol-3- ylamine (CAS 1128-56-9) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Off- white solid. MS (ISP): 321.2 ([M+H]+).
Example 164
((R)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
Figure imgf000122_0003
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and l-phenyl-lH-pyrazol-3-ylamine (CAS 1128-56-9) instead of 5-trifluoromethyl-pyrimidin-2-ylamine in step (a). Light yellow solid. MS (ISP): 321.2
([M+H]+).
Example 165
((S)-4-Morpholin-2-yl-phenyl)-(5-oxetan-3-yl-pyridin-2-yl)-amine
Figure imgf000122_0004
a) 2-Chloro-5-oxetan-3-yl-pyridine
To a solution of 2-chloropyridine-5-boronic acid (315 mg, CAS 444120-91-6) in isopropanol (2 ml) in a 10 mL microwave vial were added nickel iodide (18.8 mg), trans-2-aminocyclohexanol hydrochloride (9.21 mg) and sodium bis(trimethylsilyl)amide (387 mg). Argon was bubbled into the reaction mixture for 5 min. A solution of 3-iodo-oxetane (190 mg, CAS 26272-85-5) in isopropanol (0.25 ml) was then added. The vial was then capped and heated in the microwave at 80 °C for 20 min. TLC at t = 20 min showed the reaction was complete. The reaction mixture was diluted with EtOH and filtered through celite. The filter cake was washed with EtOH and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford 2-chloro-5-oxetan-3-yl-pyridine (40 mg, 24%) as a white solid. b) ((S)-4-Morpholin-2-yl-phenyl)-(5-oxetan-3-yl-pyridin-2-yl)-amine
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-oxetan-3-yl-pyridine instead of 2,5-dichloropyridine in step (a). Light brown solid. MS (ISP): 312.3 ([M+H]+).
Example 166
((R)-2-Methyl-4-morpholin-2- l-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000123_0001
The title compound was obtained in analogy to example 106 using (+)-(R)-tert-butyl 2-(4-amino- 3-methylphenyl)morpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)-pyrimidine (CAS 69034-12-4) instead of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 339.3 ([M+H]+).
Example 167
((S)-2-Methyl-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000123_0002
The title compound was obtained in analogy to example 106 using (-)-(S)-tert-butyl 2-(4-amino- 3-methylphenyl)morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4-amino-3- methylphenyl)morpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)-pyrimidine (CAS 69034-12-4) instead of 2-chloro-5-ethylpyrimidine in step (b). White solid. MS (ISP): 339.3 ([M+H]+).
Example 168
((R)-2-Chloro-4-morpholin- - -phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000124_0001
a) (RS)-2-r3-Chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyll-moipholine-4- carboxylic acid tert-butyl ester
The title compound was obtained in analogy to example 149 step (h) using 2-chloro-5- (trifluoromethyl)-pyrimidine (CAS 69034-12-4) instead of 2-chloro-5-cyclopropylpyrimidine.
Colourless gum. MS (ISP): 461.3 ([{37C1}M+H]+), 459.3 ([{35C1}M+H]+), 405.3 ([{37C1}M+H- C4H8]+), 403.2 ([{35C1}M+H-C4H8]+). b) (+)-(R)-2-r3-Chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyll-morpholine-4- carboxylic acid tert-butyl ester & (-)-(S)-2-r3-Chloro-4-(5-trifluoromethyl-pyrimidin-2- ylamino)-phenyll-morpholine-4-carboxylic acid tert-butyl ester
The enantiomers of (RS)-2-[3-chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholine-4-carboxylic acid tert-butyl ester (130 mg) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 30 % isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording:
(+)-(R)-2-[3-Chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester (35 mg, white solid)
Retention time = 62 min
(-)-(S)-2-[3-Chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (33 mg, white solid)
Retention time = 92 min c) ((R)-2-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine The title compound was obtained in analogy to example 149 step (i) using (+)-(R)-2-[3-chloro-4- (5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester in place of (RS)-2-[3-chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester. White solid. MS (ISP): 361.1 ([{37C1}M+H]+), 359.1
([{35C1}M+H]+).
Example 169
((S)-2-Chloro-4-morpholin-2- -phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000125_0001
The title compound was obtained in analogy to example 168 using (-)-(S)-2-[3-chloro-4-(5- trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester in place of (+)-(R)-2-[3-chloro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4- carboxylic acid tert-butyl ester in step (c). Colourless gum. MS (ISP): 361.1 ([{37C1}M+H]+), 359.1 ([{35C1}M+H]+).
Example 170
(R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
Figure imgf000125_0002
a) (+)-(R)-tert-Butyl 2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate & (-HS)-tert-Butyl 2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate
The enantiomers of (RS) -tert-butyl 2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (2.0 g, Example 149(g)) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 10 % isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording:
(+)-(R)-tert-Butyl 2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (894 mg, white solid) Retention time = 60 min
(-)-(S)-tert-Butyl 2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (934 mg, white solid) Retention time = 76 min b) (R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cvclopropylpyrimidin-2-amine The title compound was obtained in analogy to example 149 (h)-(i) using (+)-(R)-tert-butyl 2-(4- amino-3-chlorophenyl)morpholine-4-carboxylate in place of (RS)-tert-butyl 2-(4-amino-3- chlorophenyl)morpholine-4-carboxylate in step (h). White solid. MS (ISP): 333.1
([{37C1}M+H]+), 331.1 ([{35C1}M+H]+).
Example 171
(S)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
Figure imgf000126_0001
The title compound was obtained in analogy to example 170 using (-)-(S)-tert-butyl 2-(4- 3-chlorophenyl)morpholine-4-carboxylate in place of (+)-(R)-tert-butyl 2-(4-amino-3- chlorophenyl)morpholine-4-carboxylate in step (b). Off-white solid. MS (ISP): 333.1
([{37C1}M+H]+), 331.1 ([{35C1}M+H]+).
Example 172
((R)-4-Morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000126_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 935252-67-8) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 355.1 ([M+H]+).
Example 173
(R)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine
Figure imgf000126_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-trifluoromethylpyrimidine (CAS 33034-67-2) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 325.1 ([M+H]+).
Example 174
(R)-5-(5-(Difluoromethoxy)pyrimidin-2-yloxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2- amine
Figure imgf000127_0001
a) 2-Chloro-5-(5-(difluoromethoxy)pyrimidin-2-yloxy)pyrimidine
2-Chloropyrimidin-5-ol (0.5 g) was combined with DMF (5 ml) to give a colourless solution. K2CO3 (582 mg) and ethyl 2-chloro-2,2-difluoroacetate (534 μΐ) were then added. The reaction mixture was stirred at 70 °C overnight to afford a brown suspension. The reaction mixture was then poured into EtOAc and washed sequentially with water and with saturated brine. The organic layer was separated, dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 60% EtOAc in hexanes) to afford 2-chloro-5-(5-(difluoromethoxy)pyrimidin-2-yloxy)pyrimidine (154 mg, 15%) as a yellow solid. MS (ISP): 277.0 ([{37C1}M+H]+), 275.0 ([{35C1}M+H]+). b) (R)-5-(5-(Difluoromethoxy)pyrimidin-2-yloxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2- amine
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(5- (difluoromethoxy)pyrimidin-2-yloxy)pyrimidine instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 417.1 ([M+H]+). Example 175
(R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-(5-(difluoromethoxy)pyrimidin-2- yloxy)pyrimidin-2-amine
F
Figure imgf000128_0001
The title compound was obtained in analogy to example 170 using 2-chloro-5-(5-
(difluoromethoxy)pyrimidin-2-yloxy)pyrimidine (Example 174(a)) in place 2-chloro-5- cyclopropylpyrimidine in step (b). Colourless amorphous solid. MS (ISP): 453.1
([{37C1}M+H]+), 451.1 ([{35C1}M+H]+). Example 176
(R)-N-(4-(Morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000128_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-pyrimidine (CAS 1722-12-9) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 257.1 ([M+H]+).
Example 177
((R)-4-Morpholin-2-yl-phenyl)-quinazolin-2-yl-amine
Figure imgf000128_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4 phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloroquinazoline (CAS 6141-13-5) instead of 2,5-dichloropyridine in step (a). Light yellow solid. MS (ISP): 307.2 ([M+H]+).
Example 178
(4-Methyl-6-trifluoromethyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-
Figure imgf000129_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 4-methyl-6-(trifluoromethyl)pyrimidin-2-amine (CAS 5734- 63-4) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 339.1 ([M+H]+).
Example 179
(R)-5-(Difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000129_0002
a) (R)-tert-Butyl 2-(4-(5-(benzyloxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate The title compound was obtained in analogy to example 5 using ®-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(phenylmethoxy)- pyrimidine (CAS 138274-14-3) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 463.2 ([M+H]+), 407.3 ([M+H-C4H8]+). b) (R)-tert-Butyl 2-(4-(5-hvdroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate
(R)-tert-Butyl 2-(4-(5-(benzyloxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.36 g) was combined with MeOH (15 ml) and THF (5 ml) to give a light brown solution. The mixture was degassed by bubbling through argon for several minutes. Palladium on charcoal (41.4 mg, 10%) was added. The reaction mixture was then stirred under a balloon filled with argon overnight. The reaction mixture was then filtered through celite and concentrated in vacuo to afford (R) -tert-butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (311 mg, quant.) as a light brown foam which was used in the next step without further purification. MS (ISP): 373.2 ([M+H]+). c) (R)-tert-Butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2-ylamino)phenyl)morpholine-4- carboxylate
(R)-tert-Butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.24 g) and K2CO3 (124 mg) were combined with DMF (2 ml) to give a brown solution. Ethyl 2-chloro- 2,2-difluoroacetate (152 mg) was then added. The reaction mixture was stirred at 80 °C for 1.5 h to afford a dark brown suspension. TLC & HPLC showed the reaction was complete. The reaction mixture was poured into EtOAc and washed sequentially with water and with saturated brine. The organic layer was separated, dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2- ylamino)phenyl)morpholine-4-carboxylate (60 mg, 24%) as a yellow oil. MS (ISP): 423.1 ([M+H]+), 367.0 ([M+H-C4H8]+). d) (R)-5-(Difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(R)-tert-Butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (58 mg) was combined with acetonitrile (2 ml) and water (6 ml). Trifluoroacetic acid (138 μΐ) was added. The vial was capped and shaken at 80 °C for 4 hours. The reaction mixture was then poured into EtOAc/THF (1: 1) and washed with 1 M aq. NaOH. The organic layer was separated, dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (R)-5-(difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (31 mg, 70%) as a white solid. MS (ISP): 323.1 ([M+H]+).
Example 180
(4-Chloro-6-methoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-
Figure imgf000130_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 2-amino-4-chloro-6-methoxypyrimidine (CAS 5734-64-5) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 323.3 ([{37C1}M+H]+), 321.2 ([{35C1}M+H]+).
Example 181
2-((R)-4-Morpholin-2- -phenylamino)-pyrimidine-4-carbonitrile
Figure imgf000131_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloropyrimidine-4-carbonitrile (CAS 75833-38-4) instead of 2,5-dichloropyridine in step (a). Light yellow solid. MS (ISP): 282.2 ([M+H]+).
Example 182
(4,6-Dimethyl-pyrimid -2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000131_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4,6-dimethylpyrimidine (CAS 4472-44-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 285.1 ([M+H]+).
Example 183
(4,6-Dimethoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000131_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4,6-dimethoxypyrimidine (CAS 13223-25-1) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 317.1 ([M+H]+).
Example 184
((R)-2-Chloro-4-morpholin-2- -phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000132_0001
The title compound was obtained in analogy to example 170 using 2-chloro-5-(2,2,2- trifluoroethoxy)-pyrimidine (CAS 145948-01-2) in place of 2-chloro-5-cyclopropylpyrimidine in step (b). White solid. MS (ISP): 391.3 ([{37C1}M+H]+), 389.2 ([{35C1}M+H]+).
Example 185
(R)-3-Chloro-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000132_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,3-dichloro-5- (trifluoromethyl)pyridine (CAS 69045-84-7) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 358.1 ([{35C1}M+H]+), 360.1 ([{37C1}M+H]+).
Example 186
(S)-2,5-Dichloro-N-(4- morpholin-2-yl)phenyl)pyrimidin-4-amine
Figure imgf000132_0003
a) (S)-tert-Butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate
A mixture of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 2,4,5-trichloropyrimidine (66 mg, 0.36 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in 2-propanol (1.5 ml) and stirred at 80 °C overnight. For work-up most of the solvent was evaporated, then aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, 10 to 30 % ethyl acetate in heptane) to yield a white solid (141 mg, 92%). MS (ISP): 425.1 ([{35C1}M+H]+), 427.1 ([{37C1}M+H]+). b) (S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine hydrochloride
(S)-tert-Butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (45 mg, 0.106 mmol) was dissolved in dioxane (0.5 ml) and a solution of HC1 in dioxane (4 M, 0.3 ml, 1.27 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. After cooling, ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2,5-dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine hydrochloride (38 mg, 99%) as a white solid. MS (ISP): 325.1 ([{35C1}M+H]+), 327.1 ([{37C1}M+H]+). Example 187
((S)-4-Morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000133_0001
The title compound was obtained in analogy to example 5 using (S)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-43-6) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-(2,2,2-trifluoroethoxy)- pyrimidine (CAS 935252-67-8) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 355.2 ([M+H]+).
Example 188
[5-Fluoro-4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000133_0002
a) 2-Chloro-5-fluoro-4-(2,2,2-trifluoro-ethoxy)-pyrimidine
2,4-Dichloro-5-fluoropyrimidine (100 mg, CAS 2927-71-1) was combined with trifluoroethanol (1.09 ml) to give a colourless solution. Potassium carbonate (82.8 mg) was added. The reaction mixture was stirred at room temperature for 30 min. TLC at t = 30 min showed the reaction was complete. The reaction mixture was filtered through sintered glass and concentrated in vacuo. The residue was triturated with diethyl ether, then filtered through sintered glass and dried in vacuo.
b) r5-Fluoro-4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yll-((R)-4-morpholin-2-yl-phenyl)-amine The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-fluoro-4-(2,2,2-trifluoro- ethoxy)-pyrimidine instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 373.2 ([M+H]+).
Example 189
(4-Cyclopropyl-pyrimidin-2- l)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000134_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-cyclopropylpyrimidine (CAS 954237-31-1) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 297.3 ([M+H]+).
Example 190
(4-Cyclopropyl-5-fluoro-p rimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
Figure imgf000134_0002
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2-chloro-4-cyclopropyl-5-fluoro- pyrimidine (CAS 1312535-71-9) instead of 2,5-dichloropyridine in step (a). Off-white solid. MS (ISP): 315.2 ([M+H]+). Example 191
(4-Pentafluorosulfany -phenyl)-((R)-4-morpholin-2-yl-phenyl)-
Figure imgf000135_0001
The title compound was obtained in analogy to example 19 using (R)-2-(4-bromo-phenyl)- morpholine-4-carboxylic acid tert-butyl ester instead of (S)-2-(4-bromo-phenyl)-morpholine-4- carboxylic acid tert-butyl ester and 4-(pentafluorosulfanyl)aniline (CAS 2993-24-0) instead of 2,5-dichloropyridine in step (a). White solid. MS (ISP): 381.2 ([M+H]+).
Example 192
(R)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000135_0002
a) 1 - (4 -B romo-2-fluorophenyl) -2-chloroethanone
To a stirred solution of 4-bromo-2-fluorobenzoyl chloride (33 g, CAS 151982-51-3) in acetonitrile (150 ml) and THF (150ml) at 0-5 °C was added dropwise
(trimethylsilyl)diazomethane (83.4 ml, 2 M solution in hexane). The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the reaction was complete. 37%
Hydrochloric acid (23.2 ml) was then added dropwise at 0-5 °C and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2C03 solution, water and saturated brine. The organic layer was then dried over Na2S04 and concentrated in vacuo to afford a ca 1: 1 mixture of 2-bromo-l- (4-bromo-3-fluoro-phenyl)-ethanone and 2-chloro-l-(4-bromo-3-fluoro-phenyl)-ethanone (34.4 g, 98%) as a yellow solid which was used in the next step without further purification. MS (EI): 203 ([{ 81Br}M-CH2Cl]+, 201 ([{79Br}M-CH2Cl]+). b) (RS)-2-(4-Bromo-2-fluorophenyl)oxirane
To a stirred solution of l-(4-bromo-2-fluorophenyl)-2-chloroethanone (5.57 g) in ethanol (100 ml) at 5 °C was added portionwise over 5 min NaBH4 (838 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (2.06 ml, 30% solution in methanol) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed the reaction was complete. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2S04 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 5% to 40% EtOAc in heptane) to afford (RS)-2-(4-bromo-2-fluorophenyl)oxirane (1.35 g, 28%) as a light yellow oil which was used in the next step without further purification. MS (EI): 218 ([{81Br}M]+, 216 ([{79Br}M]+). c) (RS)-l-(4-Bromo-2-fluorophenyl)-2-(2-hvdroxyethylamino)ethanol
To a stirred solution of (RS)-2-(4-bromo-2-fluorophenyl)oxirane (12.3 g) in THF (40 ml) was added 2-aminoethanol (33.9 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (3: 1) and washed with saturated brine. The organic layer was separated, dried over Na2S04 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 0% to 35% MeOH in
dichloromethane containing a few drops of aq. NH3) to afford (RS)-l-(4-bromo-2-fluorophenyl)- 2-(2-hydroxyethylamino)ethanol (12.0 g, 76%) as a brown oil. MS (ISP): 280.0 ([{81Br}M+H]+), 278.0 ([{79Br}M+H]+). d) (RS)-tert-Butyl 2-(4-bromo-2-fluorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate
To a stirred solution of (RS)-l-(4-bromo-2-fluorophenyl)-2-(2-hydroxyethylamino)ethanol (12.0 g) in THF (70 ml) at 0 °C was added Boc20 (10.4 g) and the mixture was stirred at 0 °C for 1 hour and then at room temperature overnight. The reaction mixture was then poured into EtOAc and the mixture washed sequentially with 1 M aq. NaOH solution and saturated brine, then dried over Na2S04 and concentrated in vacuo to afford (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)-2- hydroxyethyl(2-hydroxyethyl)carbamate (15.5 g, 95%) as a yellow oil which was used in the next step without further purification. MS (ISP): 380.0 ([{ 81Br}M+H]+), 378.0 ([{79Br}M+H]+). e) (RS)-tert-Butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate
To a stirred solution of (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)-2-hydroxyethyl(2- hydroxyethyl)carbamate (15.5 g) and triethylamine (9.85 ml) in THF (120 ml) at 0-5 °C was added dropwise methanesulfonyl chloride (3.35 ml). The reaction mixture was then stirred at room temperature for 1 hour to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5 °C and potassium 2-methyl-2-butoxide (36.2 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 20 min and then poured into EtOAc and washed sequentially with 1 M aq. HC1, water and saturated brine. The organic phase was separated, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-tert- butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (6.46 g, 44%) as a yellow oil. MS (EI): 305 ([{81Br}M-C4H8]+), 303 ([{79Br}M-C4H8]+), 260 ([{81Br}M-C4H8-C02H]+), 258 ([{79Br}M-C4H8-C02H]+). f) (-HS)-tert-Butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate & (+)-(R)-tert-Butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate
The enantiomers of afford (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (6.46 g) were separated using chiral HPLC (column: Chiralpak AD, 5 x 50 cm; eluent: 4% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) affording:
(-)-(S)-tert-Butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (2.79 g, light yellow solid)
Retention time = 28 min
(+)-(R)-tert-Butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (2.84 g, white solid) Retention time = 35 min g) (R)-tert-Butyl 2-(4-(diphenylmethyleneamino)-2-fluorophenyl)morpholine-4-carboxylate To a stirred solution of (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (4.3 g) and benzophenone imine (2.2 ml) in toluene (20 ml) was added sodium tert-butoxide (1.84 g). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2'-
Bis(diphenylphosphino)-l,l'-binaphthyl (743 mg) and tris(dibenzylideneacetone)dipalladium(0) (328 mg) were added and the reaction mixture was heated to 90 °C and stirred for 90 min. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 40% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4- (diphenylmethyleneamino)-2-fluorophenyl)morpholine-4-carboxylate 5.95 g, quant.) as a yellow amorphous solid. MS (ISP): 461.2 ([M+H]+). h) (R)-tert-Butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate
To a stirred solution of (R)-tert-butyl 2-(4-(diphenylmethyleneamino)-2- fluorophenyl)morpholine-4-carboxylate (5.95 g) in methanol (50 ml) were added sodium acetate (2.93 g) and hydroxylamine hydrochloride (1.82 g). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-amino-2- fluorophenyl)morpholine-4-carboxylate (3.0 g, 85%) as a yellow solid. MS (ISP): 296 ([M]+), 240 ([M-C4H8]+), 195 ([M+H-C4H8-C02H]+). i) (R)-tert-Butyl 2-(4-(5-cvclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4- carboxylate
(R)-tert-Butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate (300 mg), 2-chloro-5- cyclopropylpyrimidine (188 mg, CAS 166740-44-9) and cesium carbonate (495 mg) were combined with dioxane (8 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (35.1 mg) and
tris(dibenzylideneacetone)dipalladium chloroform complex (31.4 mg) were then added. The reaction mixture was then capped and stirred at 120 °C for 3 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 55% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2- fluorophenyl)morpholine-4-carboxylate (180 mg, 43%) as a yellow solid. MS (ISP): 415.2 ([M+H]+). j) (R)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
To a stirred solution of (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2- fluorophenyl)morpholine-4-carboxylate (180 mg) in acetonitrile (2 ml) and water (6 ml) was added trifluoroacetic acid (335 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and poured into EtOAc and washed with 4 M aq. NaOH. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel; gradient: CH2Cl2/MeOH/aq. NH3) to afford (R)-5-cyclopropyl-N-(3-fluoro-4-(morpholin-2- yl)phenyl)pyrimidin-2-amine (57 mg, xx%) as an off-white solid. MS (ISP): 315.2 ([M+H]+). Example 193
((S)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine
Figure imgf000139_0001
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a) and (-)-(S)- tert-butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2- (4-bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g). White solid. MS (ISP): 333.2 ([{37C1}M+H]+), 331.2 ([{35C1}M+H]+).
Example 194
((R)-3-Chloro-4-morpholi -2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine
Figure imgf000139_0002
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a) and (+)-(R)- tert-butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2- (4-bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g). White solid. MS (ISP): 333.2 ([{37C1}M+H]+), 331.2 ([{35C1}M+H]+).
Example 195
(S)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000139_0003
The title compound was obtained in analogy to example 192 using (-)-(S)-tert-butyl 2-(4-bromo 2-fluorophenyl)morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4-bromo-2- fluorophenyl)morpholine-4-carboxylate in step (g). White solid. MS (ISP): 315.2 ([M+H]+).
Example 196
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine
Figure imgf000140_0001
a) (R)-tert-Butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4 carboxylate
To a 25 ml glass vial was added (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4- carboxylate (300 mg, example 192(f)) and 5-trifluoromethyl-pyrimidin-2-ylamine (156 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl (58.3 mg), tris(dibenzylideneacetone)dipalladium(0) (30.5 mg) and sodium tert-butoxide (89.8 mg) were then added. The vial was capped and heated at 100 °C for 2 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford (R)-tert-butyl 2-(2-fluoro-4-(5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (304 mg, 83%) as an amorphous yellow solid. MS (ISP): 441.2 ([M-H]"). b) (R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine
To a stirred solution of (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)morpholine-4-carboxylate (300 mg) in acetonitrile (2 ml) and water (6 ml) was added trifluoroacetic acid (522 μΐ). The reaction mixture was then capped and the mixture was shaken at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and poured into 4 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, CH2Cl2/MeOH/aq. NH3) to afford (R)-N-(3-fluoro-4-(morpholin-2- yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (171 mg, 74%) as an off-white solid. MS (ISP): 343.1 ([M+H]+).
Example 197
(S)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine
Figure imgf000140_0002
The title compound was obtained in analogy to example 196 using (-)-(S)-tert-butyl 2-(4-bromo- 2-fluorophenyl)morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4-bromo-2- fluorophenyl)morpholine-4-carboxylate in step (a). White solid. MS (ISP): 343.1 ([M+H]+). Example 198
(R)-N-(4-(Morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine
Figure imgf000141_0001
a) (R)-tert-Butyl 2-(4-(6-trifluoromethylpyrimidin-4-ylamino)phenyl)moipholine-4-carboxylate A mixture of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (72 mg, 0.4 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in dimethylacetamide (1.3 ml) and stirred at 80 °C overnight. For work-up water was added, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, 20 to 40 % ethyl acetate in heptane) to yield a white solid (135 mg, 89%). MS (ISP): 425.2 ([M+H]+). b) (R)-N-(4-(Morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine hydrochloride
(R)-tert-Butyl 2-(4-(6-trifluoromethylpyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (130 mg, 0.3 mmol) was dissolved in dioxane (1.2 ml) and a solution of HC1 in dioxane (4 M, 1.15 ml, 4.59 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (R)-N-(4-(morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine hydrochloride (96 mg, 87%) as a light yellow solid. MS (ISP): 325.2 ([M+H]+).
Example 199
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine
Figure imgf000141_0002
The title compound was obtained in analogy to example 198 using 4,6-dichloropyrimidine instead of 4-chloro-6-(trifluoromethyl)pyrimidine in step a). Light yellow solid. MS (ISP): 291.1 ([{35C1}M+H]+), 293.2 ([{37C1}M+H]+).
Example 200
(R)-N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)pyrimidin-4-amine
Figure imgf000142_0001
The title compound was obtained in analogy to example 198 using 4-chloro-6-(trifluoromethyl)- pyrimidine instead of 4-chloro-6-(trifluoromethyl)pyrimidine in step a). Light yellow solid. MS (ISP): 325.2 ([M+H]+).
Example 201
(R)-N-(4-(Morpholin- -yl)phenyl)-5-(trifluoromethyl)pyrazin-2-amine
Figure imgf000142_0002
The title compound was obtained in analogy to example 198 using 2-chloro-5-(trifluoromethyl)- pyrazine instead of 4-chloro-6-(trifluormethyl)pyrimidine in step a). Off-white solid. MS (ISP): 325.2 ([M+H]+).
Example 202
((R)-3-Chloro-4-morph ro-pyrimidin-2-yl)-amine
Figure imgf000142_0003
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a), (+)-(R)-tert- butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4- bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g), and 2,5-dichloro-pyrimidine (CAS 22536-67-0) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 325.4 ([{37C135C1}M+H]+), 323.4([{35C1}M+H]+). Example 203
((R)-3-Chloro-4-morpholin-2- -phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000143_0001
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a), (+)-(R)-tert- butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4- bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g), and 2-chloro-5-(2,2,2- trifluoroethoxy)-pyrimidine (CAS 145948-01-2) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 389.4 ([{37C1}M+H]+), 387.5 ([{35C1}M+H]+).
Example 204
((R)-3-Chloro-4-morpholin- -yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
Figure imgf000143_0002
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a), (+)-(R)-tert- butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4- bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g), and 2-chloro-5- (trifluoromethyl)pyrimidine (CAS 69034-12-4) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). Light yellow solid. MS (ISP): 359.4 ([{37C1}M+H]+), 357.4 ([{35C1}M+H]+).
Example 205
(R)-5-Chloro-N-( -(morpholin-2-yl)phenyl)pyrazin-2-
Figure imgf000143_0003
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,5-dichloro-pyrazine instead of 2,5- dichloropyridine in step (a). Light yellow. MS (ISP): 291.4 ([{35C1}M+H]+), 293.4 ([{37C1}M+H]+).
Example 206
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrazin-2-amine
Figure imgf000144_0001
The title compound was obtained in analogy to example 5 using (R)-2-(4-amino-phenyl)- morpholine-4-carboxylic acid tert-butyl ester (CAS 1260220-42-5) in place of (RS)-2-(4-amino- phenyl)-morpholine-4-carboxylic acid tert-butyl ester and 2,6-dichloro-pyrazine instead of 2,5- dichloropyridine in step (a). Orange solid. MS (ISP): 291.4 ([{35C1}M+H]+), 293.4
([{37C1}M+H]+).
Example 207
(R)-N-(3-Fluoro-4-(morpholi -2-yl)phenyl)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-amine
Figure imgf000144_0002
The title compound was obtained in analogy to example 192 using 2-chloro-5-(2,2,2- trifluoroethoxy)-pyrimidine (CAS 145948-01-2) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 373.1 ([M+H]+).
Example 208
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine
Figure imgf000144_0003
The title compound was obtained in analogy to example 192 using 2-chloro-4-(2,2,2- trifluoroethoxy)-pyrimidine (CAS 935252-67-8) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 373.1 ([M+H]+). Example 209
(R)-5-Fluoro-N-(3-fluoro-4-(morpholin-2-yl)phenyl)-4-(2,2,2-trifluoroethoxy)pyrimidin-2- amine
Figure imgf000145_0001
The title compound was obtained in analogy to example 192 using 2-chloro-5-fluoro-4-(2,2,2- trifluoro-ethoxy)-pyrimidine (Example 188(a)) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 391.1 ([M+H]+).
Example 210
(R)-5-Chloro-N-(3-fluo -4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
Figure imgf000145_0002
The title compound was obtained in analogy to example 192 using 2,5-dichloro-pyrimidine (CAS 22536-67-0) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 311.1 ([{37C1}M+H]+), 309.1 ([{37C1}M+H]+).
Example 211
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
Figure imgf000145_0003
The title compound was obtained in analogy to example 192 using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-2-fluorobenzoyl chloride in step (a), (+)-(R)-tert- butyl 2-(4-bromo-2-chloro-phenyl)-morpholine-4-carboxylate instead of (+)-(R)-tert-butyl 2-(4- bromo-2-fluorophenyl)morpholine-4-carboxylate in step (g), and 2-chloro-4-(2,2,2- trifluoroethoxy)-pyrimidine (CAS 935252-67-8) instead of 2-chloro-5-cyclopropylpyrimidine in step (i). White solid. MS (ISP): 389.5 ([{37C1}M+H]+), 387.6 ([{35C1}M+H]+). The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the
compounds of the present invention have a good affinity to the trace amine associated
receptors (TAARs), especially TAAR1.
The compounds were investigated in accordance with the test given hereinafter.
Materials and Methods
Construction of TAAR expression plasmids and stably transfected cell lines
For the construction of expression plasmids the coding sequences of human, rat and mouse TAAR 1 were amplified from genomic DNA essentially as described by Lindemann et al. [14]. The Expand High Fidelity PCR System (Roche Diagnostics) was used with 1.5 mM Mg2+ and purified PCR products were cloned into pCR2.1-TOPO cloning vector (Invitrogen) following the instructions of the manufacturer. PCR products were subcloned into the pIRESneo2 vector (BD Clontech, Palo Alto, California), and expression vectors were sequence verified before introduction in cell lines.
HEK293 cells (ATCC # CRL-1573) were cultured essentially as described by Lindemann et al. (2005). For the generation of stably transfected cell lines HEK293 cells were transfected with the pIRESneo2 expression plasmids containing the TAAR coding sequences (described above) with Lipofectamine 2000 (Invitrogen) according to the instructions of the manufacturer, and 24 hrs post transfection the culture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs, Switzerland). After a culture period of about 10 d clones were isolated, expanded and tested for responsiveness to trace amines (all compounds purchased from Sigma) with the cAMP Biotrak Enzyme immunoassay (EIA) System (Amersham) following the non-acetylation EIA procedure provided by the manufacturer. Monoclonal cell lines which displayed a stable EC50 for a culture period of 15 passages were used for all subsequent studies.
Radioligand binding assay on rat TAAR1
Membrane Preparation and Radioligand Binding.
HEK-293 cells stably expressing rat TAAR1 were maintained at 37 °C and 5% C02 in DMEM high glucose medium, containing fetal calf serum (10%, heat inactivated for 30 min at 56 °C), penicillin/streptomycin (1%), and 375 μg/ml geneticin (Gibco). Cells were released from culture flasks using trypsin/ EDTA, harvested, washed twice with ice-cold PBS (without Ca2+ and Mg2+), pelleted at Γ000 rpm for 5 min at 4 °C, frozen and stored at -80 °C. Frozen pellets were suspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 10 mM EDTA and homogenized with a Polytron (PT 6000, Kinematica) at 14Ό00 rpm for 20 s. The homogenate was centrifuged at 48Ό00 x g for 30 min at 4 °C. Subsequently, the supernatant was removed and discarded, and the pellet resuspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 0.1 mM EDTA using the Polytron (20 s at 14Ό00 rpm). This procedure was repeated and the final pellet resuspended in HEPES-NaOH containing 0.1 mM EDTA and homogenized using the Polytron. Typically, aliquots of 2 ml membrane portions were stored at -80 °C. With each new membrane batch the dissociation constant (Kd) was determined via a saturation curve. The TAAR1 radioligand [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (described in WO 2008/098857) was used at a concentration equal to the calculated Kd value, that was usually around 2.3 nM, resulting in the binding of approximately 0.2% of the radioligand and a specific binding representing approximately 85% of the total binding. Nonspecific binding was defined as the amount of [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2- ylamine bound in the presence of 10 μΜ unlabeled ligand. All compounds were tested at a broad range of concentrations (10 pM to 10 μΜ) in duplicates. The test compounds (20 μΐ/well) were transferred into a 96 deep well plate (TreffLab), and 180 μΐ of HEPES-NaOH (20 mM, pH 7.4) containing MgCl2 (10 mM) and CaCl2 (2 mM) (binding buffer), 300 μΐ of the radioligand 3[H]- (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine at a concentration of 3.3 x Kd in nM and 500 μΐ of the membranes (resuspended at 50 μg protein per ml) added. The 96 deep well plates were incubated for 1 hr at 4 °C. Incubations were terminated by rapid filtration through Unifilter-96 plates (Packard Instrument Company) and glass filters GF/C (Perkin Elmer) presoaked for 1 hr in polyethylenimine (0.3%) and washed 3 times with 1 ml of cold binding buffer. After addition of 45 μΐ of Microscint 40 (PerkinElmer) the Unifilter-96 plate was sealed and after 1 hr the ratioactivity counted using a TopCount Microplate Scintillation Counter (Packard Instrument Company).
Radioligand binding assay on mouse TAAR1
Membrane Preparation and Radioligand Binding.
HEK-293 cells stably expressing mouse TAAR1 were maintained at 37 °C and 5% C02 in DMEM high glucose medium, containing fetal calf serum (10%, heat inactivated for 30 min at 56 °C), penicillin/streptomycin (1%), and 375 μg/ml geneticin (Gibco). Cells were released from culture flasks using trypsin/ EDTA, harvested, washed twice with ice-cold PBS (without Ca2+ and Mg2+), pelleted at 000 rpm for 5 min at 4 °C, frozen and stored at -80 °C. Frozen pellets were suspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 10 mM EDTA and homogenized with a Polytron (PT 6000, Kinematica) at 14Ό00 rpm for 20 s. The homogenate was centrifuged at 48Ό00 x g for 30 min at 4 °C. Subsequently, the supernatant was removed and discarded, and the pellet resuspended in 20 ml HEPES-NaOH (20 mM, pH 7.4) containing 0.1 mM EDTA using the Polytron (20 s at 14Ό00 rpm). This procedure was repeated and the final pellet resuspended in HEPES-NaOH containing 0.1 mM EDTA and homogenized using the Polytron. Typically, aliquots of 2 ml membrane portions were stored at -80 °C. With each new membrane batch the dissociation constant (Kd) was determined via a saturation curve. The TAAR1 radioligand [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (described in WO 2008/098857) was used at a concentration equal to the calculated Kd value, that was usually around 0.7 nM, resulting in the binding of approximately 0.5% of the radioligand and a specific binding representing approximately 70% of the total binding.
Nonspecific binding was defined as the amount of [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]- 4,5-dihydro-oxazol-2-ylamine bound in the presence of 10 μΜ unlabeled ligand. All compounds were tested at a broad range of concentrations (10 pM to 10 μΜ) in duplicates. The test compounds (20 μΐ/well) were transferred into a 96 deep well plate (TreffLab), and 180 μΐ of HEPES-NaOH (20 mM, pH 7.4) containing MgCl2 (10 mM) and CaCl2 (2 mM) (binding buffer), 300 μΐ of the radioligand [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2- ylamine at a concentration of 3.3 x Kd in nM and 500 μΐ of the membranes (resuspended at 60 μg protein per ml) added. The 96 deep well plates were incubated for 1 hr at 4 °C. Incubations were terminated by rapid filtration through Unifilter-96 plates (Packard Instrument Company) and glass filters GF/C (Perkin Elmer) presoaked for 1 hr in polyethylenimine (0.3%) and washed 3 times with 1 ml of cold binding buffer. After addition of 45 μΐ of Microscint 40 (PerkinElmer) the Unifilter-96 plate was sealed and after 1 hr the ratioactivity counted using a TopCount Microplate Scintillation Counter (Packard Instrument Company).
The preferred compounds show a Ki value (μΜ) in mouse or rat on TAAR1 in the range of <0.1 μΜ. In the table below are shown the data of examples 1 - 211.
Example Ki (μΜ) Example Κΐ(μΜ) Example Ki (μΜ)
mouse/rat mouse/rat mouse/rat
1 0.074/1.5108 72 0.0171/0.22 143 0.4185/0.2836 4.2857/3.5145 73 0.0096/0.035 144 0.0042/0.0049
0.0157/0.0251 74 0.0059/0.0295 145 0.0034/0.0067
0.1223/0.0785 75 0.0141/0.228 146 0.0046/0.1404
0.0011/0.029 76 0.0024/0.045 147 0.0009/0.0197
0.0133/0.2322 77 0.0053/0.1304 148 0.0017/0.0083
0.0033/0.0425 78 0.11/3.1921 149 0.0011/0.0014
0.0005/0.0325 79 0.0047/0.0716 150 0.0134/0.1486
0.0181/0.0893 80 0.0026/0.0626 151 0.048/0.0954
0.0015/0.0337 81 0.0162/0.2027 152 0.0196/0.2677
0.0015/0.0233 82 0.0008/0.0101 153 0.007/0.8397
0.0055/0.2588 83 0.0006/0.0222 154 0.0096/0.8627
0.0266/0.1085 84 0.0015/0.057 155 0.6002/-
0.0122/0.504 85 0.0014/0.0194 156 0.0093/0.8327
0.0028/0.0466 86 0.0024/0.009 157 0.0132/>10
0.0276/0.4483 87 0.0071/0.037 158 1.0168/1.8542
0.0017/0.0131 88 0.008/0.0874 159 1.3362/1.7562
0.0054/0.3133 89 0.0139/0.1767 160 0.0061/2.749
0.0056/0.0236 90 0.0196/0.2324 161 0.0016/0.2229
0.0453/0.7641 91 0.0081/0.1233 162 0.002/0.1273
0.002/0.0245 92 0.0229/0.2748 163 0.0026/0.0332
0.0375/0.468 93 0.005/0.0222 164 0.0006/0.025
0.0514/1.644 94 0.0035/0.0489 165 0.011/0.3395 0.0119/0.149 95 0.0057/0.0223 166 0.0301/0.1589
0.0124/0.0705 96 0.0062/0.0216 167 0.1115/1.3539
0.002/0.0083 97 0.0029/0.0056 168 0.0077/0.0065
0.0438/0.8083 98 0.0028/0.0033 169 0.0243/0.0397
0.2762/0.561 99 0.0008/0.0185 170 0.0016/0.0012
0.0042/0.1555 100 0.0053/0.0164 171 0.0008/0.0011
0.0051/0.0417 101 0.0032/0.0041 172 0.0035/0.0162
0.0452/0.2222 102 0.0047/0.0126 173 0.0044/0.0625
0.0357/1.2375 103 0.0044/0.05 174 0.0088/0.0628
0.047/0.5444 104 0.0041/0.1048 175 0.006/0.0066
0.0042/0.0181 105 0.0116/0.1265 176 0.1516/>10
0.0096/0.1883 106 0.0086/0.0814 177 0.0028/0.0299
0.0288/0.1633 107 0.005/0.0877 178 0.0043/0.0298
0.1292/1.1738 108 0.0122/0.2157 179 0.0047/0.0517
0.0011/0.0544 109 0.0077/0.3624 180 0.0058/0.033
0.004/0.2514 110 0.0026/0.0306 181 0.0084/0.3981
0.0026/0.1882 111 0.0044/0.0322 182 0.0144/0.4465
0.2704/1.0809 112 0.0038/0.1966 183 0.0094/0.1737
0.0023/0.0518 113 0.0011/0.0877 184 0.002/0.002
0.0269/0.6484 114 0.0212/0.9959 185 0.0549/0.0888
0.0007/0.0118 115 0.0079/0.2349 186 0.138/1.1018
0.0061/0.1261 116 0.0039/0.007 187 0.0021/0.01 0.0008/0.0643 117 0.0034/0.0104 188 0.0016/0.0033
0.0012/0.0067 118 0.0038/0.003 189 0.1089/0.0605
0.1218/0.2336 119 0.0025/0.0051 190 0.0031/0.0422
0.0266/0.1038 120 0.0058/0.0364 191 0.001/0.0032
0.005/0.0608 121 0.0058/0.0096 192 0.0025/0.0026
0.0363/0.2803 122 0.0079/0.0847 193 0.0038/0.0196
0.0005/0.0084 123 0.0174/0.0796 194 0.0021/0.0011
0.0012/0.0045 124 0.0036/0.0348 195 0.0017/0.0252
0.0008/0.0138 125 0.0045/0.0278 196 0.0049/0.004
0.7376/1.9843 126 0.004/0.0096 197 0.0031/0.0315
0.0372/0.211 127 0.003/0.0165 198 0.0419/0.1628
0.0023/0.0866 128 0.0049/0.0039 199 0.0231/0.056
0.0704/0.5844 129 0.0043/0.0068 200 0.0089/0.0588
0.0049/0.2073 130 0.0051/0.0199 201 0.008/0.0626
0.0222/0.7582 131 0.0028/0.0379 202 0.0032/0.0065
0.0591/0.5024 132 0.0047/0.0182 203 0.0022/0.0017
0.0005/0.0094 133 0.0052/0.0387 204 0.0038/0.0021
0.3728/1.4897 134 0.0069/0.0079 205 0.0026/0.1621
0.0027/0.101 135 0.0057/0.0198 206 0.005/0.0963
0.0131/0.6291 136 0.0051/0.0494 207 0.0043/0.0102
0.2169/0.2569 137 0.0037/0.0026 208 0.003/0.0035
0.0074/0.2917 138 0.0641/1.3566 209 0.0032/0.0025 68 0.0094/0.0751 139 0.0667/1.0607 210 0.0047/0.0266
69 0.0014/0.0438 140 0.0386/5.251 211 0.0042/0.0011
70 0.5235/4.0665 141 0.0027/0.0129
71 0.0118/0.168 142 0.0027/0.0146
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
Tablet Formulation (Wet Granulation)
Item Ingredients mg/tablet
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Lactose Anhydrous DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1 1 1 1
Total 167 167 167 831
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press. Capsule Formulation
Item Ingredients mg/capsule
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Hydrous Lactose 159 123 148 —
3. Corn Starch 25 35 40 70
4. Talc 10 15 10 25
5. Magnesium Stearate 1 2 2 5
Total 200 200 300 600
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.

Claims

Claims
1. Compounds of formula
Figure imgf000155_0001
wherein is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, nitro, C3_6-cycloalkyl, -CH2-C3_6-cycloalkyl, -0-CH2-C3-6-cycloalkyl, -0-(CH2)2-0-lower alkyl, S(0)2CH3 , SF5, -C(0)NH-lower alkyl, phenyl, -O-pyrimidinyl, optionally substituted by lower alkoxy substituted by halogen, or is benzyl, oxetanyl or furanyl; m Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, or 1,3,4-oxadiazolyl;
Y is a bond, -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)-;
R2 is hydrogen or lower alkyl;
A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl;
R' is hydrogen or halogen; with the proviso that when R' is halogen, then A is CH;
B is CH or N; n is 0, 1 or 2; X is a bond, -CH2- or -0-; or pharmaceutical active acid addition salts thereof.
2. Compounds of formula IA according to claim 1
Figure imgf000156_0001
wherein
R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, nitro, C3_6-cycloalkyl, S(0)2CH3 or phenyl; m is 1 or 2;
Ar is aryl or heteroaryl, selected from the group consisting of phenyl, naphthyl, pyrimidinyl, pyridinyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazolyl or 1,3,4-oxadiazolyl; Y is a bond, -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)-;
R is hydrogen or lower alkyl;
A is CR or N; and R is hydrogen, cyano, halogen or lower alkyl; B is CH or N; n is 0, 1 or 2; X is a bond, -CH2- or -0-; or pharmaceutical active acid addition salts thereof.
3. Compounds of formula I, wherein A is CR, and B is CH.
4. Compounds of formula I according to claim 3, wherein Y is a bond and Ar is phenyl or naphthyl.
5. Compounds of formula I according to claim 4, wherein the compounds are
(RS)-(4-Chloro-phenyl)-(4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-naphthalen-2-yl-amine (S)-4-Chloro-2-fluoro-N-(4-(morpholin-2-yl)phenyl)aniline
(4-Chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine
(RS)-(4-Chloro-phenyl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine
[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine or
[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
6. Compounds of formula I according to claim 3, wherein Y is a bond and Ar is pyridinyl, pyrimidinyl, pyrazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8- tetrahydro-quinazolinyl, pyrazinyl, pyridazinyl or 1,3,4-oxadiazolyl.
7. Compounds of formula I according to claim 6, wherein the compounds are
(RS)-(4,6-Dimethyl-pyrimidin-2-yl)-(4-pyrrolidin-3-yl-phenyl)-amine; hydrochloride
(RS)-(5-Chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(5-Chloro-pyrimidin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(5-Bromo-pyrimidin-2-yl)-(4-morpholin-2-yl-phenyl)-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
(5-Methoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Fluoro-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
2-((S)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carbonitrile
(5-Cyclopropyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5 -Methyl-pyrimidin-2- yl)-((S)-4 -morpholin-2- yl-phenyl) - amine
((S)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(6-Chloro-benzothiazol-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5 -Ethoxy-pyrimidin-2- yl)-((S)-4 -morpholin-2- yl-phenyl) - amine
(5-Chloro-pyridin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-4-Methoxy-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-6-Chloro-5-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-3-(trifluoromethyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine
(S)-5-Fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine ((S)-4-Morpholin-2-yl-phenyl)-quinolin-2-yl-amine
(S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-2-Methyl-N-(4-(morpholin-2-yl)phenyl)quinolin-8-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-2,8-bis(trifluoromethyl)quinolin-4-amine (S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)quinazolin-4-amine
(S)-8-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(S)-4-Chloro-N-(4-(morpholin-2-yl)phenyl)quinolin-2-amine
(2-Fluoro-pyridin-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-5-Bromo-3-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-5-Bromo-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-3,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-3,5-Dibromo-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-5-Bromo-4-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyridin-4-amine
(S)-4-Bromo-5-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)benzo[d][l,3]dioxol-5-amine
(S)-5-Bromo-N-(4-(morpholin-2-yl)phenyl)quinolin-8-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(R)-5-Ethyl-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(S)-6-Chloro-5-ethoxy-N-(4-(morpholin-2-yl)phenyl)pyridin-3-amine
(5-Ethyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine (5-Isopropyl-4-methyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine ((S)-4-Morpholin-2-yl-phenyl)-(5,6,7,8-tetrahydro-quinazolin-2-yl)-amine ((S)-4-Morpholin-2-yl-phenyl)-(5-nitro-pyrimidin-2-yl)-amine
(RS)-5-Bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (S)-5-Chloro-3-fluoro-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine
(5-Methanesulfonyl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine (RS)-(5-Chloro-pyridin-2-yl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine (RS)-(5-Chloro-pyrimidin-2-yl)-(2-methyl-4-morpholin-2-yl-phenyl)-amine (S)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2-amine (S)-5-Chloro-4-methyl-N-(4-(morpholin-2-yl)phenyl)pyridin-2-amine (RS)-5-Chloro-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (RS)-5-Bromo-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (5-Cyclopropyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(RS)-5-Cyclopropyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (RS)-5-Ethyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
((R)-4-Morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(5-Bromo-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
(RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(RS)-5-Cyclopropyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (RS)-5-Chloro-N-(2-fluoro-4-(morpholin-2-yl)phenyl)pyridin-2-amine
(RS)-(5-Ethoxy-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine (RS)-(5-Bromo-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(S)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(5-Ethoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-2-methyl-4-morpholin-2-yl-phenyl)-amine (5-Cyclopropyl-pyrimidin-2-yl)-((S)-2-methyl-4-morpholin-2-yl-phenyl)-amine (5-Ethyl-pyrimidin-2-yl)-((S)-4-piperidin-3-yl-phenyl)-amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-phenyl- lH-pyrazol-3-amine
(5 -Ethoxy-pyrimidin-2- yl)-((S)-4 -piperidin-3 - yl-phenyl) - amine
(S)-N-(4-(Morpholin-2-yl)phenyl)-5-phenyl-l,3,4-oxadiazol-2-amine
(5-Ethyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Cyclopropyl-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine (5-Cyclopropyl-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine (RS)-(2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine (5-Isopropoxy-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine (5-Isopropoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(S)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(R)-5-(Cyclopropylmethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(5-Bromo-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Bromo-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-propyl-pyrimidin-2-yl)-amine
(5-Chloro-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Chloro-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethoxy-pyrimidin-2-yl)-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
(5-Ethoxy-pyrimidin-2-yl)-((S)-2-fluoro-4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine ((S)-4-Morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
((R)-4-Morpholin-2-yl -phenyl)- [5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl] -amine
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((S)-4-morpholin-2-yl-phenyl)-amine
[5-(2-Methoxy-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
(RS)-(l-Methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
(RS)-(4-Bromo-l-methyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine (RS)-(l-Cyclopropylmethyl-lH-pyrazol-3-yl)-(4-morpholin-2-yl-phenyl)-amine
(5-Furan-2-yl-pyrimidin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Furan-2-yl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(RS)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
(RS)-[l-(2,2-Difluoro-ethyl)-lH-pyrazol-3-yl]-(4-morpholin-2-yl-phenyl)-amine
((R)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine ((S)-2-Fluoro-4-morpholin-2-yl-phenyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amine ((S)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(2-trifluoromethyl-pyrimidin-5-yl)-amine
(RS)-(4-Morpholin-2-yl-phenyl)-(lH-pyrazol-3-yl)-amine
(5-Methyl-pyrazin-2-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(5-Methyl-pyrazin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine 2-((S)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide 2-((R)-4-Morpholin-2-yl-phenylamino)-pyrimidine-5-carboxylic acid methylamide
(6-Methyl-pyridazin-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(l-Benzyl-lH-pyrazol-3-yl)-((S)-4-morpholin-2-yl-phenyl)-amine
(l-Benzyl-lH-pyrazol-3-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
((R)-4-Morpholin-2-yl-phenyl)-(l-phenyl-lH-pyrazol-3-yl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(5-oxetan-3-yl-pyridin-2-yl)-amine
((R)-2-Methyl-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-2-Methyl-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((R)-2-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
((S)-2-Chloro-4-morpholin-2-yl-phenyl)-(5-trifluoromethyl-pyrimidin-2-yl)-amine
(R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
(S)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine
((R)-4-Morpholin-2-yl -phenyl)- [4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl] -amine
(R)-N-(4-(Morpholin-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine
(R)-5-(5-(Difluoromethoxy)pyrimidin-2-yloxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (R)-N-(2-Chloro-4-(morpholin-2-yl)phenyl)-5-(5-(difluoromethoxy)pyrimidin-2- yloxy)pyrimidin-2-amine
(R) -N- (4 -(Morpholin-2- yl)phenyl)pyrimidin-2- amine
((R)-4-Morpholin-2-yl-phenyl)-quinazolin-2-yl-amine
(4-Methyl-6-trifluoromethyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(R)-5-(Difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(4-Chloro-6-methoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
2-((R)-4-Morpholin-2-yl-phenylamino)-pyrimidine-4-carbonitrile
(4,6-Dimethyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
(4,6-Dimethoxy-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine
((R)-2-Chloro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine (R)-3-Chloro-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine
(S)-2,5-Dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine
((S)-4-Morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-amine
[5-Fluoro-4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-((R)-4-morpholin-2-yl-phenyl)-amine
(4-Cyclopropyl-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine (4-Cyclopropyl-5-fluoro-pyrimidin-2-yl)-((R)-4-morpholin-2-yl-phenyl)-amine (4-Pentafluorosulfanyl-phenyl)-((R)-4-morpholin-2-yl-phenyl)-amine
(R)-5-Cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
((S)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-cyclopropyl-pyrimidin-2-yl)-amine
(S)-5-Cyclopropyl-N-(3-iluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(trilluoromethyl)pyrimidin-2-amm^
(S)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(tri^
(R)-N-(4-(Morpholin-2-yl)phenyl)-6-(trifluoromethyl)pyrimidin-4-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine
(R)-N-(4-(morpholin-2-yl)phenyl)-2-(trilluoromethyl)pyrimidin-4-amin^
(R)-N-(4-(Morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrazin-2-amine
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-chloro-pyrimidin-2-yl)-amine
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-[5-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-am
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-(5-trilluoromethyl-pyrimidin-2-yl)-am
(R)-5-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrazin-2-amine
(R)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)pyrazin-2-amine
(R)-N-(3-Fluoro-4-(morpholin-2-yl)phenyl)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-amm^ (R) -N- (3 -Fluoro -4- (morpholin-2-yl)^^
(R)-5-Fluoro-N-(3-fluoro-4-(morpholin-2-yl)phenyl)-4-(2,2,2-trilluoroethoxy)pyrimidm
(R)-5-Chloro-N-(3-iluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine or
((R)-3-Chloro-4-morpholin-2-yl-phenyl)-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2-yl]-am
8. Compounds of formula I according to claim 3, wherein Y is -CH2-,
-CH2CH2-, -CH(CF3)- or -CH(CH3)- and Ar is phenyl or naphthyl.
9. Compounds of formula I according to claim 8, wherein the compounds are
[(RS)-l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2-pyrrolidin-3-yl-ethyl)-phenyl]- amine
(RS)-[l-(4-Chloro-phenyl)-2,2,2-trifluoro-ethyl]-[(RS)-4-(2-piperidin-3-yl-ethyl)-phenyl]-amine (RS)-(4-Chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-phenethyl-amine
(4-Methoxy-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine (4-Methyl-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
4-[((S)-4-Morpholin-2-yl-phenylamino)-methyl]-benzonitrile
((S)-4-Morpholin-2-yl-phenyl)-(4-trifluoromethyl-benzyl)-amine
((S)-4-Morpholin-2-yl-phenyl)-(4-trifluoromethoxy-benzyl)-amine
(3,4-Dichloro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
[2-(4-Chloro-phenyl)-ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Chloro-2-fluoro-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Ethyl-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(4-Bromo-benzyl)-((S)-4-morpholin-2-yl-phenyl)-amine or
[(RS)-l-(4-Chloro-phenyl)-ethyl]-((S)-4-morpholin-2-yl-phenyl)-amine.
10. Compounds of formula I according to claim 3, wherein Y is -CH2-, -CH2CH2-, -CH(CF3)- or -CH(CH3)- and Ar is furyl, pyridinyl, pyrimidinyl, pyrazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzo[d][1.3]dioxolyl, 5,6,7,8-tetrahydro-quinazolinyl or 1,3,4- oxadiazoly.
11. Compounds of formula I according to claim 10, which compounds are
[(RS)-l-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-((RS)-4-pyrrolidin-3-yl-phenyl)-amine (5-Bromo-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(6-Methoxy-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine
(S)-N-((6-Chloropyridin-3-yl)methyl)-4-(morpholin-2-yl)aniline
(S)-4-(Morpholin-2-yl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)aniline
(5-Fluoro-pyridin-2-ylmethyl)-((S)-4-morpholin-2-yl-phenyl)-amine or
(S)-N-((2-Chloroquinolin-3-yl)methyl)-4-(morpholin-2-yl)aniline.
12. A compound of formula I according to claim 1, wherein A is N, B is CH, Y is a bond and Ar is pyridinyl, pyrimidinyl.
13. A compound of formula I according to claim 12, which compounds are
(RS)-5-Chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
(RS)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine
(RS)-5-Cyclopropyl-N-(5-(morpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine (R)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine or
(S)-5-Bromo-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine.
14. A compound of formula I according to claim 1, wherein A is CR, B is N, Y is a bond and Ar is pyridinyl.
15. A compound of formula I according to claim 14, wherein the compound is
(RS)-N-(5-Bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine.
16. A process for the manufacture of a compound of formula I as defined in any one of claims 1 - 15, which process comprises a) cleaving off the N-protecting group from compounds of formula
Figure imgf000164_0001
a compound of formula
Figure imgf000164_0002
PG is a N-protecting group selected from -C(0)0-tert-butyl, and
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
17. A compound according to any one of claims 1 - 15, when manufactured by a process according to claim 16.
18. Pharmaceutical composition comprising a compound according to any one of claims 1 - 15 and a pharmaceutical acceptable carrier and/or adjuvant.
19. Pharmaceutical composition comprising a compound according to any one of claims 1 - 15 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
20. Compounds according to any one of claims 1 - 15 for use as therapeutic active substances.
21. Compounds according to any one of claims 1 - 15 for use as therapeutic active substances in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, substance abuse, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
22. Compounds according to any one of claims 1 - 15 for use as therapeutic active substances in the treatment of CNS diseases selected from depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, substance abuse or migraine.
23. Compounds according to any one of claims 1 - 15 for use as therapeutic active substances in the treatment of metabolic disorders selected from eating disorders, diabetes, diabetic complications or obesity.
24. The use of a compound according to any one of claims 1 - 15 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, substance abuse, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
25. The invention as hereinbefore described.
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