HK1232869A1

HK1232869A1 - 2-oxa-5-azabicyclo [2.2.1] heptan-3-yl derivatives

Info

Publication number: HK1232869A1
Application number: HK17106552.8A
Authority: HK
Inventors: 朱塞佩．切切里; 吉多．加利; 胡逸民; 罗杰．诺克罗斯; 菲利普．普夫利格; 沈宏
Original assignee: 豪夫迈·罗氏有限公司
Priority date: 2014-08-01
Filing date: 2015-07-29
Publication date: 2018-01-19

Description

2-oxa-5-azabicyclo [2.2.1] hept-3-yl derivatives

The invention relates to compounds of formula I

Wherein

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

R¹is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen, lower alkyl substituted by halogen or

A heteroaryl group that is phenyl or a group selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein the phenyl and heteroaryl groups are optionally substituted with 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-a cycloalkyl group;

x is CH or N;

or to pharmaceutically suitable acid addition salts thereof, to all racemic mixtures, to all their corresponding enantiomers and/or optical isomers.

It has now been found that the compounds of formula I have a good affinity for Trace Amine Associated Receptors (TAARs), especially TAAR 1.

The compounds may be used in the treatment of: depression (depression), anxiety disorders (anxiety disorders), bipolar disorders (bipolar disorder), Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders (stress-related disorders), psychotic disorders such as schizophrenia (schizophrenia), neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy (epilepsy), migraine (migraine), hypertension (hypertension), substance abuse (metastasizing disorder) and metabolic disorders such as eating disorders (eating disorders), obesity (obesity), metabolic disorders such as obesity (obesity), metabolic disorders such as eating disorders, assimilation disorders (obesity), obesity (obesity), metabolic disorders (diabetes), obesity (obesity-related disorders), stress-related disorders (depression), mental disorders (depression), stress-related disorders (depression), and metabolic disorders such as eating disorders (depression), anxiety disorders (depression), stress-related disorders (obesity, obesity (diabetes), obesity-related disorders (obesity, obesity-related disorders (obesity, sleep and circadian rhythm disorders (disorders of sleep and circadianrythhm), and cardiovascular diseases (cardiovascular disorders).

Some of the physiological effects reported for compounds that can bind to adrenergic receptors (i.e. cardiovascular effects, hypotension, sedation induction) (WO02/076950, WO97/12874 or EP 0717037) may be considered as undesirable side effects in the case of drugs intended to treat central nervous system disorders as described above. It is therefore desirable to obtain a drug which is selective for the TAAR1 receptor compared to the adrenergic receptor. The objects of the invention show selectivity for the TAAR1 receptor over the adrenergic receptor, especially good selectivity compared to the human and rat α 1 and α 2 adrenergic receptors.

Classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play an important role as neurotransmitters in the central and peripheral nervous system [1 ]. Their synthesis and storage, as well as their degradation and resorption upon release, are tightly regulated. Imbalances in biogenic amine levels are known to be responsible for altered brain function in many pathological situations [2-5 ]. The second class of endogenous amine compounds, known as Trace Amines (TAs), significantly overlaps with classical biogenic amines in structure, metabolism, and subcellular localization. TA includes p-tyramine, β -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at levels generally lower than classical biogenic amines [6 ].

Their dysregulation is associated with a variety of psychiatric disorders such as schizophrenia and depression [7], and other conditions such as attention deficit hyperactivity disorder, migraine, parkinson's disease, substance abuse and eating disorders [8, 9 ].

For a long time, TA-specific receptors have only been hypothesized based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10, 11 ]. Thus, the pharmacological effects of TA are believed to be mediated via the well-known mechanism of classical biogenic amines by: or by causing their release, inhibiting their resorption or by "cross-reacting" with their receptor systems [9, 12, 13 ]. This view has changed dramatically with the recent recognition of several members of the new GPCR family, namely the Trace Amine Associated Receptors (TAARs) [7, 14 ]. There are 9 TAAR genes (including 3 pseudogenes) in humans and 16 genes (including 1 pseudogene) in mice. The TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located adjacent to each other on the same chromosomal segment. Phylogenetic relationships of receptor genes, consistent with in-depth GPCR pharmacophore similarity comparisons and pharmacological data, suggest that these receptors form three distinct subfamilies [7, 14 ]. TAAR1 is in the first subclass of four genes (TAAR1-4) that are highly conserved between humans and rodents. TA activates TAAR1 via Ga. Dysregulation of TA has been shown to contribute to the etiology of a variety of diseases such as depression, psychosis, attention deficit hyperactivity disorder, substance abuse, parkinson's disease, migraine, eating disorders, metabolic disorders, and thus TAAR1 ligands have a high potential for treatment of these diseases.

Therefore, there is a wide interest in increasing knowledge about trace amine associated receptors.

The references used are:

1 Deutch, a.y. and Roth, r.h. (1999) neutransmiters, in fundamental neuroscience (2 nd edition) (zigbee, m.j., Bloom, f.e., Landis, s.c., Roberts, j.l. and Squire, l.r. editor), page 193-234-;

2 Wong, M.L. and Licinio, J. (2001) Research and treatment protocols to achieve the expression. Nat. Rev. neurosci.2, 343-;

3 Carlsson, A. et al (2001) Interactions between monoamines, glutamate, and GABA in schizochrysia: new evaluation, annu, rev, pharmacol, toxicol, 41, 237-;

4 Tuite, P. and Riss, J. (2003) Recent considerations in the pharmacological evaluation of Parkinson's disease. expert Opin. investig. drugs 12, 1335-1352;

5 Castellanos, F.X. and Tannock, R. (2002) Neuroscience of attribute-specific/hyperactive recorder: the search for endophthhenotyping. Nat. Rev. Neurosci.3, 617-628;

6 Usedin, Earl; sandler, Merton; editors, Psychopharmacology Series, volume 1: trace Amines and the Brain [ Proceedings of a Study Group at the14th annual meeting of the American College of neuropsychological, San Juan, puerto Rico ] (1976);

7 Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines a novel GPCR family.trends in Pharmacol.Sci.26, 274-281;

8 Branchek, T.A. and Blackburn, T.P. (2003) Trace amine receivers as targetsrefor novel therapeutics: legend, myth and fact. curr. opin. pharmacol.3, 90-97;

9 Premont, R.T., et al (2001) Following the trace of applied amines, Proc. Natl. Acad. Sci. U.S.A.98, 9474-9475;

10 Mousseau, D.D. and Butterworth, R.F. (1995) A high-affinity [3H ] tryptamine binding site in human blue.prog.brain Res.106, 285-291;

11 McCormac, J.K., et al (1986) Autoadographic localization of tryptophanic sites in the rat and dog Central nervous system, J.Neurosci.6, 94-101;

12 Dyck，L.E.(1989)Release of some endogenous trace amines from ratstriatal slices in the presence and absence of a monoamine oxidaseinhibitor.Life Sci.44，1149-1156；

13 Parker, e.m. and cube, L.X. (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamin efflux, dopamin up and diazophenol binding.j.pharmacol. exp. ther.245, 199-210;

14 Lindemann, L, et al (2005) Trace amine associated receivers for measuring and functional disorders of minor G protein-coupled devices.genomics 85, 372 385.

The invention relates to novel compounds of formula (I) and pharmaceutically acceptable salts thereof, to the use thereof for producing medicaments, said medicaments are useful for the treatment of disorders related to the biological function of trace amine associated receptors, their preparation, and medicaments for use in the control or prevention of disorders 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, based on compounds according to the invention.

Preferred indications for use of the compounds of the invention are depression, psychosis, parkinson's disease, anxiety, Attention Deficit Hyperactivity Disorder (ADHD) and diabetes.

As used herein, the term "lower alkyl" denotes a saturated straight or branched chain group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, and the like. Preferred alkyl groups are those having 1 to 4 carbon atoms.

As used herein, the term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.

The term "halogen" denotes chlorine, iodine, fluorine and bromine. A preferred halogen group is fluorine.

As used herein, the term "halogen-substituted lower alkyl" denotes a saturated straight or branched chain group comprising 1 to 7 carbon atoms as defined for the term "lower alkyl", wherein at least one hydrogen atom is replaced by a halogen atom. The preferred halogen atom is fluorine. An example of such a group is CF₃、CHF₂、CH₂F、CH₂CF₃Or CH₂CHF₂。

As used herein, the term "lower alkoxy substituted by halogen" denotes a lower alkoxy group as defined above, and wherein at least one hydrogen atom is replaced by a halogen atom. An example of such a group is OCF₃、OCHF₂、OCH₂F、OCH₂CF₃Or OCH₂CHF₂。

The term "cycloalkyl" denotes a saturated carbocyclic ring comprising 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "pharmaceutically acceptable acid addition salts" includes 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.

An embodiment of the invention are compounds of formula I, wherein R¹Is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen or lower alkyl substituted by halogen and L is as described above, e.g. 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] hept-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] hept-3-yl ] aniline

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

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

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

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

(1R, 3R, 4R) -3- (2-pyridinyl) -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.

An embodiment of the invention is further a compound of formula I, wherein R is¹Is phenyl, optionally substituted with 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 halogenAlkyl, cycloalkyl or O-CH₂Cycloalkylphenyl, 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] hept-3-yl ] phenyl ] benzamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

An embodiment of the invention are compounds of formula I, wherein R¹Is pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl, optionally substituted with 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-CH₂Cycloalkylphenyl, and L is as described above, for example the following compounds

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (6-chloro-3-pyridinyl) -4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-3-yl ] benzamide

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

N- (6-ethoxy-3-pyridinyl) -4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-3-yl ] benzamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (6-chloro-3-pyridinyl) -4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-3-yl ] benzamide

N- (6-ethoxy-3-pyridinyl) -4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-3-yl ] benzamide

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

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

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

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

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

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

The preparation of the compounds of formula I according to the invention can be carried out sequentially or in a convergent synthetic route. The synthesis of the compounds of the invention is shown in schemes 1 to 8 below and in the description of 106 specific examples. The skills required for carrying out the reaction and purification of the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and symbols used in the following description of the methods have the meanings given herein before.

In more detail, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence given in schemes 1 to 8, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.

The compounds of formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example, by a method comprising

a) Cleaving the N-Protecting Group (PG) from a compound of the formula

To give a compound of the formula

Wherein PG is an N-protecting group selected from the group consisting of-C (O) O-t-Butyl (BOC), and the other definitions are as described above, and,

if desired, the compound obtained is converted into a pharmaceutically acceptable acid addition salt.

General procedure

Scheme 1

Step A: the conversion of lactone 1 to ketone 2 can be accomplished by addition of phenyl grignard reagent with lactone 1 and me (meo) NH · HCl in anhydrous aprotic organic solvents such as THF, diethyl ether, DME, TBME at temperatures from-78 ℃ to 0 ℃ under an inert atmosphere.

Preferred conditions are the use of phenylmagnesium bromide in THF at-70 ℃ for 10 hours.

And B: the reduction of the ketone 2 to the corresponding diol 3 can be carried out in a solvent such as THF, diethyl ether, DME, 1, 4-bisIn an alkane and TBME, methanol or ethanol, with a reducing agent such as NaBH₄、LiBH₄、ZnBH₄9-BBN, borane-THF complex, LiAlH₄Or DIBAL-H treatment.

Preferred conditions are NaBH₄As reducing agent in MeOH at 0 ℃ for 2 hours.

And C: cyclization of diol 3 can be accomplished by Mitsunobu-type reactions, acid-mediated cationic cyclization, or stepwise processes involving sulfonate ester intermediates.

In a Mitsunobu-type reaction, the conversion may be carried out in an ether solvent such as diethyl ether, diethyl etherAlkane, THF or TBME, or other aprotic organic solvents such as toluene and benzene, with triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).

In acid-mediated cationic cyclization, the conversion may be effected by use of a mineral acid such as H at elevated temperature₂SO₄、H₃PO₄By treatment with an organic acid such as trifluoroacetic acid, BF in a solvent such as dichloromethane, 1, 2-dichloroethane or toluene at temperatures from 0 ℃ to room temperature₃·Et₂O (optionally with additives such as Et₃SiH) treatment.

In a stepwise process, the conversion may be carried out by reacting at from 0 ℃ to 50 ℃ in the presence of an organic base such as pyridine, triethylamine, N-diisopropylethylamine or N-methylmorpholine in an ethereal solvent such as diethyl ether, diethyl etherIn an alkane, THF or TBME, or using an organic base as a solvent, by treating diol 3 with one equivalent of a sulfonyl chloride such as methanesulfonyl chloride or toluenesulfonyl chloride. Can be prepared by dissolving in an ether solvent such as diethyl ether or diethyl etherThe resulting sulfonate ester is converted to the protected bridged-morpholine 4 by treatment with a non-nucleophilic base such as sodium hydride, potassium tert-butoxide or potassium 2-methyl-2-butoxide in alkane, THF or TBME.

Preferred conditions are the Mitsunobu-type process: diol 3 was treated with DIAD and triphenylphosphine in toluene at 0 ℃ and the reaction was continued at room temperature for 16 h.

Step D: deprotection can be accomplished by base-induced reactions or stepwise processes involving benzyl-protected intermediates.

In a base-induced reaction, deprotection can be achieved by reaction in a solvent such as methanol, ethanol, at elevated temperatures such as 90 ℃ toAt 150 ℃ with bases such as hydrazine, KOH, NaOH or Cs₂CO₃Is processed to be carried out.

In a stepwise procedure, a benzoyl protecting group can be converted to a benzyl protecting group by: in ethereal solvents such as diethyl ether, diethyl etherIn an alkane, THF or TBME at 0-60 deg.C with a reducing agent such as LiAlH₄、BH₃THF and BH₃·Me₂And S, processing. The benzyl group obtained can be removed by hydrogenation catalyzed by Pd catalysts or by: with chloroformic acid esters, e.g. ClCOOCH₂CH₂Cl、ClCOOCH(Cl)Me、ClCOOCH₂Ph and ClCOOCH₂CCl₃And optionally with a base such as triethylamine, diisopropylethylamine and sodium hydroxide in a solvent such as toluene, THF, diethyl ether, diethyletherIn an alkane or TBME, at room temperature to elevated temperature.

Preferred conditions are a stepwise process using LiAlH in THF for the first step₄At 0 ℃ to room temperature for 2 hours, followed by reaction with ClCOOCH₂CH₂Cl was treated in toluene at 110 ℃ for 16 hours.

Step E: the bridged-morpholines 5 can be protected by reaction with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate or cesium carbonate, in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an etheric solvent such as diethyl ether, diethyl etherIn alkane, THF or TBME.

Preferred conditions are THF in the presence of potassium carbonate as base at room temperature for up to 10 hours.

Step F: iodination of the bridged-morpholine 6 can be accomplished by treatment with a halogenating agent such as iodine and iodosuccinimide, or polyvalent iodine along with iodine such as [ bis (trifluoroacetoxy) iodine ] benzene/iodine and bis (acetoxy) phenyl iodine/iodine in a halogenated solvent such as dichloromethane, chloroform or tetrachloromethane at room temperature to 80 ℃.

Preferred conditions are bis (trifluoroacetoxy) iodo ] benzene/iodide in tetrachloromethane at room temperature.

Step G: coupling of iodide 7 with benzophenone imine can be carried out in the presence of a palladium or copper catalyst, a ligand and a base in a solvent such as a bisIn alkanes, DME, THF, toluene and DMSO, at elevated temperatures, for example using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris (dibenzylideneacetone) dipalladium (0), catalytic 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) and Cs₂CO₃In toluene at 100 ℃ for 5 hours.

Step H: the removal of the N-diphenylmethylene group in 8 can be carried out by hydrogenation with hydrogen at atmospheric or elevated pressure or by using ammonium formate or cyclohexadiene as hydrogen source, using catalysts such as PtO₂Pd-C or Raney nickel (Raney nickel) in a solvent such as MeOH, EtOH, H₂O, twoTransfer hydrogenation in an alkane, THF, EtOAc, dichloromethane, chloroform, DMF or mixtures thereof.

The transformation can also be carried out by using hydroxylamine hydrochloride in combination with a base such as sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate in a solvent such as MeOH, EtOH, dioxaneAlkane, THF, DMF or a mixture thereof.

Preferred conditions are hydroxylamine hydrochloride, together with sodium acetate, in MeOH at room temperature for 2 hours.

Alternatively, the N-diphenylmethylene-protected aniline 8 can be prepared by the sequence of reactions described in scheme 2.

Scheme 2

Step A: the Grignard addition can be carried out by reacting a phenyl Grignard reagent (10, X)₁Formed in situ by treatment of p-bromophenyl bromide or iodide) with lactone 1 in an anhydrous aprotic organic solvent such as THF and diethyl ether at a temperature of-78 ℃ to 0 ℃ under an inert atmosphere.

Preferred conditions are the use of para-bromophenyl magnesium bromide (10, X) in anhydrous THF at-78 deg.C₁Br) for 30 minutes.

And B: the reduction of the ketone 11 to the corresponding diol 12 can be carried out in a solvent such as THF, diethyl ether, DME, 1, 4-bisIn an alkane and TBME, methanol or ethanol, with a reducing agent such as NaBH₄、LiBH₄、ZnBH₄9-BBN, borane-THF complex, LiAlH₄Or DIBAL-H treatment.

Preferred conditions are NaBH₄As reducing agent in MeOH at 0 ℃ for 2 hours.

And C: cyclization of diol 12 can be accomplished by Mitsunobu-type reactions, acid-mediated cationic cyclization, or stepwise processes involving sulfonate ester intermediates.

In acid-mediated cationic cyclization, the conversion can be effected by using a mineral acid such as H at elevated temperature₂SO₄、H₃PO₄By treatment with an organic acid such as trifluoroacetic acid, BF in a solvent such as dichloromethane, 1, 2-dichloroethane or toluene at temperatures from 0 ℃ to room temperature₃·Et₂O (optionally with additives such as Et₃SiH), and processing.

In a stepwise process, the conversion may be carried out by reacting at from 0 ℃ to 50 ℃ in the presence of an organic base such as pyridine, triethylamine, N-diisopropylethylamine or N-methylmorpholine in an ethereal solvent such as diethyl ether, diethyl etherIn an alkane, THF, or TBME, or using an organic base as a solvent, by treating diol 12 with one equivalent of a sulfonyl chloride such as methanesulfonyl chloride or toluenesulfonyl chloride. Can be prepared by dissolving in an ether solvent such as diethyl ether or diethyl etherThe resulting sulfonate ester is converted to the protected bridged-morpholine 13 by treatment with a non-nucleophilic base such as sodium hydride, potassium tert-butoxide or potassium 2-methyl-2-butoxide in alkane, THF or TBME.

Preferred conditions are the Mitsunobu-type process: the diol 12 was treated with DIAD and triphenylphosphine in toluene at 0 ℃ and the reaction was continued at room temperature for 12 hours.

In a base-induced reaction, deprotection can be achieved by treatment with a base such as hydrazine, KOH, NaOH or Cs in a solvent such as methanol, ethanol, at elevated temperatures such as 90 ℃ to 150 ℃₂CO₃Treatment ofTo proceed with.

Preferred conditions are a base-induced reaction using KOH as base and MeOH as solvent in a sealed tube at 110 ℃ for 30 minutes.

Step E: the bridged-morpholines 14 can be protected by reaction with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate or cesium carbonate, in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an etheric solvent such as diethyl ether, diethyl etherIn alkane, THF or TBME.

Step F: coupling of iodide 15 to benzophenone imine can be carried out in the presence of a palladium or copper catalyst, a ligand and a base in a solvent such as a bisIn alkanes, DME, THF, toluene and DMSO, at elevated temperatures, for example using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris (dibenzylideneacetone) dipalladium (0), catalytic 2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP) and KO^tBu, in toluene, by microwave heating at 90 ℃ for 30 minutes.

Scheme 3

Step A: the nitration of phenylmorpholine 5 may be accomplished by treatment with fuming nitric acid or nitric acid, together with other organic and inorganic acids such as trifluoroacetic acid and sulfuric acid, at-40 ℃ to room temperature, optionally in a hydrocarbon or halogenated hydrocarbon solvent such as hexane, dichloromethane or 1, 2-dichloroethane. Alternatively, the reaction may be carried out by treating phenylmorpholine 5 with a nitrate salt such as potassium nitrate, sodium nitrate or cesium nitrate in other organic and inorganic acids such as trifluoroacetic acid and sulfuric acid at-40 ℃ to room temperature. 16-a and 16-b can be either separated by chromatography or as a mixture to the next step.

Preferred conditions are treatment with fuming nitric acid at 0-5 ℃.

And B: the bridged-morpholines 16-a, 16-b or mixtures thereof from step A can be protected by reaction with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate or cesium carbonate, in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane, or an etheric solvent such as diethyl ether, diethyl etherIn alkane, THF or TBME.

Preferred conditions are THF in the presence of potassium carbonate as a base at room temperature for 10 hours. 17-a and 17-b can be either separated by chromatography or as a mixture to the next step.

And C: the reduction of the nitro group of 17-a, 17-B or mixtures thereof from step B may be carried out by using a reducing agent such as SnCl₂、Na₂S₂O₄Or Zn powder, optionally treated with acetic acid or trifluoroacetic acid as an additive in MeOH or EtOH as a solvent at elevated temperature. Alternatively, the conversion may be carried out by hydrogenation with hydrogen at atmospheric or elevated pressure, or by using ammonium formate or cyclohexadiene as hydrogen source, with a catalyst such as PtO₂Pd-C or Raney nickel in a solvent such as MeOH, EtOH, H₂O, twoAlkane, THF, HOAc, EtOAc, CH₂Cl₂DMF or a mixture thereof. The anilines 9 and 18 can be separated at this stage by silica chromatography.

Preferred conditions are the use of SnCl₂As reducing agent, acetic acid was used as additive in EtOH at reflux temperature.

Scheme 4

Wherein X₁Is halogen, L¹Is a bond, -C (O) -, CH₂C(O)-、-CH₂-or-nhc (o) -; and R is¹Is phenyl or heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein phenyl and heteroaryl are optionally substituted with 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-a cycloalkyl group.

Step A: aryl halides 19 (including 7, wherein X₁I, and 15, wherein X₁Br) with arylamine (20-a), arylamide (20-b), arylurea (20-c) or arylmethylamine (20-d) can be prepared by using a palladium or copper catalyst, a ligand and a base in a solvent such as a bisAlkane, DMF, THF, toluene, DMF and DMSO, treatment at elevated temperature, for example using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris (dibenzylideneacetone) dipalladium (0), catalytic 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) and Cs₂CO₃In twoIn an alkane at 90 ℃ for 16 hours.

And B: removal of the BOC N-protecting group can be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂O, at 0-80 ℃.

Preferred conditions are CF₃COOH as acid in CH₂Cl₂At room temperature for 2 hours.

Scheme 5

Step A: amide formation of aniline 9 or 18 and carboxylic acid 22-a can be carried out by reacting aniline 9 or 18 and carboxylic acid 22-a 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-diisopropylethylamine or N-methylmorpholine in a solvent such as dichloromethane, 1, 2-dichloroethane, DMF, DMSO or mixtures comprising diethyl ether,IIAlkane, THF, DME or TBME in ether solvent.

Preferred conditions are HATU together with N, N-diisopropylethylamine in DMF at room temperature for 12 hours.

The urea formation of aniline 9 or 18 and isocyanate 22-b can be accomplished by reaction in a halogenated solvent such as dichloromethane, 1, 2-dichloroethane, chlorobenzene in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine.

Preferred conditions are triethylamine as base in dichloromethane at room temperature for 16 hours.

Scheme 6

Step A: aryl halides 19 (including 7, wherein X₁I, and 15, wherein X₁Br) with alkylamine (24) can be carried out using a palladium or copper catalyst, a ligand and a base in a solvent such as a bisIn alkanes, DMF, THF, toluene, DMF and DMSO, at elevated temperatures, for example using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris (dibenzylideneacetone) dipalladium (0), catalytic 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos), and Cs₂CO₃In twoIn an alkane at 90 ℃ for 16 hours.

Scheme 7

Step A: aryl halides 19 (including 7, wherein X₁I, and 15, wherein X₁Br) with an alkylcarboxylic acid (26) can be obtained by coupling 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-diisopropylethylamine or N-methylmorpholine, in a solvent such as dichloromethane, 1, 2-dichloroethane, DMF, DMSO or a solvent including diethyl ether, di-ethyl ether, di-N-methyl morpholineAlkane, THF, DME or TBME in ether solvent.

Scheme 8

Step A: the carbonylation of halide 19 may be carried out by using an alkyllithium reagent in an anhydrous solvent such as diethyl ether, diethyl etherLithiation in alkanes, THF, DME or TBME, followed by addition of CO₂And (5) realizing. Alternatively, this transformation can be achieved by coupling with Co in the presence of transition metal catalysts, such as Pd, Mo, Co, Cu catalysts, along with ligands and additives. The solvent can be selected from DMF, THF, diAlkane, DMSO, ethanol, and water.

Preferred conditions are lithiation with nBuLi at-78 ℃ in anhydrous THF, followed by drying the CO₂The reaction solution was bubbled.

And B: the coupling of the acid 27 to the amine 28 may be carried out by reacting 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-diisopropylethylamine or N-methylmorpholine in a solvent such as dichloromethane, 1, 2-dichloroethane, DMF, DMSO or a mixture comprising diethyl ether, or the likeEther solvent reaction of alkane, THF, DME or TBME.

Preferred conditions are HATU together with N, N-diisopropylethylamine in DMF at room temperature for 2 hours.

And C: removal of the BOC N-protecting group can be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂O, at 0-80 ℃.

Isolation and purification of Compounds

Isolation and purification of the compounds and intermediates described herein can be accomplished, if desired, by any suitable isolation 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 obtained by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures may 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 can also be separated using chiral HPLC.

Salts of the compounds of formula I

The compounds of formula I are basic and can be converted into the corresponding acid addition salts. The conversion is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as 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, etc., and the acid is added to a similar solvent. The temperature is maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.

Example 1

a) [ (2R, 4R) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanones

At-78 ℃ in N₂To (1R, 4R) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1] under atmosphere]Heptan-3-one (21.7g, prepared by the procedure reported in CAS: 444313-68-2, Tetrahedron, 2007, 63(32), 7523-7531) and N, O-dimethylhydroxylamine hydrochloride (11.6g, CAS: 6638-79-5) in anhydrous tetrahydrofuran (1.5L) was added phenylmagnesium bromide (133mL, 3M in diethyl ether, CAS: 100-58-3). The reaction was stirred at-70 ℃ for 10 hours. LCMS indicated reaction completion. Reacting with saturated NH₄Aqueous Cl (100ml) was quenched. The mixture was extracted with ethyl acetate (2 × 500 ml). The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. Flash chromatography (silica gel, petroleum ether: ethyl acetate volume ratio ═ 1: 1) afforded [ (2R, 4R) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]Phenyl-methanone (6.67g, 23% yield) as a white solid.

MS(ESI)：296.1([M+H]⁺)。

b) [ (2R, 4R) -4-hydroxy-2- [ (S) -hydroxy (phenyl) methyl]Pyrrolidin-1-yl radical]-phenyl-methanones

To [ (2R, 4R) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl group at 0 deg.C]-phenyl-methanones(6g) A solution in MeOH (200mL) was added NaBH in portions₄(3g) In that respect The reaction was stirred for 1.5h until TLC analysis indicated completion of the reaction. Acetone (10mL) was added to quench excess NaBH₄. The mixture was concentrated under reduced pressure. Adding saturated NH₄Aqueous Cl (100 mL). The mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 1: 2 petroleum ether/EtOAc by volume) to give [ (2R, 4R) -4-hydroxy-2- [ (S) -hydroxy (phenyl) methyl group]Pyrrolidin-1-yl radical]Phenyl-methanone (5.5g, 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]Hept-5-yl]Ketone

To [ (2R, 4R) -4-hydroxy-2- [ (S) -hydroxy (phenyl) methyl group at 0 deg.C]Pyrrolidin-1-yl radical]-phenyl-methanone (5.5g) and PPh₃(5.82g) to a mixture in toluene (100mL) was added diisopropyl azodicarboxylate (DIAD, 4.49g, CAS: 2446-83-5). The reaction was stirred at rt overnight. The mixture was concentrated under reduced pressure and 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 volume) to give phenyl- [ (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] phenyl]Hept-5-yl]Methanone (4.1g, 79% yield) as a white solid.

MS(ESI)：280.1([M+H]⁺)。

¹HNMR(CDCl₃，400MHz)：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 (Heptane)

To phenyl- [ (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] at 0 deg.C]Hept-5-yl]To a mixture of methanone (10g) in THF (200mL) was added LiAlH₄(5.3g)。The reaction was stirred at room temperature for 2 hours until LCMS indicated complete consumption of the starting material. Adding Na₂SO₄·10H₂O (10g) to quench excess LiAlH₄. The mixture was filtered. The filtrate was concentrated under reduced pressure and further dried 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 directly in the next step without purification. Ms (esi): 266.1([ M + H)]⁺)。

¹HNMR(CDCl₃，400MHz)：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 (Heptane)

To (1R, 3S, 4R) -5-benzyl-3-phenyl-2-oxa-5-azabicyclo [2.2.1] under nitrogen]To a solution of heptane (16g) in toluene (250ml) was added ClCOOCH dropwise₂CH₂Cl (17 g). The reaction mixture was heated under reflux for 16 hours until TLC indicated complete consumption of the starting material. The reaction was then cooled to room temperature. MeOH (5mL) was added and the reaction was stirred for one hour. The volatiles were removed under reduced pressure. By flash chromatography (silica gel, CH by volume)₂Cl₂MeOH ═ 10: 0 to 5: 1) to give (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [ 2.2.1)]Heptane (4.5g, 45% yield) as a yellow oil.

¹HNMR(CDCl₃，400MHz)：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 (Heptane)

(1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] in fuming nitric acid (15mL) at-20 deg.C]Heptane (1.4g) in CH₂Cl₂(1 mL). The reaction was stirred for 0.5 h. The mixture was poured into ice water. NaOH was added to adjust the 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, CH by volume)₂Cl₂MeOH 10: 0 to 5: 1) to give (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]A mixture of heptanes (1.25g, total yield 71.0%) as a yellow oil.

¹HNMR(CDCl₃，400MHz)：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) (1R, 3S, 4R) -3- (3-Nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester And (1R, 3S, 4R) -3- (4-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- (3-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1] S at room temperature]Heptane and (1R, 3S, 4R) -3- (4-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]To a mixture of heptane (1.1g) in THF (20mL) was added K₂CO₃(2.1g) and Boc₂O (1.3 g). The reaction was stirred for 16 hours until TLC analysis indicated complete consumption of the starting material. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with brine (20 ml). Subjecting the mixture to CH₂Cl₂(3 × 20 ml). The combined organic layers were passed over Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 10: 0 to 5: 1 by volume) to give (1R, 3S, 4R) -3- (3-nitrophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-carboxylic acid tert-butyl ester and (1R, 3S, 4R) -3- (4-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]]A mixture of tert-butyl heptane-5-carboxylate (1.45g, 91% total yield) was a white solid.

¹HNMR(CDCl₃，400MHz)：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) (1R, 3S, 4R) -3- (3-aminophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- (3-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester and (1R, 3S, 4R) -3- (4-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1]]To a mixture of tert-butyl heptane-5-carboxylate (1.2g) in ethanol (50mL) were added tin (II) chloride dihydrate (4.51g, CAS: 10025-69-1) and acetic acid (2.4 g). In N₂The reaction was stirred at 50 ℃ for 4 hours under atmosphere until TLC analysis indicated complete consumption of the starting material. The mixture was washed with saturated NaHCO₃Diluting with aqueous solution, and adding CH₂Cl₂Extracting with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative TLC (1: 1 petroleum ether/EtOAc by volume) to give (1R, 3S, 4R) -3- (3-aminophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (240mg, 20.6% yield) as a yellow solid.

MS(ESI)：291.0([M+H]⁺)，235.0([M-C₄H₈+H]⁺)，191.0([M-C₄H₈-CO₂+H]⁺)。

i) (1R, 3S, 4R) -3- [3- [ (3-chlorobenzoyl) amino]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1] Heptane-5-carboxylic acid tert-butyl ester

3-chlorobenzoic acid (38mg, CAS: 535-80-8), HATU (114mg, CAS: 148893-10-1) and DIPEA (0.17mL, CAS: 7087-68-5) in CH₂Cl₂The solution in (2mL) was stirred at room temperature for 30 min. (1R, 3S, 4R) -3- (3-aminophenyl) -2-oxa-5-azabicyclo [2.2.1] is added to the reaction mixture]Tert-butyl 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. Reacting the mixture with CH₂Cl₂(50mL) dilution.The solution is treated with NH₄Washed with aqueous Cl (50mL) and Na₂SO₄Dried and concentrated under reduced pressure. Further dried under high vacuum to give crude (1R, 3S, 4R) -3- [3- [ (3-chlorobenzoyl) amino group]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate as a brown solid.

j) 3-chloro-N- [3- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl]Phenyl radical]Benzamide derivatives

(ii) subjecting the crude (1R, 3S, 4R) -3- [3- [ (3-chlorobenzoyl) amino group from step (i)]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (as a brown solid) is dissolved in CH₂Cl₂(2mL) and trifluoroacetic acid (TFA, 0.5mL, CAS: 76-05-1). The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C18 column) to obtain 3-chloro-N- [3- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1]Hept-3-yl]Phenyl radical]Benzamide (18mg, 27% yield in two steps) was purified as a white solid.

MS：331.1({³⁷Cl}M+H)⁺，329.1([³⁵Cl}M+H)⁺。

¹H NMR (400MHz, methanol-d)⁴)：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

Analogously to example 1, inThe title compound was obtained 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

a) (1R, 3S, 4R) -3- [3- [ [4- (trifluoromethyl) phenyl ] methyl ester]Carbamoylamino]Phenyl radical]-2-oxa-5-aza Bicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- (3-aminophenyl) -2-oxa-5-azabicyclo [2.2.1] S at room temperature]Heptane-5-carboxylic acid tert-butyl ester (44mg) and Et₃N (23mg, CAS: 121-44-8) in CH₂Cl₂To the solution (1mL) was added 4- (trifluoromethyl) phenyl isocyanate (34mg, CAS: 1548-13-6). The reaction was stirred overnight. Reacting the mixture with CH₂Cl₂(20ml) diluted with NaHCO₃Washed with aqueous solution (5ml) over Na₂SO₄Dried and concentrated under reduced pressure. Further drying under high vacuum to obtain (1R, 3S, 4R) -3- [3- [ [4- (trifluoromethyl) phenyl group]Carbamoylamino]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (50mg, 70% yield) as a brown solid.

b)1- [3- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl]Phenyl radical]-3- [4- (trifluoromethyl) Radical) phenyl]Urea

To (1R, 3S, 4R) -3- [3- [ [4- (trifluoromethyl) phenyl ] from step (a)]Carbamoylamino]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (50mg) in CH₂Cl₂Solution in (2mL)To the solution was added TFA (0.5ml, CAS: 76-05-1). The reaction was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The crude mixture was passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C18 column) to obtain 1- [3- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [ 2.2.1)]Hept-3-yl]Phenyl radical]-3- [4- (trifluoromethyl) phenyl]Urea (10mg, 26% yield) as a white solid.

MS(ESI)：378.1([M+H]⁺)

¹H NMR: (methanol-d)⁴，400MHz)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

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). A white solid. Ms (esi): 346.1([{³⁷Cl}M+H]⁺)，344.1([{³⁵Cl}M+H]⁺)。

Example 5

Similar to the implementationExample 3 the title compound was obtained using 3-chlorophenyl isocyanate (CAS: 2909-38-8) instead of 4- (trifluoromethyl) phenyl isocyanate in step (a). 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

The title compound was prepared in step (e), example 1.

MS(ESI)：176.1([M+H]⁺)

Example 7

a) (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] at 0 deg.C]To a solution of heptane (3.85g) in THF (100mL) was added K₂CO₃(5.88g, CAS: 584-08-7) and Boc₂O (5.88g, CAS: 24424-99-5). The reaction was stirred at rt overnight. TLC analysis indicated the reaction was complete. 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 volume) to give (1R, 3S, 4R) -3-phenyl-2-oxa-5-aza-eBicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (5.9g, 98% yield) as a white solid.

¹H NMR(CDCl₃，400MHz)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) (1R, 3S, 4R) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

In N₂Under the atmosphere, (1R, 3S, 4R) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]]Heptane-5-carboxylic acid tert-butyl ester (1.1g), [ bis (trifluoroacetoxy) iodide]Benzene (2.1g, CAS: 2712-78-9), and iodine (1.1g, CAS: 7553-56-2) in CCl₄The solution in (10mL) was stirred at room temperature overnight. LC-MS analysis indicated over 90% conversion. The reaction mixture is treated with NaHSO₃Diluting with aqueous solution, and adding CH₂Cl₂Extracted and washed with brine. The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (C-18, MeCN/water 0.1% NH)₃) Purifying to obtain (1R, 3S, 4R) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (560mg, 35% yield) 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 [2.2.1] S]Hept-3-yl]Phenyl radical]Benzamide derivatives

In N₂Under the atmosphere, (1R, 3S, 4R) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (40mg), 4-chlorobenzamide (23mg, CAS: 619-56-7), tris (dibenzylideneacetone) dipalladium (0) (18mg, CAS: 51364-51-3), bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 10mg, CAS: 161265-03-8), and Cs₂CO₃(162mg, CAS: 534-17-8) in twoThe solution in alkane (1mL) was stirred at 90 ℃ overnight. TLC analysis indicated the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (C-18 column, H)₂0.1% NH in O₃MeCN) gave a crude intermediate as a brown oil. Dissolving the crude intermediate in CH₂Cl₂(2 mL). TFA (0.5mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to obtain 4-chloro-N- [4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [ 2.2.1%]Hept-3-yl]Phenyl radical]Benzamide (10mg, 30% yield in 2 steps) as a white solid. Ms (esi): 331.0([{³⁷Cl}M+H]⁺)，329.0([{³⁵Cl}M+H]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

a) [ (2S, 4S) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]-phenyl-methanones

(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).

To (1S, 4S) -5-benzoyl-2-oxa-5 at-70 ℃ in 10 hours under nitrogen-azabicyclo [2.2.1]Heptan-3-one (32g) and N, O-dimethylhydroxylamine hydrochloride (17g, CAS: 6638-79-5) in dry THF (2.0L) was added phenylmagnesium bromide (133mL, 3M in diethyl ether, CAS: 100-58-3). TLC analysis indicated the reaction was complete. Then the reaction is saturated with NH₄The Cl solution was quenched with water and extracted with EtOAc. The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc 1: 1 by volume) to give [ (2S, 4S) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]Phenyl-methanone (50g, 38% yield) as a white solid. Ms (esi): 296.2([ M + H)]⁺)

b) [ (2S, 4S) -4-hydroxy-2- [ (R) -hydroxy (phenyl) methyl]Pyrrolidin-1-yl radical]-phenyl-methanones

To [ (2S, 4S) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl group at 0 deg.C]-phenyl-methanone (50g) in MeOH (500mL) NaBH was added in portions₄(25g, CAS: 16940-66-2). The reaction mixture was stirred at 0 ℃ for 1.5 hours until LCMS analysis indicated the reaction was complete. Acetone was added to quench excess NaBH₄. Volatiles were removed under reduced pressure. Adding saturated NH₄Aqueous Cl solution. The mixture was extracted with EtOAc. The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 1: 2 petroleum ether/EtOAc by volume) to give [ (2S, 4S) -4-hydroxy-2- [ (R) -hydroxy (phenyl) methyl group]Pyrrolidin-1-yl radical]Phenyl-methanone (33g, 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]Hept-5-yl]Ketone

To [ (2S, 4S) -4-hydroxy-2- [ (R) -hydroxy (phenyl) methyl group at 0 deg.C]Pyrrolidin-1-yl radical]-phenyl-methanone (16g) and PPh₃(17g, CAS: 603-35-0) to a solution in dry toluene (200mL) was added diisopropyl azodicarboxylate (DIAD, 14g, CAS: 2446-83-5). The reaction was stirred at rt overnight. Volatiles were removed under reduced pressure. Dissolving the residueCleaved in tert-butyl methyl ether (MTBE, 200mL, 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 volume) to give phenyl- [ (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] phenyl]Hept-5-yl]Methanone (11.5g, yield: 77%) as a white solid. Ms (esi): 280.2([ M + H)]⁺)

¹H NMR(CDCl₃，400MHz)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-azabicyclo [2.2.1]Heptane (Heptane)

To phenyl- [ (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1] at 0 deg.C]Hept-5-yl]To a solution of methanone (3g) in anhydrous THF (30mL) was added LiAlH₄(1.7g, CAS: 16853-85-3). The reaction was stirred at room temperature for 2 hours. Adding solid Na₂SO₄·10H₂O (10g, CAS: 7727-73-3) 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 (3g, quantitative 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-azabicyclo [2.2.1]Heptane (Heptane)

To the crude (1S, 3R, 4S) -5-benzyl-3-phenyl-2-oxa-5-azabicyclo [2.2.1] from step (d)]To a solution of heptane (3g, 11mmol) in toluene (40ml) was added 2-chloroethyl chloroformate (3.2g, CAS: 627-11-2) dropwise. The reaction was heated at 110 ℃ under N₂Stir under atmosphere overnight. MeOH (20mL) was added and the reaction was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂∶MeOH＝10∶1，1％NH₃·H₂Adding O into mobile phase) to obtain(1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]Heptane (350mg, yield: 17%) as a yellow solid.

MS(ESI)：176.1([M+H]⁺)

¹HNMR(CDCl₃，400MHz)：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) (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]To a solution of heptane (10g) in anhydrous THF (150mL) was added K₂CO₃(24g) And Boc₂O (14g, CAS: 24424-99-5). The reaction was stirred at rt overnight. Volatiles were removed under reduced pressure. Saturated NaCl solution (100mL) was added. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petrol ether/EtOAc 20: 1 by volume) to give (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [ 2.2.1)]Tert-butyl heptane-5-carboxylate (4.2g, yield: 25%) as a yellow solid.

¹HNMR(CDCl₃，400MHz)：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) (1S, 3R, 4S) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1S, 3R, 4S) -3-phenyl-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (1.0g) in CCl₄(12mL) to the solution was added [ bis (trifluoroacetoxy) iodide]Benzene (1.88g, CAS: 2712-78-9) and iodine (1.0g, CAS: 7553-56-2). In N₂The reaction was stirred at room temperature under an atmosphere overnight. The mixture was diluted with chloroform (200 mL). The solution was treated with 5% NaHSO₃(2x50mL) and 10% aqueous NaCl (5x50 mL). Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, petrol ether/EtOAc 20: 1 by volume) to give (1S, 3R, 4S) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Tert-butyl heptane-5-carboxylate (600mg) as a brown oil.

MS(ESI)：345.8(M-C₄H₈+H)⁺，301.9(M-C₄H₈-CO₂+H)⁺。

h) 3-chloro-N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl]Phenyl radical]Benzamide derivatives

In N₂Under the atmosphere, (1S, 3R, 4S) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (40mg), 3-chlorobenzamide (22mg, CAS: 618-48-4), tris (dibenzylideneacetone) dipalladium (0) (18mg, CAS: 51364-51-3), bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 19mg, CAS: 161265-03-8), and Cs₂CO₃(163mg, CAS: 534-17-8) in twoThe solution in alkane (1mL) was stirred at 90 ℃ overnight. TLC analysis indicated the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (C-18 column, H)₂0.1% NH in O₃MeCN) gave a crude intermediate as a brown oil. Dissolving the crude intermediate in CH₂Cl₂(2 mL). TFA (0.5mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to obtain 3-chloro-N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Hept-3-yl]Phenyl radical]Benzamide (10mg, 30% yield in 2 steps) as a white solid. Ms (esi): 331.0([{³⁷Cl}M+H]⁺)，329.0([{³⁵Cl}M+H]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

The title compound was prepared in step (e), example 8.

MS(ESI)：176.1([M+H]⁺)

Example 10

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

Example 11

In N₂Under the atmosphere, (1R, 3S, 4R) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (40mg), 2-amino-5- (trifluoromethyl) pyridine (24mg, CAS: 74784-70-6), tris (dibenzylideneacetone) dipalladium (0) (18mg, CAS: 51364-51-3), bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 10mg, CAS: 161265-03-8), and Cs₂CO₃(162mg, CAS: 534-17-8) in twoThe solution in alkane (1mL) was stirred at 90 ℃ overnight. TLC analysis indicated the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (C-18 column, H)₂0.1% NH in O₃MeCN) gave a crude intermediate as a brown oil. Dissolving the crude intermediate in CH₂Cl₂(2 mL). TFA (0.5mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to give the title compound (12mg, 36% yield in 2 steps) as a yellow solid.

MS(ESI)：336.2([M+H]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

a)4- (cyclopropylmethoxy) benzamide

4- (Cyclopropylmethoxy) benzoic acid (384mg, CAS: 355391-05-8), HATU (836mg, CAS: 148893-10-1) and Et at room temperature₃N (606mg, CAS: 121-44-8) in DMF (2.0mL) was added NH in water₃(25% to 28%, 1.0 mL). The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was subjected to reverse phase chromatography (C-18 column, mobile phase: A, H)₂O; b, with 0.5% NH₃·H₂CH of O₃CN) to give 4- (cyclopropylmethoxy) benzamide as a white solid (275mg, 72% yield). Ms (esi): 192.1(M + H)⁺。

b)4- (cyclopropylmethoxy) -N- [4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl] Phenyl radical]Benzamide derivatives

The title compound was obtained in analogy to example 7, using 4- (cyclopropylmethoxy) benzamide instead of 4-chlorobenzamide in step (c). A white solid. Ms (esi): 365.1([ M + H)]⁺)。

Example 13

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). A white solid. Ms (esi): 340.2([ M + H)]⁺)。

Example 14

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

Example 15

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). A white solid. Ms (esi): 340.2([ M + H)]⁺)。

Example 16

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). A white solid. Ms (esi): 394.1([ M + H)]⁺)。

Example 17

The title compound was obtained in analogy to example 8, using 4-ethoxybenzamide (CAS: 55836-71-0) instead of 3-chlorobenzamide in step (h). A white solid. Ms (esi): 339.2([ M + H)]⁺)。

Example 18

a) 2-cyclopropylpyrimidine-5-carboxamides

2-Cyclopropylpyrimidine-5-carboxylic acid (328mg, CAS: 648423-79-4), HATU (836mg, CAS: 148893-10-1) and Et were added at room temperature₃N (606mg, CAS: 121-44-8) in DMF (2.0mL) was added NH in water₃(25% to 28%, 1.0 mL). The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was subjected to reverse phase chromatography (C-18 column, mobile phase: A, H)₂O; b, with 0.5% NH₃·H₂CH of O₃CN) to give 2-cyclopropylpyrimidine-5-carboxamide as a white solid (241mg, 74% yield). Ms (esi): 164.1(M + H)⁺。

b) 2-cyclopropyl-N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl]Phenyl radical]Pyrimidine as one kind of food Pyridine-5-carboxamides

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). A white solid. Ms (esi): 337.2([ M + H)]⁺)。

Example 19

In N₂Under the atmosphere, (1S, 3R, 4S) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (50mg), 2-amino-5- (trifluoromethyl) pyridine (80mg, CAS: 74784-70-6), tris (dibenzylideneacetone) dipalladium (0) (20mg, CAS: 51364-51-3), bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 20mg, CAS: 161265-03-8), and Cs₂CO₃(120mg, CAS: 534-17-8) in twoThe solution in alkane (3mL) was stirred at 90 ℃ overnight. TLC analysis indicated the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (C-18 column, H)₂0.1% NH in O₃MeCN) gave a crude intermediate as a brown oil. Dissolving the crude intermediate in CH₂Cl₂(2 mL). TFA (0.5mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to give the title compound (16mg, 32% yield in 2 steps) as a yellow solid.

MS(ESI)：336.1([M+H]⁺)。

Example 20

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. A white solid. Ms (esi): 304.0([{³⁷Cl}M+H]⁺)，302.0([{³⁵Cl}M+H]⁺)。

Example 21

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. A white solid. Ms (esi): 337.1([ M + H)]⁺)。

Example 22

The title compound was obtained in analogy to example 19, using 5-trifluoromethyl-2-aminopyrazine (CAS: 69650-38-2) instead of 2-amino-5- (trifluoromethyl) pyridine. A white solid. Ms (esi): 337.0([ M + H)]⁺)。

Example 23

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. A white solid. Ms (esi): 337.0([ M + H)]⁺)。

Example 24

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. A white solid. Ms (esi): 304.1([{³⁷Cl}M+H]⁺)，302.1([{³⁵Cl}M+H]⁺)。

Example 25

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). A white solid. Ms (esi): 364.1([ M + H)]⁺)。

Example 26

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. A white solid. Ms (esi): 364.1([ M + H)]⁺)。

Example 27

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. A white solid. Ms (esi): 394.2([ M + H)]⁺)。

Example 28

The title compound was obtained in analogy to example 11, using 4-ethoxybenzamide (CAS: 55836-71-0) instead of 2-amino-5- (trifluoromethyl) pyridine. A white solid. Ms (esi): 339.2([ M + H)]⁺)。

Example 29

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. A white solid. Ms (esi): 337.2([ M + H)]⁺)。

Example 30

In analogy to example 11, 5-trifluoromethyl-2-aminopyrazine (CAS: 69650-38-2) was used instead of 2-amino-5- (trifluoromethyl) pyri-dinePyridine to obtain the title compound. A white solid. Ms (esi): 337.1([ M + H)]⁺)。

Example 31

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. A white solid. Ms (esi): 337.2([ M + H)]⁺)。

Example 32

The title compound was obtained in analogy to example 8, using 4- (cyclopropylmethoxy) benzamide instead of 3-chlorobenzamide in step (h). A white solid. Ms (esi): 365.1([ M + H)]⁺)。

Example 33

In N₂Under the atmosphere, (1S, 3R, 4S) -3- (4-iodophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (40mg), 4-chlorophenyl urea (22mg, CAS: 140-38-5), tris (dibenzylideneacetone) dipalladium (0) (18mg, CAS: 51364-51-3), bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 19mg, CAS: 161265-03-8), and Cs₂CO₃(163mg, CAS: 534-17-8) in twoThe solution in alkane (1mL) was stirred at 90 ℃ overnight. TLC analysis indicated the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (C-18 column, H)₂0.1% NH in O₃MeCN) gave a crude intermediate as a brown oil. Dissolving the crude intermediate in CH₂Cl₂(2 mL). TFA (0.5mL, CAS: 76-05-1) was added. The solution was stirred at room temperature for one hour. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to give the title compound (4mg, 12% yield in 2 steps) as a white solid.

MS(ESI)：346.1([{³⁷Cl}M+H]⁺)，344.1([{³⁵Cl}M+H]⁺)。

Example 34

a) 2-ethylpyrimidine-5-carboxamides

To 2-ethylpyrimidine-5-carboxylic acid (304mg, CAS: 72790-16-0), HATU (836mg, CAS: 148893-10-1) andEt₃n (606mg, CAS: 121-44-8) in DMF (2.0mL) was added NH in water₃(25% to 28%, 1.0 mL). The reaction was stirred overnight. Volatiles were removed under reduced pressure. The mixture was subjected to reverse phase chromatography (C-18 column, mobile phase: A, H)₂O; b, with 0.5% NH₃·H₂CH of O₃CN) to give 2-ethylpyrimidine-5-carboxamide as a white solid (120mg, 40% yield). Ms (esi): 152.2(M + H)⁺。

b) 2-Ethyl-N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1] S]Hept-3-yl]Phenyl radical]Pyrimidine- 5-carboxamides

The title compound was obtained in analogy to example 8, using 2-ethylpyrimidine-5-carboxamide instead of 3-chlorobenzamide in step (h). A waxy solid. Ms (esi): 325.0([ M + H)]⁺)。

Example 35

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

To a solution of 1, 4-dibromobenzene (30g, CAS: 106-37-6) in anhydrous THF (500mL) was added dropwise a solution of n-butyllithium (2.5M in hexanes, 52mL, CAS: 109-72-8) at-78 ℃. Stirring was continued for 30 minutes. This solution was then slowly added to (1S, 4S) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1] at-78 deg.C]Heptan-3-one (25g) in dry THF (1.0L). The reaction was stirred for 30 minutes. Adding saturated NH₄Aqueous Cl (300mL) to quench the reaction. Volatiles were removed under reduced pressure. Dissolving the residue in CH₂Cl₂(1.0L). The organic layer was collected. Will be provided withCH for aqueous layer₂Cl₂(3 × 500 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 1: 3 by volume) to give [ (2S, 4S) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]- (4-bromophenyl) methanone (20g, 53mmol, yield: 41%) as a white solid.

MS(ESI)：375.9([{⁸¹Br}M+H]⁺)，373.9([{⁷⁹Br}M+H]⁺)。

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

To [ (2S, 4S) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl group at 0 deg.C]- (4-bromophenyl) methanone (20g, 53mmol, from step a) to a solution in MeOH (100mL) was added NaBH₄(8.1g, 213 mmol). The reaction mixture was stirred at 0 ℃ for 1.5 hours. Acetone was added to quench excess NaBH₄. Volatiles were removed under reduced pressure. Adding saturated NH₄Aqueous Cl solution. The mixture was extracted with EtOAc and over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 1: 1 by volume) to give [ (2S, 4S) -2- [ (R) - (4-bromophenyl) -hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]Phenyl-methanone (15g, 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] S]Hept-5-yl]-phenyl-methanones

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

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

To [ (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]]Hept-5-yl]To a solution of phenyl-methanone (10g) in MeOH (28mL) was added KOH (31 g). The reaction was stirred at reflux temperature for 30 minutes until TLC analysis indicated completion of the reaction. Volatiles were removed under reduced pressure. Dissolving the residue in CH₂Cl₂(200mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, MeOH: CH by volume)₂Cl₂1: 20) to yield (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane (6.3g, yield: 89%) as a clear oil.

MS(ESI)：256.0([{⁸¹Br}M+H]⁺)，254.0([{⁷⁹Br}M+H]⁺)。

¹H NMR(CDCl₃，400MHz)：7.44(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) (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]To a solution of heptane (6.3g) in THF (100mL) was added K₂CO₃(10.3g) 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. Dissolving the residue in CH₂Cl₂(200mL) and filtered. The filtrate was collected and concentrated under reduced pressure. The residue is led toPurification by flash chromatography (silica gel, 20: 1 by volume petroleum ether: ethyl acetate) afforded (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Tert-butyl heptane-5-carboxylate (4.0g, yield: 45%) as a white solid.

¹H NMR(CDCl₃，400MHz)：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]]Hept-3-yl]Phenyl radical]-2- (trifluoromethyl) Pyridin-4-amines

To 4-amino-2- (trifluoromethyl) pyridine (33mg, CAS: 147149-98-2) and (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]]Heptane-5-carboxylic acid tert-butyl ester (50mg) in bisCs was added to a solution in alkane (3mL)₂CO₃(136mg, CAS: 534-17-8), tris (dibenzylideneacetone) dipalladium (0) (20mg, CAS: 51364-51-3) and bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 20mg, CAS: 161265-03-8). The reaction was heated at 90 ℃ under N₂Stir under atmosphere overnight. Volatiles were removed under reduced pressure. Dissolving the residue in CH₂Cl₂(10mL) and filtered through a thin pad of silica. The filtrate was concentrated and dried under high vacuum to give crude (1S, 3R, 4S) -3- [4- [ [2- (trifluoromethyl) -4-pyridinyl]Amino group]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (40mg) as a brown oil, which was used directly in the next step.

To (1S, 3R, 4S) -3- [4- [ [2- (trifluoromethyl) -4-pyridinyl group]Amino group]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (40mg) in anhydrous CH₂Cl₂To a solution in (2mL) was added TFA (0.5mL, CAS: 76-05-1). The mixture was stirred at room temperature for 30 minutes. The volatiles were then removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: c with 0.1% TFAH₃CN, C-18 column) to obtain N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1]Hept-3-yl]Phenyl radical]-2- (trifluoromethyl) pyridin-4-amine (24mg, 34% yield over 2 steps) as a white solid. Ms (esi): 336.1([ M + H)]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

a) (1S, 3R, 4S) -3- [4- (diphenylmethyleneamino) phenyl]-2-oxa-5-azabicyclo [2.2.1]Heptane- 5-Carboxylic acid tert-butyl ester

To (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (1.0g), 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (BINAP, 200mg, CAS: 98327-87-8), tris (dibenzylideneacetone) dipalladium (0) (200mg, CAS: 51364-51-3) and sodium t-butoxide (806mg, CAS: 865-48-5) in dry toluene (10mL) was added benzophenone imine (610mg, CAS: 1013-88-3). Reaction mass was heated in a microwave at 90 ℃ to N₂Stirred under atmosphere for 30 minutes. LCMS indicated reaction completion. The mixture was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20mL) and over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 5: 1 by volume) to give (1S, 3R, 4S) -3- [4- (diphenylmethyleneamino) phenyl]-2-oxa-5-azabicyclo [2.2.1]Heptane (Heptane)Tert-butyl 5-carboxylate (1.15g, 89% yield) as a yellow solid. Ms (esi): 455.2([ M + H)]⁺)。

b) (1S, 3R, 4S) -3- (4-aminophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1S, 3R, 4S) -3- [4- (diphenylmethyleneamino) phenyl at 0 DEG C]-2-oxa-5-azabicyclo [2.2.1]To a solution of tert-butyl heptane-5-carboxylate (1.15g) in anhydrous MeOH (10mL) was added sodium acetate (802mg, CAS: 127-09-3) and hydroxylamine hydrochloride (348mg, CAS: 5470-11-1). The reaction was stirred at 0 ℃ for 30 minutes until TLC analysis indicated completion of the reaction. Subjecting the mixture to CH₂Cl₂Diluted (100mL) and saturated Na₂CO₃Aqueous (50mL) wash. Subjecting the organic layer to Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether: ethyl acetate 1: 1 by volume) to give (1S, 3R, 4S) -3- (4-aminophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Tert-butyl heptane-5-carboxylate (500mg, 68% yield) as a yellow solid.

MS(ESI)：291.2([M+H]⁺)。

¹H NMR(CDCl₃，400MHz)：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]]Hept-3-yl]Phenyl radical]-5- (trifluoromethyl) Pyridine-2-carboxamides

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

To crude (1S, 3R, 4S) -3- [4- [ [5- (trifluoromethyl) pyridine-2-carbonyl]Amino group]Phenyl radical]-2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (40mg) in anhydrous CH₂Cl₂To a solution in (2mL) was added TFA (0.5mL, CAS: 76-05-1). The mixture was stirred at room temperature for 30 minutes. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to obtain N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1]Hept-3-yl]Phenyl radical]-5- (trifluoromethyl) pyridine-2-carboxamide (6mg) as a white solid. Ms (esi): 455.2([ M + H)]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

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). A white solid. Ms (esi): 361.2([{³⁷Cl}M+H]⁺)，359.2([{³⁵Cl}M+H]⁺)。

Example 38

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). A white solid. Ms (esi): 317.1([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 39

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). A white solid. Ms (esi): 349.2([ M + H)]⁺)。

Example 40

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). A white solid. Ms (esi): 299.2([ M + H)]⁺)。

EXAMPLE 41

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

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). A white solid.

MS(ESI)：247.2([M+H]⁺)。

Example 42

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). A white solid. Ms (esi): 365.2([ M + H)]⁺)。

Example 43

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). A white solid. Ms (esi): 327.3([ M + H)]⁺)。

Example 44

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). A waxy solid. Ms (esi): 364.2([ M + H)]⁺)。

Example 45

a) 3-hydroxy-1H-pyrazole-5-carboxylic acid methyl ester

To a solution of hydrazine monohydrate (3.85g, CAS: 7803-57-8) in toluene (30mL) was added acetic acid (15mL) and dimethyl acetylenedicarboxylate (10g, CAS: 762-42-5). The reaction 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 3-hydroxy-1H-pyrazole-5-carboxylate (7.5g, 75% yield) as a white solid.

¹H NMR(DMSO-d⁶，400MHz)：12.81(1H)，10.03(1H)，5.96(1H)，3.77(3H)。

b) 3-ethoxy-1H-pyrazole-5-carboxylic acid methyl ester

To a solution of methyl 3-hydroxy-1H-pyrazole-5-carboxylate (4g) in DMF (25mL) was added K₂CO₃(5.83g) and iodoethane (4.8g, 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 (30mL) and Na₂SO₄Dried and concentrated under reduced pressure. Passing the crude product from CH₂Cl₂Purification by recrystallization (10ml) gave methyl 3-ethoxy-1H-pyrazole-5-carboxylate (2.2g, 46% yield) as a white solid.

¹H NMR(DMSO-d⁶，400MHz)：13.12(1H)，6.22(1H)，4.13～4.08(2H)，3.81～3.75(3H)，1.32～1.25(3H)。

c) 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylic acid methyl ester

To a solution of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (2.2g) in DMF (40mL) at 0 deg.C was added N-chlorosuccinimide (2.06g, CAS: 128-09-6). The reaction was warmed to 50 ℃ and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The mixture was poured into water. 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 methyl ester (1.65g, 63% yield) as a white solid.

¹H NMR(DMSO-d⁶，400MHz)：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

To a solution of 4-chloro-3-ethoxy-1H-pyrazole-5-carboxylic acid methyl ester (1.65g) in THF/MeOH (V/V ═ 1: 1, 30mL) was added 1M aqueous NaOH (16mL) with cooling in an ice bath. The reaction was stirred at reflux 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 (1.4g, 92% yield) as a white solid.

¹H NMR(DMSO-d⁶，400MHz)：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] S]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

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). A white solid. Ms (esi): 365.1([{³⁷Cl}M+H]⁺)，363.2([{³⁵Cl}M+H]⁺)。

Example 46

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). A white solid. Ms (esi): 335.2([{³⁷Cl}M+H]⁺)，333.2([{³⁵Cl}M+H]⁺)。

Example 47

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). A white solid. Ms (esi): 299.0([ M + H)]⁺)。

Example 48

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). A white solid. Ms (esi): 377.2([{³⁷Cl}M+H]⁺)，375.2([{³⁵Cl}M+H]⁺)。

Example 49

In analogy to example 36, 4-chloro-3-propyl-1H-pyrazole-5-carboxylic acid (c)CAS: 1340578-20-2) instead of 5- (trifluoromethyl) pyridine-2-carboxylic acid, the title compound was obtained. A white solid. Ms (esi): 363.2([{³⁷Cl}M+H]⁺)，361.2([{³⁵Cl}M+H]⁺)。

Example 50

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). A white solid. Ms (esi): 327.2([ M + H)]⁺)。

Example 51

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). A white solid. Ms (esi): 394.3([ M + H)]⁺)。

Example 52

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). A white solid. Ms (esi): 365.1([ M + H)]⁺)。

Example 53

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

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

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

To a solution of 1, 4-dibromobenzene (54.5g, CAS: 106-37-6) in anhydrous THF (1.0L) was added dropwise a solution of n-butyllithium (2.5M in hexanes, 91mL, CAS: 109-72-8) at-78 ℃. Stirring was continued for 30 minutes. Then theThe solution was slowly added to (1R, 4R) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1] at-78 deg.C]Heptan-3-one (50g) in dry THF (1.0L). The reaction was stirred for 30 minutes. Adding saturated NH₄Aqueous Cl (300mL) to quench the reaction. Volatiles were removed under reduced pressure. Dissolving the residue in CH₂Cl₂(1.0L). The organic layer was collected. The aqueous layer is replaced by CH₂Cl₂(3 × 500 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 5: 1 to 1: 3 by volume) to give [ (2R, 4R) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl]- (4-bromophenyl) methanone (30g, yield: 35%) as a white solid.

MS(ESI)：376.0([{⁸¹Br}M+H]⁺)，374.0([{⁷⁹Br}M+H]⁺)。

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

To [ (2R, 4R) -1-benzoyl-4-hydroxy-pyrrolidin-2-yl group at 0 deg.C]- (4-bromophenyl) methanone (33g) in MeOH (300mL) NaBH₄(13g) In that respect The reaction mixture was stirred at 0 ℃ for 1.5 hours. Acetone is added to quench excess NaBH₄. Volatiles were removed under reduced pressure. Adding saturated NH₄Aqueous Cl (200 mL). The mixture was extracted with EtOAc (3X500mL) over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 1: 2 by volume) to give [ (2R, 4R) -2- [ (S) - (4-bromophenyl) -hydroxy-methyl]-4-hydroxy-pyrrolidin-1-yl]Phenyl-methanone (25g, yield: 76%) as a white solid.

MS(ESI)：378.0([{⁸¹Br}M+H]⁺)，376.0([{⁷⁹Br}M+H]⁺)。

c) [ (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] S]Hept-5-yl]-phenyl-methanones

To the resulting [ (2R, 4R) -2- [ (S) - (4-bromophenyl) -hydroxy-methyl group at 0 deg.C]-4-hydroxy-pyrrolidin-1-yl]-phenyl-methanone (22g) and PPh₃(18g) To a solution in dry toluene (300mL) was added DIAD (14g, CAS: 2446-83-5). The mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was dissolved in tert-butyl methyl ether (600mL) 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 volume) to give [ (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]]Hept-5-yl]Phenyl-methanone (12g, 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 (Heptane)

To [ (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]]Hept-5-yl]To a solution of phenyl-methanone (12.5g) in MeOH (35mL) was added KOH (39 g). The reaction was stirred at reflux temperature for one hour until LCMS analysis indicated completion of the reaction. Volatiles were removed under reduced pressure. Dissolving the residue in CH₂Cl₂(200mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, MeOH: CH by volume)₂Cl₂1: 20 to 1: 5) to give (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane (7g, yield: 75%) as a clear oil.

MS(ESI)：256.0([{⁸¹Br}M+H]⁺)，254.0([{⁷⁹Br}M+H]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

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

To (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] at-78 deg.C]To a solution of tert-butyl heptane-5-carboxylate (800mg, 2.25mmol) in THF (20mL) was added a solution of n-butyllithium (2.5M in hexane, 1.2mL, 2.9mmol, CAS: 109-72-8). Stirring was continued for 30 minutes at-78 ℃. Drying the CO₂Bubble into the solution for 10 minutes. The solution was warmed to room temperature. Adding 1M HCl aqueous solution into the reaction solution to adjust the pH value to 4-5. Subjecting the mixture to CH₂Cl₂(3X 30 mL). The combined organic layers were passed over Na₂SO₄And (5) drying. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂(MeOH) 100/1-30/1) to obtain 4- [ (1S, 3R, 4S) -5-tert-butoxycarbonyl-2-oxa-5-azabicyclo [2.2.1]]Hept-3-yl]Benzoic acid (450mg, 62% yield) as a yellow solid.

¹H NMR(400MHz，CDCl₃)：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]Hept-3-yl]Benzamide derivatives

To 4- [ (1S, 3R, 4S) -5-tert-butoxycarbonyl-2-oxa-5-azabicyclo [2.2.1] e]Hept-3-yl]To a solution of benzoic acid (40mg, 0.125mmol) in DMF (1mL) were added HATU (52mg, 0.14mmol, CAS: 148893-10-1), DIPEA (49mg, 0.38mmol, CAS: 7087-68-5) and 4-chloroaniline(16mg, 0.125mmol, CAS: 106-47-8). The solution was stirred at room temperature overnight. Then the reaction mixture is treated with CH₂Cl₂(10mL) dilution. The solution was washed with brine (20mL) and Na₂SO₄Dried and concentrated under reduced pressure. Dissolving the residue in CH₂Cl₂(1mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: CH3CN, C-18 column with 0.1% TFA) to yield N- (4-chlorophenyl) -4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2.2.1]]Hept-3-yl]Benzamide (25mg, 61% yield) as a white solid.

¹H NMR (400MHz, methanol-d)⁴)：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

The title compound was obtained in analogy to example 55, using 4-bromoaniline (CAS: 106-40-1) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：374.9([{⁸¹Br}M+H]⁺)，372.9([{⁷⁹Br}M+H]⁺)。

Example 57

The title compound was obtained in analogy to example 55, using 4-fluoroaniline (CAS: 371-40-4) instead of 4-chloroaniline in step (b). A white solid. Ms (esi): 313.0([ M + H)]⁺)。

Example 58

The title compound was obtained in analogy to example 55, using 4-ethoxyaniline (CAS: 156-43-4) instead of 4-chloroaniline in step (b). A white solid. Ms (esi): 339.0([ M + H)]⁺)。

Example 59

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). A white solid. Ms (esi): 363.0([ M + H)]⁺)。

Example 60

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). A white solid.

MS(ESI)：332.1([{³⁷Cl}M+H]⁺)，330.1([{³⁵Cl}M+H]⁺)。

Example 61

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). A white solid. Ms (esi): 336.2([ M + H)]⁺)。

Example 62

The title compound was obtained in analogy to example 55, using 6-ethoxy-3-pyridylamine (CAS: 52025-34-0) in place of 4-chloroaniline in step (b). A white solid. Ms (esi): 340.2([ M + H)]⁺)。

Example 63

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). A white solid. Ms (esi): 377.1([ M + H)]⁺)。

Example 64

The title compound was obtained in analogy to example 55, using 4-chlorobenzylamine (CAS: 104-86-9) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：345.1([{³⁷Cl}M+H]⁺)，343.1([{³⁵Cl}M+H]⁺)。

Example 65

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). A white solid. Ms (esi): 263.1([ M + H)]⁺)。

Example 66

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). A white solid. Ms (esi): 331.1([ M + H)]⁺)。

Example 67

a) (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]To a solution of heptane (6.8g, 27mmol) in THF (150mL) was addedK₂CO₃(11g, 81mmol) and Boc₂O (7g, 32mmol, 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, 20: 1 petroleum ether: ethyl acetate by volume) to give (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] as]Tert-butyl heptane-5-carboxylate (4.0g, yield: 45%) as a white solid.

¹H NMR(CDCl₃，400MHz)：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) (1R, 3S, 4R) -3- [4- (diphenylmethyleneamino) phenyl]-2-oxa-5-azabicyclo [2.2.1]Heptane- 5-Carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (1.0g, 3mmol), 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (BINAP, 373mg, 0.6mmol, CAS: 98327-87-8), tris (dibenzylideneacetone) dipalladium (0) (275mg, 0.3mmol, CAS: 51364-51-3) and sodium tert-butoxide (873mg, 9mmol, CAS: 865-48-5) in dry toluene (10mL) was added benzophenone imine (652mg, 3.6mmol, CAS: 1013-88-3). The reaction was heated at 90 ℃ in a microwave under N₂Stirred under atmosphere for 30 minutes. LCMS indicated reaction completion. The mixture was cooled to room temperature, diluted with water (10mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20mL) and over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 10: 1 by volume) to give (1R, 3S, 4R) -3- [4- (diphenylmethyleneamino) phenyl]-2-oxa-5-azabicyclo [2.2.1]Tert-butyl heptane-5-carboxylate (1.1g, 81% yield) as a yellow solid.

MS(ESI)：455.2([M+H]⁺)。

c) (1R, 3S, 4R) -3- (4-aminobenzene)Yl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester

To (1R, 3S, 4R) -3- [4- (diphenylmethyleneamino) phenyl at 0 DEG C]-2-oxa-5-azabicyclo [2.2.1]To a solution of tert-butyl heptane-5-carboxylate (454mg, 1mmol) in anhydrous MeOH (5mL) was added sodium acetate (328mg, 4mmol, CAS: 127-09-3) and hydroxylamine hydrochloride (138mg, 2.0mmol, CAS: 5470-11-1). The reaction was stirred at 0 ℃ for 30 minutes until TLC analysis indicated completion of the reaction. Subjecting the mixture to CH₂Cl₂Diluted (100mL) and washed with aqueous NaOH (50 mL). Subjecting the organic layer to Na₂SO₄Dried 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 (1R, 3S, 4R) -3- (4-aminophenyl) -2-oxa-5-azabicyclo [ 2.2.1)]Tert-butyl heptane-5-carboxylate (200mg, 72% yield) as a yellow solid.

¹H NMR(CDCl₃，400MHz)：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]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

To a solution of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid (20mg, 0.129mmol, CAS: 957129-38-3) in anhydrous DMF (1mL) were added HATU (52mg, 0.129mmol, CAS: 148893-10-1) and DIPEA (26mg, 0.258mmol, CAS: 7087-68-5). The solution was stirred at room temperature for 30 minutes. Adding (1R, 3S, 4R) -3- (4-aminophenyl) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester (25mg, 0.086 mmol). The reaction was stirred at rt overnight. TLC analysis indicated the reaction was complete. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: with 0.3% NH₃·H₂CH of O₃CN, C-18 column) to obtain (1R, 3S, 4R) -3- [4- [ (3-ethyl-4-methyl-1H-pyrazole-5-carbonyl) amino]Phenyl radical]-2-oxa-5-nitrogenHetero-bicyclo [2.2.1]Heptane-5-carboxylic acid tert-butyl ester, as a white solid, was subsequently dissolved in anhydrous CH₂Cl₂(2mL) and TFA (1mL, CAS: 76-05-1). The mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue is passed through preparative HPLC (mobile phase A: H)₂O, B: with 0.5% NH₃·H₂CH of O₃CN, C-18 column) to obtain 3-ethyl-4-methyl-N- [4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [ 2.2.1%]Hept-3-yl]Phenyl radical]-1H-pyrazole-5-carboxamide (6mg, 21% over 2 steps) as a white solid. Ms (esi): 327.2([ M + H)]⁺)。

¹H NMR (methanol-d)⁴，400MHz)：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

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). A white solid. Ms (esi): 363.0([{³⁷Cl}M+H]⁺)，361.0([{³⁵Cl}M+H]⁺)。

Example 69

a) 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

At room temperature under N₂To a solution of sodium ethoxide (7.6g, 0.112mol, CAS: 141-52-6) in anhydrous ethanol (150ml) was added diethyl oxalate (16.4g, 0.112mol, CAS: 95-92-1) in portions under an atmosphere. After which ethyl cyclopropyl ketone was added. The mixture was stirred at 50 ℃ for 20 hours. The solution was cooled to room temperature. Acetic acid (9g, 0.15mmol) and hydrazine monohydrate (98% purity, 8.1g, 0.15mol, CAS: 7803-57-8). The reaction was stirred at 50 ℃ 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 (400mL) and washed with brine (40 mL). Subjecting the solution to Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, petroleum ether: ethyl acetate 20: 1 by volume) afforded the product, ethyl 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate (1g, 4.6% yield), as a white solid. Ms (esi): 195.1([ M + H)]⁺)。

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

To a solution of ethyl 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylate (1g, 5mmol) in ethanol/H₂To a solution in O (V/V5: 1, 12mL) was added NaOH (0.6g, 15 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and acidified with 2N HCl (20mL) to pH-2. Subjecting the mixture to CH₂Cl₂(2X50 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and concentrated under reduced pressure. Further drying under high vacuum gave 3-cyclopropyl-4-methyl-1H-pyrazole-5-carboxylic acid (250mg, 30% yield) as a white solid.

MS(ESI)：167.1([M+H]⁺)。

¹HNMR (methanol-d)⁴，400MHz)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] S]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

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). A white solid. Ms (esi): 339.0([ M + H)]⁺)。

Example 70

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). A white solid. Ms (esi): 345.2([ M + H)]⁺)。

Example 71

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). A white solid. Ms (esi): 364.1([ M + H)]⁺)。

Example 72

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). A white solid. Ms (esi): 364.1([ M + H)]⁺)。

Example 73

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). A white solid. Ms (esi): 331.1([ M + H)]⁺)。

Example 74

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). A white solid. Ms (esi): 325.1([ M + H)]⁺)。

Example 75

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). A white solid. Ms (esi): 327.2([ M + H)]⁺)。

Example 76

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). A white solid. Ms (esi): 349.1([{³⁷Cl}M+H]⁺)，347.1([{³⁵Cl}M+H]⁺)。

Example 77

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). A white solid. Ms (esi): 343.2([ M + H)]⁺)。

Example 78

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). A white solid. Ms (esi): 345.2([ M + H)]⁺)。

Example 79

In analogy to example 35, 2-amino-4- (2, 2, 2-trifluoroethoxy) was used in step (f)) Pyrimidine (CAS: 852921-89-2) instead of 4-amino-2- (trifluoromethyl) pyridine, the title compound was obtained. A white solid. Ms (esi): 367.1([ M + H)]⁺)。

Example 80

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). A white solid. Ms (esi): 367.1([ M + H)]⁺)。

Example 81

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). A white solid. Ms (esi): 365.1([ M + H)]⁺)。

Example 82

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). A white solid. Ms (esi): 361.1([{³⁷Cl}M+H]⁺)，359.1([{³⁵Cl}M+H]⁺)。

Example 83

In analogy to example 80, using (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] in a palladium-catalyzed coupling step]Replacement of (1S, 3R, 4S) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] with tert-butyl heptane-5-carboxylate]Tert-butyl heptane-5-carboxylate to yield the title compound. A white solid. Ms (esi): 367.2([ M + H)]⁺)。

Example 84

The title compound was obtained in analogy to example 36, using 4, 4, 4-trifluorobutanoic acid (CAS: 406-93-9) instead of 5- (trifluoromethyl) pyridine-2-carboxylic acid in step (c).A white solid. Ms (esi): 315.1([ M + H)]⁺)。

Example 85

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

To (1R, 3S, 4R) -3- (4-bromophenyl) -2-oxa-5-azabicyclo [2.2.1] at-78 deg.C]To a solution of tert-butyl heptane-5-carboxylate (800mg, 2.25mmol, prepared in example 67, step a) in THF (20mL) was added n-butyllithium (2.5M in hexane, 1.17mL, 2.93 mmol). Stirring was continued for 30 minutes. Drying the CO₂Bubble into solution for 10 min. The solution was warmed to room temperature. TLC analysis indicated complete consumption of starting material. Adding 1M HCl aqueous solution into the reaction solution to adjust the pH value to 4-5. Subjecting the mixture to CH₂Cl₂And (4) extracting. The combined organic layers were passed over Na₂SO₄Dried and concentrated under reduced pressure. The residue was diluted with petroleum ether (100mL) and stirred for 30 min. 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]]Hept-3-yl]Benzoic acid (300mg, 42% yield) as a yellow solid.

¹H NMR(400MHz，CDCl3)：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] compounds]Hept-3-yl]Phenyl radical]T-shirt Amides of carboxylic acids

To 4- [ (1R, 3S, 4R) -5-tert-butoxycarbonyl-2-oxa-5-azabicyclo [2.2.1] e]Hept-3-yl]To a solution of benzoic acid (40mg, 0.125mmol) in anhydrous DMF (1mL) was added HATU (52.4mg, 0.138mmol, CAS: 148893-10-1), diisopropylethylamine (48.6mg, 0.376mmol), and 4-chloroaniline (16mg, 0.125mmol, CAS: 106-47-8). The solution was stirred at room temperature overnight. The reaction solution was treated with CH₂Cl₂(10mL) dilution. The mixture was washed with brine (20mL) and Na₂SO₄Dried and concentrated under reduced pressure.

Dissolving the residue in CH₂Cl₂(1mL) 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 is passed through preparative HPLC (mobile phase A: H)₂O, B: CH with 0.1% TFA₃CN, C-18 column) to obtain 4, 4, 4-trifluoro-N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [ 2.2.1%]Hept-3-yl]Phenyl radical]Butyramide (20mg, 0.061mmol, 48% yield) as a white solid.

¹H NMR (400MHz, methanol-d)⁴)：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([{³⁷Cl}M+H]⁺)，329.0([{³⁵Cl}M+H]⁺)。

Example 86

The title compound was obtained in analogy to example 85, using 4-bromoaniline (CAS: 106-40-1) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：374.9([{⁸¹Br}M+H]⁺)，372.9([{⁷⁹Br}M+H]⁺)。

Example 87

The title compound was obtained in analogy to example 85, using 4-fluoroaniline (CAS: 371-40-4) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：313.0([M+H]⁺)。

Example 88

The title compound was obtained in analogy to example 85, using 4-ethoxyaniline (CAS: 156-43-4) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：339.0([M+H]⁺)。

Example 89

a) 5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of hydrazine monohydrate (44.8g, 0.894mol, CAS: 7803-57-8) in a mixture of toluene (300mL) and acetic acid (180mL) was added dimethyl acetylenedicarboxylate (100mL, 0.813mol, 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 (67.5g, 59% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：12.81(s，1H)，10.03(br，1H)，5.91(br，1H)，3.78(s，3H)。

b)5- (2, 2, 2-Trifluoroethoxy) -1H-pyrazole-3-carboxylic acid methyl ester

To a solution of methyl 5-hydroxy-1H-pyrazole-3-carboxylate (10g, 70.4mmol) in DMF (100ml) was added Cs₂CO₃(25g, 77.5mmol) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (16.3g, 70.4mmol, CAS: 6226-25-1). The solution was stirred at room temperature overnight. The mixture was then carefully poured into 500ml of ice water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give methyl 5- (2, 2, 2-trifluoroethoxy) -1H-pyrazole-3-carboxylate (12g, 76% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：13.41(s，1H)，6.73(s，1H)，4.86(m，2H)，3.84(s，3H)

c) 2-isopropyl-5- (2, 2, 2-trifluoroethoxy) pyrazole-3-carboxylic acid methyl ester

To methyl 5- (2, 2, 2-trifluoroethoxy) -1H-pyrazole-3-carboxylate (12.0g, 53.4mmol), Cs₂CO₃(52.0g, 161mmol) in DMF (100.0ml)2-bromopropane (7.2g, 56.0mmol, CAS: 75-26-3) was added in portions. The solution was stirred at room temperature overnight. The solution was then concentrated under reduced pressure and poured into water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give methyl 2-isopropyl-5- (2, 2, 2-trifluoroethoxy) pyrazole-3-carboxylate (10.3g, 74% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：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

A solution of methyl 2-isopropyl-5- (2, 2, 2-trifluoroethoxy) pyrazole-3-carboxylate (4.3g, 16.2mmol), NaOH (1.9g, 48.5mmol) in a mixture of MeOH/water (V/V ═ 3: 1, 50.0ml) was stirred at room temperature overnight. The pH of the solution was then adjusted to 4-5 with concentrated HCl (5ml) at 0 ℃. The solution was carefully poured into 500ml of ice water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give 2-isopropyl-5- (2, 2, 2-trifluoroethoxy) pyrazole-3-carboxylic acid (3.86g, 95% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：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] S]Hept-3-yl]Phenyl radical]-5- (2, 2, 2-trifluoroethoxy) pyrazole-3-carboxamide

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). A white solid. Ms (esi): 425.2([ M + H)]⁺)。

Example 90

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). A white solid. Ms (esi): 345.1([ M + H)]⁺)。

Example 91

The title compound was obtained in analogy to example 67, using 4, 4, 4-trifluorobutanoic acid (CAS: 406-93-9) instead of 5-ethyl-4-methyl-2H-pyrazole-3-carboxylic acid in step (d). A white solid. Ms (esi): 315.1([ M + H)]⁺)。

Example 92

a) 3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester

To a solution of EtONa (13.2g, 0.2mol, CAS: 141-52-6) in absolute ethanol (400mL) at 0-5 deg.C was added diethyl oxalate (29.2g, 0.2mol, CAS:95-92-1) and 2-hexanone (20g, 0.2mol, CAS: 591-78-6). The solution was warmed to 50 ℃ and stirring was continued overnight. The mixture was cooled to 0-5 ℃. Acetic acid (12g, 0.2mol) was added followed by hydrazine monohydrate (10g, 0.2mol, CAS: 7803-57-8). The mixture was stirred at 30 ℃ for 12 hours. Volatiles were removed under reduced pressure. The residue was taken up in saturated NaHCO₃Aqueous solution (500 mL). The mixture was extracted with ethyl acetate (1L). The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂MeOH 200/1-80/1) to give ethyl 3-butyl-1H-pyrazole-5-carboxylate (13g, 33% yield) as a yellow solid.

b) 3-butyl-4-fluoro-1H-pyrazole-5-carboxylic acid ethyl ester

To ethyl 3-butyl-1H-pyrazole-5-carboxylate (8.0g, 40.8mmol) in CH at 0 deg.C₃To a solution in CN (500mL) was added a fluorinating reagent (Selectfluor) (17.3g, 48.9mmol, CAS: 140681-55-6). The solution was then stirred at 70 ℃ for 15 hours. Volatiles were removed under reduced pressure. The residue was diluted with aqueous HCl (3N, 200mL) and CH₂Cl₂(500mL) was extracted. The organic layer was washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂MeOH 200/1-100/1) to give ethyl 3-butyl-4-fluoro-1H-pyrazole-5-carboxylate (1.4g, 16% yield) as a yellow oil.

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

To a solution of ethyl 3-butyl-4-fluoro-1H-pyrazole-5-carboxylate (1.4g, 6.53mmol) in THF/MeOH (20/20mL) at 0 deg.C was added 1M aqueous NaOH solution (13.1mL, 13.1 mmol). The solution was then 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 (10mL) to give 3-butyl-4-fluoro-1H-pyrazole-5-carboxylic acid (0.4g, 33% yield) as a yellow solid.

¹H NMR(400MHz，DMSO-d⁶)：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]Hept-3-yl]Phenyl radical]- 1H-pyrazole-5-carboxamides

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). A white solid.

¹H NMR (400MHz, methanol-d)⁴)：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

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

To a solution of ethyl 3-butyl-1H-pyrazole-5-carboxylate (5.0g, 25.5mmol) in THF/MeOH (30/30mL) at 0 deg.C was added aqueous 1M NaOH (51mL, 51 mmol). The solution was then refluxed for 3 hours. The reaction mixture was poured into water and acidified with concentrated HCl to about pH 1. 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 (50mL) to give 3-butyl-1H-pyrazole-5-carboxylic acid (2.0g, 47% yield) as a yellow solid.

¹H NMR(400MHz，DMSO-d⁶)：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] S]Hept-3-yl]Phenyl radical]-1H-pyridine Azole-5-carboxamides

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). A white solid. Ms (esi): 341.2([ M + H)]⁺)。

Example 94

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). A white solid.

MS(ESI)：332.1([{³⁷Cl}M+H]⁺)，330.1([{³⁵Cl}M+H]⁺)。

Example 95

The title compound was obtained in analogy to example 85, using 6-ethoxy-3-pyridylamine (CAS: 52025-34-0) instead of 4-chloroaniline in step (b). A white solid.

MS(ESI)：340.2([M+H]⁺)。

Example 96

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

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). A 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] hept-3-yl ] benzamide

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

a) 5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of hydrazine monohydrate (3.85g, 0.077mol, CAS: 7803-57-8) in toluene (30mL) was added acetic acid (15mL) and dimethyl acetylenedicarboxylate (10g, 0.07mol, 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 (7.5g, 75% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：12.81(s，1H)，10.04(br，1H)，5.96(br，1H)，3.77(s，3H)。

b) 5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of methyl 5-hydroxy-1H-pyrazole-3-carboxylate (4g, 28.17mmol) in DMF (25mL) was added K₂CO₃(5.83g, 42.2mmol) and CH₃CH₂I (4.8g, 31mmol, CAS: 75-03-6). The solution was stirred at room temperature for 15 hours. The mixture was then poured into water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30mL) and Na₂SO₄Dried and concentrated under reduced pressure. Passing the crude product from CH₂Cl₂Purification by recrystallization (10ml) gave methyl 5-ethoxy-1H-pyrazole-3-carboxylate (2.2g, 46% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：13.13(s，1H)，6.23(s，1H)，4.11(m，2H)，3.81(s，3H)，1.28(m，3H)。

c) 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of methyl 5-ethoxy-1H-pyrazole-3-carboxylate (2.2g, 12.94mmol) in DMF (40mL) at 0 deg.C was added N-chlorosuccinimide (2.06g, 15.5mmol, CAS: 128-09-6). The reaction was warmed to 50 ℃ and stirring was continued for 15 hours. Most of the volatiles were removed under reduced pressure. The residue was poured into water. 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 methyl ester (1.65g, 63% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：13.45(br，1H)，4.23(m，2H)，1.32(t，3H)。

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

To a solution of 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester (1.65g, 8.06mmol) in THF/MeOH (V/V ═ 1: 1, 30mL) at 0 ℃ was added 1M aqueous NaOH (16.1mL, 16.1 mmol). The solution was then refluxed for 3 hours. The reaction mixture was poured into water and acidified with concentrated HCl to pH-1. 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 (1.4g, 92% yield) as a white solid.

¹H NMR(400MHz，DMSO-d⁶)：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] S]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

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). A white solid.

¹H NMR (400MHz, methanol-d)⁴)：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

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). A white solid.

MS(ESI)：393.1([{⁸¹Br}M+H]⁺)，391.1([{⁷⁹Br}M+H]⁺)。

Example 100

a) 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester

To CH₃CH₂A solution of ONa (7g, 0.1mol) in absolute ethanol (150mL) was added diethyl oxalate (15g, 0.1mol, CAS: 95-92-1) and 4-methyl-2-pentanone (10g, 0.1mol, CAS: 108-10-1). The mixture was stirred at 50 ℃ for 20 hours. The reaction solution containing ethyl 6-methyl-2, 4-dioxo-heptanoate was used directly in the next step.

To the above solution of ethyl 6-methyl-2, 4-dioxo-heptanoate was added acetic acid (9g, 0.15mol) and hydrazine monohydrate (8.1g, 0.15mol, 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. Subjecting the organic layer to Na₂SO₄Dried, 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 volume) to give 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (13g, 68% yield).

MS(ESI)：197.2([M+H]⁺)。

b) 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester

To 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester (5.0g, 25.5mmol) in CH at 0 deg.C₃To a solution in CN (300mL) was added a fluorinating reagent (Selectfluor) (18.0g, 51.0mmol, CAS: 140681-55-6). The solution was stirred at 70 ℃ for 15 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with aqueous HCl (3N, 200mL) and CH₂Cl₂(100mL) was extracted. The organic layer was washed with brine (20mL) and Na₂SO₄Dried and concentrated under reduced pressure. By flash chromatography (silica gel, CH by volume)₂Cl₂MeOH 200/1-100/1) to give 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4g, 26% yield) as a yellow oil.

¹H NMR(400MHz，CDCl₃)：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

To a solution of 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4g, 6.54mmol) in THF/MeOH (V/V ═ 1: 1, 20mL) at 0 ℃ was added 1M aqueous NaOH (13.1mL, 13.1 mmol). The solution was then 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 (20mL) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (30mL) to give 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid (1.2g, 99% yield) as a yellow solid.

¹H NMR(400MHz，DMSO-d⁶)：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-isobutyl N- [4- [ (1R, 3S, 4R) -2-oxa-5-azabicyclo [2.2.1]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

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). A white solid. Ms (esi): 359.2([ M + H)]⁺)。

Example 101

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

To a solution of ethyl 5-isobutyl-1H-pyrazole-3-carboxylate (3g, 15.3mmol) in ethanol/water (V/V ═ 5: 1, 60mL) was added NaOH (1.8g, 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 × 100 mL). The combined organic layers were washed with brine (40mL) and Na₂SO₄Dried and concentrated under reduced pressure. Further drying under high vacuum gave 5-isobutyl-1H-pyrazole-3-carboxylic acid (2g, 80% yield) asA white solid.

¹H NMR (400MHz, methanol-d)⁴)：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] S]Hept-3-yl]Phenyl radical]-1H- Pyrazole-5-carboxamides

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). A 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] hept-3-yl ] phenyl ] -1H-pyrazole-5-carboxamide

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). A 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] hept-3-yl ] phenyl ] -1H-pyrazole-5-carboxamide

a) 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

To CH at 0 ℃₃CH₂To a solution of ONa (23g, 0.34mol) in anhydrous EtOH (500mL) was added diethyl oxalate (50g, 0.34mol, CAS: 95-92-1) and 3-methyl-2-butanone (29g, 0.34mol, CAS: 563-80-4). The solution was stirred at 50 ℃ overnight. The mixture was cooled to 0-5 ℃ and acetic acid (20.4g, 0.34mol) was added followed by hydrazine monohydrate (17.2g, 0.34mol, CAS: 7803-57-8). The mixture was stirred at 30 ℃ overnight and then cooled to room temperature. Volatiles were removed under reduced pressure. The residue was taken up in saturated NaHCO₃The aqueous solution (500mL) was diluted and extracted with ethyl acetate (1L). The organic layer was washed with brine and concentrated under reduced pressure to give the desired crude product. By flash chromatography (silica gel, CH by volume)₂Cl₂MeOH 200/1-80/1) to give crude 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (30g, 48% yield) as a yellow solid.

MS(ESI)：183.1([M+H]⁺)。

b) 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

To ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (5.0g, 0.027mmol) in CH at 0 deg.C₃To a solution in CN (300mL) was added a fluorinating reagent (Selectfluor) (12.65g, 35.67mmol, CAS: 140681-55-6). The solution was stirred at 70 ℃ for 15 hours and then cooled to room temperature. Volatiles were removed under reduced pressure. The residue was diluted with aqueous HCl (3N, 200mL) and CH₂Cl₂(100mLx 2). The organic layer was washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure. By flash chromatography (silica gel, CH by volume)₂Cl₂MeOH 200/1-100/1) to give ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylate (900mg, 17% yield) as a yellow oil.

MS(ESI)：201.1([M+H]⁺)。

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

To a solution of ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylate (900mg, 4.49mmol) in THF/MeOH (10/10mL) at 0 deg.C was added 1M aqueous NaOH (9mL, 8.98 mmol). The solution was then refluxed for 3 hours. The reaction solution was poured into water and acidified to pH-1 with concentrated HCl. The mixture was extracted with EtOAc (100mL x 2). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (10mL) to give 4-fluoro-5-isopropyl-1H-pyrazole-3-carboxylic acid (450mg, 58% yield) as a white solid.

¹H NMR (400MHz, methanol-d)⁴)：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]Hept-3-yl]Benzene and its derivatives Base of]-1H-pyrazole-5-carboxamide

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). A white solid.

MS(ESI)：345.2([M+H]⁺)。

Example 104

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

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

To 2-bromopyridine (3.64g, 0.023mol, CAS: 109-04-6) in THF (60 ℃ C.) at-70 ℃mL) was added n-BuLi (2.5M, 9.2mL, 0.023 mol). The mixture was stirred for 30 minutes. The above solution was then added dropwise to (1R, 4R) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1] at-70 deg.C]Heptan-3-one (5g, 0.023mol, CAS: 444313-68-2) in THF (100 mL). The reaction was stirred for 30 minutes. Then by adding NH₄The reaction solution was quenched with aqueous Cl (100 mL). Subjecting the mixture to CH₂Cl₂(100mL × 2) and washed with brine (50mL × 2) over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂(MeOH) 200/1-50/1) to give [ (2R, 4R) -4-hydroxy-2- (pyridine-2-carbonyl) pyrrolidin-1-yl group]Phenyl-methanone (1.0g, 15% 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 radical]-phenyl-methanones

To [ (2R, 4R) -4-hydroxy-2- (pyridine-2-carbonyl) pyrrolidin-1-yl group at 0 deg.C]To a solution of-phenyl-methanone (1.0g, 3.35mmol) in MeOH (20mL) was added NaBH₄(255mg, 6.7 mol). The solution was stirred at room temperature for 2 hours. The reaction solution was then poured into water (50 mL). Subjecting the mixture to CH₂Cl₂(50mL × 2) the combined organic layers were washed with brine (50mL × 2) and Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography (CH by volume)₂Cl₂(iii) MeOH 200/1-50/1) to give [ (2R, 4R) -4-hydroxy-2- [ (R) -hydroxy (2-pyridyl) methyl group]Pyrrolidin-1-yl radical]Phenyl-methanone (720mg, 72% yield) as a white solid.

MS(ESI)：299.0([M+H]⁺)。

c) Phenyl- [ (1R, 3R, 4R) -3- (2-pyridyl) -2-oxa-5-azabicyclo [2.2.1]Hept-5-yl]Ketone

To [ (2R, 4R) -4-hydroxy-2- [ (R) -hydroxy (2-pyrazine) at 0 DEG CPyridyl) methyl group]Pyrrolidin-1-yl radical]To a solution of-phenyl-methanone (0.72g, 2.41mmol) in toluene (20mL) was added PPh₃(758mg, 2.89mol) and diisopropyl azodicarboxylate (584mg, 2.89mmol, CAS: 2446-83-5). The solution was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH by volume)₂Cl₂Ethyl acetate 10/1-1/1) to give phenyl- [ (1R, 3R, 4R) -3- (2-pyridyl) -2-oxa-5-azabicyclo [ 2.2.1)]Hept-5-yl]Methanone (350mg, 52% yield) as a yellow solid.

MS(ESI)：281.1([M+H]⁺)。

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

To phenyl- [ (1R, 3R, 4R) -3- (2-pyridyl) -2-oxa-5-azabicyclo [2.2.1]Hept-5-yl]To a solution of methanone (0.75g, 2.67mmol) in MeOH (3mL) was added KOH (3g, 53.5 mmol). The mixture was stirred at reflux temperature for 1 h. The reaction mixture was cooled to room temperature and diluted with MeOH (50 mL). Concentrated HCl was added to adjust the pH to 7. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase A: with 0.5% NH)₃·H₂H of O₂O，B：CH₃CN, C18 column) to obtain (1R, 3R, 4R) -3- (2-pyridyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane (10mg, 2.1% yield) as a white solid.

¹H NMR (400MHz, methanol-d)⁴)：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-pyridinyl) -2-oxa-5-azabicyclo [2.2.1] heptane

In analogy to example 104, in step (a) was used (1S, 4S) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1]]Hept-3-one (CAS: 31560-25-5) instead of (1R, 4R) -5-benzoyl-2-oxa-5-azabicyclo [2.2.1]]Hept-3-one to obtain the title compound. Ms (esi): 177.1([ M + H)]⁺)。

Example 106

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

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 (400MHz, methanol-d)⁴)：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

For the construction of expression plasmids, essentially as described by Lindemann et al [14]The coding sequence for human, rat and mouse TAAR1 was amplified from genomic DNA as described. At 1.5mM Mg²⁺The purified P was purified using the extended High Fidelity PCR System (Roche Diagnostics) according to the manufacturer's instructionsThe CR product was cloned into pCR2.1-TOPO cloning vector (Invitrogen). The PCR products were subcloned into pIRESneo2 vector (BD Clontech, Palo Alto, California) and the expression vectors were sequence verified prior to introduction into cell lines.

HEK293 cells (ATCC # CRL-1573) were cultured essentially as described in Lindemann et al (2005). To generate stably transfected cell lines, HEK293 cells were transfected with pIRESneo2 expression plasmid containing the TAAR coding sequence (described above) with Lipofectamine 2000(Invitrogen) according to the manufacturer's instructions and 24 hours post transfection the medium was supplemented with 1mg/ml G418(Sigma, Buchs, switzerland). After a culture period of about 10d, the clones were isolated, expanded and tested for reactivity to trace amines (all compounds purchased from Sigma) with the cAMP Biotrak Enzyme Immunoassay (EIA) system (Amersham) according to the non-acetylated EIA program provided by the manufacturer. Will show stable EC for a culture period of 15 passages₅₀The monoclonal cell line of (3) was used in all subsequent studies.

Radioligand binding assay for rat TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing rat TAAR1 were subjected to inactivation by heat at 56 ℃ for 30min in DMEM high glucose medium containing fetal bovine serum (10%, heat-inactivated at 56 ℃), penicillin/streptomycin (1%), and 375. mu.g/ml geneticin (Gibco) at 37 ℃ and 5% CO₂And (4) maintaining. Cells were released from flasks using trypsin/EDTA, harvested, and frozen-cold PBS (Ca free)² ⁺And Mg²⁺) Washed twice, precipitated at 1' 000rpm for 5min at 4 ℃, frozen and stored at-80 ℃. The frozen pellet was suspended in 20ml HEPES-NaOH containing 10mM EDTA (20mM, pH 7.4) and homogenized with Polytron (PT 6000, Kinematica) at 14' 000rpm for 20 s. The homogenate was centrifuged at 48' 000x g for 30min at 4 ℃. Thereafter, the supernatant was removed and discarded, and the pellet was resuspended in 20ml HEPES-NaOH (20mM, pH 7.4) containing 0.1mM EDTA using Polytron (at 14' 000rpm, 20 s). This procedure was repeated and the final pellet was resuspended in a suspension containing0.1mM EDTA in HEPES-NaOH, and homogenized using Polytron. Typically, 2ml aliquots of the membrane fraction were stored at-80 ℃. For each new membrane batch, the dissociation constant (K) was determined by saturation curve_d). TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamine (described in WO 2008/098857) with calculated K_dEquivalent concentrations, which are typically about 2.3nM, are used, resulting in about 0.2% binding of the radioligand and about 85% specific binding of the total binding. Non-specific binding is defined as binding in the presence of 10. mu.M unlabeled ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Amount of oxazol-2-ylamine. All compounds were tested in duplicate at a wide range of concentrations (10pM to 10 μ M). Test compounds (20. mu.l/well) were transferred to a 96-well plate (TreffLab) and 180. mu.l of MgCl containing was added₂(10mM) and CaCl₂(2mM) HEPES-NaOH (20mM, pH 7.4) (binding buffer), 300. mu.l in nM concentration 3.3x K_dOf a radioactive ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine and 500. mu.l of membrane (resuspended at 50. mu.g protein/ml). The 96 deep well plate was incubated at 4 ℃ for 1 hr. The incubation was terminated by rapid filtration through a Unifilter-96 plate (packard Instrument Company) and glass filter GF/C (Perkin Elmer) pre-soaked in polyethyleneimine (0.3%) for 1hr and washed 3 times with 1ml cold binding buffer. After addition of 45. mu.l Microscint 40(PerkinElmer), the Unifilter-96 plates were sealed and the radioactivity was counted after 1hr using a TopCount microplate scintillation counter (Packard Instrument Company).

Radioligand binding assay against mouse TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing mouse TAAR1 were cultured in DMEM high glucose medium containing fetal bovine serum (10%, heat-inactivated at 56 ℃ for 30min), penicillin/streptomycin (1%), and 375. mu.g/ml Geneticin (Gibco) at 37 ℃ and 5% CO₂And (4) maintaining. Cells were released from flasks using trypsin/EDTA, harvested, and frozen-cold PBS (Ca free)²⁺And Mg²⁺) Washed twice, precipitated at 1' 000rpm for 5min at 4 ℃, frozen and stored at-80 ℃. The frozen pellet was suspended in 20ml HEPES-NaOH containing 10mM EDTA (20mM, pH 7.4) and homogenized with Polytron (PT 6000, Kinematica) at 14' 000rpm for 20 s. The homogenate was centrifuged at 48' 000x g for 30min at 4 ℃. Thereafter, the supernatant was removed and discarded, and the pellet was resuspended in 20ml HEPES-NaOH (20mM, pH 7.4) containing 0.1mM EDTA using Polytron (at 14' 000rpm, 20 s). This procedure was repeated and the final pellet was resuspended in HEPES-NaOH containing 0.1mM EDTA and homogenized using Polytron. Typically, 2ml aliquots of the membrane fraction were stored at-80 ℃. For each new membrane batch, the dissociation constant (K) was determined by saturation curve_d). TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamine (described in WO 2008/098857) with calculated K_dEquivalent concentrations, which are typically about 0.7nM, are used, resulting in about 0.5% binding of the radioligand and about 70% specific binding of the total binding. Non-specific binding is defined as binding in the presence of 10. mu.M unlabeled ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Amount of oxazol-2-ylamine. All compounds were tested in duplicate at a wide range of concentrations (10pM to 10 μ M). Test compounds (20. mu.l/well) were transferred to a 96-deep well plate (TreffLab) and 180. mu.l of MgCl containing was added₂(10mM) and CaCl₂(2mM) HEPES-NaOH (20mM, pH 7.4) (binding buffer), 300. mu.l in nM concentration 3.3x K_dOf a radioactive ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine and 500. mu.l of membrane (resuspended at 60. mu.g protein/ml). The 96 deep well plate was incubated at 4 ℃ for 1 hr. The incubation was terminated by rapid filtration through a Unifilter-96 plate (packard Instrument Company) and glass filter GF/C (Perkin Elmer) pre-soaked in polyethyleneimine (0.3%) for 1hr and washed 3 times with 1ml cold binding buffer. After addition of 45. mu.l Microscint 40(PerkinElmer), the Unifilter-96 plates were sealed and the radioactivity was counted after 1hr using a TopCount microplate scintillation counter (Packard Instrument Company).

The compounds show K to TAAR1 in mice or rats as shown in the table below_iValues (in μ M).

The compounds of formula I and pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I may be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as those carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as are processes for their preparation, which comprise bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The most preferred indications according to the invention are those comprising disorders of the central nervous system, such as depression, psychosis, parkinson's disease, anxiety disorders, Attention Deficit Hyperactivity Disorder (ADHD) and the treatment or prevention of diabetes.

The dosage can vary within wide limits and should of course be adjusted in each particular case to the individual requirements. In the case of oral administration, the dosage for adults may vary within the following ranges: from about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses and, in addition, may exceed the upper limit when it is deemed necessary.

Tablet formulation (Wet granulation)

Preparation procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add item 5 and mix for three minutes; pressing on a suitable press.

Capsule preparation

Preparation procedure

1. Items 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Filling into suitable capsules.

Claims

1. A compound of formula I

Wherein

R¹is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogenOr lower alkyl substituted by halogen or

Is phenyl or heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl, and wherein phenyl and heteroaryl are optionally substituted with 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-a cycloalkyl group;

x is CH or N;

or a pharmaceutically suitable acid addition salt, all racemic mixtures, all their corresponding enantiomers and/or optical isomers thereof.

2. A compound of formula I according to claim 1, wherein R¹Is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen or lower alkyl substituted by halogen and L is as described in claim 1.

3. A compound of formula I according to claim 2, which is

(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] hept-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

(1R, 3R, 4R) -3- (2-pyridinyl) -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 R¹Is phenyl, optionally substituted with 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 in claim 1.

5. A compound of formula I according to claim 4, which is

6. A compound of formula I according to claim 1, wherein R¹Is pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl, optionally substituted with 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 in claim 1.

7. A compound of formula I according to claim 6, which is

N- [4- [ (1S, 3R, 4S) -2-oxa-5-azabicyclo [2-2.1] hept-3-yl ] phenyl ] -2- (trifluoromethyl) pyrimidin-4-amine

8. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 7, which process comprises

a) Cleaving the N-Protecting Group (PG) from a compound of the formula

To give a compound of the formula

Wherein PG is an N-protecting group selected from the group consisting of-C (O) O-t-Butyl (BOC) and the other definitions are as described in claim 1, and,

9. A compound according to any one of claims 1-7, when manufactured according to a process of claim 8.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier and/or adjuvant.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier and/or adjuvant for 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.

12. A compound according to any one of claims 1-7 for use as therapeutically active substance.

13. A compound according to any one of claims 1-7 for use as therapeutically active substance 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.

14. The use of a compound according to any one of claims 1-7 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of depression, anxiety disorders, bipolar disorder, Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, parkinson's disease, neurodegenerative disorders, alzheimer's disease, epilepsy, migraine, 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.

15. The invention as herein before described.