(19)
(11)EP 3 174 886 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.02.2021 Bulletin 2021/07

(21)Application number: 15742309.6

(22)Date of filing:  29.07.2015
(51)Int. Cl.: 
C07D 491/06  (2006.01)
A61K 31/407  (2006.01)
A61K 31/35  (2006.01)
A61P 25/28  (2006.01)
(86)International application number:
PCT/EP2015/067353
(87)International publication number:
WO 2016/016292 (04.02.2016 Gazette  2016/05)

(54)

2-OXA-5-AZABICYCLO[2.2.1]HEPTAN-3-YL DERIVATIVES

2-OXA-5-AZABICYCLO[2.2.1]HEPTAN-3-YL-DERIVATE

DERIVES DE 2-OXA-5-AZABICYCLO[2.2.1]HEPTAN-3-YL


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Validation States:
MA

(30)Priority: 01.08.2014 WO PCT/CN2014/083549

(43)Date of publication of application:
07.06.2017 Bulletin 2017/23

(73)Proprietor: F. Hoffmann-La Roche AG
4070 Basel (CH)

(72)Inventors:
  • CECERE, Giuseppe
    CH-4057 Basel (CH)
  • GALLEY, Guido
    79618 Rheinfelden (DE)
  • HU, Yimin
    Shanghai 201203 (CN)
  • NORCROSS, Roger
    CH-4305 Olsberg (CH)
  • PFLIEGER, Philippe
    F-68130 Schwoben (FR)
  • SHEN, Hong
    Shanghai 201203 (CN)

(74)Representative: Salud, Carlos E. et al
F. Hoffmann-La Roche AG Patent Department Grenzacherstrasse 124
4070 Basel
4070 Basel (CH)


(56)References cited: : 
WO-A1-2014/072257
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description


    [0001] The present invention relates to a compound of formula

    wherein
    L
    is a bond, -C(O)NH-, -NHC(O)-, -CH2NHC(O)-, CH2C(O)NH-, -CH2NH-, -NH- or -NHC(O)NH-;
    R1
    is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen, lower alkyl substituted by halogen or
    is phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein phenyl and heteroaryl are optionally substituted by one, two or three substituents selected from the group consisting of
    halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl or O-CH2-cycloalkyl;
    X
    is CH or N;
    or to a pharmaceutically suitable acid addition salt thereof, to all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

    [0002] It has now been found that the compounds of formulas 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.

    [0003] 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, WO97/12874 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 TAAR1 receptor vs adrenergic receptors. Objects of the present invention show selectivity for TAAR1 receptor over adrenergic receptors, in particular good selectivity vs the human and rat alpha1 and alpha2 adrenergic receptors.

    [0004] 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].

    [0005] 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].

    [0006] 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 recent 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 (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via Gαs. 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 WO2014/072257 discloses compounds which are useful for the treatment of various disorders which are likewise encompassed by the current application and from which the compounds of claim 1 structurally differ in that the heterocyclic moiety is 2-oxa-5 azabicyclo[2.2.1]heptane.

    [0007] Therefore, there is a broad interest to increase the knowledge about trace amine associated receptors.

    References used:



    [0008] 
    1. 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. 2 Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2, 343-351;
    3. 3 Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu. Rev. Pharmacol. Toxicol. 41, 237-260;
    4. 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. 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. 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. 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. 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. 9 Premont, R.T. et al. (2001) Following the trace of elusive amines. Proc. Natl. Acad. Sci. U. S. A. 98, 9474-9475;
    10. 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. 11 McCormack, J.K. et al. (1986) Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101;
    12. 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. 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. 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.


    [0009] 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.

    [0010] The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety, attention deficit hyperactivity disorder (ADHD) and diabetes.

    [0011] 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.

    [0012] 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.

    [0013] The term "halogen" denotes chlorine, iodine, fluorine and bromine. The preferred halogen group is fluorine.

    [0014] As used herein, the term "lower alkyl substituted by halogen" denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms as defined for the term "lower alkyl", wherein at least one hydrogen atom is replaced by a halogen atom. A preferred halogen atom is fluoro. Examples of such groups are CF3, CHF2, CH2F, CH2CF3 or CH2CHF2 .

    [0015] As used herein, the term "lower alkoxy substituted by halogen" denotes a lower alkoxy group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom. Examples of such groups are OCF3, OCHF2, OCH2F, OCH2CF3 or OCH2CHF2.

    [0016] The term "cycloalkyl" denotes a saturated carbon ring, containing from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

    [0017] 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, methanesulfonic acid, p-toluenesulfonic acid and the like.

    [0018] One embodiment of the invention are compounds of formula I, wherein R1 is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen or lower alkyl substituted by halogen and L is as described above, for example the following compounds (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane N-butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane N-(3-methoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3 trifluoropropoxy)acetamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide 4,4,4-trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluoropropoxy)acetamide 4,4,4-trifluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide (1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1S,3S,4S)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1R,3S,4R)-3-(2-fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane.

    [0019] One embodiment of the invention are further compounds of formula I, wherein R1 is phenyl, which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl or O-CH2-Cycloalkylphenyl, and L is as described above, for example the following compounds 3-chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 1-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea 1-(4-chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea 1-(3-chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea 4-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 3-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 3-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-(cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide 4-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-(cyclopropylmethoxy)-N-[4-[(lS,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide 1-(4-chlorophenyl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea N-[(4-chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl] methyl] aniline N-[(4-fluorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluoromethoxy)phenyl]methyl]aniline N-(4-chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-bromophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-fluorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo [2.2.1]heptan-3-yl]benzamide N-(4-ethoxyphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluoromethyl)phenyl]benzamide 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluoromethyl)phenyl]methyl]benzamide N-[(4-chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4,4,4-trifluoro-N-[4-[(lS,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide N-(4-bromophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-fluorophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-ethoxyphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide or N-[(4-chlorophenyl)methyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide.

    [0020] One embodiment of the invention are compounds of formula I, wherein R1 is pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, which are optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl or O-CH2-cycloalkylphenyl, and L is as described above, for example the following compounds N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine 6-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide 6-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-cyclopropyl-N-[4-[(lS,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine 5-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine N-[4-[1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidin-4-amine N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine N-[4-[(lS,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine 5-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide N-[4-[(lR,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine 2-ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amine N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide 4-chloro-3-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide 3-isopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide 4-chloro-3-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-chloro-3-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-chloro-1-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-propyl-pyrazole-3-carboxamide 4-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide 3-ethyl-4-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide N-(6-chloro-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridin-3-amine N-(6-ethoxy-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 3-ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide 3-cyclopropyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide 2-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide 3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-chloro-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-cyclopropyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide 4-chloro-3-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine 2-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide 3-butyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-(6-chloro-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(6-ethoxy-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-chloro-3-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-bromo-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-fluoro-3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-chloro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide or 4-fluoro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5 -carboxamide.

    [0021] 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 to 8 and in the description of 106 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.

    [0022] 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 8, 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.

    [0023] 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
    1. a) cleaving off the N-protecting group (PG) from compounds of formula

      to a compound of formula

      wherein PG is a N-protecting group selected from -C(O)O-tert-butyl (BOC) and the other definitions are as described above, and,
      if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

    GENERAL PROCEDURE



    [0024] 



    [0025] Step A: Conversion of lactone 1 to ketone 2 can be accomplished by the addition of phenyl Grignard reagent to a lactone 1 and Me(MeO)NH•HCl in anhydrous non-protic organic solvents such as THF, diethyl ether, DME, TBME at a temperatrue of -78°C to 0°C, under inert atmosphere.
    Preferred conditions are using phenyl magnesium bromide in THF at -70°C for 10 hours.

    [0026] Step B: Reduction of ketone 2 to the corresponding diol 3 can be accomplished by treatment with a reducing reagent, such as NaBH4, LiBH4, ZnBH4, 9-BBN, Borane-THF complex, LiAlH4, or DIBAL-H, in solvents such as THF, diethyl ether, DME, 1,4-dioxane, and TBME, methanol, or ethanol.
    Preferred conditions are NaBH4 as the reducing reagent in MeOH at 0°C for 2 hours.

    [0027] Step C: Cyclisation of diol 3 can be accomplished by a Mitsunobu-type reaction, an acid-mediated cation cyclisation, or a stepwise process involving sulphonate ester intermediates.
    In the Mitsunobu-type reaction, the conversion can be accomplished by treatment with triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in ethereal solvents such as diethyl ether, dioxane, THF, or TBME, or other non-protic organic solvents such as toluene and benzene.
    In the acid-mediated cation cyclisation, the conversion can be accomplished by treatment with inorganic acids such as H2SO4, H3PO4 at elevated temperatures, or by treatment with organic acids such as trifluoroacetic acid, BF3•Et2O, optionally with an additive such as Et3SiH, in solvents such as dichloromethane, 1,2-dichloroethane, or toluene, at 0°C to room temperature.
    In the stepwise process, the conversion can be accomplished by treatment of diol 3 with one equivalent of sulfonyl chloride, such as methanesulfonyl chloride or toluenesulfonlyl chloride, in the presence of an organic base, such as pyridine, triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in ethereal solvents such as diethyl ether, dioxane, THF, or TBME, or using organic base as the solvent, at 0°C to 50°C. The resulting sulphonate ester can be converted to protected bridged-morpholine 4 by treatment with a non-nucloephilic base such as sodium hydride, potassium tert-butoxide, or potassium 2-methyl-2-butoxide, in ethereal solvents such as diethyl ether, dioxane, THF, or TBME.
    Preferred conditions are the Mitsunobu-type process: treating diol 3 with DIAD and triphenylphosphine in toluene at 0°C and continuing the reaction at room temperature for 16 hours.

    [0028] Step D: Deprotection can be accomplished by either a base-induced reaction or a stepwise process involving a benzyl-protected intermediate.
    In the base-induced reaction, deprotection can be effected by treatment with an base such as hydrazine, KOH, NaOH, or Cs2CO3, in solvents such as methanol, ethanol at elevated temperatures such as 90°C to 150°C.
    In the stepwise process, the benzoyl protecting group can be converted to a benzyl protecting group by treatment with reducing regents such as LiAlH4, BH3•THF, and BH3•Me2S in ethereal solvents such as diethyl ether, dioxane, THF, or TBME at 0°C to 60°C. The resulting benzyl group can be removed by either a hydrogenation reaction catalyzed by a Pd catalyst or treatment with chloroformates such as ClCOOCH2CH2Cl, ClCOOCH(Cl)Me, ClCOOCH2Ph, and ClCOOCH2CCl3, and optionally with an base such as triethylamine, diisopropylethylamine, and sodium hydroxide, in solvents such as toluene, THF, diethyl ether, dioxane, or TBME, at room temperature to elevated temperatures.
    Preferred conditions are the stepwise process, using LiAlH4 in THF at 0°C to room temperature for 2 hours for the first step, followed by treatment with ClCOOCH2CH2Cl in toluene at 110°C for 16 hours.

    [0029] Step E: Protection of the bridged-morpholine 5 can be accomplished by treatment with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, or cesium carbonate, 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 presence of potassium carbonate as the base at room temperature for 10 hours.

    [0030] Step F: Iodination of bridged-morpholine 6 can be accomplished by treatment with halogenating reagents such as iodine and iodosuccinimide, or polyvalent iodines together with iodine, such as [bis(trifluoroacetoxy)iodo]benzene/iodine and bis(acetoxy)phenyliodine/iodine, in halogenated solvents such as dichloromethane, chloroform, or tetrachloromethane, at room temperature to 80°C.
    Preferred conditions are bis(trifluoroacetoxy)iodo]benzene/iodine in tetrachloromethane at room temperature.

    [0031] Step G: Coupling of iodide 7 with benzophenone imine can be accomplished in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
    Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 4,5-Bis(diphenylphosphino)-9,9-dimethylxanth (Xantphos), and Cs2CO3, in toluene at 100°C for 5 hours.

    [0032] Step H: Removal of the N-diphenylmethylene group in 8 can be accomplished by hydrogenation with hydrogen under nomal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as PtO2, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H2O, dioxane, THF, EtOAc, dichloromethane, chloroform, DMF or mixtures therof.
    The transformation can also be effected by treatment with hydroxylamine hydrochloride, together with a base such as sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate in solvents such as MeOH, EtOH, dioxane, THF, DMF or mixtures therof.
    Preferred condtions are hydroxylamine hydrochloride, together with sodium acetate, in MeOH at room temperature for 2 hours.
    Alternatively, N-diphenylmethylene-protected aniline 8 can be prepared by the sequence of reactions depicted in Scheme 2.



    [0033] Step A: Grignard addition can be accomplished by the addition of phenyl Grignard reagent (10, X1 = Cl or Br, formed in-situ by treatment of p-bromophenyl bromide or iodide) with lactone 1 in anhydrous non-protic organic solvents such as THF and diethyl ether at the temperature of -78°C to 0°C, under inert atmosphere.
    Preferred conditions are using p-bromophenylmagnesium bromide (10, X1=Br) in anhydrous THF at -78°C for 30 minutes.

    [0034] Step B: Reduction of ketone 11 to the corresponding diol 12 can be accomplished by treatment with a reducing reagent, such as NaBH4, LiBH4, ZnBH4, 9-BBN, Borane-THF complex, LiAlH4, or DIBAL-H, in solvents such as THF, diethyl ether, DME, 1,4-dioxane, and TBME, methanol, or ethanol.
    Preferred conditions are NaBH4 as the reducing reagent in MeOH at 0°C for 2 hours.

    [0035] Step C: Cyclisation of diol 12 can be accomplished by a Mitsunobu-type reaction, an acid-mediated cation cyclisation, or a stepwise process involving sulphonate ester intermendiates. In the Mitsunobu-type reaction, the conversion can be accomplished by treatment with triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in ethereal solvents such as diethyl ether, dioxane, THF, or TBME, or other non-protic organic solvents such as toluene and benzene.
    In the acid-mediated cation cyclisation, the conversion can be accomplished by treatment with inorganic acids such as H2SO4, H3PO4 at elevated temperatures, or by treatment with organic acids such as trifluoroacetic acid, BF3•Et2O, optionally with an additive such as Et3SiH, in solvents such as dichloromethane, 1,2-dichloroethane, or toluene, at 0°C to room temperature. In the stepwise process, the conversion can be accomplished by treatment of diol 12 with one equivalent of sulfonyl chloride, such as methanesulfonyl chloride or toluenesulfonlyl chloride, in the presence of an organic base, such as pyridine, triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in ethereal solvents such as diethyl ether, dioxane, THF, or TBME, or using organic base as the solvent, at 0°C to 50°C. The resulting sulphonate ester can be converted to protected bridged-morpholine 13 by treatment with a non-nucloephilic base such as sodium hydride, potassium tert-butoxide, or potassium 2-methyl-2-butoxide, in ethereal solvents such as diethyl ether, dioxane, THF, or TBME.
    Preferred conditions are the Mitsunobu-type process: treating diol 12 with DIAD and triphenylphosphine in toluene at 0°C and continuing the reaction at room temperature for 12 hours.

    [0036] Step D: Deprotection can be accomplished by either a base-induced reaction or a stepwise process involving a benzyl-protected intermediate.
    In the base-induced reaction, deprotection can be effected by treatment with an base such as hydrazine, KOH, NaOH, or Cs2CO3, in solvents such as methanol, ethanol at elevated temperatures such as 90°C to 150°C.
    In the stepwise process, the benzoyl protecting group can be converted to the benzyl protecting group by treatment with reducing regents such as LiAlH4, BH3•THF, and BH3•Me2S in ethereal solvents such as diethyl either, dioxane, THF, or TBME at 0°C to 60°C. The resulting benzyl group can be removed by either a hydrogenation reaction catalyzed by a Pd catalyst or treatment with chloroformates such as ClCOOCH2CH2Cl, ClCOOCH(Cl)Me, ClCOOCH2Ph, and ClCOOCH2CCl3, and optionally with an base such as triethylamine, diisopropylethylamine, and sodium hydroxide, in solvents such as toluene, THF, diethylether, dioxane, or TBME, at room temperature to elevated temperatures.
    Preferred conditions are the base-induced reaction, using KOH as the base and MeOH as the solvent in a seal tube at 110°C for 30 minutes.

    [0037] Step E: Protection of the bridged-morpholine 14 can be accomplished by treatment with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, or cesium carbonate, 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 presence of potassium carbonate as the base at room temperature for 10 hours.

    [0038] Step F: Coupling of iodide 15 with benzophenone imine can be accomplished in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene and DMSO at elevated temperatures, for instance using a palladium-catalysed Buchwald-Hartwig reaction.
    Preferred conditions are catalytic tris(dibenzylidineacetone)dipalladium(0), catalytic 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and KOtBu, in toluene at 90°C for 30 minutes by microwave heating.



    [0039] Step A: Nitration of phenylmorpholine 5 can be accomplished by treatment with fuming nitric acid or nitric acid with other oganic and inorganic acids such as trifluoroacetic acid and sulfuric acid, at -40°C to room temparature, optionally in hydrocarbon or halogenated hydrocarbon solvent such as hexanes, dichloromethane, or 1,2-dichloroethane. Alternatively, the reaction can be performed by treatment of phenylmorpholine 5 with nitric acid salts, such as potassium nitrate, sodium nitrate or cesium nitrate, in other organic and inorganic acids such trifluoroacetic acid and sulfuric acid, at -40°C to room temparature. 16-a and 16-b can be either separated by chromatography or carried out to the next step as the mxiture.
    Preferred conditions are treatment with fuming nitric acid at 0-5°C.

    [0040] Step B: Protection of the bridged-morpholines 16-a, 16-b, or their mixture from step A, can be accomplished by treatment with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, or cesium carbonate, 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 presence of potassium carbonate as the base at room temperature for 10 hours. 17-a and 17-b can be either separated by chromatography or carried to the next step as the mixture.

    [0041] Step C: Reduction of the nitro group of 17-a, 17-b, or their mixture from step B, can be accomplished by treatment with a reducing reagent such as SnCl2, Na2S2O4, or Zn powder, optionally with acetic acid or trifluoroacetic acid as the additive, in MeOH or EtOH as the solvents at elevated temperatures. Alternatively, the conversion 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 PtO2, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H2O, dioxane, THF, HOAc, EtOAc, CH2Cl2, DMF or mixtures thereof. Anilines 9 and 18 can be separated by silica chromatography at this stage. Preferred conditions are using SnCl2 as the reducting reagent, with acetic acid as the additive, in EtOH at refluxing temperature.

    wherein X1 is halogen, L1 is a bond, -C(O)-, CH2C(O)-, -CH2-, or -NHC(O)-; and R1 is phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein phenyl and heteroaryl are optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl or O-CH2-cycloalkyl.

    [0042] Step A: Coupling of aryl halide 19 (including 7 with X1=I and 15 with X1=Br) with aryl amine (20-a), aryl amide (20-b), aryl urea (20-c), or aryl methanamine (20-d) can be accomplished by treatment with a palladium or copper catalyst, a ligand, and a base in solvents such as dioxane, DMF, 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 4,5-bis(diphenylphosphino)-9,9-dimethylxanth (Xantphos), and Cs2CO3, in dioxane at 90°C for 16 hours.

    [0043] Step B: Removal of BOC N-protecting group can be effected with mineral acids such as HCl, H2SO4, or H3PO4 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2Cl2, CHCl3, THF, MeOH, EtOH, or H2O at 0-80°C.
    Preferred conditions are CF3COOH as the acid in CH2Cl2 at room temperature for 2 hours.



    [0044] Step A: Amide formation with aniline 9 or 18 and carboxylic acid 22-a can be accomplished by reaction in the presence of a coupling reagent such as DCC, EDC, TBTU, HBTU or HATU in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in solvents such as dichloromethane, 1,2-dichloroethane, DMF, DMSO, or ethereal solvents including diethyl ether, dioxane, THF, DME, or TBME.
    Preferred conditions are HATU with N,N-diisopropylethylamine in DMF at room temperature for 12 hours.
    Urea formation with aniline 9 or 18 and isocyanate 22-b can be accomplished by reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in halogenated solvents such as dichloromethane, 1,2-dichloroethane, chlorobenzene.
    Preferred conditions are triethylamine as the base in dichloromethane at room temperature for 16 hours.

    [0045] Step B: Removal of BOC N-protecting group can be effected with mineral acids such as HCl, H2SO4, or H3PO4 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2Cl2, CHCl3, THF, MeOH, EtOH, or H2O at 0-80°C.
    Preferred conditions are CF3COOH as the acid in CH2Cl2 at room temperature for 2 hours.



    [0046] Step A: Coupling of aryl halide 19 (including 7 with X1=I and 15 with X1=Br) with alkyl amine (24) can be accomplished by treatment with a palladium or copper catalyst, a ligand, and a base in solvents such as dioxane, DMF, 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 4,5-bis(diphenylphosphino)-9,9-dimethylxanth (Xantphos), and Cs2CO3, in dioxane at 90°C for 16 hours.

    [0047] Step B: Removal of BOC N-protecting group can be effected with mineral acids such as HCl, H2SO4, or H3PO4 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2Cl2, CHCl3, THF, MeOH, EtOH, or H2O at 0-80°C.
    Preferred conditions are CF3COOH as the acid in CH2Cl2 at room temperature for 2 hours.



    [0048] Step A: Coupling of aryl halide 19 (including 7 with X1=I and 15 with X1=Br) with alkyl carboxylic acid (26) can be accomplished by reaction in the presence of a coupling reagent such as DCC, EDC, TBTU, HBTU or HATU in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in solvents such as dichloromethane, 1,2-dichloroethane, DMF, DMSO, or ethereal solvents including diethyl ether, dioxane, THF, DME, or TBME.
    Preferred conditions are HATU with N,N-diisopropylethylamine in DMF at room temperature for 12 hours.

    [0049] Step B: Removal of BOC N-protecting group can be effected with mineral acids such as HCl, H2SO4, or H3PO4 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2Cl2, CHCl3, THF, MeOH, EtOH, or H2O at 0-80°C.
    Preferred conditions are CF3COOH as the acid in CH2Cl2 at room temperature for 2 hours.



    [0050] Step A: Carbonylation of halide 19 can be achieved by lithiation with alkyl lithium reagents in anhydrous solvent such as diethyl ether, dioxane, THF, DME, or TBME, followed by addition of CO2. Alternatively, such transformation can be achieved by coupling with CO in the presence of transition metal catalysts, such as Pd, Mo, Co, Cu catalysts together with ligands and additives. Choice of solvents can be DMF, THF, dioxane, DMSO, ethanol, and water.
    Preferred conditions are lithiation with nBuLi at -78°C in anhydrous THF, followed by bubbling dry CO2 into the reaction solution.

    [0051] Step B: Coupling of acid 27 with amine 28 can be achieved by reaction in the presence of a coupling reagent such as DCC, EDC, TBTU, HBTU or HATU in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in solvents such as dichloromethane, 1,2-dichloroethane, DMF, DMSO, or ethereal solvents including diethyl ether, dioxane, THF, DME, or TBME.
    Preferred conditions are HATU with N,N-diisopropylethylamine in DMF at room temperature for 2 hours.

    [0052] Step C: Removal of BOC N-protecting group can be effected with mineral acids such as HCl, H2SO4, or H3PO4 or organic acids such as CF3COOH, CHCl2COOH, HOAc or p-toluenesulfonic acid in solvents such as CH2Cl2, CHCl3, THF, MeOH, EtOH, or H2O at 0-80°C.
    Preferred conditions are CF3COOH as the acid in CH2Cl2 at room temperature for 2 hours.

    Isolation and purification of the compounds



    [0053] 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. Racemic mixtures of chiral synthetic intermediates may also be separated using chiral HPLC.

    Salts of compounds of formula I



    [0054] 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.

    Example 1


    3-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0055] 


    a) [(2R,4R)-1-Benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone



    [0056] To a solution of (1R,4R)-5-Benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (21.7 g, CAS: 444313-68-2, prepared according to the reported procedure in Tetrahedron, 2007, 63(32), 7523-7531) and N,O-dimethylhydroxylamine hydrochloride (11.6 g, CAS: 6638-79-5) in anhydrous tetrahydrofuran (1.5 L) was added phenylmagnesium bromide (133 mL, 3 M in diethyl ether, CAS: 100-58-3) at -78 °C under N2 atmosphere. The reaction was stirred at -70 °C for 10 hours. LCMS indicated the completion of the reaction. The reaction was quenched with saturated aqueous NH4Cl solution (100 ml). The mixture was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, petroleum ether : ethyl acetate = 1:1 by vol) gave [(2R,4R)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone (6.67 g, yield 23 %) as a white solid. MS (ESI): 296.1 ([M+H]+).

    b) [(2R,4R)-4-Hydroxy-2-[(S)-hydroxy(phenyl)methyl]pyrrolidin-1-yll-phenyl-methanone



    [0057] To a solution of [(2R,4R)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone (6 g) in MeOH (200 mL) at 0 °C was added NaBH4 (3 g) in portions. The reaction was stirred for 1.5 h until TLC analysis indicated completion of the reaction. Acetone (10 mL) was added to quench excess NaBH4. The mixture was concentrated under reduced pressure. Saturated aqueous NH4Cl solution (100 mL) was added. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc=1:2 by vol) to give [(2R,4R)-4-hydroxy-2-[(S)-hydroxy(phenyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (5.5 g, 92 %) as a white solid. MS (ESI): 298.1 ([M+H]+).

    c) Phenyl-[(1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone



    [0058] To a mixture of [(2R,4R)-4-hydroxy-2-[(S)-hydroxy(phenyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (5.5 g) and PPh3 (5.82 g) in toluene (100 mL) was added diisopropyl azodicarboxylate (DIAD, 4.49 g, CAS: 2446-83-5) at 0 °C. The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and was diluted with tert-butyl methyl ether. The suspension was stirred and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc=1:1 by vol) to give phenyl-[(1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (4.1 g, yield 79 %) as a white solid.
    MS (ESI): 280.1 ([M+H]+).
    1HNMR (CDCl3, 400MHz): δ 7.625-7.285 (10H), 5.25 (1H), 4.96(1H), 4.56 (1H), 3.65 (2H), 1.93 (1H),1.51 (1H).

    d) (1R,3S,4R)-5-Benzyl-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane



    [0059] To a mixture of phenyl-[(1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (10 g) in THF (200 mL) was added LiAlH4 (5.3 g) at 0 °C. The reaction was stirred at room temperature for 2 hours until LCMS indicated complete consumption of the starting material. Na2SO4•10H2O (10 g) was added to quench excess LiAlH4. The mixture was filtered. The filtrate was concentrated under reduced pressure and dried further under high vacuum to give crude (1R,3S,4R)-5-benzyl-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (10g, quantitative yield), which was used in next step directly without purification. MS (ESI): 266.1 ([M+H]+).
    1HNMR (CDCl3, 400MHz): δ 7.46-7.24 (10H), 5.29 (1H), 4.63 (1H), 4.01-3.92 (2H), 3.40 (1H), 3.02 (1H), 3.00 (1H), 1.72 (1H), 1.67 (1H).

    e) (1R,3S,4R)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane



    [0060] Under nitrogen, to a solution of (1R,3S,4R)-5-benzyl-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (16 g) in toluene (250 ml) was added ClCOOCH2CH2Cl (17 g) dropwise. The reaction mixture was heated under refluxing conditions for 16 hours until TLC indicated complete consumption of the starting material. The reaction was then cooled to room temperature. MeOH (5 mL) was added and the reaction was stirred for an hour. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2 : MeOH=10:0 to 5:1 by vol) to give (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (4.5 g, yield 45 %) as a yellow oil.
    1HNMR (CDCl3, 400MHz): δ 7.37-7.24 (5H), 4.91 (1H), 4.70 (1H), 3.62 (1H), 3.16 (1H), 3.02 (1H), 1.83 (1H), 1.51 (1H).

    f) (1R,3S,4R)-3-(3-Nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0061] At -20 °C, to fuming nitric acid (15 mL) was added a solution of (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (1.4 g) in CH2Cl2 (1 mL). The reaction was stirred for 0.5 h. The mixture was poured into ice water. NaOH was added to adjust pH to -10. The mixture was concentrated under reduced pressure and diluted with MeOH (50 ml). The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2: MeOH= 10:0 to 5:1 by vol) to give mixture of (1R,3S,4R)-3-(3-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.25 g, total yield 71.0 %) as a yellow oil.
    1HNMR (CDCl3, 400MHz): δ 8.23-8.11 (2H), 7.76-7.47(2H), 4.98 (1H), 4.78-4.77(1H), 3.78-3.70 (1H), 3.18-3.08 (2H), 1.76-1.56 (2H).

    g) tert-Butyl (1R,3S,4R)-3-(3-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate and tert-butyl (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0062] To the mixture of (1R,3S,4R)-3-(3-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane and (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.1 g) in THF (20 mL) were added K2CO3 (2.1 g) and Boc2O (1.3 g) at room temperature. The reaction was stirred for 16 hours until TLC analysis indicated complete consumption of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with brine (20 ml). The mixture was extracted with CH2Cl2 (3x20 ml). The combined organic layers were dried over Na2SO4 and was subsequently concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 10 : 0 to 5:1 by vol) to give a mixture of tert-butyl (1R,3S,4R)-3-(3-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate and tert-butyl (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.45 g, total yield 91 %) as a white solid.
    1HNMR (CDCl3, 400MHz): δ 8.24-8.14 (2H), 7.68-7.45 (2H), 5.10 (1H), 4.83(1H), 4.51-4.37 (1H), 3.59-3.37 (2H), 1.75-1.69 (2H), 1.57 (9H).

    h) tert-Butyl (1R,3S,4R)-3-(3-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0063] To a mixture of tert-butyl (1R,3S,4R)-3-(3-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate and tert-butyl (1R,3S,4R)-3-(4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.2 g) in ethanol (50 mL) were added tin(II) chloride dihydrate (4.51g, CAS: 10025-69-1) and acetic acid (2.4 g). The reaction was stirred at 50 °C for 4 hours under N2 atmosphere until TLC analysis indicated the complete consumption of starting materials. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with CH2Cl2, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/EtOAc=1:1 by vol) to give tert-butyl (1R,3S,4R)-3-(3-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (240 mg, yield 20.6 %) as a yellow solid.
    MS (ESI): 291.0 ([M+H]+), 235.0 ([M-C4H8+H]+), 191.0([M- C4H8-CO2+H]+).

    i) tert-Butyl (1R,3S,4R)-3-[3-[(3-chlorobenzoyl)amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0064] A solution 3-chlorobenzoic acid (38 mg, CAS: 535-80-8), HATU (114 mg, CAS: 148893-10-1) and DIPEA (0.17 mL, CAS: 7087-68-5) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min. To the reaction mixture was added tert-butyl (1R,3S,4R)-3-(3-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (58 mg). The reaction was stirred at room temperature for 3 hours until TLC analysis indicated complete consumption of the starting material. The reaction mixture was diluted with CH2Cl2 (50 mL). The solution was washed with NH4Cl aqueous solution (50 mL), dried over Na2SO4, and concentrated under reduced pressure. Further drying under high vacuum gave crude tert-butyl (1R,3S,4R)-3-[3-[(3-chlorobenzoyl)amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate as a brown solid.

    i) 3-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0065] Crude tert-butyl (1R,3S,4R)-3-[3-[(3-chlorobenzoyl)amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate as a brown solid from step (i) was dissolved in the mixture of CH2Cl2 (2 mL) and trifluoroacetic acid (TFA, 0.5 mL, CAS: 76-05-1). The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was purified by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1% TFA, C18 column) to give 3-chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide (18 mg, 27 % yield in two steps) as a white solid.
    MS: 331.1 ({37Cl}M+H)+, 329.1 ({35Cl}M+H)+.
    1H NMR (400MHz, Methanol-d4): δ 7.98 (1H), 7.89 (1H), 7.68 (1H), 7.60 (2H), 7.54 (1H), 7.36 (1H), 7.12 (1H), 4.95 (1H), 4.73 (1H), 3.65 (1H), 3.05 (1H), 2.96 (1H), 1.88 (1H), 1.54 (1H).

    Example 2


    4-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0066] 



    [0067] The title compound was obtained in analogy to example 1 using 4-chlorobenzoic acid (CAS: 74-11-3) instead of 3-chlorobenzoic acid in step (i). Off-white solid. MS (ESI): 331.0
    ([{37Cl}M+H]+), 329.1 ([{35Cl}M+H]+).

    Example 3


    1-[3-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluoromethyl)phenyl] urea



    [0068] 


    a) tert-Butyl (1R,3S,4R)-3-[3-[[4-(trifluoromethyl)phenyl]carbamoylamino]phenyl]-2-oxa-5-azabicyclo[2.2.]heptane-5-carboxylate



    [0069] To a solution of tert-butyl (1R,3S,4R)-3-(3-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (44 mg) and Et3N (23 mg, CAS: 121-44-8) in CH2Cl2 (1 mL) was added 4-(trifluoromethyl)phenyl isocyanate (34 mg, CAS: 1548-13-6) at room temperature. The reaction was stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 ml), washed with NaHCO3 aqueous solution (5 ml), dried over Na2SO4, and concentrated under reduced pressure. Further drying under high vacuum gave tert-butyl (1R,3S,4R)-3-[3-[[4-(trifluoromethyl)phenyl]carbamoylamino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (50 mg, yield 70 %) as a brown solid.

    b) 1-[3-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-4-(trifluoromethyl)phenyl]urea



    [0070] To a solution of tert-butyl (1R,3S,4R)-3-[3-[[4-(trifluoromethyl)phenyl]carbamoylamino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (50 mg) from step (a) in CH2Cl2 (2 mL) was added TFA (0.5 ml, CAS: 76-05-1). The reaction was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The crude mixture was purified by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C18 column) to give 1-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea (10 mg, yield 26 %) as a white solid.
    MS (ESI): 378.1 ([M+H]+)
    1H NMR: (Methanol-d4, 400MHz) δ 7.663-7.583 (4H), 7.44 (1H), 7.33-7.28(2H), 7.00 (1H), 4.92 (1H), 4.72 (1H), 3.63 (1H), 3.06-2.94 (2H), 1.86 (1H), 1.53 (1H).

    Example 4


    1-(4-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea



    [0071] 



    [0072] The title compound was obtained in analogy to example 3 using 4-chlorophenyl isocyanate (CAS: 104-12-1) instead of 4-(trifluoromethyl)phenyl isocyanate in step (a). White solid. MS (ESI): 346.1 ([{37Cl}M+H]+), 344.1 ([{35Cl}M+H]+).

    Example 5


    1-(3-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea



    [0073] 



    [0074] The title compound was obtained in analogy to example 3 using 3-chlorophenyl isocyanate (CAS: 2909-38-8) instead of 4-(trifluoromethyl)phenyl isocyanate in step (a). White solid. MS (ESI): 346.1 ([{37Cl}M+H]+), 344.1 ([{35Cl}M+H]+).

    Example 6


    (1R,3S,4R)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane



    [0075] 



    [0076] The title compound was prepared in step (e), example 1.
    MS (ESI): 176.1 ([M+H]+)

    Example 7


    4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0077] 


    a) tert-Butyl (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0078] To a solution of (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (3.85 g) in THF (100 mL) were added K2CO3 (5.88 g, CAS: 584-08-7) and Boc2O (5.88 g, CAS: 24424-99-5) at 0 °C. The reaction was stirred at room temperature overnight. TLC analysis indicated completion of the reaction. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 10:0 to 5:1 by vol) to give tert-butyl (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (5.9 g, yield 98 %) as a white solid.
    1H NMR (CDCl3, 400MHz) δ 7.36-7.285 (m, 5H), 5.056 (1H), 4.78 (1H), 4.41 (1H), 3.51 (1H), 3.37 (1H), 1.86 (1H), 1.67-1.52 (10H).

    b) tert-Butyl (1R,3S,4R)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0079] Under N2 atmosphere, a solution of tert-butyl (1R,3S,4R)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.1 g), [bis(trifluoroacetoxy)iodo]benzene (2.1 g, CAS: 2712-78-9), and iodine (1.1 g, CAS: 7553-56-2) in CCl4 (10 mL) was stirred at room temperature overnight. LC-MS analysis indicated over 90% conversion. The reaction mixture was diluted with NaHSO3 aqueous solution, extracted with CH2Cl2, and washed with brine. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (C-18, MeCN/0.1 % NH3 in water) to give tert-butyl (1R,3S,4R)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (560 mg, yield 35 %) as a brown solid.
    MS (ESI): 424.0 (M+Na)+, 346.0 (M-C4H8+H)+, 302.0 (M-C4H8-CO2+H)+.

    c) 4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.]heptan-3-yl]phenyl]benzamide



    [0080] Under N2 atmosphere, a solution of tert-butyl (1R,3S,4R)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg), 4-chlorobenzamide (23 mg, CAS: 619-56-7), tris(dibenzylidineacetone)dipalladium(0) (18 mg, CAS: 51364-51-3), bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 10mg, CAS: 161265-03-8), and Cs2CO3 (162 mg, CAS: 534-17-8) in dioxane (1 mL) was stirred at 90 °C overnight. TLC analysis indicated the completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C-18 column, 0.1 % NH3 in H2O/MeCN) to give the crude intermediate as brown oil. The crude intermediate was dissolved in CH2Cl2 (2 mL). TFA (0.5 mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was purified by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1% TFA, C-18 column) to give 4-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide (10 mg, 30% yield in 2 steps) as a white solid. MS (ESI): 331.0 ([{37Cl}M+H]+), 329.0 ([{35Cl}M+H]+).
    1H NMR (Methanol-d4, 400MHz): δ 7.95 (2H), 7.76 (2H), 7.56 (2H), 7.38 (2H), 5.18 (1H), 4.96 (1H), 4.42 (1H), 3.47 (1H), 3.37 (1H), 2.15 (1H), 1.83 (1H).

    Example 8


    3-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0081] 


    a) [(2S,4S)-1-Benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone



    [0082] (1S,4S)-5-Benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (CAS: 31560-25-5) can be prepared according to the reported procedure (Tetrahedron, 1971, 27(5), 961-967).
    Under nitrogen, to a solution of (1S,4S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (32 g) and N,O-dimethylhydroxylamine hydrochloride (17 g, CAS: 6638-79-5) in anhydrous THF (2.0 L) was added phenylmagnesium bromide (133 mL, 3 M in diethyl ether, CAS: 100-58-3) at -70 °C over 10 hours. TLC analysis indicated the completion of the reaction. Then the reaction was quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc=1:1 by vol) to give [(2S,4S)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone (50 g, yield 38 %) as a white solid. MS (ESI): 296.2 ([M+H]+)

    b) [(2S,4S)-4-Hydroxy-2-[(R)-hydroxy(phenyl)methyl]pyrrolidin-1-yl]-phenyl-methanone



    [0083] To a solution of [(2S,4S)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanone (50 g) in MeOH (500 mL) at 0 °C was added NaBH4 (25 g, CAS: 16940-66-2) in portions. The reaction mixture was stirred at 0 °C for 1.5 hours until LCMS analysis indicated the completion of the reaction. Acetone was added to quench excess NaBH4. Volatiles were removed under reduced pressure. Saturated aqueous NH4Cl solution was added. The mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc = 1:2 by vol) to give [(2S,4S)-4-hydroxy-2-[(R)-hydroxy(phenyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (33 g, yield: 65 %) as a white solid. MS (ESI): 298.2 ([M+H]+)

    c) Phenyl-[(1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone



    [0084] To a solution of [(2S,4S)-4-hydroxy-2-[(R)-hydroxy(phenyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (16 g) and PPh3 (17 g, CAS: 603-35-0) in dry toluene (200 mL) was added diisopropyl azodicarboxylate (DIAD, 14 g, CAS: 2446-83-5) at 0 °C. The reaction was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was dissolved in tert-butyl methyl ether (MTBE, 200 mL, CAS: 1634-04-4). The suspension was filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc=1:1 by vol) to give phenyl-[(1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (11.5 g, yield: 77 %) as a white solid. MS (ESI): 280.2 ([M+H]+)
    1H NMR (CDCl3, 400 MHz) δ 7.61-7.13 (10H), 5.20 (1H), 4.96 (1H), 4.82 (1H), 3.70-3.51 (2H), 1.90 (1H), 1.67 (1H).

    d) (1S,3R,4S)-5-Benzyl-3-phenyl-2-oxa-5-azabicyclor2.2.1]heptane



    [0085] To a solution of phenyl-[(1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (3 g) in anhydrous THF (30 mL) was added LiAlH4 (1.7 g, CAS: 16853-85-3) at 0 °C. The reaction was stirred at room temperature for 2 hours. Solid Na2SO4•10H2O (10 g, CAS: 7727-73-3) was added to quench excess LiAlH4. The mixture was filtered. The filtrate was concentrated under reduced pressure and dried under high vacuum to give crude (1S,3R,4S)-5-benzyl-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane as a yellow oil (3 g, quantative yield), which was used in the next step without purification. MS (ESI): 266.2 ([M+H]+)

    e) (1S,3R,4S)-3-Phenyl-2-oxa-5-azabicyclor2.2.1]heptane



    [0086] To a solution of crude (1S,3R,4S)-5-benzyl-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (3 g, 11 mmol) from step (d) in toluene (40 ml) was added 2-chloroethyl chloroformate (3.2 g, CAS: 627-11-2) dropwise. The reaction was stirred at 110 °C under N2 atmosphere overnight. MeOH (20 mL) was added and the reaction was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2: MeOH=10:1 by vol, 1 % NH3•HzO added to the mobile phase) to give (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (350 mg, yield: 17%) as a yellow solid.
    MS (ESI): 176.1 ([M+H]+)
    1HNMR (CDCl3, 400MHz): δ 7.38-7.29 (5H), 5.55 (1H), 4.88 (1H), 4.36 (1H), 3.57 (1H), 3.42 (1H), 2.10 (1H), 1.98 (1H).

    f) tert-Butyl (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0087] To a solution of (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (10 g) in anhydrous THF (150 mL) were added K2CO3 (24 g) and Boc2O (14 g, CAS: 24424-99-5). The reaction was stirred at room temperature overnight. Volatiles were removed under reduced pressure. Saturated NaCl solution (100 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc = 20:1 by vol) to give tert-butyl (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (4.2 g, yield: 25%) as a yellow solid.
    1HNMR (CDCl3, 400MHz): δ 7.38-7.26 (5H), 5.04 (1H), 4.76 (1H), 4.39 (1H), 3.50 (1H), 3.35 (1H), 1.84 (1H), 1.63 (1H), 1.51(9H).

    g) tert-Butyl (1S,3R,4S)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbolylate



    [0088] To a solution of tert-butyl (1S,3R,4S)-3-phenyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.0 g) in CCl4 (12 mL) were added [bis(trifluoroacetoxy)iodo]benzene (1.88 g, CAS: 2712-78-9), and iodine (1.0 g, CAS: 7553-56-2). The reaction was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with chloroform (200 mL). The solution was washed with 5% NaHSO3 (2 x 50 mL) and 10 % NaCl aqueous solution (5 x 50 mL). Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc=20:1 by vol) to give tert-butyl (1S,3R,4S)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (600 mg) as a brown oil.
    MS (ESI): 345.8 (M-C4H8+H)+, 301.9 (M-C4H8-CO2+H)+.

    h) 3-Chloro-N-r4-r(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0089] Under N2 atmosphere, a solution of tert-butyl (1S,3R,4S)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg), 3-chlorobenzamide (22 mg, CAS: 618-48-4), tris(dibenzylidineacetone)dipalladium(0) (18 mg, CAS: 51364-51-3), bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 19 mg, CAS: 161265-03-8), and Cs2CO3 (163 mg, CAS: 534-17-8) in dioxane (1 mL) was stirred at 90 °C overnight. TLC analysis indicated the completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C-18 column, 0.1 % NH3 in H2O/MeCN) to give the crude intermediate as brown oil. The crude intermediate was dissolved in CH2Cl2 (2 mL). TFA (0.5 mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give 3-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide (10 mg, 30 % yield in 2 steps) as a white solid. MS (ESI): 331.0 ([{37Cl}M+H]+), 329.0 ([{35Cl}M+H]+).
    1H NMR (Methanol-d4, 400MHz): δ 7.95 (1H), 7.87 (1H), 7.75 (2H), 7.60 (1H), 7.53 (1H), 7.37 (2H), 5.15 (1H), 4.95 (1H), 4.39 (1H), 3.46 (1H), 3.36 (1H), 2.13 (1H), 1.82 (1H).

    Example 9


    (1S,3R,4S)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane



    [0090] 



    [0091] The title compound was prepared in step (e), example 8.
    MS (ESI): 176.1 ([M+H]+)

    Example 10


    3-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0092] 



    [0093] The title compound was obtained in analogy to example 7 using 3-chlorobenzamide (CAS: 618-48-4) instead of 4-chlorobenzamide in step (c). White solid. MS (ESI): 331.0 ([{37Cl}M+H]+), 329.0 ([{35Cl}M+H]+).

    Example 11


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine



    [0094] 



    [0095] Under N2 atmosphere, a solution of tert-butyl (1R,3S,4R)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg), 2-amino-5-(trifluoromethyl)pyridine (24 mg, CAS: 74784-70-6), tris(dibenzylidineacetone)dipalladium(0) (18 mg, CAS: 51364-51-3), bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 10mg, CAS: 161265-03-8), and Cs2CO3 (162 mg, CAS: 534-17-8) in dioxane (1 mL) was stirred at 90 °C overnight. TLC analysis indicated the completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C-18 column, 0.1 % NH3 in H2O/MeCN) to give the crude intermediate as brown oil. The crude intermediate was dissolved in CH2Cl2 (2 mL). TFA (0.5 mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give the title compound (12 mg, 36% yield in 2 steps) as a yellow solid.
    MS (ESI): 336.2 ([M+H]+).
    1H NMR (Methanol-d4, 400MHz): δ 8.40 (1H), 7.78 (1H), 7.76 (2H), 7.33 (2H), 6.93 (1H), 5.17 (1H), 4.91 (1H), 4.38 (1H), 3.46 (1H), 3.37 (1H), 2.16 (1H), 1.84 (1H).

    Example 12


    4-(Cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0096] 


    a) 4-(Cyclopropylmethoxy)benzamide



    [0097] To a solution of 4-(cyclopropylmethoxy)benzoic acid (384 mg, CAS: 355391-05-8), HATU(836 mg, CAS: 148893-10-1) and Et3N (606 mg, CAS: 121-44-8) in DMF (2.0 mL) was added NH3 in water (25 %∼28 %, 1.0 mL) at room temperature. The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was purified through reverse phase chromatography (C-18 column, mobile phase: A, H2O; B, CH3CN with 0.5% NH3•H2O) to give 4-(cyclopropylmethoxy)benzamide as a white solid (275 mg, yield 72 %). MS (ESI): 192.1 (M+H)+.

    b) 4-(Cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0098] The title compound was obtained in analogy to example 7 using 4-(cyclopropylmethoxy)benzamide instead of 4-chlorobenzamide in step (c). White solid. MS (ESI): 365.1 ([M+H]+).

    Example 13


    6-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide



    [0099] 



    [0100] The title compound was obtained in analogy to example 7 using 6-ethoxypyridine-3-carboxamide (CAS: 473693-84-4) instead of 4-chlorobenzamide in step (c). White solid. MS (ESI): 340.2 ([M+H]+).

    Example 14


    4-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0101] 



    [0102] The title compound was obtained in analogy to example 8 using 4-chlorobenzamide (CAS: 619-56-7) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 331.1 ([{37Cl}M+H]+), 329.1 ([{35Cl}M+H]+).

    Example 15


    6-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide



    [0103] 



    [0104] The title compound was obtained in analogy to example 8 using 6-ethoxypyridine-3-carboxamide (CAS: 473693-84-4) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 340.2 ([M+H]+).

    Example 16


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide



    [0105] 



    [0106] The title compound was obtained in analogy to example 8 using 6-(2,2,2-trifluoroethoxy) pyridine-3-carboxamide (CAS: 676533-51-0) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 394.1 ([M+H]+).

    Example 17


    4-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0107] 



    [0108] The title compound was obtained in analogy to example 8 using 4-ethoxybenzamide (CAS: 55836-71-0) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 339.2 ([M+H]+).

    Example 18


    2-Cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0109] 


    a) 2-Cyclopropylpyrimidine-5-carboxamide



    [0110] To a solution of 2-cyclopropylpyrimidine-5-carboxylic acid (328 mg, CAS: 648423-79-4), HATU(836 mg, CAS: 148893-10-1) and Et3N (606 mg, CAS: 121-44-8) in DMF (2.0 mL) was added NH3 in water (25 %∼28 %, 1.0 mL) at room temperature. The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was purified through reverse phase chromatography (C-18 column, mobile phase: A, H2O; B, CH3CN with 0.5 % NH3•H2O) to give 2-cyclopropylpyrimidine-5-carboxamide as a white solid (241 mg, yield 74%). MS (ESI): 164.1 (M+H)+.

    b) 2-Cyclopropyl-N[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0111] The title compound was obtained in analogy to example 8 using 2-cyclopropylpyrimidine-5-carboxamide (CAS: 1447607-18-2) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 337.2 ([M+H]+).

    Example 19


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine



    [0112] 



    [0113] Under N2 atmosphere, a solution of tert-butyl (1S,3R,4S)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (50 mg), 2-amino-5-(trifluoromethyl)pyridine (80 mg, CAS: 74784-70-6), tris(dibenzylidineacetone)dipalladium(0) (20 mg, CAS: 51364-51-3), bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 20mg, CAS: 161265-03-8), and Cs2CO3 (120 mg, CAS: 534-17-8) in dioxane (3 mL) was stirred at 90 °C overnight. TLC analysis indicated the completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C-18 column, 0.1 % NH3 in H2O/MeCN) to give the crude intermediate as brown oil. The crude intermediate was dissolved in CH2Cl2 (2 mL). TFA (0.5 mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give the title compound (16 mg, 32 % yield in 2 steps) as a yellow solid.
    MS (ESI): 336.1 ([M+H]+).

    Example 20


    5-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine



    [0114] 



    [0115] The title compound was obtained in analogy to example 19 using 2-amino-5-chloropyridine (CAS: 1072-98-6) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 304.0 ([{37Cl}M+H]+), 302.0 ([{35Cl}M+H]+).

    Example 21


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidin-4-amine



    [0116] 



    [0117] The title compound was obtained in analogy to example 19 using 2-(trifluoromethyl)pyrimidin-4-amine (CAS: 672-42-4) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.1 ([M+H]+).

    Example 22


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine



    [0118] 



    [0119] The title compound was obtained in analogy to example 19 using 5-trifluoromethyl-2-aminopyrazine (CAS: 69816-38-2) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.0 ([M+H]+).

    Example 23


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3- yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine



    [0120] 



    [0121] The title compound was obtained in analogy to example 19 using 5-(trifluoromethyl)pyrimidin-2-amine (CAS: 69034-08-8) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.0 ([M+H]+).

    Example 24


    5-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine



    [0122] 



    [0123] The title compound was obtained in analogy to example 11 using 2-amino-5-chloropyridine (CAS: 1072-98-6) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 304.1 ([{37Cl}M+H]+), 302.1 ([{35Cl}M+H]+).

    Example 25


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide



    [0124] 



    [0125] The title compound was obtained in analogy to example 8 using 4-amino-2-(trifluoromethyl) pyridine (CAS: 147149-98-2) instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 364.1 ([M+H]+).

    Example 26


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide



    [0126] 



    [0127] The title compound was obtained in analogy to example 11 using 4-amino-2-(trifluoromethyl) pyridine (CAS: 147149-98-2) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 364.1 ([M+H]+).

    Example 27


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide



    [0128] 



    [0129] The title compound was obtained in analogy to example 11 using 6-(2,2,2-trifluoroethoxy) pyridine-3-carboxamide (CAS: 676533-51-0) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 394.2 ([M+H]+).

    Example 28


    4-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0130] 



    [0131] The title compound was obtained in analogy to example 11 using 4-ethoxybenzamide (CAS: 55836-71-0) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 339.2 ([M+H]+).

    Example 29


    2-Cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0132] 



    [0133] The title compound was obtained in analogy to example 11 using 2-cyclopropylpyrimidine-5-carboxamide (CAS: 1447607-18-2) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.2 ([M+H]+).

    Example 30


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine



    [0134] 



    [0135] The title compound was obtained in analogy to example 11 using 5-trifluoromethyl-2-aminopyrazine (CAS: 69816-38-2) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.1 ([M+H]+).

    Example 31


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine



    [0136] 



    [0137] The title compound was obtained in analogy to example 11 using 5-(trifluoromethyl)pyrimidin-2-amine (CAS: 69034-08-8) instead of 2-amino-5-(trifluoromethyl)pyridine. White solid. MS (ESI): 337.2 ([M+H]+).

    Example 32


    4-(Cyclopropylmethoxy)-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide



    [0138] 



    [0139] The title compound was obtained in analogy to example 8 using 4-(cyclopropylmethoxy)benzamide instead of 3-chlorobenzamide in step (h). White solid. MS (ESI): 365.1 ([M+H]+).

    Example 33


    1-(4-Chlorophenyl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea



    [0140] 



    [0141] Under N2 atmosphere, a solution of tert-butyl (1S,3R,4S)-3-(4-iodophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg), 4-chlorophenylurea (22 mg, CAS: 140-38-5), tris(dibenzylidineacetone)dipalladium(0) (18 mg, CAS: 51364-51-3), bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 19 mg, CAS: 161265-03-8), and Cs2CO3 (163 mg, CAS: 534-17-8) in dioxane (1 mL) was stirred at 90°C overnight. TLC analysis indicated the completion of the reaction. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C-18 column, 0.1 % NH3 in H2O/MeCN) to give the crude intermediate as brown oil. The crude intermediate was dissolved in CH2Cl2 (2 mL). TFA (0.5 mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for an hour. Volatiles were removed under reduced pressure. The residue was by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give the title compound (4 mg, 12 % yield in 2 steps) as a white solid.
    MS (ESI): 346.1 ([{37Cl}M+H]+), 344.1 ([{35Cl}M+H]+).

    Example 34


    2-Ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0142] 


    a) 2-Ethylpyrimidine-5-carboxamide



    [0143] To a solution of 2-ethylpyrimidine-5-carboxylic acid (304 mg, CAS: 72790-16-0), HATU (836 mg, CAS: 148893-10-1) and Et3N (606 mg, CAS: 121-44-8) in DMF (2.0 mL) was added NH3 in water (25 %∼28 %, 1.0 mL) at room temperature. The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was purified through reverse phase chromatography (C-18 column, mobile phase: A, H2O; B, CH3CN with 0.5 % NH3•H2O) to give 2-ethylpyrimidine-5-carboxamide as a white solid (120 mg, yield 40%). MS (ESI): 152.2 (M+H)+.

    b) 2-Ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0144] The title compound was obtained in analogy to example 8 using 2-ethylpyrimidine-5-carboxamide instead of 3-chlorobenzamide in step (h). Waxy solid. MS (ESI): 325.0 ([M+H]+).

    Example 35


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amine



    [0145] 


    a) [(2S,4S)-1-Benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone



    [0146] To a solution of 1,4-dibromobenzene (30 g, CAS: 106-37-6) in anhydrous THF (500 mL) was added n-butyllithium solution (2.5 M in hexanes, 52 mL, CAS: 109-72-8) dropwise at -78 °C. Stirring was continued for 30 minutes. This solution was then added slowly to a solution of (1S,4S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (25 g) in anhydrous THF (1.0 L) at - 78 °C. The reaction was stirred for 30 minutes. Saturated NH4Cl aqueous solution (300 mL) was added to quench the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (1.0 L). The organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3x500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate=1:3 by vol) to give [(2S,4S)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone (20 g, 53 mmol, yield: 41 %) as a white solid.
    MS (ESI): 375.9 ([{81Br}M+H]+), 373.9 ([{79Br}M+H]+).

    b) [(2S,4S)-2-[(R)-(4-Bromot)henyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone



    [0147] To a solution of [(2S,4S)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone (20 g, 53 mmol, from step a) in MeOH (100 mL) at 0 °C was added NaBH4 (8.1 g, 213 mmol). The reaction mixture was stirred at 0 °C for 1.5 hours. Acetone was added to quench excess NaBH4. Volatiles were removed under reduced pressure. Saturated aqueous NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate=1: 1 by vol) to give [(2S,4S)-2-[(R)-(4-bromophenyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone (15 g, yield: 41 %) as a white solid.
    MS (ESI): 378.0 ([{81Br}M+H]+), 376.0 ([{79Br}M+H]+).

    c) [(1S,3R,4S)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone



    [0148] To a solution of give [(2S,4S)-2-[(R)-(4-bromophenyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone (9.5 g) and PPh3 (8.5 g, CAS: 603-35-0) in dry toluene (100 mL) was added DIAD (6.6 g, CAS: 2446-83-5) at 0°C. The mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate=5:1 by vol) to give [(1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone (4 g, yield: 45 %) as a white solid. MS (ESI): 360.1 ([{81Br}M+H]+), 358.1 ([{79Br}M+H]+).

    d) (1S,3R,4S)-3-(4-Bromophenvl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0149] To a solution of [(1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone (10 g) in MeOH (28 mL) was added KOH (31 g). The reaction was stirred at refluxing temperature for 30 minutes until TLC analysis indicated the completion of the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, MeOH: CH2Cl2=1: 20 by vol) to give (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (6.3 g, yield: 89 %) as a clear oil.
    MS (ESI): 256.0 ([{81Br}M+H]+), 254.0 ([{79Br}M+H]+).
    1H NMR (CDCl3, 400MHz): 87.44 (2H), 7.15 (2H), 4.81 (1H), 4.67 (1H), 3.56 (1H), 3.11 (1H), 2.99 (1H), 1.73 (1H), 1.49 (1H).

    e) tert-Butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0150] To a solution of (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (6.3 g) in THF (100 mL) were added K2CO3 (10.3 g) and Boc2O (6.5 g). The mixture was stirred at room temperature overnight until TLC analysis indicated completion of the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL) and filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 20:1 by vol) to give tert-butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (4.0 g, yield: 45%) as a white solid.
    1H NMR (CDCl3, 400MHz): δ 7.48 (2H), 7.22 (1H), 7.14 (1H), 4.97 (1H), 4.75 (1H), 4.35 (1H), 3.48 (1H), 3.34 (1H), 1.77 (1H), 1.63 (1H), 1.554-1.499 (9H).

    f) N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amine



    [0151] To a solution of 4-amino-2-(trifluoromethyl)pyridine (33 mg, CAS: 147149-98-2) and tert-butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (50 mg) in dioxane (3 mL) were added Cs2CO3 (136 mg, CAS: 534-17-8), tris(dibenzylidineacetone)dipalladium(0) (20 mg, CAS: 51364-51-3) and bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 20 mg, CAS: 161265-03-8). The reaction was stirred at 90 °C under N2 atmosphere overnight. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10mL) and filtered through a thin silica pad. The filtrate was concentrated and dried under high vacuum to give crude tert-butyl (1S,3R,4S)-3-[4-[[2-(trifhioromethyl)-4-pyridyl]amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg) as a brown oil, which was used in next step directly.

    [0152] To a solution of tert-butyl (1S,3R,4S)-3-[4-[[2-(trifluoromethyl)-4-pyridyl]amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg) in dry CH2Cl2 (2 mL) was added TFA (0.5 mL, CAS: 76-05-1). The mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure. The residue was purified by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amine (24 mg, 34% yield over 2 steps) as a white solid. MS (ESI): 336.1 ([M+H]+).
    1H NMR (methanol-d4, 400MHz): δ 8.27 (1H), 7.47 (2H), 7.36 (2H), 7.31 (1H), 7.18 (1H), 5.20 (1H), 4.95 (1H), 4.43 (1H), 3.45 (1H), 3.36 (1H), 2.11 (1H), 1.84 (1H).

    Example 36


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine- 2-carboxamide



    [0153] 


    a) tert-Butyl (1S,3R,4S)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0154] To a solution of tert-butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.0 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP, 200 mg, CAS: 98327-87-8), tris(dibenzylidineacetone)dipalladium(0) (200 mg, CAS: 51364-51-3) and sodium tert-butoxide (806 mg, CAS: 865-48-5) in anhydrous toluene (10 mL) was added benzophenone imine (610 mg, CAS: 1013-88-3). The reaction was stirred under N2 atmosphere for 30 minutes at 90 °C in the microwave. LCMS indicated completion of the reaction. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 5:1 by vol) to give tert-butyl (1S,3R,4S)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.15 g, 89 % yield) as a yellow solid. MS (ESI): 455.2 ([M+H]+).

    b) tert-Butyl (1S,3R,4S)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0155] To a solution of tert-butyl (1S,3R,4S)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.15 g) in anhydrous MeOH (10 mL) was added sodium acetate (802 mg, CAS: 127-09-3) and hydroxylamine hydrochloride (348 mg, CAS: 5470-11-1) at 0°C. The reaction was stirred at 0 °C for 30 minutes until TLC analysis indicated the completion of the reaction. The mixture was diluted with CH2Cl2 (100 mL), and washed with saturated Na2CO3 aqueous solution (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether: ethyl acetate = 1: 1 by vol) to give tert-butyl (1S,3R,4S)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (500 mg, 68 % yield) as a yellow solid.
    MS (ESI): 291.2 ([M+H]+).
    1H NMR (CDCl3, 400MHz): δ 7.11 (1H), 7.05 (1H), 6.68 (2H), 4.94 (1H), 4.72 (1H), 4.31 (1H), 3.66 (2H), 3.47 (1H), 3.32 (1H), 1.86 (1H), 1.61 (1H), 1.54-1.50 (9H).

    c) N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide



    [0156] To a solution of tert-butyl (1S,3R,4S)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg) in anhydrous DMF (1 mL) was added HATU (67 mg ,CAS: 148893-10-1) and DIPEA (104 mg, CAS: 7087-68-5). The mixture was stirred at room temperature for 30 minutes. 5-(Trifluoromethyl)pyridine-2-carboxylic acid (50 mg, CAS: 80194-69-0) was added. The reaction was stirred at room temperature for 2 hours until LCMS analysis indicated the completion of the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL), and washed with water and brine. The organic layer was concentrated under reduced pressure and dried under high vacuum to give crude tert-butyl (1S,3R,4S)-3-[4-[[5-(trifluoromethyl)pyridine-2-carbonyl]amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg) as a yellow solid, which was used in next step directly.

    [0157] To a solution of crude tert-butyl (1S,3R,4S)-3-[4-[[5-(trifluoromethyl)pyridine-2-carbonyl]amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (40 mg) in dry CH2Cl2 (2 mL) was added TFA (0.5 mL, CAS: 76-05-1). The mixture was stirred at room temperature for 30 minutes. Volatiles were removed under reduced pressure. The residue was purified by prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide (6 mg) as a white solid. MS (ESI): 455.2 ([M+H]+).
    1H NMR (methanol-d4, 400MHz): δ 9.04 (1H), 8.39 (2H), 7.87 (2H), 7.40 (2H), 5.16 (1H), 4.95 (1H), 4.40 (1H), 3.46 (1H), 3.36 (1H), 2.14 (1H), 1.82 (1H).

    Example 37


    4-Chloro-3-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0158] 



    [0159] The title compound was obtained in analogy to example 36 using 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid (CAS: 1291275-83-6) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 361.2 ([{37Cl}M+H]+), 359.2 ([{35Cl}M+H]+).

    Example 38


    N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline



    [0160] 



    [0161] The title compound was obtained in analogy to example 35 using 4-chlorobenzylamine (CAS: 104-86-9) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 317.1 ([{37Cl}M+H]+), 315.2 ([{35Cl}M+H]+).

    Example 39


    4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]aniline



    [0162] 



    [0163] The title compound was obtained in analogy to example 35 using 4-(trifluoromethyl) benzylamine (CAS: 3300-51-4) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 349.2 ([M+H]+).

    Example 40


    N-[(4-Fluorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline



    [0164] 



    [0165] The title compound was obtained in analogy to example 35 using 4-fluorobenzylamine (CAS: 140-75-0) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 299.2 ([M+H]+).

    Example 41


    N-Butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline



    [0166] 



    [0167] The title compound was obtained in analogy to example 35 using n-butylamine (CAS: 109-73-9) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid.
    MS (ESI): 247.2 ([M+H]+).

    Example 42


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide



    [0168] 



    [0169] The title compound was obtained in analogy to example 36 using 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (CAS: 878742-59-7) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 365.2 ([M+H]+).

    Example 43


    3-Isopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0170] 



    [0171] The title compound was obtained in analogy to example 36 using 3-isopropylpyrazole-5-carboxylic acid (CAS: 92933-47-6) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 327.3 ([M+H]+).

    Example 44


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide



    [0172] 



    [0173] The title compound was obtained in analogy to example 36 using 6-trifluoromethylnicotinic acid (CAS: 231291-22-8) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). Waxy solid. MS (ESI): 364.2 ([M+H]+).

    Example 45


    4-Chloro-3-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0174] 


    a) Methyl 3-hydroxy-1H-pyrazole-5-carboxylate



    [0175] To a solution of hydrazine monohydrate (3.85 g, CAS: 7803-57-8) in toluene (30 mL) was added acetic acid (15 mL) and dimethyl acetylenedicarboxylate (10 g, CAS: 762-42-5). The reaction was stirred at room temperature for 3 hours. The mixture was poured into iced water. The precipitate was collected through filtration, washed with water, and dried under high vacuum to give methyl 3-hydroxy-1H-pyrazole-5-carboxylate (7.5 g, 75 % yield) as a white solid.
    1H NMR (DMSO-d6, 400 MHz): δ 12.81 (1H), 10.03 (1H), 5.96 (1H), 3.77 (3H).

    b) Methyl 3-ethoxy-1H-pyrazole-5-carboxylate



    [0176] To a solution of methyl 3-hydroxy-1H-pyrazole-5-carboxylate (4 g) in DMF (25 mL) was added K2CO3 (5.83 g) and iodoethane (4.8 g, CAS: 75-03-6). The reaction was stirred at room temperature for 15 hours. The mixture was poured into water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by recrystallization from CH2Cl2 (10 ml) to give methyl 3-ethoxy-1H-pyrazole-5-carboxylate (2.2 g, 46% yield) as a white solid.
    1H NMR (DMSO-d6, 400 MHz): δ 13.12 (1H), 6.22 (1H), 4.13∼4.08 (2H), 3.81∼3.75 (3H), 1.32∼1.25 (3H).

    c) Methyl 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylate



    [0177] To a solution of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (2.2 g) in DMF (40 mL) was added N-chlorosuccinimide (2.06 g, CAS: 128-09-6) at 0 °C. The reaction was warmed to 50 °C and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The mixture was poured into water. The precipitate was collected through filtration, washed with water, and dried under high vacuum to give methyl 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylate (1.65 g, 63% yield) as a white solid.
    1H NMR (DMSO-d6, 400 MHz): δ 13.44 (1H), 4.26∼4.20 (2H), 3.85 (3H), 1.33∼1.30 (3H).

    d) 4-Chloro-3-ethoxy-1H-pyrazole-5-carboxylic acid



    [0178] To a solution of methyl 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylate (1.65 g) in THF/MeOH (V/V=1:1, 30 mL) was added 1 M aqueous NaOH (16 mL) under ice-bath cooling. The reaction was stirred under reflux conditions for 3 hours. The reaction solution was poured into water and the pH was adjusted to 1 with concentrated HCl solution. The precipitate was collected by filtration, washed with water, and dried under high vacuum to give 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylic acid (1.4 g, 92 % yield) as a white solid.
    1H NMR (DMSO-d6, 400 MHz): δ 13.25 (1H), 4.25∼4.20 (2H), 1.33∼1.30 (3H).

    e) 4-Chloro-3-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0179] The title compound was obtained in analogy to example 36 using 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylic acid instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 365.1 ([{37Cl}M+H]+), 363.2 ([{35Cl}M+H]+).

    Example 46


    4-Chloro-3-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0180] 



    [0181] The title compound was obtained in analogy to example 36 using 4-chloro-3-methyl-1H-pyrazole-5-carboxylic acid (CAS: 29400-84-8) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 335.2 ([17Cl}M+H]+), 333.2 ([{35Cl}M+H]+).

    Example 47


    4-Methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0182] 



    [0183] The title compound was obtained in analogy to example 36 using 4-methylpyrazole-3-carboxylic acid (CAS: 82231-51-4) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 299.0 ([M+H]+).

    Example 48


    4-Chloro-1-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-propyl-pyrazole-3-carboxamide



    [0184] 



    [0185] The title compound was obtained in analogy to example 36 using 4-chloro-1-methyl-5-propyl-pyrazole-3-carboxylic acid (CAS: 1248078-41-2) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 377.2 ([17Cl}M+H]+), 375.2 ([{35Cl}M+H]+).

    Example 49


    4-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide



    [0186] 



    [0187] The title compound was obtained in analogy to example 36 using 4-chloro-3-propyl-1H-pyrazole-5-carboxylic acid (CAS: 1340578-20-2) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 363.2 ([17Cl}M+H]+), 361.2 ([{35Cl}M+H]+).

    Example 50


    3-Ethyl-4-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0188] 



    [0189] The title compound was obtained in analogy to example 36 using 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid (CAS: 957129-38-3) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 327.2 ([M+H]+).

    Example 51


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide



    [0190] 



    [0191] The title compound was obtained in analogy to example 36 using 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (CAS: 881409-53-6) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 394.3 ([M+H]+).

    Example 52


    4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]aniline



    [0192] 



    [0193] The title compound was obtained in analogy to example 35 using 4-(trifluoromethoxy) benzylamine (CAS: 93919-56-3) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 365.1 ([M+H]+).

    Example 53


    (1S,3R,4S)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0194] 



    [0195] The title compound was obtained in step (d) during the preparation of example 35.
    MS (ESI): 256.0 ([{81Br}M+H]+), 254.0 ([{79Br}M+H]+).

    Example 54


    (1R,3S,4R)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0196] 


    a) [(2R,4R)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone



    [0197] To a solution of 1,4-dibromobenzene (54.5 g, CAS: 106-37-6) in anhydrous THF (1.0 L) was added n-butyllithium solution (2.5 M in hexanes, 91 mL, CAS: 109-72-8) dropwise at -78 °C. Stirring was continued for 30 minutes. This solution was then added slowly to a solution of (1R,4R)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (50 g) in anhydrous THF (1.0 L) at-78 °C. The reaction was stirred for 30 minutes. Saturated NH4Cl aqueous solution (300 mL) was added to quench the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (1.0 L). The organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate=5:1 to 1:3 by vol) to give [(2R,4R)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone (30 g, yield: 35 %) as a white solid.
    MS (ESI): 376.0 ([{81Br}M+H]+), 374.0 ([{9Br}M+H]+).

    b) [(2R,4R)-2-[(S)-(4-Bromophenyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone



    [0198] To a solution of [(2R,4R)-1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-(4-bromophenyl)methanone (33 g) in MeOH (300 mL) at 0 °C was added NaBH4 (13 g). The reaction mixture was stirred at 0 °C for 1.5 hours. Acetone was added to quench excess NaBH4. Volatiles were removed under reduced pressure. Saturated aqueous NH4Cl solution (200 mL) was added. The mixture was extracted with EtOAc (3 x 500 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate=1: 2 by vol) to give [(2R,4R)-2-[(S)-(4-bromophenyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone (25 g, yield: 76 %) as a white solid.
    MS (ESI): 378.0 ([{81Br}M+H]+), 376.0 ([{9Br}M+H]+).

    c) [(1R,3S,4R)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone



    [0199] To a solution of give [(2R,4R)-2-[(S)-(4-bromophenyl)-hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone (22 g) and PPh3 (18 g) in dry toluene (300 mL) was added DIAD (14 g, CAS: 2446-83-5) at 0 °C. The mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was dissolved in tert-butyl methyl ether (600 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate=5:1 to 1:1 by vol) to give [(1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone (12 g, yield: 57 %) as a white solid. MS (ESI): 360.0 ([{81Br}M+H]+), 358.0 ([{79Br}M+H]+).

    d) (1R,3S,4R)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0200] To a solution of [(1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-phenyl-methanone (12.5 g) in MeOH (35 mL) was added KOH (39 g). The reaction was stirred at refluxing temperature for an hour until LCMS analysis indicated the completion of the reaction. Volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, MeOH: CH2Cl2=1: 20 to 1:5 by vol) to give (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (7 g, yield: 75 %) as a clear oil.
    MS (ESI): 256.0 ([{81Br}M+H]+), 254.0 ([{9Br}M+H]+).
    1H NMR (methanol-d4, 400MHz): δ 7.51 (d, 2H), 7.24 (d, 2H), 4.90 (s, 1H), 4.73 (s, 1H), 3.66 (s, 1H), 3.07 (d, 1H), 2.98 (d, 1H), 1.79 (d, 1H), 1.54 (d, 1H).

    Example 55


    N-(4-Chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0201] 


    a) 4-[(1S,3R,4S)-5-tert-Butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid



    [0202] To a solution of tert-butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (800 mg, 2.25 mmol) in THF (20 mL) was added n-butyllithium solution (2.5 M in hexanes, 1.2 mL, 2.9 mmol, CAS: 109-72-8) at -78 °C. Stirring was continued at -78 °C for 30 minutes. Dry CO2 was bubbled into the solution for 10 minutes. The solution was warmed to room temperature. To the reaction solution was added 1 M aq HCl to adjust the pH to 4-5. The mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over Na2SO4 Volatiles were removed under reduced pressure. The residue was purified through flash chromatography (silica gel, CH2Cl2/MeOH= 100/1 -30/1 by vol) to give 4-[(1S,3R,4S)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid (450 mg, 62 % yield) as a yellow solid.
    1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 7.42 (dd, 2H), 5.09 (d, 1H), 4.80 (s, 1H), 4.43 (d, 1H), 3.52 (m, 1H), 3.37 (t, 1H), 1.78 (d, 1H), 1.67 (m, 1H), 1.57∼1.55 (m, 9H).

    b) N-(4-Chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0203] To a solution of 4-[(1S,3R,4S)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid (40 mg, 0.125 mmol) in DMF (1 mL) were added HATU (52 mg, 0.14 mmol, CAS: 148893-10-1), DIPEA (49 mg, 0.38 mmol, CAS: 7087-68-5), and 4-chloroaniline (16 mg, 0.125 mmol, CAS: 106-47-8). The solution was stirred at room temperature overnight. The reaction mixture was then diluted with CH2Cl2 (10 mL). The solution was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in a mixture of CH2Cl2 (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was purified through prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give N-(4-chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide (25 mg, 61% yield) as a white solid.
    1H NMR (400 MHz, Methanol-d4): δ 7.98 (d, 2H), 7.71 (d, 2H), 7.52 (d, 2H), 7.36 (d, 2H), 5.22 (s, 1H), 4.98 (s, 1H), 4.47 (s, 1H), 3.48 (d, 1H), 3.36 (d, 1H), 2.09 (d, 1H), 1.84 (d, 1H).
    MS (ESI): 330.9 ([{37Cl}M+H]+), 329.0 ([{35Cl}M+H]+).

    Example 56


    N-(4-Bromophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0204] 



    [0205] The title compound was obtained in analogy to example 55 using 4-bromoaniline (CAS: 106-40-1) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 374.9 ([{81Br}M+H]+), 372.9 ([{79Br}M+H]+).

    Example 57


    N-(4-Fluorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0206] 



    [0207] The title compound was obtained in analogy to example 55 using 4-fluoroaniline (CAS: 371-40-4) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 313.0 ([M+H]+).

    Example 58


    N-(4-Ethoxyphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0208] 



    [0209] The title compound was obtained in analogy to example 55 using 4-ethoxyaniline (CAS: 156-43-4) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 339.0 ([M+H]+).

    Example 59


    4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluoromethyl)phenyl]benzamide



    [0210] 



    [0211] The title compound was obtained in analogy to example 55 using 4-(trifluoromethyl)aniline (CAS: 455-14-1) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 363.0 ([M+H]+).

    Example 60


    N-(6-Chloro-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0212] 



    [0213] The title compound was obtained in analogy to example 55 using 3-amino-6-chloropyridine (CAS: 5350-93-6) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 332.1 ([17Cl}M+H]+), 330.1 ([{35Cl}M+H]+).

    Example 61


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridin-3-amine



    [0214] 



    [0215] The title compound was obtained in analogy to example 35 using 5-amino-2-trifluoromethylpyridine (CAS: 106877-33-2) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 336.2 ([M+H]+).

    Example 62


    N-(6-Ethoxy-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0216] 



    [0217] The title compound was obtained in analogy to example 55 using 6-ethoxy-3-pyridinamine (CAS: 52025-34-0) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 340.2 ([M+H]+).

    Example 63


    4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide



    [0218] 



    [0219] The title compound was obtained in analogy to example 55 using 4-(trifluoromethyl)benzylamine (CAS: 3300-51-4) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 377.1 ([M+H]+).

    Example 64


    N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0220] 



    [0221] The title compound was obtained in analogy to example 55 using 4-chlorobenzylamine (CAS: 104-86-9) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 345.1 ([17Cl}M+H]+), 343.1 ([{35Cl}M+H]+).

    Example 65


    N-(3-Methoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline



    [0222] 



    [0223] The title compound was obtained in analogy to example 35 using 3-methoxypropylamine (CAS: 5332-73-0) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 263.1 ([M+H]+).

    Example 66


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)acetamide



    [0224] 



    [0225] The title compound was obtained in analogy to example 36 using 2-(2,2,2-trifluoroethoxy)acetic acid (CAS: 675-67-2) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 331.1 ([M+H]+).

    Example 67


    3-Ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0226] 


    a) tert-Butyl (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0227] To a solution of (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (6.8 g, 27 mmol) in THF (150 mL) were added K2CO3 (11 g, 81mmol) and Boc2O (7 g, 32 mmol, CAS: 24424-99-5). The solution was stirred at room temperature overnight. The mixture was filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 20:1 by vol) to give tert-butyl (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (4.0 g, yield: 45 %) as a white solid.
    1H NMR (CDCl3, 400MHz): δ 7.49 (m, 2H), 7.23 (d, 1H), 7.16 (d, 1H), 4.98 (d, 1H), 4.77 (s, 1H), 4.36 (d, 1H), 3.50 (dd, 1H), 3.36 (t, 1H), 1.78 (d, 1H), 1.65-1.51 (m, 10H).

    b) tert-Butyl (1R,3S,4R)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0228] To a solution of tert-butyl (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.0 g, 3 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP, 373 mg, 0.6 mmol, CAS: 98327-87-8), tris(dibenzylidineacetone)dipalladium(0) (275 mg, 0.3 mmol, CAS: 51364-51-3) and sodium tert-butoxide (873 mg, 9 mmol, CAS: 865-48-5) in anhydrous toluene (10 mL) was added benzophenone imine (652 mg, 3.6 mmol, CAS: 1013-88-3). The reaction was stirred under N2 atmosphere for 30 minutes at 90 °C in the microwave. LCMS indicated completion of the reaction. The mixture was cooled to room temperature, diluted with water (10mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 10:1 by vol) to give tert-butyl (1R,3S,4R)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (1.1 g, 81% yield) as a yellow solid.
    MS (ESI): 455.2 ([M+H]+).

    c) tert-Butyl (1R,3S,4R)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate



    [0229] To a solution of tert-butyl (1R,3S,4R)-3-[4-(benzhydrylideneamino)phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (454 mg, 1 mmol) in anhydrous MeOH (5 mL) was added sodium acetate (328 mg, 4 mmol, CAS: 127-09-3) and hydroxylamine hydrochloride (138 mg, 2.0 mmol, CAS: 5470-11-1) at 0°C. The reaction was stirred at 0 °C for 30 minutes until TLC analysis indicate the completion of the reaction. The mixture was diluted with CH2Cl2 (100 mL), and washed with aqueous NaOH solution (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether: ethyl acetate = 1:0 to 1:1 with 0.1 % triethylamine) to give tert-butyl (1R,3S,4R)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (200 mg, 72 % yield) as a yellow solid.
    1H NMR (CDCl3, 400MHz): δ 7.13 (d, 1H), 7.06 (d, 1H), 6.69 (2H), 4.96 (d, 1H), 4.73 (s, 1H), 4.33 (1H), 3.48 (dd, 1H), 3.34 (t, 1H), 1.87 (d, 1H), 1.65-1.51 (m, 10H).

    d) 3-Ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0230] To a solution of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid (20 mg, 0.129 mmol, CAS: 957129-38-3) in anhydrous DMF (1 mL) was added HATU (52 mg, 0.129 mmol, CAS: 148893-10-1) and DIPEA (26 mg, 0.258 mmol, CAS: 7087-68-5). The solution was stirred at room temperature for 30 minutes. tert-Butyl (1R,3S,4R)-3-(4-aminophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (25 mg, 0.086 mmol) was added. The reaction was stirred at room temperature overnight. TLC analysis indicated the completion of the reaction. Volatiles were removed under reduced pressure. The residue was purified by prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.3% NH3•H2O, C-18 column) to give tert-butyl (1R,3S,4R)-3-[4-[(3-ethyl-4-methyl-1H-pyrazole-5-carbonyl)amino]phenyl]-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate as a white solid, which was then dissolved in a mixture of dry CH2Cl2 (2 mL) and TFA (1 mL, CAS: 76-05-1). The mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was purified by prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.5 % NH3•H2O, C-18 column) to give 3-ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide (6 mg, 21% over 2 steps) as a white solid. MS (ESI): 327.2 ([M+H]+). 1H NMR (methanol-d4, 400MHz): δ 7.70 (d, 2H), 7.31 (d, 2H), 5.04 (s, 1H), 4.84 (s, 1H), 4.05 (s, 1H), 3.27 (d, 1H), 3.17 (d, 1H), 2.68 (m, 2H), 2.25 (s, 3H), 2.01 (d, 1H), 1.69 (d, 1H), 1.24 (t, 3H).

    Example 68


    4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide



    [0231] 



    [0232] The title compound was obtained in analogy to example 67 using 4-chloro-3-propyl-1H-pyrazole-5-carboxylic acid (CAS: 1340578-20-2) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 363.0 ([17Cl}M+H]+), 361.0 ([{35Cl}M+H]+).

    Example 69


    3-Cyclopropyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0233] 


    a) Ethyl 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate



    [0234] To a solution of sodium ethoxide (7.6 g, 0.112 mol, CAS: 141-52-6) in anhydrous ethanol (150 ml) was added diethyl oxalate (16.4 g, 0.112 mol, CAS: 95-92-1) in portions at room temperature under N2 atmosphere. Ethyl cyclopropyl ketone was added afterwards. The mixture was stirred at 50 °C for 20 hours. The solution was cooled to room temperature. Acetic acid (9 g, 0.15 mmol) and hydrazine monohydrate (98% purity, 8.1 g, 0.15 mol, CAS: 7803-57-8). The reaction was stirred at 50 °C for 12 hours until LCMS analysis indicated completion of the reaction. The reaction solution was cooled to room temperature. Volatiles were removed under reduced pressure. The residue was dissolved in dichloromethane (400 mL) and washed with brine (40 ml). The solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, petroleum ether : ethyl acetate = 20:1 by vole) give product ethyl 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate (1 g, 4.6% yield) as a white solid. MS (ESI): 195.1 ([M+H]+).

    b) 3-Cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid



    [0235] To a solution of ethyl 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate (1 g, 5 mmol) in ethanol/H2O (V/V=5:1, 12 mL) was added NaOH (0.6 g, 15 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and acidified to pH=∼2 with 2N HCl (20 mL). The mixture was extracted with CH2Cl2 (2 x 50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Further drying under high vacuum gave 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid (250 mg, 30 % yield) as a white solid.
    MS (ESI): 167.1 ([M+H]+).
    1HNMR (Methanol-d4, 400MHz) δ 2.28 (s, 3H), 1.82 (m, 1H), 0.93 (m, 2H), 0.76 (m, 2H).

    c) 3-Cyclopropyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0236] The title compound was obtained in analogy to example 67 using 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 339.0 ([M+H]+).

    Example 70


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluoropropoxy)acetamide



    [0237] 



    [0238] The title compound was obtained in analogy to example 36 using 2-(3,3,3-trifluoropropoxy)acetic acid (CAS: 840489-14-7) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 345.2 ([M+H]+).

    Example 71


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide



    [0239] 



    [0240] The title compound was obtained in analogy to example 67 using 5-(trifluoromethyl)pyridine-2-carboxylic acid (CAS: 80194-69-0) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 364.1 ([M+H]+).

    Example 72


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide



    [0241] 



    [0242] The title compound was obtained in analogy to example 67 using 6-(trifluoromethyl)pyridine-3-carboxylic acid (CAS: 231291-22-8) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 364.1 ([M+H]+).

    Example 73


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)acetamide



    [0243] 



    [0244] The title compound was obtained in analogy to example 67 using 2-(2,2,2-trifluoroethoxy)acetic acid (CAS: 675-67-2) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 331.1 ([M+H]+).

    Example 74


    2-Ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide



    [0245] 



    [0246] The title compound was obtained in analogy to example 67 using 2-ethylpyrimidine-5-carboxylic acid (CAS: 72790-16-0) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 325.1 ([M+H]+).

    Example 75


    3-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0247] 



    [0248] The title compound was obtained in analogy to example 67 using 3-isopropylpyrazole-5-carboxylic acid (CAS: 92933-47-6) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 327.2 ([M+H]+).

    Example 76


    4-Chloro-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0249] 



    [0250] The title compound was obtained in analogy to example 67 using 4-chloro-3-ethyl-1H-pyrazole-5-carboxylic acid (CAS: 158668-22-5) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 349.1 ([{37Cl}M+H]+), 347.1 ([{35Cl}M+H]+).

    Example 77


    3-Cyclopropyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0251] 



    [0252] The title compound was obtained in analogy to example 67 using 5-Cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-74-2) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 343.2 ([M+H]+).

    Example 78


    4-Fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide



    [0253] 



    [0254] The title compound was obtained in analogy to example 67 using 4-fluoro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 681034-64-0) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 345.2 ([M+H]+).

    Example 79


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine



    [0255] 



    [0256] The title compound was obtained in analogy to example 35 using 2-amino-4-(2,2,2-trifluoroethoxy)pyrimidine (CAS: 852921-89-2) instead of 4-amino-2-(trifluoromethyl)pyridine in step (f). White solid. MS (ESI): 367.1 ([M+H]+).

    Example 80


    N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine



    [0257] 



    [0258] The title compound was obtained in analogy to example 35 using 2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine (CAS: 1431654-73-7) instead of 4-amino-2-(trifluoromethyl) pyridine in step (f). White solid. MS (ESI): 367.1 ([M+H]+).

    Example 81


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide



    [0259] 



    [0260] The title compound was obtained in analogy to example 67 using 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (CAS: 878742-59-7) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 365.1 ([M+H]+).

    Example 82


    4-Chloro-3-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0261] 



    [0262] The title compound was obtained in analogy to example 67 using 4-chloro-3-cyclopropyl-1H-pyrazole-5-carboxylic acid (CAS: 1291275-83-6) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 361.1 ([{37Cl}M+H]+), 359.1 ([{35Cl}M+H]+).

    Example 83


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine



    [0263] 



    [0264] The title compound was obtained in analogy to example 80 using tert-butyl (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate instead of tert-butyl (1S,3R,4S)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate in the palladium catalyzed coupling step. White solid. MS (ESI): 367.2 ([M+H]+).

    Example 84


    4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide



    [0265] 



    [0266] The title compound was obtained in analogy to example 36 using 4,4,4-trifluorobutyric acid (CAS: 406-93-9) instead of 5-(trifluoromethyl)pyridine-2-carboxylic acid in step (c). White solid. MS (ESI): 315.1 ([M+H]+).

    Example 85


    4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide



    [0267] 


    a) 4-[(1R,3S,4R)-5-tert-Butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid



    [0268] To a solution of tert-butyl (1R,3S,4R)-3-(4-bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (800 mg, 2.25 mmol, prepared in step a, example 67) in THF (20 mL) was added n-butyl lithium (2.5 M in hexane, 1.17 mL, 2.93 mmol) at -78°C. Stirring was continued for 30 minutes. Dry CO2 was bubbled into the solution for 10 min. The solution was warmed to room temperature. TLC analysis indicated complete consumption of the starting material. To the reaction solution was added 1 M aqueous HCl to adjust the pH to 4∼5. The mixture was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was diluted with petroleum ether (100 mL) and stirred for 30 minutes. The precipitate was collected by filtration and dried under high vacuum to give 4-[(1R,3S,4R)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid (300 mg, 42% yield) as a yellow solid.
    1H NMR (400 MHz, CDCl3): δ 8.10 (t, 2H), 7.46 (d, 1H), 7.39 (d, 1H), 5.09 (d, 1H), 4.80 (s, 1H), 4.43 (d, 1H), 3.52 (m, 1H), 3.37 (t, 1H), 1.78 (d, 1H), 1.65 (m, 1H), 1.55 (d, 9H).

    b) 4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide



    [0269] To a solution of 4-[(1R,3S,4R)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzoic acid (40 mg, 0.125 mmol) in dry DMF (1 mL) were added HATU (52.4 mg, 0.138 mmol, CAS: 148893-10-1), diisopropylethylamine (48.6 mg, 0.376 mmol), and 4-chloroaniline (16 mg, 0.125 mmol, CAS: 106-47-8). The solution was stirred at room temperature overnight. The reaction solution was diluted with CH2Cl2 (10 mL). The mixture was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure.

    [0270] The residue was dissolved in a mixture of CH2Cl2 (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (mobile phase A: H2O, B: CH3CN with 0.1 % TFA, C-18 column) to give 4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide (20 mg, 0.061 mmol, 48% yield) as a white solid.
    1H NMR (400 MHz, methanol-d4): δ 7.97 (d, 2H), 7.71 (dd, 2H), 7.52 (d, 2H), 7.36 (dd, 2H), 5.22 (s, 1H), 4.98 (s, 1H), 4.47 (s, 1H), 3.4 (d, 1H), 3.37 (d, 1H), 2.09 (d, 1H), 1.84 (dd, 1H). MS (ESI): 331.0 ([{37C1}M+H]+), 329.0 ([{35Cl}M+H]+).

    Example 86


    N-(4-Bromophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0271] 



    [0272] The title compound was obtained in analogy to example 85 using 4-bromoaniline (CAS: 106-40-1) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 374.9 ([{81Br}M+H]+), 372.9 ([(9Br}M+H]+).

    Example 87


    N-(4-Fluorophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0273] 



    [0274] The title compound was obtained in analogy to example 85 using 4-fluoroaniline (CAS: 371-40-4) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 313.0 ([M+H]+).

    Example 88


    N-(4-Ethoxyphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0275] 



    [0276] The title compound was obtained in analogy to example 85 using 4-ethoxyaniline (CAS: 156-43-4) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 339.0 ([M+H]+).

    Example 89


    2-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide



    [0277] 


    a) Methyl 5-hydroxy-1H-pyrazole-3-carboxylate



    [0278] To a solution of hydrazine monohydrate (44.8 g, 0.894 mol, CAS: 7803-57-8) in a mixture of toluene (300 mL) and acetic acid (180 mL) was added dimethyl acetylenedicarboxylate (100 mL, 0.813 mol, CAS: 762-42-5). The solution was stirred at room temperature for 3 hours. The mixture was poured into ice-water. The precipitate was collected by filtration, washed with water, dried under high vacuum to give methyl 5-hydroxy-1H-pyrazole-3-carboxylate (67.5 g, 59 % yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 10.03 (br, 1H), 5.91 (br, 1H), 3.78 (s, 3H).

    b) Methyl 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylate



    [0279] To a solution of methyl 5-hydroxy-1H-pyrazole-3-carboxylate (10 g, 70.4 mmol) in DMF (100 ml) were added CS2CO3 (25 g, 77.5 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (16.3 g, 70.4 mmol, CAS: 6226-25-1). The solution was stirred at room temperature overnight. Then the mixture was poured into 500 ml ice-water carefully. The precipitate was collected through filtration, washed with cold water, and dried under high vacuum to give methyl 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylate (12 g, 76% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 13.41 (s, 1H), 6.73 (s, 1H), 4.86 (m, 2H), 3.84 (s, 3H)

    c) Methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate



    [0280] To a solution of methyl 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylate (12.0 g, 53.4 mmol), Cs2CO3 (52.0 g, 161 mmol) in DMF (100.0 ml) was added 2-bromopropane (7.2 g, 56.0 mmol, CAS: 75-26-3) in portions. The solution was stirred at room temperature overnight. Then the solution was concentrated under reduced pressure and poured into water. The precipitate was collected through filtration, washed with cold water, and dried under high vacuum to give methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate (10.3 g, 74% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 6.45 (s, 1H), 5.35 (m, 1H), 4.82 (m, 2H), 3.83 (s, 3H), 1.36 (d, 6H).

    d) 2-Isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid



    [0281] A solution of methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate (4.3 g, 16.2 mmol), NaOH (1.9 g, 48.5 mmol) in the mixture of MeOH/water (V/V=3:1, 50.0 ml) was stirred at room temperature overnight. Then the pH of the solution was adjusted to 4-5 with concentrated HCl (5 ml) at 0°C. The solution was poured into 500 ml ice-water carefully. The precipitate was collected by filtration, washed with cooled water, and dried under high vacuum to give 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (3.86 g, 95% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 6.37 (s, 1H), 5.38 (m, 1H), 4.79 (m, 2H), 1.34 (d, 6H).

    e) 2-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide



    [0282] The title compound was obtained in analogy to example 67 using 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 425.2 ([M+H]+).

    Example 90


    N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluoropropoxy)acetamide



    [0283] 



    [0284] The title compound was obtained in analogy to example 67 using 2-(3,3,3-trifluoropropoxy)acetic acid (CAS: 840489-14-7) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 345.1 ([M+H]+).

    Example 91


    4,4,4-Trifluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide



    [0285] 



    [0286] The title compound was obtained in analogy to example 67 using 4,4,4-trifluorobutyric acid (CAS: 406-93-9) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 315.1 ([M+H]+).

    Example 92


    3-Butyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0287] 


    a) Ethyl 3-butyl-1H-pyrazole-5-carboxylate



    [0288] To a solution of EtONa (13.2 g, 0.2 mol, CAS: 141-52-6) in anhydrous ethanol (400 mL) were added diethyl oxalate (29.2 g, 0.2 mol, CAS: 95-92-1) and 2-hexanone (20 g, 0.2 mol, CAS: 591-78-6) at 0-5°C. The solution was warmed to 50°C and stirring was continued overnight. The mixture was cooled to 0-5°C. Acetic acid (12 g, 0.2 mol) was added, followed by hydrazine monohydrate (10 g, 0.2 mol, CAS: 7803-57-8). The mixture was stirred at 30 °C for 12 hours. Volatiles were removed under reduced pressure. The residue was diluted with saturated NaHCO3 aqueous solution (500 mL). The mixture was extracted with ethyl acetate (1 L). The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/MeOH = 200/1 ∼ 80/1 by vol) to give ethyl 3-butyl-1H-pyrazole-5-carboxylate (13 g, 33% yield) as a yellow solid.

    b) Ethyl 3-butyl-4-fluoro-1H-pyrazole-5-carboxylate



    [0289] To a solution of ethyl 3-butyl-1H-pyrazole-5-carboxylate (8.0 g, 40.8 mmol) in CH3CN (500 mL) was added Selectfluor (17.3 g, 48.9 mmol, CAS: 140681-55-6) at 0°C. Then the solution was stirred at 70°C for 15 hours. Volatiles were removed under reduced pressure. The residue was diluted with aqueous HCl (3N, 200 mL) and extracted with CH2Cl2 (500 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/MeOH = 200/1 ∼ 100/1 by vol) to give ethyl 3-butyl-4-fluoro-1H-pyrazole-5-carboxylate (1.4 g, 16% yield) as a yellow oil.

    c) 3-Butyl-4-fluoro-1H-pyrazole-5-carboxylic acid



    [0290] To a solution of ethyl 3-butyl-4-fluoro-1H-pyrazole-5-carboxylate (1.4 g, 6.53 mmol) in THF/MeOH (20/20 mL) was added 1 M aqueous NaOH (13.1 mL, 13.1 mmol) at 0°C. Then the solution was refluxed for 3 hours. The reaction mixture was poured into water, and acidified to pH∼1 with concentrated HCl. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (10 mL) to give 3-butyl-4-fluoro-1H-pyrazole-5-carboxylic acid (0.4 g, 33% of yield) as a yellow solid.
    1H NMR (400 MHz, DMSO-d6): δ 13.30 (br, 1H), 2.55 (t, 2H), 1.55 (m, 2H), 1.29 (m, 2H), 0.88 (t, 3H).
    MS(ESI): 187.0 ([M+H]+), 209.0 ([M+Na]+).

    d) 3-Butyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0291] The title compound was obtained in analogy to example 67 using 3-butyl-4-fluoro-1H-pyrazole-5-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid.
    1H NMR (400 MHz, methanol-d4): δ 7.73 (d, 2H), 7.34 (d, 2H), 5.15 (s, 1H), 4.93 (s, 1H), 4.37 (s, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 2.70 (t, 2H), 2.12 (d, 1H), 1.82 (d, 1H), 1.67 (m, 2H), 1.39 (m, 2H), 0.96 (t, 3H).
    MS (ESI): 359.2 ([M+H]+).

    Example 93


    3-Butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0292] 


    a) 3-Butyl-1H-pyrazole-5-carboxylic acid



    [0293] To a solution of ethyl 3-butyl-1H-pyrazole-5-carboxylate (5.0 g, 25.5 mmol) in THF/MeOH (30/30 mL) was added 1 M aqueous NaOH (51 mL, 51 mmol) at 0°C. Then the solution was refluxed for 3 hours. The reaction mixture was poured into water and acidified to about pH=1 with concentrated HCl. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (50 mL) to give 3-butyl-1H-pyrazole-5-carboxylic acid (2.0 g, 47% yield) as a yellow solid.
    1H NMR (400 MHz, DMSO-d6): δ 12.9 (br, 2H), 6.47 (s, 1H), 2.59 (t, 2H), 1.55 (m, 2H), 1.29 (m, 2H), 0.89 (t, 3H).

    b) 3-Butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0294] The title compound was obtained in analogy to example 67 using 3-butyl-1H-pyrazole-5-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 341.2 ([M+H]+).

    Example 94


    N-(6-Chloro-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0295] 



    [0296] The title compound was obtained in analogy to example 85 using 3-amino-6-chloropyridine (CAS: 5350-93-6) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 332.1 ([{37Cl}M+H]+), 330.1 ([{35Cl}M+H]+).

    Example 95


    N-(6-Ethoxy-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0297] 



    [0298] The title compound was obtained in analogy to example 85 using 6-ethoxy-3-pyridinamine (CAS: 52025-34-0) instead of 4-chloroaniline in step (b). White solid.
    MS (ESI): 340.2 ([M+H]+).

    Example 96


    4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide



    [0299] 



    [0300] The title compound was obtained in analogy to example 85 using 4-(trifluoromethyl)benzylamine (CAS: 3300-51-4) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 377.2 ([M+H]+).

    Example 97


    N-[(4-Chlorophenyl)methyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide



    [0301] 



    [0302] The title compound was obtained in analogy to example 85 using 4-chlorobenzylamine (CAS: 104-86-9) instead of 4-chloroaniline in step (b).
    MS (ESI): 345.1 ([{37Cl}M+H]+), 343.1 ([{35Cl}M+H]+).

    Example 98


    4-Chloro-3-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0303] 


    a) Methyl 5-hydroxy-1H-pyrazole-3-carboxylate



    [0304] To a solution of hydrazine monohydrate (3.85 g, 0.077 mol, CAS: 7803-57-8) in toluene (30 mL) were added acetic acid (15 mL) and dimethyl acetylenedicarboxylate (10 g, 0. 07 mol, CAS: 762-42-5). The solution was stirred at room temperature for 3 hours. The mixture was poured into ice-water. The precipitate was collected by filtration, washed with water, and dried under high vacuum to give methyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.5 g, 75% of yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 10.04 (br, 1H), 5.96 (br, 1H), 3.77 (s, 3H).

    b) Methyl 5-ethoxy-1H-pyrazole-3-carboxylate



    [0305] To a solution of methyl 5-hydroxy-1H-pyrazole-3-carboxylate (4 g, 28.17 mmol) in DMF (25 mL) were added K2CO3 (5.83 g, 42.2 mmol) and CH3CH2I (4.8 g, 31 mmol, CAS: 75-03-6). The solution was stirred at room temperature for 15 hours. Then the mixture was poured into water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by recrystallization from CH2Cl2 (10 ml) to give methyl 5-ethoxy-1H-pyrazole-3-carboxylate (2.2 g, 46% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 6.23 (s, 1H), 4.11 (m, 2H), 3.81 (s, 3H), 1.28 (m, 3H).

    c) Methyl 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylate



    [0306] To a solution of methyl 5-ethoxy-1H-pyrazole-3-carboxylate (2.2 g, 12.94 mmol) in DMF (40 mL) was added N-chlorosuccinimide (2.06 g, 15.5 mmol, CAS: 128-09-6) at 0°C. The reaction was warmed to 50°C and stirring was continued for 15 hours. The majority of the volatiles were removed under reduced pressure. The residule was poured into water. The precipitate was collected by filtration, washed with water, and dried under high vacuum to give methyl 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylate (1.65 g, 63% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 13.45 (br, 1H), 4.23 (m, 2H), 1.32 (t, 3H).

    d) 4-Chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid



    [0307] To a solution of methyl 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylate (1.65 g, 8.06 mmol) in THF/MeOH (V/V=1:1, 30 mL) was added 1 M aqueous NaOH (16.1 mL, 16.1 mmol) at 0°C. Then the solution was refluxed for 3 hours. The reaction mixture was poured into water and acidified to pH=∼1 with concentrated HCl. The precipitate was collected by filtration, washed with water, and dried under high vacuum to give 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid (1.4 g, 92% yield) as a white solid.
    1H NMR (400 MHz, DMSO-d6): δ 13.25 (s, 1H), 4.23 (m, 2H), 1.32 (t, 3H).

    e) 4-Chloro-3-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0308] The title compound was obtained in analogy to example 67 using 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid.
    1H NMR (400 MHz, methanol-d4): δ 7.65 (d, 2H), 7.29 (d, 2H), 4.91 (s, 1H), 4.69 (s, 1H), 4.30 (m, 2H), 3.57 (s, 1H), 3.00 (m, 2H), 1.80 (d, 1H), 1.50 (d, 1H), 1.40 (t, 3H).
    MS (ESI): 365.1 ([{37Cl}M+H]+), 363.1 ([{35Cl}M+H]+).

    Example 99


    4-Bromo-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0309] 



    [0310] The title compound was obtained in analogy to example 67 using 4-bromo-3-ethyl-1H-pyrazole-5-carboxylic acid (CAS: 1291177-22-4) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid.
    MS (ESI): 393.1 ([{81Br}M+H]+), 391.1 ([{79Br}M+H]+).

    Example 100


    4-Fluoro-3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0311] 


    a) Ethyl 5-isobutyl-1H-pyrazole-3-carboxylate



    [0312] To a solution of CH3CH2ONa (7 g, 0.1 mol) in anhydrous ethanol (150 mL) were added diethyl oxalate (15 g, 0.1 mol, CAS: 95-92-1) and 4-methyl-2-pentanone (10 g, 0.1 mol, CAS: 108-10-1). The mixture was stirred at 50°C for 20 hours. The reaction solution containing ethyl 6-methyl-2,4-dioxo-heptanoate was used in next step directly.

    [0313] To the above solution of ethyl 6-methyl-2,4-dioxo-heptanoate was added acetic acid (9 g, 0.15 mol) and hydrazine monohydrate (8.1 g, 0.15 mol, CAS: 7803-57-8). The reaction mixture was stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 20:1 to 2:1 by vol to give ethyl 5-isobutyl-1H-pyrazole-3-carboxylate as a white solid (13 g, 68% yield).
    MS (ESI): 197.2 ([M+H]+).

    b) Ethyl 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylate



    [0314] To a solution of ethyl 5-isobutyl-1H-pyrazole-3-carboxylate (5.0 g, 25.5 mmol) in CH3CN (300 mL) was added Selectfluor (18.0 g, 51.0 mmol, CAS: 140681-55-6) at 0°C. The solution was stirred at 70°C for 15 hours. Then reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with aqueous HCl (3N, 200 mL) and extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/MeOH = 200/1 ∼ 100/1 by vol) gave ethyl 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylate (1.4 g, 26% yield) as a yellow oil.
    1H NMR (400 MHz, CDCl3): δ 4.42 (m, 2H), 2.55 (d, 2H), 2.00 (m, 1H), 1.40 (t, 3H), 0.95 (d, 6H).

    c) 4-Fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid



    [0315] To a solution of ethyl 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylate (1.4 g, 6.54 mmol) in THF/MeOH (V/V=1:1, 20 mL) was added 1 M aqueous NaOH (13.1 mL, 13.1 mmol) at 0°C. Then the solution was refluxed for 3 hours. The reaction solution was poured into water and acidified to pH∼1 with concentrated HCl. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (30 mL) to give 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid (1.2 g, 99 % of yield) as a yellow solid.
    1H NMR (400 MHz, DMSO-d6): δ 3.37 (br, 1H), 2.44 (d, 2H), 1.89 (m, 1H), 0.87 (d, 6H).
    MS (ESI): 187.1 ([M+H]+).

    d) 4-Fluoro-3-isobutvl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0316] The title compound was obtained in analogy to example 67 using 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 359.2 ([M+H]+).

    Example 101


    3-Isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0317] 


    a) 5-Isobutyl-1H-pyrazole-3-carboxylic acid



    [0318] To a solution of ethyl 5-isobutyl-1H-pyrazole-3-carboxylate (3 g, 15.3 mmol) in ethanol/water (V/V=5:1, 60 mL) was added NaOH (1.8 g, 45.9 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was extracted twice with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Further drying under high vacuum gave 5-isobutyl-1H-pyrazole-3-carboxylic acid (2 g, 80% yield) as a white solid.
    1H NMR (400 MHz, methanol-d4): δ 6.58 (s, 1H), 2.57 (d, 2H), 1.95 (m, 1H), 0.96 (d, 6H). MS (ESI): 169.2 ([M+H]+).

    b) 3-Isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0319] The title compound was obtained in analogy to example 67 using 5-isobutyl-1H-pyrazole-3-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid. MS (ESI): 341.2 ([M+H]+).

    Example 102


    4-Chloro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0320] 



    [0321] The title compound was obtained in analogy to example 67 using 4-chloro-3-isopropyl-1H-pyrazole-5-carboxylic acid (CAS: 1291271-55-0) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid.
    MS (ESI): 363.1 ([{37Cl}M+H]+), 361.1 ([{35Cl}M+H]+).

    Example 103


    4-Fluoro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0322] 


    a) Ethyl 5-isopropyl-1H-pyrazole-3-carboxylate



    [0323] To a solution of CH3CH2ONa (23 g, 0.34 mol) in anhydrous EtOH (500 mL) were added diethyl oxalate (50 g, 0.34 mol, CAS: 95-92-1) and 3-methyl-2-butanone (29 g, 0.34 mol, CAS: 563-80-4) at 0°C. The solution was stirred at 50°C overnight. The mixture was cooled to 0∼5°C, and acetic acid (20.4 g, 0.34 mol) was added, followed by hydrazine monohydrate (17.2 g, 0.34 mol, CAS: 7803-57-8). The mixture was stirred at 30°C overnight and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with brine and concentrated under reduced pressure to give the desired crude product. Purification by flash chromatography (silica gel, CH2Cl2/MeOH = 200/1∼80/1 by vol) gave crude ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (30 g, 48% yield) as a yellow solid.
    MS (ESI): 183.1 ([M+H]+).

    b) Ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylate



    [0324] To a solution of ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (5.0 g, 0.027 mmol) in CH3CN (300 mL) was added Selectfluor (12.65 g, 35.67 mmol, CAS: 140681-55-6) at 0°C. The solution was stirred at 70°C for 15 hours and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with aqueous HCl (3N, 200 mL) and extracted with CH2Cl2 (100 mLx2). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/MeOH = 200/1 ∼ 100/1 by vol) gave ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylate (900 mg, 17% yield) as a yellow oil.
    MS (ESI): 201.1 ([M+H]+).

    c) 4-Fluoro-5-isopropyl-1H-pyrazole-3-carboxylic acid



    [0325] To a solution of ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylate (900 mg, 4.49 mmol) in THF/MeOH (10/10 mL) was added 1 M aqueous NaOH (9 mL, 8.98 mmol) at 0°C. Then the solution was refluxed for 3 hours. The reaction solution was poured into water and acidified with concentrated HCl to pH∼1. The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (10 mL) to give 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylic acid (450 mg, 58% yield) as a white solid.
    1H NMR (400 MHz, methanol-d4): δ 3.08 (m, 1H), 1.32 (d, 6H).
    MS (ESI): 173.1 ([M+H]+).

    d) 4-Fluoro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide



    [0326] The title compound was obtained in analogy to example 67 using 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylic acid instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). White solid.
    MS (ESI): 345.2 ([M+H]+).

    Example 104


    (1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0327] 


    a) [(2R,4R)-4-Hydroxy-2-(pyridine-2-carbonyl)pyrrolidin-1-yl]-phenyl-methanone



    [0328] To a solution of 2-bromopyridine (3.64 g, 0.023 mol, CAS: 109-04-6) in THF (60 mL) was added n-BuLi (2.5 M, 9.2 mL, 0.023 mol) at -70°C. The mixture was stirred for 30 minutes. Then the above solution was added to a solution of (1R,4R)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (5 g, 0.023 mol, CAS: 444313-68-2) in THF (100 mL) dropwise at -70°C. The reaction was stirred for 30 minutes. Then the reaction solution was quenched by the addition of aqueous NH4Cl (100 mL). The mixture was extracted with CH2Cl2 (100 mL × 2), washed with brine (50 mL × 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified through flash chromatography (silica gel, CH2Cl2/MeOH = 200/1 ∼ 50/1 by vol) to give [(2R,4R)-4-hydroxy-2-(pyridine-2-carbonyl)pyrrolidin-1-yl]-phenyl-methanone (1.0 g, 15% of yield) as a yellow oil.
    MS (ESI): 297.0 ([M+H]+).

    b) [(2R,4R)-4-Hydroxy-2-[(R)-hydroxy(2-pyridyl)methyl]pyrrolidin-1-yl]-phenyl-methanone



    [0329] To a solution of [(2R,4R)-4-hydroxy-2-(pyridine-2-carbonyl)pyrrolidin-1-yl]-phenyl-methanone (1.0 g, 3.35 mmol) in MeOH (20 mL) was added NaBH4 (255 mg, 6.7 mol) at 0°C. The solution was stirred at room temperature for 2 hours. Then the reaction solution was poured into water (50 mL). The mixture was extracted with CH2Cl2 (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH = 200/1 ∼ 50/1 by vol) to give [(2R,4R)-4-hydroxy-2-[(R)-hydroxy(2-pyridyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (720 mg, 72% of yield) as a white solid.
    MS (ESI): 299.0 ([M+H]+).

    c) Phenyl-r(1R,3R,4R)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone



    [0330] To a solution of [(2R,4R)-4-hydroxy-2-[(R)-hydroxy(2-pyridyl)methyl]pyrrolidin-1-yl]-phenyl-methanone (0.72 g, 2.41 mmol) in toluene (20 mL) were added PPh3 (758 mg, 2.89 mol) and diisopropyl azodicarboxylate (584 mg, 2.89 mmol, CAS: 2446-83-5) at 0°C. The solution was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was purified through flash chromatography (silica gel, CH2Cl2/ethyl acetate = 10/1 ∼ 1/1 by vol) to give phenyl-[(1R,3R,4R)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (350 mg, 52% yield) as a yellow solid.
    MS (ESI): 281.1 ([M+H]+).

    d) (1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0331] To a solution of phenyl-[(1R,3R,4R)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone (0.75 g, 2.67 mmol) in MeOH (3 mL) was added KOH (3 g, 53.5 mmol). The mixture was stirred at refluxing temperature for 1 h. The reaction mixture was cooled to room temperature and diluted with MeOH (50 mL). Concentrated HCl was added to adjust pH to ∼7. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (mobile phase A: H2O with 0.5% NH3•H2O, B: CH3CN, C18 column) to give (1R,3R,4R)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane (10 mg, 2.1% of yield) as a white solid.
    1H NMR (400 MHz, methanol-d4): δ 8.51 (d, 1H), 7.84 (m, 1H), 7.48 (d, 1H), 7.31 (m, 1H), 4.94 (s, 1H), 4.77 (s, 1H), 3.94 (s, 1H), 3.14 (d, 1H), 3.01 (d, 1H), 1.79 (d, 1H), 1.59 (d, 1H).
    MS (ESI): 177.1 ([M+H]+).

    Example 105


    (1S,3S,4S)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0332] 



    [0333] The title compound was obtained in analogy to example 104 using (1S,4S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (CAS: 31560-25-5) instead of (1R,4R)-5-benzoyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one in step (a). MS (ESI): 177.1 ([M+H]+).

    Example 106


    (1R,3S,4R)-3-(2-Fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane



    [0334] 



    [0335] The title compound was obtained in analogy to example 104 using 1-fluoro-2-iodobenzene (CAS: 348-52-7) instead of 2-bromopyridine in step (a).
    MS (ESI): 194.0 ([M+H]+).
    1H NMR (400 MHz, methanol-d4): δ 7.38 (m, 1H), 7.28 (m, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 5.07 (s, 1H), 4.70 (s, 1H), 3.62 (s, 1H), 3.00 (d, 1H), 2.92 (d, 1H), 1.74 (d, 1H), 1.51 (d, 1H).

    Materials and Methods


    Construction of TAAR expression plasmids and stably transfected cell lines



    [0336] 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.

    [0337] 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.



    [0338] HEK-293 cells stably expressing rat TAAR1 were maintained at 37 °C and 5% CO2 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 1'000 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 14'000 rpm for 20 s. The homogenate was centrifuged at 48'000 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 14'000 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 3[H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine bound in the presence of 10 µM unlabeled ligand. All compounds were tested at a broad range of concentrations (10 pM to 10 µM) in duplicates. The test compounds (20 µl/well) were transferred into a 96 deep well plate (TreffLab), and 180 µl of HEPES-NaOH (20 mM, pH 7.4) containing MgCl2 (10 mM) and CaCl2 (2 mM) (binding buffer), 300 µl 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 µl 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 µl of Microscint 40 (PerkinElmer) the Unifilter-96 plate was sealed and after 1 hr the radioactivity counted using a TopCount Microplate Scintillation Counter (Packard Instrument Company).

    Radioligand binding assay on mouse TAAR1


    Membrane Preparation and Radioligand Binding.



    [0339] HEK-293 cells stably expressing mouse TAAR1 were maintained at 37 °C and 5% CO2 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 1'000 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 14'000 rpm for 20 s. The homogenate was centrifuged at 48'000 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 14'000 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 3[H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine bound in the presence of 10 µM unlabeled ligand. All compounds were tested at a broad range of concentrations (10 pM to 10 µM) in duplicates. The test compounds (20 µl/well) were transferred into a 96 deep well plate (TreffLab), and 180 µl of HEPES-NaOH (20 mM, pH 7.4) containing MgCl2 (10 mM) and CaCl2 (2 mM) (binding buffer), 300 µl 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 µl 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 µl of Microscint 40 (PerkinElmer) the Unifilter-96 plate was sealed and after 1 hr the radioactivity counted using a TopCount Microplate Scintillation Counter (Packard Instrument Company).

    [0340] The compounds show a Ki value in mouse or rat on TAAR1 (in µM) as shown in the table below.
    ExampleKi (µM) mouse/ratExampleKi(µM) mouse/ratExampleKi(µM) mouse/rat
    1 2.9944/ 0.1315 37 0.0613/ 2.6655 73 0.0177 0.8566
    2 2.5142/ 0.0794 38 0.5619/ 0.1672 74 0.1086/ 0.1897
    3 0.9858/ 0.0029 39 0.0069/ 0.359 75 0.0099/ 0.2387
    4 1.2833/ 0.0102 40 0.6363/ 0.19 76 0.0047/ 0.0842
    5 1.3254/ 0.0192 41 0.0222/ 2.8253 77 0.0048/ 0.1374
    6 1.5424/ 0.8145 42 0.3375/ 10 78 0.0042/ 0.1029
    7 0.0044/ 0.1062 43 0.0144/ 0.1666 79 0.006 0.0841
    8 0.0046/ 0.2104 44 0.0111/ 0.0848 80 0.0077/ 1.0811
    9 0.0349 0.3689 45 0.0042/ 0.2099 81 0.0271/ 0.1892
    10 0.0042/ 0.055 46 0.0098/ 0.6734 82 0.0035/ 0.0339
    11 0.0039/ 0.0153 47 0.3131/ 2.3008 83 0.0097/ 0.1897
    12 0.0067/ 0.1343 48 0.0114/ 1.3512 84 0.0172/ >15
    13 0.0063/ 0346 49 0.0044/ 0.037 85 0.0164/ 1.0784
    14 0.005/ 0.1915 50 0.0128/ 0.3436 86 0.0102/ 0.8086
    15 0.0155/ 1.8982 51 0.0034/ 0.0438 87 0.145/ >1.45
    16 0.0118/ 0.142 52 0.0043/ 0.1937 88 0.0255/ >1.45
    17 0.0064/ 0.6934 53 0.0034/ 0.0052 89 0.028/ 0.0026
    18 0.038/ 2.0334 54 0.1452/ 0.0346 90 0.015/ 0.3982
    19 0.0071/ 0.0641 55 0.0007/ 0.0123 91 0.0310/ >1.45
    20 0.0041/ 0.3966 56 0.0009/ 0.0501 92 0.0033/ 0.0879
    21 0.0197/ 0.6334 57 0.0034/ 0.0458 93 0.0042/ 0.0803
    22 0.0076/ 0.3405 58 0.0013/ >10 94 0.0251/ >1.45
    23 0.0157/ 0.1464 59 0.0022/ 1.0167 95 0.0613/ >1.45
    24 0.0033/ 0.0318 60 0.0033/ 5.3353 96 0.0477/ >1.45
    25 0.0224/ 0.3267 61 0.0077 0.715 97 0.0511/ >1.45
    26 0.0223/ 0.1374 62 0.0049/ 0.1067 98 0.0068/ 0.0745
    27 0.0097/ 0.0417 63 0.0034/ 0.5934 99 0.0035/ 0.1273
    28 0.0043/ 0.1776 64 0.0033/ 1.6027 100 0.0059/ 0.0278
    29 0.0315 0.0438 65 2.0677/ 0.0702 101 0.0057/ 0.0807
    30 0.0291/ 0.2758 66 0.0123/ 3.9574 102 0.0089/ 0.0142
    31 0.0221/ 0.0777 67 0.01 0.5033 103 0.0096/ 0.0405
    32 0.0063/ 0.1643 68 0.0031/ 0.0179 104 >1.49/ >1.5
    33 0.0035/ 0.0116 69 0.0066/ 0.1526 105 0.0465/ 0.3236
    34 0.0563/ 0.4574 70 0.0094/ 0.5123 106 1.0302/ 0.8361
    35 0.011/ 0.8186 71 0.0054/ 0.0135    
    36 0.0325/ 1.281 72 0.0153/ 0.0093    


    [0341] 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, dragées, 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.

    [0342] 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, dragées 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.

    [0343] 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.

    [0344] 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.

    [0345] 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, attention deficit hyperactivity disorder (ADHD) and diabetes.

    [0346] 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)
    ItemIngredientsmg/tablet
      5 mg25 mg100 mg500 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



    [0347] 
    1. 1. Mix items 1, 2, 3 and 4 and granulate with purified water.
    2. 2. Dry the granules at 50°C.
    3. 3. Pass the granules through suitable milling equipment.
    4. 4. Add item 5 and mix for three minutes; compress on a suitable press.
    Capsule Formulation
    ItemIngredientsmg/capsule
      5 mg25 mg100 mg500 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



    [0348] 
    1. 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
    2. 2. Add items 4 and 5 and mix for 3 minutes.
    3. 3. Fill into a suitable capsule.



    Claims

    1. A compound of formula

    wherein

    L is a bond, -C(O)NH-, -NHC(O)-, -CH2NHC(O)-, CH2C(O)NH-, -CH2NH-, -NH- or -NHC(O)NH-;

    R1 is hydrogen, C1-7-alkyl, halogen, C1-7-alkoxy-alkyl, C1-7-alkoxy substituted by halogen, C1-7-alkyl substituted by halogen or is phenyl or heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein phenyl and heteroaryl are optionally substituted by one, two or three substituents selected from the group consisting of halogen, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted by halogen, C1-7-alkoxy substituted by halogen, C3-6-cycloalkyl or O-CH2-C3-6-cycloalkyl;

    X is CH or N;

    or a pharmaceutically suitable acid addition salt thereof, all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
     
    2. A compound of formula I according to claim 1, wherein R1 is hydrogen, C1-7-alkyl, halogen, C1-7-alkoxy-alkyl, C1-7-alkoxy substituted by halogen or C1-7-alkyl substituted by halogen and L is as described in claim 1.
     
    3. A compound of formula I according to claim 2, which compounds are (1R,3S,4R)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane (1S,3R,4S)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane N-Butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline (1S,3R,4S)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1R,3S,4R)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane N-(3-Methoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3 trifluoropropoxy)acetamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide 4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluoropropoxy)acetamide 4,4,4-Trifluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide (1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane (1S,3S,4S)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane or (1R,3S,4R)-3-(2-Fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane.
     
    4. A compound of formula I according to claim 1, wherein R1 is phenyl, which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted by halogen, C1-7-alkoxy substituted by halogen, C3-6-cycloalkyl or O-CH2-C3-6-cycloalkylphenyl, and L is as described in claim 1.
     
    5. A compound of formula I according to claim 4, which compounds are 3-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 1-[3-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea 1-(4-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea 1-(3-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea 4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 3-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 3-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-(Cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide 4-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide 4-(Cyclopropylmethoxy)-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide 1-(4-Chlorophenyl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]aniline N-[(4-Fluorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluoromethoxy)phenyl]methyl]aniline N-(4-Chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-Bromophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-Fluorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-Ethoxyphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluoromethyl)phenyl]benzamide 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluoromethyl)phenyl]methyl]benzamide N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide N-(4-Bromophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-Fluorophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(4-Ethoxyphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide or N-[(4-Chlorophenyl)methyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide.
     
    6. A compound of formula I according to claim 1, wherein R1 is pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, which are optionally substituted by one, two or three substituents selected from the group consisting of halogen, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted by halogen, C1-7-alkoxy substituted by halogen, C3-6-cycloalkyl or O-CH2-C3-6-cycloalkylphenyl, and L is as described in claim 1.
     
    7. A compound of formula I according to claim 6, which compounds are N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine 6-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide 6-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-Cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine 5-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidin-4-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine 5-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridme-4-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-Cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine 2-Ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide 4-Chloro-3-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide 3-Isopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide 4-Chloro-3-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Chloro-3-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Chloro-1-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-propyl-pyrazole-3-carboxamide 4-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide 3-Ethyl-4-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide N-(6-Chloro-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridin-3-amine N-(6-Ethoxy-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 3-Ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide 3-Cyclopropyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide 2-Ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide 3-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Chloro-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-Cyclopropyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazole-5-carboxamide N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide 4-Chloro-3-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.]heptan-3-yl]phenyl]-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine 2-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide 3-Butyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-Butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide N-(6-Chloro-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide N-(6-Ethoxy-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide 4-Chloro-3-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Bromo-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Fluoro-3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 3-Isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide 4-Chloro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide or 4-Fluoro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazole-5-carboxamide.
     
    8. A pharmaceutical composition comprising a compound according to any one of claims 1 -7 and a pharmaceutical acceptable carrier and/or adjuvant.
     
    9. A pharmaceutical composition comprising a compound according to any one of claims 1 - 7 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.
     
    10. Compounds according to any one of claims 1 - 7 for use as therapeutic active substances.
     
    11. Compounds according to any one of claims 1 -7 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, 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.
     


    Ansprüche

    1. Verbindung der Formel

    wobei

    L eine Bindung, -C(O)NH-, -NHC(O)-, -CH2NHC(O)-, CH2C(O)NH-, -CH2NH-, -NH- oder -NHC(O)NH- ist;

    R1 Wasserstoff, C1-7-Alkyl, Halogen, C1-7-Alkoxy-alkyl, halogensubstituiertes C1-7-Alkoxy, halogensubstituiertes C1-7-Alkyl ist oder Phenyl oder Heteroaryl ist, das aus der Gruppe, bestehend aus Pyridinyl, Pyrimidinyl, Pyrazinyl oder Pyrazolyl, ausgewählt ist, und wobei Phenyl und Heteroaryl gegebenenfalls mit einem, zwei oder drei Substituenten substituiert sind, die aus der Gruppe, bestehend aus Halogen, C1-7-Alkyl, C1-7-Alkoxy, halogensubstituiertem C1-7-Alkyl, halogensubstituiertem C1-7-Alkoxy, C3-6-Cycloalkyl oder O-CH2-C3-6-Cycloalkyl, ausgewählt sind;

    X CH oder N ist;

    oder ein pharmazeutisch geeignetes Säureadditionssalz davon, alle racemischen Gemische, alle ihre entsprechenden Enantiomere und/oder optischen Isomere.
     
    2. Verbindung der Formel I nach Anspruch 1, wobei R1 Wasserstoff, C1-7-Alkyl, Halogen, C1-7-Alkoxy-alkyl, halogensubstituiertes C1-7-Alkoxy oder halogensubstituiertes C1-7-Alkyl ist und L wie in Anspruch 1 beschrieben ist.
     
    3. Verbindung der Formel I nach Anspruch 2, wobei die Verbindungen Folgende sind (1R,3S,4R)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptan (1S,3R,4S)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptan N-Butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]anilin (1S,3R,4S)-3-(4-Bromphenyl)-2-oxa-5-azabicyclo[2.2.1]heptan (1R,3S,4R)-3-(4-Bromphenyl)-2-oxa-5-azabicyclo[2.2.1]heptan N-(3-Methoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]anilin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluorethoxy)acetamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3 trifluorpropoxy)acetamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluorethoxy)acetamid 4,4,4-Trifluor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluorpropoxy)acetamid 4,4,4-Trifluor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamid (1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptan (1S,3S,4S)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptan oder (1R,3S,4R)-3-(2-Fluorphenyl)-2-oxa-5-azabicyclo[2.2.1]heptan.
     
    4. Verbindung der Formel I nach Anspruch 1, wobei R1 Phenyl ist, das gegebenenfalls mit einem, zwei oder drei Substituenten substituiert ist, die aus der Gruppe, bestehend aus Halogen, C1-7-Alkyl, C1-7-Alkoxy, halogensubstituiertem C1-7-Alkyl, halogensubstituiertem C1-7-Alkoxy, C3-6-Cycloalkyl oder O-CH2-C3-6-Cycloalkylphenyl, ausgewählt sind, und L wie in Anspruch 1 beschrieben ist.
     
    5. Verbindung der Formel I nach Anspruch 4, wobei die Verbindungen Folgende sind 3-Chlor-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 4-Chlor-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 1-[3-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluormethyl)phenyl]harnstoff 1-(4-Chlorphenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]harnstoff 1-(3-Chlorphenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]harnstoff 4-Chlor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 3-Chlor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 3-Chlor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 4-(Cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamid 4-Chlor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 4-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 4-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamid 4-(Cyclopropylmethoxy)-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamid 1-(4-Chlorphenyl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]harnstoff N-[(4-Chlorphenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]anilin 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluormethyl)phenyl]methyl]anilin N-[(4-Fluorphenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]anilin 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluormethoxy)phenyl]methyl]anilin N-(4-Chlorphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(4-Bromphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(4-Fluorphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(4-Ethoxyphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluormethyl)phenyl]benzamid 4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluormethyl)phenyl]methyl]benzamid N-[(4-Chlorphenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid 4,4,4-Trifluor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamid N-(4-Bromphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(4-Fluorphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(4-Ethoxyphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid 4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluormethyl)phenyl]methyl]benzamid oder N-[(4-Chlorphenyl)methyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid.
     
    6. Verbindung der Formel I nach Anspruch 1, wobei R1 Pyridinyl, Pyrimidinyl, Pyrazinyl oder Pyrazolyl ist, die gegebenenfalls mit einem, zwei oder drei Substituenten substituiert sind, die aus der Gruppe, bestehend aus Halogen, C1-7-Alkyl, C1-7-Alkoxy, halogensubstituiertem C1-7-Alkyl, halogensubstituiertem C1-7-Alkoxy, C3-6-Cycloalkyl oder O-CH2-C3-6-Cycloalkylphenyl, ausgewählt sind, und L wie in Anspruch 1 beschrieben ist.
     
    7. Verbindung der Formel I nach Anspruch 6, wobei die Verbindungen Folgende sind N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyridin-2-amin 6-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-3-carboxamid 6-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-3-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluorethoxy)pyridin-3-carboxamid 2-Cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidin-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyridin-2-amin 5-Chlor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyrimidin-4-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyrazin-2-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyrimidin-2-amin 5-Chlor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyridin-4-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyridin-4-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluorethoxy)pyridin-3-carboxamid 2-Cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidin-5-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyrazin-2-amin N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyrimidin-2-amin 2-Ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidin-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyridin-4-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyridin-2-carboxamid 4-Chlor-3-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyrimidin-4-carboxamid 3-Isopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluormethyl)pyridin-3-carboxamid 4-Chlor-3-ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Chlor-3-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Chlor-1-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-propyl-pyrazol-3-carboxamid 4-Chlor-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazol-5-carboxamid 3-Ethyl-4-methyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluorethoxy)pyridin-2-carboxamid N-(6-Chlor-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluormethyl)pyridin-3-amin N-(6-Ethoxy-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid 3-Ethyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Chlor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazol-5-carboxamid 3-Cyclopropyl-4-methyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluormethyl)pyridin-2-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(trifluormethyl)pyridin-3-carboxamid 2-Ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidin-5-carboxamid 3-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Chlor-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 3-Cyclopropyl-4-fluor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Fluor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-propyl-1H-pyrazol-5-carboxamid N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-4-(2,2,2-trifluorethoxy)pyrimidin-2-amin N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluorethoxy)pyrimidin-4-amin N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluormethyl)pyrimidin-4-carboxamid 4-Chlor-3-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2-trifluorethoxy)pyrimidin-4-amin 2-Isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(2,2,2-trifluorethoxy)pyrazol-3-carboxamid 3-Butyl-4-fluor-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 3-Butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid N-(6-Chlor-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid N-(6-Ethoxy-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamid 4-Chlor-3-ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Brom-3-ethyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Fluor-3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 3-Isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid 4-Chlor-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid oder 4-Fluor-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-1H-pyrazol-5-carboxamid.
     
    8. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1 - 7 und einen pharmazeutisch unbedenklichen Träger und/oder ein pharmazeutisch unbedenkliches Adjuvans.
     
    9. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1 - 7 und einen pharmazeutisch unbedenklichen Träger und/oder ein pharmazeutisch unbedenkliches Adjuvans zur Verwendung bei der Behandlung von Depression, Angststörungen, bipolarer Störung, Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS), stressbedingten Störungen, psychotischen Störungen, Schizophrenie, neurologischen Erkrankungen, Parkinson-Krankheit, neurodegenerativen Störungen, Alzheimer-Krankheit, Epilepsie, Migräne, Hypertonie, Substanzmissbrauch, Stoffwechselstörungen, Essstörungen, Diabetes, diabetischen Komplikationen, Fettleibigkeit, Dyslipidämie, Störungen von Energieverbrauch und -assimilation, Störungen und Fehlfunktion von Körpertemperatur-Homöostase, Störungen des Schlafes und des Tag-Nacht-Rhythmus und Herz-Kreislauf-Störungen.
     
    10. Verbindungen nach einem der Ansprüche 1 - 7 zur Verwendung als therapeutisch wirksame Substanzen.
     
    11. Verbindungen nach einem der Ansprüche 1 - 7 zur Verwendung als therapeutisch wirksame Substanzen bei der Behandlung von Depression, Angststörungen, bipolarer Störung, Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS), stressbedingten Störungen, psychotischen Störungen, Schizophrenie, neurologischen Erkrankungen, Parkinson-Krankheit, neurodegenerativen Störungen, Alzheimer-Krankheit, Epilepsie, Migräne, Hypertonie, Substanzmissbrauch, Stoffwechselstörungen, Essstörungen, Diabetes, diabetischen Komplikationen, Fettleibigkeit, Dyslipidämie, Störungen von Energieverbrauch und -assimilation, Störungen und Fehlfunktion von Körpertemperatur-Homöostase, Störungen des Schlafes und des Tag-Nacht-Rhythmus und Herz-Kreislauf-Störungen.
     


    Revendications

    1. Composé de formule

    dans laquelle

    L représente une liaison, -C(O)NH-, -NHC(O)-, -CH2NHC(O)-, CH2C(O)NH-, -CH2NH-, -NH- ou -NHC(O)NH- ;

    R1 représente un hydrogène, un alkyle en C1-7, un halogène, un alcoxyalkyle en C1-7, un alcoxy en C1-7 substitué par un halogène, un alkyle en C1-7 substitué par un halogène ou représente un phényle ou un hétéroaryle choisi dans le groupe constitué par un pyridinyle, un pyrimidinyle, un pyrazinyle ou un pyrazolyle, et dans laquelle le phényle et l'hétéroaryle sont éventuellement substitués par un, deux ou trois substituants choisis dans le groupe constitué par un halogène, un alkyle en C1-7, un alcoxy en C1-7, un alkyle en C1-7 substitué par un halogène, un alcoxy en C1-7 substitué par un halogène, un cycloalkyle en C3-6 ou un O-CH2-cycloalkyle en C3-6 ;

    X représente CH ou N ;

    ou un sel d'addition d'acide pharmaceutiquement acceptable, tous les mélanges racémiques, tous leurs énantiomères et/ou isomères optiques correspondants.
     
    2. Composé de formule I selon la revendication 1, dans laquelle R1 représente un hydrogène, un alkyle en C1-7, un halogène, un alcoxyalkyle en C1-7, un alcoxy en C1-7 substitué par un halogène ou un alkyle en C1-7 substitué par un halogène et L est tel que décrit dans la revendication 1.
     
    3. Composé de formule I selon la revendication 2, lesquels composés sont le (1R,3S,4R)-3-phényl-2-oxa-5-azabicyclo[2.2.1]heptane le (1S,3R,4S)-3-phényl-2-oxa-5-azabicyclo[2.2.1]heptane la N-butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline le (1S,3R,4S)-3-(4-bromophényl)-2-oxa-5-azabicyclo[2.2.1]heptane le (1R,3S,4R)-3-(4-bromophényl)-2-oxa-5-azabicyclo[2.2.1]heptane la N-(3-méthoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(2,2,2 trifluoroéthoxy)acétamide le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(3,3,3 trifluoropropoxy)acétamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(2,2,2 trifluoroéthoxy)acétamide le 4,4,4-trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]butanamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(3,3,3-trifluoropropoxy)acétamide le 4,4,4-trifluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]butanamide le (1R,3R,4R)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane le (1S,3S,4S)-3-(2-pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane ou le (1R,3S,4R)-3-(2-fluorophényl)-2-oxa-5-azabicyclo[2.2.1]heptane.
     
    4. Composé de formule I selon la revendication 1, dans laquelle R1 représente un phényle, qui est éventuellement substitué par un, deux ou trois substituants choisis dans le groupe constitué par un halogène, un alkyle en C1-7, un alcoxy en C1-7, un alkyle en C1-7 substitué par un halogène, un alcoxy en C1-7 substitué par un halogène, un cycloalkyle en C3-6 ou un O-CH2-cycloalkyle en C3-6-phényle, et L est tel que décrit dans la revendication 1.
     
    5. Composé de formule I selon la revendication 4, lesquels composés sont le 3-chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 4-chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide la 1-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-3-[4-(trifluorométhyl)phényl]urée la 1-(4-chlorophényl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]urée la 1-(3-chlorophényl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]urée le 4-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 3-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 3-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 4-(cyclopropylméthoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phényl]benzamide le 4-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 4-éthoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 4-éthoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]benzamide le 4-(cyclopropylméthoxy)-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phényl]benzamide la 1-(4-chlorophényl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]urée la N-[(4-chlorophényl)méthyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline la 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluorométhyl)phényl]méthyl]aniline la N-[(4-fluorophényl)méthyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline la 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluorométhoxy)phényl]méthyl]aniline le N-(4-chlorophényl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(4-bromophényl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(4-fluorophényl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(4-éthoxyphényl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluorométhyl)phényl]benzamide le 4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluorométhyl)phényl]méthyl]benzamide le N-[(4-chlorophényl)méthyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le 4,4,4-trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]butanamide le N-(4-bromophényl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(4-fluorophényl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(4-éthoxyphényl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le 4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluorométhyl)phényl]méthyl]benzamide ou le N-[(4-chlorophényl)méthyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide.
     
    6. Composé de formule I selon la revendication 1, dans laquelle R1 représente un pyridinyle, un pyrimidinyle, un pyrazinyle ou un pyrazolyle, qui sont éventuellement substitués par un, deux ou trois substituants choisis dans le groupe constitué par un halogène, un alkyle en C1-7, un alcoxy en C1-7, un alkyle en C1-7 substitué par un halogène, un alcoxy en C1-7 substitué par un halogène, un cycloalkyle en C3-6 ou un O-CH2-cycloalkyle en C3-6-phényle, et L est tel que décrit dans la revendication 1.
     
    7. Composé de formule I selon la revendication 6, lesquels composés sont la N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyridin-2-amine le 6-éthoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyridine-3-carboxamide le 6-éthoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyridine-3-carboxamide le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-6-(2,2,2-trifluoroéthoxy)pyridine-3-carboxamide le 2-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyrimidine-5-carboxamide la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyridin-2-amine la 5-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyridin-2-amine la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyrimidin-4-amine la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyrazin-2-amine la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyrimidin-2-amine la 5-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyridin-2-amine le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyridine-4-carboxamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyridine-4-carboxamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-6-(2,2,2-trifluoroéthoxy)pyridine-3-carboxamide le 2-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyrimidine-5-carboxamide la N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyrazin-2-amine la N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyrimidin-2-amine le 2-éthyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyrimidine-5-carboxamide la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyridin-4-amine le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyridine-2-carboxamide le 4-chloro-3-cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyrimidine-4-carboxamide le 3-isopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-6-(trifluorométhyl)pyridine-3-carboxamide le 4-chloro-3-éthoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-chloro-3-méthyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-méthyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-chloro-1-méthyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-propyl-pyrazole-3-carboxamide le 4-chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-3-propyl-1H-pyrazole-5-carboxamide le 3-éthyl-4-méthyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(2,2,2-trifluoroéthoxy)pyridine-2-carboxamide le N-(6-chloro-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-6-(trifluorométhyl)pyridin-3-amine le N-(6-éthoxy-3-pyridyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le 3-éthyl-4-méthyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-3-propyl-1H-pyrazole-5-carboxamide le 3-cyclopropyl-4-méthyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(trifluorométhyl)pyridine-2-carboxamide le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-6-(trifluorométhyl)pyridine-3-carboxamide le 2-éthyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]pyrimidine-5-carboxamide le 3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-chloro-3-éthyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 3-cyclopropyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-3-propyl-1H-pyrazole-5-carboxamide la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-4-(2,2,2-trifluoroéthoxy)pyrimidin-2-amine la N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(2,2,2-trifluoroéthoxy)pyrimidin-4-amine le N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(trifluorométhyl)pyrimidine-4-carboxamide le 4-chloro-3-cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide la N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-2-(2,2,2-trifluoroéthoxy)pyrimidin-4-amine le 2-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-5-(2,2,2-trifluoroéthoxy)pyrazole-3-carboxamide le 3-butyl-4-fluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 3-butyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le N-(6-chloro-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le N-(6-éthoxy-3-pyridyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide le 4-chloro-3-éthoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-bromo-3-éthyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-fluoro-3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 3-isobutyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide le 4-chloro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide ou le 4-fluoro-3-isopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phényl]-1H-pyrazole-5-carboxamide.
     
    8. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 7 et un véhicule et/ou un adjuvant pharmaceutiquement acceptable.
     
    9. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 7 et un véhicule et/ou un adjuvant pharmaceutiquement acceptable pour une utilisation dans le traitement de la dépression, de troubles anxieux, d'un trouble bipolaire, d'un trouble du déficit de l'attention avec hyperactivité (TDAH), de troubles liés au stress, de troubles psychotiques, de la schizophrénie, de troubles neurologiques, de la maladie de Parkinson, de troubles neurodégénératifs, de la maladie d'Alzheimer, de l'épilepsie, de la migraine, de l'hypertension, de la toxicomanie, de troubles métaboliques, de troubles de l'alimentation, du diabète, de complications diabétiques, de l'obésité, de la dyslipidémie, de troubles de consommation et d'assimilation d'énergie, de troubles et d'un dysfonctionnement de l'homéostasie de la température corporelle, de troubles du sommeil et du rythme circadien et de troubles cardiovasculaires.
     
    10. Composés selon l'une quelconque des revendications 1 à 7 pour une utilisation en tant que substances thérapeutiquement actives.
     
    11. Composés selon l'une quelconque des revendications 1 à 7 pour une utilisation en tant que substances thérapeutiquement actives dans le traitement de la dépression, de troubles anxieux, d'un trouble bipolaire, d'un trouble du déficit de l'attention avec hyperactivité (TDAH), de troubles liés au stress, de troubles psychotiques, de la schizophrénie, de troubles neurologiques, de la maladie de Parkinson, de troubles neurodégénératifs, de la maladie d'Alzheimer, de l'épilepsie, de la migraine, de l'hypertension, de la toxicomanie, de troubles métaboliques, de troubles de l'alimentation, du diabète, de complications diabétiques, de l'obésité, de la dyslipidémie, de troubles de consommation et d'assimilation d'énergie, de troubles et d'un dysfonctionnement de l'homéostasie de la température corporelle, de troubles du sommeil et du rythme circadien et de troubles cardiovasculaires.
     




    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description




    Non-patent literature cited in the description