HK1172020A

HK1172020A - Substituted benzamide derivatives

Info

Publication number: HK1172020A
Application number: HK12112820.7A
Authority: HK
Inventors: 卡特里．格勒布科茨宾登; 罗杰．诺克罗斯; 菲利普．普夫利格
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2009-12-22
Filing date: 2010-12-17
Publication date: 2013-04-12

Description

Substituted benzamide derivatives

The invention relates to compounds of formula I

Wherein

R is hydrogen or lower alkyl;

R¹is- (CH)₂)_n-(O)_o-heterocycloalkyl or-C (O) -heterocycloalkyl, wherein heterocycloalkyl is optionally substituted by lower alkyl, hydroxy, halogen or by- (CH)₂)_p-aryl substitution;

n is 0, 1 or 2;

o is 0 or 1;

p is 0, 1 or 2;

R²is CF₃Cycloalkyl, optionally substituted by lower alkoxy or halogen, or is indan-2-yl, or is heterocycloalkyl, optionally substituted by heteroaryl,

or is aryl or heteroaryl, wherein the aromatic ring is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, halogen, heteroaryl, hydroxy, CF₃，OCF₃，OCH₂CF₃，OCH₂-cycloalkyl, OCH₂C(CH₂OH)(CH₂Cl)(CH₃) S-lower alkyl, lower alkoxy, CH₂-lower alkoxy, lower alkynyl or cyano, or optionally substituted by-C (O) -phenyl, -O-CH₂-phenyl, phenyl or-CH₂-phenyl substituted and wherein the phenyl ring may be optionally substituted by halogen, -C (O) -lower alkyl, -C (O) OH or-C (O) O-lower alkyl,

or the aromatic ring is optionally substituted with: heterocycloalkyl, OCH₂-oxetan-3-yl or O-tetrahydropyran-4-yl, optionally substituted by lower alkyl;

x is a bond, -NR', -CH₂NH-，-CHR”-，-(CHR”)_q-O-，-O-(CHR”)_q-or- (CH)₂)₂-；

Y is a bond or-CH₂-；

R' is hydrogen or lower alkyl,

r' is hydrogen, lower alkyl, CF₃A lower alkoxy group,

q is 0, 1, 2 or 3; or a pharmaceutically suitable acid addition salt thereof.

The present invention includes all racemic mixtures, all of their corresponding enantiomers and/or optical isomers. Furthermore, the invention also encompasses all tautomeric forms of the compounds of the formula I.

R¹The preferred position on the phenyl ring is the para position.

It has now been found that the compounds of formula I have a good affinity for the Trace Amine Associated Receptors (TAARs), especially TAAR 1. The compounds may be used in the treatment of: depression, anxiety disorders, bipolar disorder, Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Some of the physiological effects 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 for the treatment of 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 present 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 systems [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 to be 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 system [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 in contiguous positions 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 G α. Dysregulation of TA has been shown to contribute to the etiology of a variety of diseases such as depression, psychotic disorders, attention deficit hyperactivity disorder, substance abuse, parkinson's disease, migraine, eating disorders, and metabolic disorders, and thus TAAR1 ligands have a high potential for treatment of these diseases.

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

The references used are:

1 Deutch, a.y. and Roth, r.h. (1999) neuro metrics, in fundamental neuroscience (2 nd edition) (edited by zigbee, m.j., Bloom, F.E, Landis, s.c., Roberts, j.l and Squire, L.R), p.193-234, Academic Press;

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 AndGABA 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 attation-determination/superactivity recorder: the search for endo-xenotypies. 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 annular Meeting of the American College of neuropsychoparamology, San Juan, Puerto Rico ] (1976);

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

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

9 Premont, R.T., et al (2001) Following the trace of used 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 brand, 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) comprehensive effects of amphetamine, phenylethylamine and related drugs on dopamin efflux, dopamin up and macrobinding.j. pharmacol. exp. ther.245, 199-210;

14 Lindemann, L. et al (2005) Trace amine associated receivers for measuring and functional disorders of novel protein-coupled receivers. 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, psychotic disorders, parkinson's disease, diabetes, anxiety and Attention Deficit Hyperactivity Disorder (ADHD).

As used herein, the term "lower alkyl" denotes a saturated straight or branched chain group containing 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.

As used herein, the term "lower alkyl substituted by halogen" denotes an alkyl group as defined above wherein at least one hydrogen atom is replaced by halogen, e.g. CF₃、CHF₂、CH₂F、CH₂CF₃、CH₂CH₂CF₃、CH₂CF₂CF₃And the like.

As used herein, the term "lower alkoxy substituted by halogen" denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom and wherein at least one hydrogen atom is replaced by halogen.

The term "alkynyl" denotes a straight or branched chain hydrocarbon residue containing a triple bond and up to 7, preferably up to 4 carbon atoms, e.g. ethynyl or 2-propynyl.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "cycloalkyl" is an alkylene ring containing from 3 to 6 carbon ring atoms.

The term "aryl" relates to an aromatic carbocyclic ring such as to a phenyl or naphthyl ring, preferably a benzene ring.

The term "heteroaryl" refers to an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulfur, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, iso-thienylAzolyl group,Azolyl group,Oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indanyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoisothiazolylAzolyl, benzisoylOxazolyl, quinolinyl, and isoquinolinyl. Preferred heteroaryl groups are pyridyl, pyrazolyl, pyrimidinyl, benzimidazolyl, quinolinyl and isoquinolinyl.

The term "heterocycloalkyl" refers to a non-aromatic 5 to 7 membered monocyclic ring which may contain 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulfur, such as piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, [1.4] oxazepanyl, or thiomorpholinyl.

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.

One embodiment of the invention are compounds of formula I wherein X is NR 'and R' is hydrogen, for example, the following compounds:

(RS) -1- (4-butyl-2-methyl-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

1- (3, 4-dichloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl ] -urea

(RS) -1- (3, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (4-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (2, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (3-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (4-pyrrolidin-3-yl-phenyl) -3- (4-trifluoromethyl-phenyl) -urea

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (6-chloro-pyridin-3-yl) -3- (4-piperidin-3-yl-phenyl) -urea

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-piperidin-3-yl-phenyl) -urea

(RS) -1- (5-chloro-pyridin-2-yl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -urea

(RS) -1- (4-chloro-phenyl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -urea

(RS) -1- (4-chloro-phenyl) -3- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea

(RS) -1- (4-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-p-tolylurea

(RS) -1- (6-Chloropyridin-3-yl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (3-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-m-tolylurea

(RS) -1- (2-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4-methylbenzyl) -3- (4- (morpholin-2-yl) phenyl) urea

(R) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea or

(S) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea.

A further embodiment of the invention are compounds, wherein X is a bond, for example,

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -4-trifluoromethyl-benzamide

(RS) -2, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -3-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- [4- (1-methyl-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (1-ethyl-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxy) -phenyl ] -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -6-chloro-pyridine-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-ethoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-propyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-ethynyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-cyano-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

4-chloro-N- (4-piperidin-4-yl-phenyl) -benzamides

(RS) -4-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide

4-chloro-N- (4-piperazin-1-yl-phenyl) -benzamide

4-chloro-N- [4- ((3RS, 4RS) -4-fluoro-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [3- (pyrrolidin-3-yloxy) -phenyl ] -benzamide

(RS) -6-pyrazol-1-yl-N- (4-pyrrolidin-3-yl-phenyl) -nicotinamide

(RS) -6-chloro-N- (4-piperidin-3-yl-phenyl) -nicotinamide

(RS) -4-chloro-2-fluoro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(RS) -4-chloro-N- [4- (4-methyl-morpholin-2-yl) -phenyl ] -benzamide

(RS) -quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -isoquinoline-1-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -5-bromo-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -2-fluoro-4-methoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide

(RS) -6-methoxy-quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -3-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -4-ethoxy-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -N- (4-piperidin-3-yl-phenyl) -4-trifluoromethyl-benzamide

(RS) -4-chloro-2-fluoro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- (4-pyrrolidin-2-ylmethyl-phenyl) -benzamide

(RS) -1-chloro-isoquinoline-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-chloro-N- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -benzamide

4-chloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -amide

(RS) -N- (4-piperidin-3-yl-phenyl) -4-propyl-benzamide

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide

(RS) -4-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

4-chloro-N- ((R) -4-morpholin-2-yl-phenyl) -benzamide

4-chloro-N- ((S) -4-morpholin-2-yl-phenyl) -benzamide

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxymethyl) -phenyl ] -benzamide

(RS) -4-chloro-2-fluoro-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide

(RS) -4-chloro-N- (4-pyrrolidin-3-ylmethyl-phenyl) -benzamide

3, 4-dichloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide

(R) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide

3, 4-dichloro-N- ((S) -4-piperidin-3-yl-phenyl) -benzamide

(S) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -3, 4-dichloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -4-trifluoromethyl-benzamide

(RS) -4-fluoro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -3-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -4-ethoxy-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -5-chloro-pyrazine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(S) -6-chloro-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(R) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide

(S) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide

(RS) -4-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -5-ethoxy-N- (4- (2- (pyrrolidin-2-yl) ethyl) phenyl) picolinamide

(RS) -N- (4- (2- (piperidin-2-yl) ethyl) phenyl) -4- (trifluoromethyl) benzamide

(RS) -3, 4-dichloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -4-ethynyl-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(RS) -5-ethoxy-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(RS) -4-methyl-N- (4- (pyrrolidin-3-yl) phenyl) benzamide

(RS) -4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-methoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -N- (4- (piperidin-3-yl) phenyl) -5- (2, 2, 2-trifluoroethoxy) picolinamide

(RS) -4- (benzyloxy) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -2- (4- (6-cyanonicotinamido) phenyl) morpholine-4-chloride

(R) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-ethyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(RS) -4- (4-chlorophenoxy) -N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -5-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoic acid methyl ester

(RS) -2-chloro-4- (4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) benzoic acid methyl ester

(RS) -4-Cyclopropylmethoxy-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -2-chloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -5, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -4- (2-chloromethyl-3-hydroxy-2-methyl-propoxy) -N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -3-chloro-4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4-chloro-3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-5-carboxamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-4-carboxamide

(S) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide

(S) -4- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4- (ethylsulfanyl) -N- (4- (piperidin-3-yl) phenyl) benzamide

5-chloro-pyrazine-2-carboxylic acid ((S) -4-piperidin-3-yl-phenyl) -amide

5-chloro-pyrazine-2-carboxylic acid ((R) -4-piperidin-3-yl-phenyl) -amide

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(S) -6-methyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(S) -6- (methylthio) -N- (4- (piperidin-3-yl) phenyl) nicotinamide

(RS) -6-ethoxy-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylAzole-4-carboxamides

(S) -N- (4- (piperidin-3-yl) phenyl) -5- (2, 2, 2-trifluoroethoxy) pyrazine-2-carboxamide

(S) -5-bromo-N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide 2, 2, 2-trifluoroacetate salt

(S) -6-bromo-N- (4- (piperidin-3-yl) phenyl) nicotinamide 2, 2, 2-trifluoroacetate salt

(S) -3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -5- (methylthio) -N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide

(S) -3- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide

(R) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(R) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(R) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(R) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -3-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (pyrrolidin-1-yl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

(S) -2, 6-dichloro-N- (4- (piperidin-3-yl) phenyl) isonicotinamide

(S) -2-chloro-6-methyl-N- (4- (piperidin-3-yl) phenyl) isonicotinamide

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(R) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (pyrazin-2-yl) thiazole-4-carboxamide

(S) -N- (4- (piperidin-3-yl) phenyl) -6-propylnicotinamide

(S) -6-ethyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -1-phenyl-1H-pyrazole-3-carboxamide

(RS) -2-ethoxy-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -4-chloro-2-iodo-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -N- (4- (1, 4-oxazepan-2-yl) phenyl) -3-chlorobenzamide

3-chloro-N- (4- ((2S, 6S) -6-methylmorpholin-2-yl) phenyl) benzamide

(R) -4-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide

(R) -6-chloro-N- (4- (morpholin-2-yl) benzyl) nicotinamide

3-chloro-N- [4- ((2S, 5S) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide, or

3-chloro-N- [4- ((2S, 5R) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide.

A further embodiment of the present invention are compounds, wherein X is- (CHR ")_q-O-, for example

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-chloro-phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-fluoro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-benzyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-chloro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (3-chloro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (3-trifluoromethyl-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (2, 5-difluoro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-trifluoromethoxy-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (3, 4-dichloro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid (RS) -1- (4-chloro-phenyl) -ethyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 3- (4-chloro-phenyl) -propyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid indan-2-yl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid (RS) -1- (4-chloro-phenyl) -2, 2, 2-trifluoro-ethyl ester, or

(S) -4- (piperidin-3-yl) phenylcarbamic acid (2, 3-dihydro-1H-inden-2-yl) ester 2, 2, 2-trifluoroacetate salt.

A further embodiment of the present invention are compounds, wherein X is-O (CHR ")_q-, e.g.

(S) -2- (4-chlorophenoxy) -N- (4- (piperidin-3-yl) phenyl) acetamide or

(S) - (4-chlorobenzyl) 4- (piperidin-3-yl) phenylcarbamate.

A further embodiment of the invention are compounds, wherein X is-CHR "-, for example

(RS) -2- (4-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -acetamide

(RS) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -2- (3-trifluoromethyl-phenyl) -propionamide or

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -2- (3-trifluoromethoxy-phenyl) -propionamide.

A further embodiment of the invention are compounds, wherein X is-CH₂CH₂-, e.g.

(RS) -3- (2-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -propionamide or

(RS) -3- (4-chloro-phenyl) -N- (4-piperidin-3-yl-phenyl) -propionamide.

Compounds of formula I-A

Wherein

R is hydrogen or lower alkyl;

R¹is- (CH)₂)_n-(O)_o-heterocycloalkyl, optionally substituted by lower alkyl, hydroxy, halogen, or by- (CH)₂)_p-aryl substitution;

n is 0, 1 or 2;

o is 0 or 1;

p is 0, 1 or 2;

R²is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic ring is optionally substituted with one or two substituents selected from the group consisting of lower alkyl, halogen, heteroaryl, CF₃，OCF₃，OCH₂CF₃Lower alkoxy, CH₂-lower alkoxy, lower alkynyl or cyano;

x is a bond, -NR' -, -CH₂NH-，-CHR”，-(CH₂)_q-O-or- (CH)₂)₂-；

R' is hydrogen or lower alkyl,

r' is hydrogen, lower alkyl, lower alkoxy,

q is 0, 1 or 2;

or a pharmaceutically suitable acid addition salt thereof, are further embodiments of the invention.

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) cleavage of the N-protecting group from a compound of the formula

To obtain a compound of the following formula,

whereinIs a heterocyclic group selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl or thiomorpholinyl, PG is an N-protecting group selected from-C (O) O-tert-butyl, and the compound obtained is, if desired, converted into a pharmaceutically acceptable acid addition salt, or

b) Reacting a compound of the formula

With a compound of the formula,

to obtain a compound of the following formula,

wherein X is a bond or-CH₂And the other definitions are as described above, or

If desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt, or

c) Reacting a compound of the formula

With a compound of the formula,

to obtain a compound of the following formula,

wherein is defined as above, and

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

The preparation of the compounds of formula I according to the invention can be carried out sequentially or by convergent routes. The synthesis of the compounds of the present invention is illustrated in schemes 1-17 below and in the description of 323 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 description of the following 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 17, however, the order of the reaction steps may be freely changed according to the starting materials and their respective reactivity. 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.

General procedure

Scheme 1

For X is NR or-CH₂NH-

For example, use is made of:

the substituents are as described above, and X is N or-CH₂NH-。

Step A: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, by a coupling reaction between an amine 3 and an alkyl or aryl isocyanate compound 2. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1]And 3-f [ CAS 889947-54-0]]Piperidine derivatives such as 3-b [ CAS875798-79-1]，3-c[CAS 170011-57-1]And 3-g [ CAS908334-26-9 ]]Piperazine derivatives such as 3-d [ CAS170911-92-9]And morpholine derivatives such as 3-e [ CAS1002726-96-6]。

Preferred conditions are 3 hours at room temperature in dichloromethane.

And B: removal of the BOC N-protecting group can be accomplished 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 2

For X is-O-or-CH₂-O-

For example, use is made of:

the substituents are as described above and X is-O-or-CH₂O-。

Step A: carbamate formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisA coupling reaction between an amine 3 and an alkyl or aryl chloroformate compound 5 in the presence of a base such as triethylamine or N, N-diisopropylethylamine in an alkane, THF, DME or TBME. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1]And 3-f [ CAS 889947-54-0]]Piperidine derivatives such as 3-b [ CAS875798-79-1]，3-c[CAS 170011-57-1]And 3-g [ CAS908334-26-9 ]]Piperazine derivatives such as 3-d [ CAS170911-92-9]And morpholine derivatives such as 3-e [ CAS1002726-96-6]。

Preferred conditions are triethylamine in THF at room temperature for 18 hours.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 3

For X is a bond

For example, use is made of:

the substituents are as described above andis heterocycloalkyl which may contain some additional heteroatoms such as N, S or O.

Step A: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisA coupling reaction between an amine 3 and an alkyl or aryl chloroformamide compound 5-1 in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine in an alkane, THF, DME or TBME. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1]And 3-f [ CAS 889947-54-0]]Piperidine derivatives such as 3-b [ CAS875798-79-1]，3-c[CAS 170011-57-1]And 3-g [ CAS908334-26-9 ]]Piperazine derivatives such as 3-d [ CAS170911-92-9]And morpholine derivatives such as 3-e [ CAS1002726-96-6]。

Preferred conditions are triethylamine in THF at room temperature for 18 hours.

And B: removal of the BOCN-protecting group may be carried out using inorganic acids such as HCl, H₂SO₄Or H₃PO₄Or is provided withOrganic acids such as CF₃COOH，CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂，CHCl₃THF, MeOH, EtOH or H₂O, at 0 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 4

For X is a bond or CH₂

For example, use is made of:

the substituents are as described above and X is a bond or-CH₂-。

Step A: amide formation may be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisA coupling reaction between an amine 3 and an alkyl or aryl acid chloride compound 5-2 in an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1]And 3-f [ CAS 889947-54-0]]Piperidine derivatives such as 3-b [ CAS875798-79-1]，3-c[CAS 170011-57-1]And 3-g [ CAS908334-26-9 ]]Piperazine derivatives such as 3-d [ CAS170911-92-9]And morpholine derivatives such as 3-e [ CAS1002726-96-6]。

Preferred conditions are triethylamine in THF at room temperature for 18 hours.

Alternatively, amide formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, or mixtures thereofIn an alkane, THF, DME or TBME, in the presence of a coupling agent such as DCC, EDC, TBTU or HATU, in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, between amine 3 and carboxylic acid 5-3.

Preferred conditions are TBTU with N-methylmorpholine in THF at 50 ℃ for 18 hours.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 5

X is a bond, CHR' or- (CH)₂)₂-

For example, use is made of:

the substituents are as described above and X is a bond, -CHR' or- (CH)₂)₂-。

Step A: isocyanate formation can be achieved by treating the amine 3 with triphosgene, diphosgene or phosgene in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane in the presence of a base such as triethylamine or N, N-diisopropylethylamine. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1 ] and 3-f [ CAS 889947-54-0], piperidine derivatives such as 3-b [ CAS875798-79-1 ], 3-c [ CAS170011-57-1 ] and 3-g [ CAS908334-26-9 ], piperazine derivatives such as 3-d [ CAS170911-92-9 ] and morpholine derivatives such as 3-e [ CAS1002726-96-6 ].

Preferred conditions are triphosgene and triethylamine in dichloromethane at 45 ℃ for 18 hours.

And B: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between the isocyanate compound 7 and the amine 8.

Preferred conditions are 3 hours at room temperature in dichloromethane.

And C: removal of the BOCN-protecting group may be carried out using inorganic 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 6

For X is a bond

For example, use is made of:

the substituents are as described above.

Step A: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between the isocyanate compound 7 (see scheme 5) and the amine 9.

Preferred conditions are 3 hours at room temperature in dichloromethane.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 7

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: carbamate formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisIn an alkane, THF, DME or TBME, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between the isocyanate compound 7 (see scheme 5) and the alcohol 10.

Preferred conditions are N, N-diisopropylethylamine in THF at 110 ℃ for 18 hours.

And B: removal of the BOCN-protecting group may be carried out using inorganic 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 8

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisAlkane, THF, DME or TBME, or a polar organic solvent such as DMF, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, coupling reaction between isocyanate 11(CAS 879896-39-6) and alkylamine or arylamine 8.

Preferred conditions are 18 hours at room temperature in DMF.

Alternatively, urea formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, or mixtures thereofAlkane, THF, DME or TBME, or a polar organic solvent such as DMF, optionally in the presence of a base such as triethylamine or N, N-diisopropylethylamine, with a coupling reaction between amine 13(CAS 16153-81-4) and the alkyl or aryl isocyanate compound 12.

Preferred conditions are 2 hours at room temperature in DMF.

Scheme 9

For X is a bond or-CH₂-

For example using

The substituents are as described above and X is a bond or-CH₂-。

Step A: carbamate formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisIn an alkane, THF, DME or TBME, in the presence of a base such as triethylamine or N, N-diisopropylethylamine, by treatment of the amine 3 with ethyl chloroformate. Examples of suitable amines 3 include N-protected pyrrolidine derivatives such as 3-a [ CAS908334-28-1]Piperidine derivatives such as 3-b [ CAS875798-79-1]And 3-c [ CAS170011-57-1 ]]Piperazine derivatives such as 3-d [ CAS170911-92-9]And morpholine derivatives such as 3-e [ CAS1002726-96-6]。

Preferred conditions are triethylamine in THF at room temperature for 18 hours.

And B: the reduction may be carried out in an ethereal solvent such as THF or bisIn an alkane, carbamate 14 is treated with an aluminum hydride reducing agent, such as Red-Al, at a temperature between room temperature and the reflux temperature of the solvent.

Preferred conditions are THF at room temperature for 5 hours, then 15 minutes at 50 ℃.

And C: carbamate formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisIn an alkane, THF, DME or TBME, in the presence of a base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between the amine 15 and the alkyl or aryl chloroformate compound 5.

Preferred conditions are triethylamine in THF at room temperature for 18 hours.

Step D: removal of the BOC N-protecting group can be accomplished 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 10

For X is a bond, NR', -CH₂NH-，CHR”-，-(CH₂)_q-O-or- (CH)₂)₂-

The substituents are as described above and X is a bond, -NR', -CH₂NH-，-CHR”，-(CH₂)_q-O-or- (CH)₂)₂-；

Step A: n-alkylation can be achieved by reductive amination involving treatment of the amine compound I-8 with an aldehyde such as formaldehyde, acetaldehyde, benzaldehyde, or phenylacetaldehyde in the presence of a Bronsted or Lewis acid to form the corresponding imine compound, in situ with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

Preferred conditions when aqueous formaldehyde is used are zinc chloride, sodium acetate and sodium cyanoborohydride in methanol at 50 ℃ overnight.

The preferred conditions when acetaldehyde, benzaldehyde or phenylacetaldehyde is used are acetic acid, sodium acetate and sodium triacetoxyborohydride in 1, 2-dichloroethane at 50 ℃ overnight.

And B: n-arylation can be achieved by treating amine compound I-8 with an aryl iodide in the presence of a metal catalyst, for example using a copper-mediated Ullmann reaction or a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic iron sesquioxide, catalytic L-proline and sodium t-butoxide in DMSO overnight at 135 ℃ according to the procedure of Guo et al org.Lett.2008, 10, 4513-.

Scheme 11

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: amide formation may be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between an aryl amine and an alkyl or aryl acid chloride 5-2.

Preferred conditions are triethylamine in THF at room temperature for 4 hours.

Alternatively, amide formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, or mixtures thereofCoupling between arylamines and carboxylic acids 5-3 in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in an alkane, THF, DME or TBME in the presence of a coupling agent such as DCC, EDC, TBTU or HATUAnd (3) carrying out a reaction.

And B: o-arylation can be achieved by treating aryl iodide 16 with a hydroxypyrrolidine derivative 17(CAS 103057-44-9) in the presence of a metal catalyst, for example, using a copper-mediated Ullmann reaction or a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic copper (I) iodide, catalytic 1, 10-phenanthroline and cesium carbonate, according to the procedure of Buchwald and co-workers (org. Lett.2002, 4, 973-976), in the absence of additional solvent, overnight at 130 ℃.

And C: removal of the BOC N-protecting group can be accomplished 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 12

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: hydroxypyrrolidine derivatives 21 can be prepared as follows: by adding 4-bromo-phenyllithium to the epoxide 20 in the presence of a lewis acid such as boron trifluoride etherate (CAS114214-49-2), wherein the 4-bromo-phenyllithium can be prepared in situ by first treating 1, 4-dibromobenzene 19 with a stoichiometric equivalent of n-butyllithium. The reaction may be carried out in an ether organic solvent such as diethyl ether or THF, preferably at low temperatures.

Preferred conditions are THF at-78 deg.C for 30min to form 4-bromo-phenyllithium, followed by epoxide ring-opening at-78 deg.C for 2 hours.

And B: n-arylation can be achieved by treating the aryl bromide 21 with an amide compound 22 in the presence of a metal catalyst, for example using a copper-mediated Ullmann reaction or a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic copper (I) iodide, catalytic N, N' -dimethylethylenediamine and cesium carbonate according to the procedure of Buchwald and co-workers (org. Lett.2007, 9, 4749-In an alkane at 120 ℃ overnight.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Step D: fluorination of the alcohol 23 can be achieved by treatment with a fluorinating agent such as diethylaminosulfur trifluoride (DAST) in an aprotic organic solvent.

Preferred conditions are DAST in a mixture of acetonitrile and 1, 2-dichloroethane at a temperature between 0 ℃ and room temperature for 1 hour.

Step E: removal of the BOC N-protecting group can be accomplished 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 13

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: the arylpyrrolidinedione (pyrollidinone) 25 can be prepared using a metal catalyzed cross-coupling reaction, for example, using a rhodium catalyzed conjugate addition of an arylboronic ester 26(CAS 330793-01-6) and maleimide 27(CAS 1631-26-1).

Preferred conditions are catalytic [ RhCl (cod) ] according to the procedure of Iyer et al (tetrahedron. Lett. (tetrahedron communication) 2007, 48, 4413-]2, potassium hydroxide in IIAqueous alkane solution at 90 ℃ under microwave irradiation for 5 minutes.

And B: alkylation can be achieved by treatment with an alkyl bromide or alkyl iodide in the presence of an inorganic base such as sodium carbonate or cesium carbonate in a polar aprotic organic solvent such as DMF at a temperature between room temperature and the reflux temperature of the solvent.

Preferred conditions are the use of methyl iodide and cesium carbonate in DMF at room temperature for 1 hour.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Step D: the reduction may be carried out in an ethereal solvent such as THF or bisIn an alkane, treatment of carbamate 29 with an aluminum hydride reducing agent, such as lithium aluminum hydride, at a temperature between room temperature and the reflux temperature of the solvent.

Preferred conditions are THF at 70 ℃ for 1 hour.

Step E: amide formation may be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine, by a coupling reaction between an amine 30 and an alkyl or aryl acid chloride 5-2.

Preferred conditions are triethylamine in THF at room temperature for 3 hours.

Alternatively, amide formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, or mixtures thereofBy a coupling reaction between an amine 30 and a carboxylic acid 5-3 in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in an alkane, THF, DME or TBME in the presence of a coupling agent such as DCC, EDC, TBTU or HATU.

Step F removal of the benzyl protecting group can be carried out by hydrogenation with hydrogen at atmospheric or elevated pressure, or using ammonium formate or cyclohexadiene as catalyst for hydrogen source such as PtO₂Pd-C or Raney nickel in a solvent such as MeOH, EtOH, H₂O, twoAlkane, THF, HOAc, EtOAc, CH₂Cl₂，CHCl₃Transfer hydrogenation in DMF or mixtures thereof.

Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 100 ℃ for 1 hour.

Scheme 14

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: introduction of BOC protecting groups can be achieved as follows: in the presence of an organic base such as N, N-diisopropylethylamine or triethylamine in an aprotic solvent such as dichloromethane, 1, 2-dichloroethane,in an alkane, THF or DMF, or using an inorganic base such as sodium hydroxide or sodium carbonate in an aqueous solvent systemSuch as water, aqueous ethanol or aqueous methanol, the benzyl-pyrrolidine derivative 32(CAS 383127-68-2) is treated with di-tert-butyl dicarbonate.

Preferred conditions are N, N-diisopropylethylamine in 1, 2-dichloroethane at room temperature for 1 hour.

And B: n-arylation can be achieved by treating the aryl bromide 33 with an amide compound 34 in the presence of a metal catalyst, for example using a copper-mediated Ullmann reaction or a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

Scheme 15

X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-and Y is-CH₂-or-CH₂CH₂-。

Step A: benzyl-substituted dialkyl phosphonates 36(CAS 2609-49-6) and aldehydes 37 (e.g. (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester [ CAS 59379-02-1 ]]Or (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester [ CAS118156-93-7]) The Wittig Horner reaction between the following can be realized: by using a base such as NaH, KOtBu, NaOMe, NaOEt, n-BuLi, LiHMDS, NaHMDS, KHMDS, LDA in a solvent such as THF, bisAlkane, acetonitrile, 1, 2-dimethoxyethane, DMF, benzene, toluene or mixtures thereof at a temperature of-78-80 ℃ for 15min-8 hours, and optionally adding a crown ether to form a ylide, if appropriate, and then condensing the ylide with a carbonyl compound in the same solvent at a temperature of 0 to 80 ℃ for 1-24 hours. Alternatively, the base, the carbonyl compound and the base and optionally the crown ether may be added simultaneously to the reaction mixture without prior formation of a ylide at a temperature of-78 ℃ to 80 ℃.

Preferred conditions are formation of ylide using a solution of LDA in hexane/THF as base and THF as solvent at-78 ℃, reaction of phosphonate ester at-78 ℃ for 60min, followed by condensation with carbonyl component at-78 ℃ and then warming to room temperature overnight.

And B: the simultaneous reduction of the olefin and nitro functions can be carried out by hydrogenation with hydrogen at atmospheric or elevated pressure, or using ammonium formate or cyclohexadiene as catalyst for the hydrogen source, such as PtO₂Pd-C or Raney nickel in a solvent such as MeOH, EtOH, H₂O, twoAlkane, THF, HOAc, EtOAc, CH₂Cl₂，CHCl₃Transfer hydrogenation in DMF or mixtures thereof. Alternatively, the reduction of the olefin may be by Mg in MeOH or by LiAlH₄In THF or diethyl ether.

Preferred conditions are hydrogenation with MeOH as solvent in the presence of Pd/C as catalyst.

And C: amide formation may be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisIn an alkane, THF, DME or TBME, in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine, a coupling reaction between the amine 39 and the alkyl or aryl acid chloride 5-2.

Preferred conditions are triethylamine in THF at room temperature for 3 hours.

Alternatively, amide formation may be carried out in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, or mixtures thereofIn an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, in the presence of a coupling agent such as DCC, EDC, TBTU or HATU, a coupling reaction between amine 39 and carboxylic acid 5-3.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

In a similar manner, following steps A-D, starting from aldehyde 37 '((RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester [ CAS117625-90-8 ]) instead of aldehyde 37, the product I-16' is obtained instead of I-16.

Scheme 16

The substituents are as described above and X is-NH-or-CH₂NH-。

Step A: urea formation can be carried out in halogenated solvents such as dichloromethane or 1, 2-dichloroethane or in ethereal solvents such as diethyl ether, bisAlkyl, THF, DME or TBME, or a polar organic solvent such as DMF, in the presence of a base such as triethylamine or N, N-diisopropylethylamine, aryl amine 39 is reacted with triphosgene and with alkyl or aryl amine 41.

Preferred conditions are triphosgene and triethylamine in dichloroethane at 80 ℃ for 18 hours.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

In a similar manner, following steps A and B, starting with amine 39 'instead of amine 39, the product I-17' is obtained instead of I-17.

Scheme 17

For X is a bond or-CH₂-

The substituents are as described above and X is a bond or-CH₂-。

Step A: introduction of BOC protecting groups can be achieved as follows: in the presence of an organic base such as N, N-diisopropylethylamine or triethylamine in an aprotic solvent such as dichloromethane, 1, 2-dichloroethane,the cyclic amine 43 is treated with di-tert-butyl dicarbonate in an alkane, THF or DMF, or using an inorganic base such as sodium hydroxide or sodium carbonate in an aqueous solvent system such as water, aqueous ethanol or aqueous methanol. Examples of suitable cyclic amines 43 include pyrrolidine derivatives such as 43-a [ CAS 328546-98-1]Piperidine derivatives such as 43-b [ CAS 769944-72-1]And morpholine derivatives such as 43-c [ CAS83555-73-1 ]]。

Preferred conditions are N, N-diisopropylethylamine in THF at room temperature for 18 hours.

And B: n-arylation can be achieved by treating aryl bromide 44 with amide compound 34 in the presence of a metal catalyst, for example, using a copper-mediated Ullmann reaction or a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are a modified process (microwave heating) according to the procedure of Buchwald and co-workers (org. Lett.2007, 9, 4749-Catalytic copper (I) iodide in an alkane, catalytic N, N' dimethylethylenediamine and cesium carbonate were heated in a sealed tube at 180 ℃ for 2 hours in a microwave oven.

And C: of BOC N-protecting groupsThe removal can be carried out using 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 to 80 ℃.

Preferred conditions are 4N HCl in twoAlkane and THF at 60 ℃ overnight.

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. A detailed description of suitable separation and isolation procedures may 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.

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.

Basic acid addition salts of compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.

Example 1

(RS) -1- (4-butyl-2-methyl-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea; hydrochloride salt

The title compound was obtained in analogy to example 6 using 4-butyl-2-methyl-phenyl isocyanate (CAS 306935-81-9) instead of phenyl isocyanate. A white solid. Ms (isp): 352.4([ M + H)]⁺)。

Example 2

1- (3, 4-dichloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl ] -urea

To a stirred suspension of 4- (4-methyl-piperazin-1-yl) -phenylamine (195mg, CAS 16153-81-4) in DMF (5ml) was added 3, 4-dichlorophenyl isocyanate (191mgl, CAS 102-36-3) and stirring continued at room temperature for 2 h. The mixture was then diluted with ethyl acetate (20ml) and water (20ml), whereupon a precipitate formed. The precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give 1- (3, 4-dichloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl]Urea (317mg, 82%) as an off-white solid. Ms (isp): 381.1([{³⁷Cl}M-H]-)，379.2([{³⁷Cl³⁵Cl}M-H]-)，377.0([{³⁵Cl}M-H]^-)。

Example 3

(RS) -1- (3, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 3, 4-dichloro-phenyl isocyanate (CAS 102-36-3) instead of phenyl isocyanate. A white solid. Ms (isp): 352.1([{³⁷Cl}M-H]^-)，350.2([{³⁷Cl³⁵Cl}M-H]^-)，348.0([{³⁵Cl}M-H]^-)。

Example 4

1- [4- (4-methyl-piperazin-1-yl) -phenyl]-3-(4-Azol-5-yl-phenyl) -ureas

To a stirred suspension of 1- (4-isocyanatophenyl) -4-methylpiperazine (75mg, CAS 879896-39-6) in DMF (2ml) was added 4- (1, 3-Oxazol-5-yl) aniline (55mg, CAS 1008-95-3) and stirring continued at room temperature for 17 h. The mixture was then diluted with ethyl acetate (10ml) and water (10ml), whereupon a precipitate formed. Collecting the precipitate by filtration, washing with ethyl acetate, and vacuum drying to obtainTo 1- [4- (4-methyl-piperazin-1-yl) -phenyl]-3-(4-Oxazol-5-yl-phenyl) -urea (41mg, 31%) as a white solid. Ms (isp): 376.1([ M-H)]^-)。

Example 5

(RS) -1- (4-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 4-chloro-phenyl isocyanate (CAS 104-12-1) instead of phenyl isocyanate. A white solid. Ms (isp): 318.1([{³⁷Cl}M+H]⁺)，316.1([{³⁵Cl}M+H]⁺)。

Example 6

(RS) -1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

a)(RS) -3- [4- (3-phenyl-ureido) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate (70mg, CAS908334-28-1) in dichloromethane (2.5ml) was added phenyl isocyanate (0.03ml) and stirring continued at room temperature for 3 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- [4- (3-phenyl-ureido) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (102mg, q)urant.) as a pale yellow solid. Ms (isp): 404.3([ M + Na ]]⁺)，399.2([M+NH₄]⁺)，382.2([M+H]⁺)，326.3([M+H-C₄H₈]⁺)。

b) (RS) -1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

To (RS) -3- [4- (3-phenyl-ureido) -phenyl]A stirred solution of tert-butyl-pyrrolidine-1-carboxylate (92mg) in THF (2ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.60ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with diethyl ether (5 ml). The resulting crystals were collected by filtration, washed with diethyl ether and dried under vacuum at 60 ℃ to give (RS) -1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride (52mg, 68%) as a white crystalline solid. Ms (isp): 282.2([ M + H)]⁺)。

Example 7

(RS) -1- (2, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 2, 4-dichloro-phenyl isocyanate (CAS 2612-57-9) instead of phenyl isocyanate. A white solid. Ms (isp): 354.1([{³⁷Cl}M+H]⁺)，352.1([{³⁷Cl³⁵Cl}M+H]⁺)，350.1([{³⁵Cl}M+H]⁺)。

Example 8

(RS) -1- (3-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 3-chloro-phenyl isocyanate (CAS 2909-38-8) instead of phenyl isocyanate. A white solid. Ms (isp): 318.1([{³⁷Cl}M+H]⁺)，316.1([{³⁵Cl}M+H]⁺)。

Example 9

(RS) -1-benzyl-3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using benzyl isocyanate instead of phenyl isocyanate. Off-white solid. Ms (isp): 296.2([ M + H)]⁺)。

Example 10

(RS) -1-cyclohexyl-3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using cyclohexyl isocyanate instead of phenyl isocyanate. Off-white solid. Ms (isp): 288.2([ M + H)]⁺)。

Example 11

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester hydrochloride

a)(RS) -3- (4-Phenoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate (80mg, CAS908334-28-1) in THF (2ml) were added triethylamine (0.05ml) and phenyl chloroformate (0.04ml) in succession and stirring was continued at room temperature for 18 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- (4-phenoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (102mg, 87%) as a white solid. Ms (isp): 405.3([ M + Na ]]⁺)，400.1([M+NH₄]⁺)，327.2([M+H-C₄H₈]⁺)。

b)(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester hydrochloride

To a stirred solution of (RS) -3- (4-phenoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (98mg) in THF (2ml) was added dropwise hydrogen chloride in bisA solution in alkane (0.64ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with diethyl ether (5 ml). The resulting crystals were collected by filtration, washed with diethyl ether, and dried under vacuum at 60 ℃ to give (RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester hydrochloride (52mg, 68%) as a white crystalline solid. Ms (isp): 283.1([ M + H)]⁺)。

Example 12

(RS) -2-phenyl-N- (4-pyrrolidin-3-yl-phenyl) -acetamide hydrochloride

a)(RS) -3- (4-Phenylacetylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, CAS908334-28-1) in THF (2ml) were added successively triethylamine (0.05ml) and phenylacetyl chloride (0.04ml) and stirring was continued at room temperature for 18 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- (4-phenylacetylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (95mg, 82%) as a white solid. Ms (isp): 403.2([ M + Na ]]⁺)，398.2([M+NH₄]⁺)，325.3([M+H-C₄H₈]⁺)。

b)(RS) -2-phenyl-N- (4-pyrrolidin-3-yl-phenyl) -acetamide hydrochloride

To a stirred solution of (RS) -3- (4-phenylacetylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (91mg) in THF (2ml) was added dropwise hydrogen chloride in bis (tert-butyl) acetateA solution in alkane (0.60ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with diethyl ether (5 ml). The resulting crystals were collected by filtration, washed with diethyl ether and dried under vacuum at 60 ℃ to give (RS) -2-phenyl-N- (4-pyrrolidin-3-yl-phenyl) -acetamide hydrochloride (63mg, 83%) as an off-white crystalline solid. Ms (isp): 281.2([ M + H)]⁺)。

Example 13

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 12 using benzoyl chloride instead of phenylacetyl chloride. A white solid. Ms (isp): 267.1([ M + H)]⁺)。

Example 14

(RS) -1-methyl-1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea

The title compound was obtained in analogy to example 11 using N-methyl-N-phenylcarbamoyl chloride instead of phenyl chloroformate. A colorless oil. Ms (isp): 296.3([ M + H)]⁺)。

Example 15

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-phenyl ester hydrochloride

The title compound was obtained in analogy to example 11 using 4-fluoro-phenyl chloroformate instead of phenyl chloroformate. A white solid. Ms (isp): 301.1([ M + H)]⁺)。

Example 16

(RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 12 using 4-chloro-benzoyl chloride instead of phenylacetyl chloride. A white solid. Ms (isp): 303.1([{³⁷Cl}M+H]⁺)，301.1([{³⁵Cl}M+H]⁺)。

Example 17

(RS) -2- (4-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -acetamide hydrochloride

The title compound was obtained in analogy to example 12 using 4-chloro-phenylacetyl chloride instead of phenylacetyl chloride. A white solid. Ms (isp): 317.1([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 18

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -4-trifluoromethyl-benzamide hydrochloride

The title compound was obtained in analogy to example 12 using 4-trifluoromethyl-benzoyl chloride instead of phenylacetyl chloride. A white solid. Ms (isp): 335.1([ M + H)]⁺)。

Example 19

(RS) -2, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 12 using 2, 4-dichloro-benzoyl chloride instead of phenylacetyl chloride. Off-white solid. Ms (isp): 339.1([{³⁷Cl}M+H]⁺)，337.1([{³⁷Cl³⁵Cl}M+H]⁺)，335.1([{³⁵Cl}M+H]⁺)。

Example 20

(RS) -3-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 12 using 3-chloro-benzoyl chloride instead of phenylacetyl chloride. Off-white solid. Ms (isp): 303.1([{³⁷Cl}M+H]⁺)，301.1([{³⁵Cl}M+H]⁺)。

Example 21

(RS) -morpholine-4-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 11 using 4-morpholinecarbonyl chloride instead of phenyl chloroformate. Ash ofA white solid. Ms (isp): 276.2([ M + H)]⁺)。

Example 22

(RS) -methyl- (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester

a)(RS) -3- (4-ethoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in analogy to example 11(a) using ethyl chloroformate instead of phenyl chloroformate. A white solid. Ms (isp): 357.2([ M + Na ]]⁺)，352.2([M+NH₄]⁺)，279.2([M+H-C₄H₈]⁺)。

b) (RS) -3- (4-methylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -3- (4-ethoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (690mg) in THF (9ml) was added dropwise Red-Al solution (1.77ml, 3.5M solution in toluene), and the mixture was stirred at room temperature for 5h and at 50 ℃ for 15 min. The mixture was then cooled to 0 ℃ and quenched by dropwise addition of 1M aqueous sodium hydroxide solution. The mixture was diluted with ethyl acetate and then washed with saturated brine. Separating the organic phase over Na₂SO₄Dried and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- (4-methylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (580mg, quant) as a colorless oil. Ms (isp): 299.4([ M + Na ]]⁺)，221.3([M+H-C₄H₈]⁺)。

c) (RS) -3- [4- (methyl-phenoxycarbonyl-amino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in analogy to example 11(a) using (RS) -3- (4-methylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester. A colorless oil. Ms (isp): 419.3([ M + Na ]]⁺)，414.3([M+NH₄]⁺)，341.2([M+H-C₄H₈]⁺)。

d) (RS) -methyl- (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester

In analogy to example 11(b), use is made of (RS) -3- [4- (methyl-phenoxycarbonyl-amino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester instead of (RS) -3- (4-phenoxycarbonylamino-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained. A colorless oil. Ms (isp): 297.3([ M + NH)₄]⁺)。

Example 23

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-chloro-phenyl ester hydrochloride

The title compound was obtained in analogy to example 11 using 4-chloro-phenyl chloroformate instead of phenyl chloroformate. A white solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 24

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -2- (4-trifluoromethyl-phenyl) -acetamide

The title compound was obtained in analogy to example 12 using 4-trifluoromethyl-phenylacetyl chloride instead of phenylacetyl chloride. A colorless oil. Ms (isp): 349.2([ M + H)]⁺)。

Example 25

(RS) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 12 using 2-phenyl-propionyl chloride instead of phenylacetyl chloride. A colorless oil. Ms (isp): 295.3([ M + H)]⁺)。

Example 26

(RS) -1- (6-chloro-pyridin-3-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 2-chloro-5-isocyanatopyridine (CAS 125117-96-6) instead of phenyl isocyanate. Off-white solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 27

(RS) -1- (4-pyrrolidin-3-yl-phenyl) -3- (4-trifluoromethyl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 4-trifluoromethyl-phenyl isocyanate instead of phenyl isocyanate. Off-white solid. Ms (isp): 250.2([ M + H)]⁺)。

Example 28

(RS) -piperidine-1-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

The title compound was obtained in analogy to example 11 using 1-piperidinecarbonyl chloride instead of phenyl chloroformate. A colorless amorphous solid. Ms (isp): 274.3([ M + H)]⁺)。

Example 29

(R) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

a) (RS) -3- [4- ((R) -2-phenyl-propionylamino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (70mg, CAS908334-28-1) in THF (2ml) were successively added N-methylmorpholine (0.12ml), TBTU (171mg) and (R) -2-phenylpropionic acid (60mg), and the mixture was heated at 50 ℃ for 18 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- [4- ((R) -2-phenyl-propionyl)Amino-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (107mg, quant.) as a colorless oil. Ms (isp): 417.3([ M + Na ]]⁺)，412.3([M+HN₄]⁺)，395.2([M+H]⁺)，339.2([M+H-C₄H₈]⁺)。

b) (R) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

To (RS) -3- [4- ((R) -2-phenyl-propionylamino) -phenyl]A stirred solution of tert-butyl-pyrrolidine-1-carboxylate (100mg) in THF (2ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.95ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and made basic by the addition of 5M aqueous sodium hydroxide. The mixture was diluted with ethyl acetate/THF (1: 1) and the phases were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to afford (R) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide (63mg, 83%) as an amorphous colorless solid. Ms (isp): 295.2([ M + H)]⁺)。

Example 30

(S) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using (S) -2-phenylpropionic acid instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 295.2([ M + H)]⁺)。

Example 31

(RS) -3- (2-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using 3- (2-chloro-phenyl) propionic acid instead of (R) -2-phenylpropionic acid. A colorless amorphous solid. Ms (isp): 331.1([{³⁷Cl}M+H]⁺)，329.1([{³⁵Cl}M+H]⁺)。

Example 32

(RS) -4-chloro-N- [4- (1-methyl-pyrrolidin-3-yl) -phenyl ] -benzamide

To a stirred suspension of (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride (100mg, example 16) in methanol (5ml) were successively added sodium acetate (24mg), formaldehyde (0.11ml, 37% aqueous solution), zinc chloride (162mg) and sodium cyanoborohydride (65mg), and the mixture was heated at 50 ℃ overnight. The mixture was then cooled to room temperature and made basic by dropwise addition of 25% aqueous ammonia solution. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (Flash-NH₂From Separtis; gradient: heptane/ethyl acetate/methanol) to provide (RS) -4-chloro-N- [4- (1-methyl-pyrrolidin-3-yl) -phenyl]Benzamide (80mg, 86%), white solid. Ms (isp): 317.2([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 33

(RS) -4-chloro-N- [4- (1-ethyl-pyrrolidin-3-yl) -phenyl ] -benzamide

To a stirred suspension of (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride (100mg, example 16) in 1, 2-dichloroethane (6ml) were successively added sodium acetate (24mg), acetaldehyde (0.08ml), acetic acid (0.02ml) and sodium triacetoxyborohydride (189mg), and the mixture was heated at 50 ℃ overnight. The mixture was then cooled to room temperature and made basic by dropwise addition of 25% aqueous ammonia solution. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (Flash-NH₂From Separtis; gradient: heptane/ethyl acetate/methanol) to provide (RS) -4-chloro-N- [4- (1-ethyl-pyrrolidin-3-yl) -phenyl]Benzamide (86mg, 88%) as an off-white solid. Ms (isp): 331.3([{³⁷Cl}M+H]⁺)，329.3([{³⁵Cl}M+H]⁺)。

Example 34

(RS) -N- [4- (1-benzyl-pyrrolidin-3-yl) -phenyl ] -4-chloro-benzamide

The title compound was obtained in analogy to example 33 using benzaldehyde instead of acetaldehyde. A white solid. Ms (isp): 393.2([{³⁷Cl}M+H]⁺)，391.2([{³⁵Cl}M+H]⁺)。

Example 35

(RS) -N- [4- (1-benzyl-pyrrolidin-3-yl) -phenyl ] -4-chloro-benzamide

The title compound was obtained in analogy to example 33 using phenylacetaldehyde instead of acetaldehyde. A colorless oil. Ms (isp): 407.4([{³⁷Cl}M+H]⁺)，405.4([{³⁵Cl}M+H]⁺)。

Example 36

(RS) -4-chloro-N- [4- (1-phenyl-pyrrolidin-3-yl) -phenyl ] -benzamide

To a stirred solution of (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride (200mg, example 16) in DMSO (3ml) was added iodobenzene (242mg), ferric oxide (19mg), L-proline (27mg) and sodium t-butoxide (171mg) successively, and the mixture was heated at 135 ℃ overnight. The mixture was then cooled to room temperature and diluted with ethyl acetate. The mixture was washed successively with water and with saturated brine, and then the organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -4-chloro-N- [4- (1-phenyl-pyrrolidin-3-yl) -phenyl]Benzamide (28mg, 13%) as a pale yellow solid. Ms (isp): 407.4([{³⁷Cl}M+H]⁺)，405.4([{³⁵Cl}M+H]⁺)。

Example 37

(RS) -2- (4-chloro-phenyl) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using 4-chloro- α -methylphenylacetic acid instead of (R) -2-phenylpropionic acid. A yellow oil. Ms (isp): 331.1([{³⁷Cl}M+H]⁺)，329.2([{³⁵Cl}M+H]⁺)。

Example 38

(RS) -2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -butyramide

The title compound was obtained in analogy to example 29 using (RS) -2-phenylbutyric acid instead of (R) -2-phenylpropionic acid. A yellow oil. Ms (isp): 309.2([ M + H)]⁺)。

Example 39

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxy) -phenyl ] -benzamide hydrochloride

a) 4-chloro-N- (4-iodo-phenyl) -benzamide

To a stirred suspension of 4-iodoaniline (1.50g) in THF (20ml) were added successively triethylamine (1.90ml) and 4-chlorobenzaldehydeAcid chloride (0.88ml) and stirring was continued at room temperature for 4 h. The mixture was then diluted with ethyl acetate and washed successively with 0.5N aqueous sodium hydroxide solution, saturated brine, 0.5N aqueous hydrochloric acid solution, and finally with saturated brine. Separating the organic phase over Na₂SO₄Dried and concentrated in vacuo to afford 4-chloro-N- (4-iodo-phenyl) -benzamide (2.55g, quant.) as a light brown solid. Ms (ei): 359({³⁷Cl}M⁺)，357(³⁵Cl}M⁺)，141([{³⁷Cl}M-IC₆H₄NH]⁺)，139([³⁵Cl}M-IC₆H₄NH]⁺)。

b) (RS) -3- [4- (4-chloro-benzoylamino) -phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester

A stirred suspension of 4-chloro-N- (4-iodo-phenyl) -benzamide (500mg), 1-BOC-3-hydroxypyrrolidine (2.10g, CAS 103057-44-9, copper (I) iodide (27mg), 1-10-phenanthroline (50mg) and cesium carbonate (0.91g) was heated at 130 ℃ overnight₂(ii) a Gradient: heptane/EtOAc) to provide (RS) -3- [4- (4-chloro-benzoylamino) -phenoxy ] -4]Tert-butyl-pyrrolidine-1-carboxylate (47mg, 8%) as a light brown solid. Ms (isp): 436.2([{³⁷Cl}M+NH₄]⁺)，434.4([{³⁵Cl}M+NH₄]⁺)，363.1([{³⁷Cl}M+H-C₄H₈]⁺)，361.2([{³⁵Cl}M+H-C₄H₈]⁺)。

c) (RS) -4-chloro-N- [4- (pyrrolidin-3-yloxy) -phenyl]-benzamide hydrochloride

To (RS) -3- [4- (4-chloro-benzoylamino) -phenoxy]A stirred solution of tert-butyl-pyrrolidine-1-carboxylate (45mg) in THF (2ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.40ml, 4M solution), and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with diethyl ether (5 ml). The resulting crystals were collected by filtration, washed with diethyl ether and dried under vacuum at 60 ℃ to give (RS) -4-chloro-N- [4- (pyrrolidin-3-yloxy) -phenyl]Benzamide hydrochloride (31mg, 81%) as a light brown crystalline solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 40

(RS) -N- [4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenyl ] -4-chloro-benzamide

a) (RS) - [4- (1-benzyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl]-carbamic acid tert-butyl ester

4- (BOC-amino) phenylboronic acid pinacol ester (4.40g, CAS 330793-01-6), N-benzylmaleimide (2.84g, CAS 1631-26-1), potassium hydroxide powder (0.77g) and [ RhCl (cod)]₂(0.27g) in twoA stirred suspension in alkane (48ml) and water (8ml) was heated in a sealed tube under microwave irradiation at 90 ℃ for 5 minutes. The mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) - [4- (1-benzyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl]Tert-butyl carbamate (3.83g, 73%) as off-white solid. Ms (isp): 398.2([ M + NH)₄]⁺)，325.3([M+H-C₄H₈]⁺)。

b) (RS) - [4- (1-benzyl-3-methyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl]-carbamic acid tert-butyl ester

To (RS) - [4- (1-benzyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl at 0 deg.C]A stirred suspension of tert-butyl carbamate (3.80g) and cesium carbonate (9.76g) in DMF (20ml) was added dropwise to a solution of methyl iodide (0.50ml) in DMF (2ml) and the mixture was stirred at room temperature for 1 hour. The mixture was then diluted with ethyl acetate and the resulting mixture was washed successively with water and with saturated brine. The phases were separated, the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) - [4- (1-benzyl-3-methyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl]Tert-butyl carbamate (0.95g, 24%) as yellow solid. Ms (isp): 412.4([ M + NH ]₄]⁺)，339.3([M+H-C₄H₈]⁺)。

c) (RS) -3- (4-amino-phenyl) -1-benzyl-3-methyl-pyrrolidine-2, 5-dione

To (RS) - [4- (1-benzyl-3-methyl-2, 5-dioxo-pyrrolidin-3-yl) -phenyl]A stirred solution of tert-butyl carbamate (0.94g) in THF (15ml) was added hydrogen chloride dropwise to the solution in bisA solution in alkane (8.9ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with ethyl acetate. The mixture was then made basic by the addition of 5M aqueous sodium hydroxide. The phases were then separated and the organic layer was washed with saturated brine. The phases were then separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to afford (RS) -3- (4-amino-phenyl) -1-benzyl-3-methyl-pyrrolidine-2, 5-dione (0.57g, 81%) as a yellow solid. Ms (isp): 295.3([ M + H)]⁺)。

d)(RS) -4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenylamine

To a stirred solution of (RS) -3- (4-amino-phenyl) -1-benzyl-3-methyl-pyrrolidine-2, 5-dione (0.56g) in THF (20ml) was added lithium aluminium hydride (0.29g) in portions, and the mixture was stirred at 70 ℃ for 1 hour. The mixture was then cooled to 0 ℃ and quenched by dropwise addition of 4M aqueous hydrochloric acid. The mixture was then made basic by the addition of 5N aqueous sodium hydroxide, followed by dilution with ethyl acetate/THF (2: 1), and then washed with saturated brine. Separating the organic phase over Na₂SO₄Dried and concentrated in vacuo to afford (RS) -4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenylamine (424mg, 84%) as yellow oil. Ms (isp): 267.2([ M + H)]⁺)。

e) (RS) -N- [4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenyl]-4-chloro-benzamide

To a stirred suspension of ((RS) -4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenylamine (420mg) in THF (5ml) were added successively triethylamine (0.55ml) and 4-chlorobenzoyl chloride (0.30ml) and stirring was continued at room temperature for 3h then the mixture was diluted with ethyl acetate then washed successively with water and with saturated brine₂SO₄Dried and concentrated in vacuo. The residue was purified by column chromatography (Flash-NH₂From Separtis; gradient: heptane/ethyl acetate/methanol) to provide (RS) -N- [4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenyl]-4-chloro-benzamide (262mg, 41%) as an off-white solid. Ms (isp): 407.4([{³⁷Cl}M+H]⁺)，405.4([{³⁵Cl}M+H]⁺)。

EXAMPLE 41

(RS) -N- [4- (3-methyl-pyrrolidin-3-yl) -phenyl ] -benzamide

To (RS) -N- [4- (1-benzyl-3-methyl-pyrrolidin-3-yl) -phenyl]A stirred suspension of-4-chloro-benzamide (36mg) in methanol (2ml) was added ammonium formate (90mg) and palladium on charcoal (19mg, 10 wt%), and the mixture was heated at 100 ℃ for 1 hour. The mixture was then cooled to room temperature, filtered through celite and the filtrate concentrated in vacuo. The residue was poured into ethyl acetate, and the resulting solution was washed with saturated brine. The organic phase is then separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (Flash-NH₂From Separtis; gradient: heptane/dichloromethane/methanol) to give (RS) -N- [4- (3-methyl-pyrrolidin-3-yl) -phenyl]Benzamide (12mg, 48%) as a yellow solid. Ms (isp): 281.2([ M + H)]⁺)。

Example 42

(RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 5-chloro-2-pyridinecarboxylic acid (CAS 86873-60-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 304.1([{³⁷Cl}M+H]⁺)，302.2([{³⁵Cl}M+H]⁺)。

Example 43

(RS) -6-chloro-pyridine-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 6-chloronicotinic acid (CAS5326-23-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 304.1([{³⁷Cl}M+H]⁺)，302.2([{³⁵Cl}M+H]⁺)。

Example 44

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6 using 5-chloro-2-isocyanatopyridine (CAS 95735-68-5) instead of phenyl isocyanate. Off-white solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 45

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4, 4-difluoro-cyclohexyl ester

a) (RS) -3- (4-isocyanato-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, CAS908334-28-1) in dichloromethane (8ml) were successively added triethylamine (0.53ml) and triphosgene (209mg), and the mixture was heated at 45 ℃ for 18 h. The mixture was then concentrated in vacuo and the residue was resuspended in diethyl ether (15ml) and stirred at room temperature for 5 min. The resulting crystals were removed by filtration and the filtrate was concentrated in vacuo to afford (RS) -3- (4-isocyanato-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (600mg, quant.) as a yellow oil, which was used in the next step without further purification.

b) (RS) -3- [4- (4, 4-difluoro-cyclohexyloxycarbonylamino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of (RS) -3- (4-isocyanato-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (110mg) in THF (1ml) were added N, N-diisopropylethylamine (0.13ml) and 4, 4-difluorocyclohexanol (68mg, CAS 22419-35-8) successively and the mixture was heated at 110 ℃ for 18 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- [4- (4, 4-difluoro-cyclohexyloxycarbonylamino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (20mg, 12%) as an off-white solid. Ms (isp): 447.4([ M + Na ]]⁺)，442.4([M+NH₄]⁺)，369.2([M+H-C₄H₈]⁺)。

c) (RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4, 4-difluoro-cyclohexyl ester

To (RS) -3- [4- (4, 4-difluoro-cyclohexyloxycarbonylamino) -phenyl]A stirred solution of tert-butyl-pyrrolidine-1-carboxylate (20mg) in THF (2ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.18ml, 4M solution), and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and made basic by the addition of 5M aqueous sodium hydroxide. The mixture was diluted with ethyl acetate/THF (1: 1) and the phases were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography(Flash-NH₂From Separtis; gradient: heptane/dichloromethane/methanol) to afford (RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4, 4-difluoro-cyclohexyl ester (10mg, 65%) as an amorphous yellow solid. Ms (isp): 325.4([ M + H)]⁺)。

Example 46

The title compound was obtained in analogy to example 45 using 4-fluoro-phenylethanol instead of 4, 4-difluorocyclohexanol. Yellow amorphous solid. Ms (isp): 329.3([ M + H)]⁺)。

Example 47

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-benzyl ester hydrochloride

The title compound was obtained in analogy to example 45 using 4-fluoro-benzyl alcohol instead of 4, 4-difluorocyclohexanol. A white solid. Ms (isp): 351.2([ M + H)]⁺)。

Example 48

(S) -2-methoxy-2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -acetamide

The title compound was obtained in analogy to example 29 using (S) - α -methoxyphenylacetic acid (CAS 26164-26-1) instead of (R) -2-phenylpropionic acid. A yellow oil. Ms (isp): 311.3([ M + H)]⁺)。

Example 49

(R) -2-methoxy-2-phenyl-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -acetamide

The title compound was obtained in analogy to example 29 using (R) - α -methoxyphenylacetic acid (CAS 3966-32-3) instead of (R) -2-phenylpropionic acid. A colorless oil. Ms (isp): 311.3([ M + H)]⁺)。

Example 50

(RS) -2- (4-bromo-phenyl) -2-methoxy-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -acetamide

The title compound was obtained in analogy to example 29 using (RS) - (4-bromo-phenyl) -methoxy-acetic acid (CAS 16053-90-0) instead of (R) -2-phenylpropionic acid. A colorless amorphous solid. Ms (isp): 391.1([{⁸¹Br}M+H]⁺)，389.0([{⁷⁹Br}M+H]⁺)。

Example 51

(RS) -4-methoxymethyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-methoxymethyl-benzoic acid (CAS 67003-50-3) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 311.3([ M + H)]⁺)。

Example 52

(RS) -4-ethoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-ethoxy-benzoic acid (CAS 619-86-3) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 311.3([ M + H)]⁺)。

Example 53

(RS) -4-propyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-propyl-benzoic acid (CAS 2438-05-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 309.2([ M + H)]⁺)。

Example 54

(RS) -4-ethynyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-ethynyl-benzoic acid (CAS 10602-00-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 291.2([ M + H)]⁺)。

Example 55

(RS) -4-cyano-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-cyano-benzoic acid (CAS 619-65-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 292.1([ M + H)]⁺)。

Example 56

(RS) -3, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 3, 4-dichloro-benzoic acid instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 339.2([{³⁷Cl}M+H]⁺)，337.2([{³⁷Cl³⁵Cl}M+H]⁺)，335.1([{³⁵Cl}M+H]⁺)。

Example 57

4-chloro-N- (4-piperidin-4-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using tert-butyl 4- (4-aminophenyl) -1-piperidinecarboxylate (CAS170011-57-1) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-benzoic acid instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 317.1([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 58

(RS) -4-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-benzoic acid instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 317.1([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 59

4-chloro-N- (4-piperazin-1-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using tert-butyl 4- (4-aminophenyl) -1-piperazinecarboxylate (CAS170911-92-9) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-benzoic acid instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 318.1([{³⁷Cl}M+H]⁺)，316.1([{³⁵Cl}M+H]⁺)。

Example 60

(RS) -2- (4-chloro-phenyl) -2-methoxy-N- ((RS) -4-pyrrolidin-3-yl-phenyl) -acetamide

The title compound was obtained in analogy to example 29 using (4-chloro-phenyl) -methoxy-acetic acid (CAS 4674-24-2) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 347.2([{³⁷Cl}M+H]⁺)，345.1([{³⁵Cl}M+H]⁺)。

Example 61

(RS) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -2- (3-trifluoromethyl-phenyl) -propionamide

(RS) -2- (3-trifluoromethyl) is used in analogy to example 29Phenyl-propionic acid (CAS68718-08-1) instead of (R) -2-phenylpropionic acid the title compound was obtained. A colorless amorphous solid. Ms (isp): 363.3(M + H)]⁺)。

Example 62

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -2- (3-trifluoromethoxy-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using (RS) -2- (3-trifluoromethoxy-phenyl) -propionic acid instead of (R) -2-phenylpropionic acid. Yellow amorphous solid. Ms (isp): 379.3(M + H)]⁺)。

Example 63

4-chloro-N- [4- ((3RS, 4SR) -4-hydroxy-pyrrolidin-3-yl) -phenyl ] -benzamide hydrochloride

a) (3RS, 4SR) -3- (4-bromo-phenyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1, 4-dibromobenzene (3.49g) in anhydrous THF (30ml) was added dropwise a solution of n-butyllithium (9.25ml, 1.6M solution in hexane) under an argon atmosphere at-78 deg.C and stirring was continued for 30 min. Boron trifluoride etherate (1.86ml) was then added dropwise and stirring continued for another 10 min. Then (1R, 5S) -6-oxa-3-aza-bicyclo [3.1.0 ] is added dropwise]A solution of hexane-3-carboxylic acid tert-butyl ester (1.37g, CAS114214-49-2) in THF (4ml) and the mixture was stirred at-78 deg.C for a further 2h, then by dropwise addition of aqueous sodium bicarbonate solution (20 m)l) quenching. The mixture was allowed to warm to room temperature and then diluted with ethyl acetate/THF (1: 1). The mixture was washed with saturated brine, then the phases were separated and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (3RS, 4SR) -3- (4-bromo-phenyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless amorphous solid. Ms (isp): 344.0([{⁸¹Br}M+H]⁺)，342.0 ([{⁷⁹Br}M+H]⁺)，288.0 ([{⁸¹Br}M+H-C₄H₈]⁺)，286.0([{⁷⁹Br}M+H-C₄H₈]⁺)。

b) (3RS, 4SR) -3- [4- (4-chloro-benzoylamino) -phenyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester Esters

(3RS, 4SR) -3- (4-bromo-phenyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (810mg), 4-chlorobenzamide (552mg), cesium carbonate (1.54g), N, N ' -dimethylethylenediamine (0.06ml) and copper (I) iodide (45mg) were added to a solution of sodium dichloroisocyanurate (Buchner's) (Buchner ' sA stirred suspension in an alkane (8ml) was heated at 120 ℃ for 18h in a sealed tube under an argon atmosphere. The mixture was then cooled to room temperature, filtered through celite and the filtrate concentrated in vacuo. The residue was poured into ethyl acetate and the resulting solution was washed successively with water and with saturated brine. The organic phase is then separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (3RS, 4SR) -3- [4- (4-chloro-benzoylamino) -phenyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (800mg, 81%) as a white solid. Ms (isp): 441.3([{³⁷Cl}M+Na]⁺)，439.3([{³⁵Cl}M+Na]⁺)，363.1([{³⁷Cl}M+H-C₄H₈]⁺)，361.2([³⁵Cl}M+H-C₄H₈]⁺)。

c) 4-chloro-N- [4- ((3RS, 4SR) -4-hydroxy-pyrroleAlk-3-yl) -phenyl]-benzamide hydrochloride

To (3RS, 4SR) -3- [4- (4-chloro-benzoylamino) -phenyl]A stirred solution of tert-butyl (47mg) -4-hydroxy-pyrrolidine-1-carboxylate in THF (1.5ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.42ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed once with THF and once with diethyl ether, and dried under vacuum at 60 ℃ to give 4-chloro-N- [4- ((3RS, 4SR) -4-hydroxy-pyrrolidin-3-yl) -phenyl]Benzamide hydrochloride (31mg, 81%) as a white crystalline solid. Ms (isp): 319.0([{³⁷Cl}M+H]⁺)，317.1([{³⁵Cl}M+H]⁺)。

Example 64

(RS) -2- (3-benzoyl-phenyl) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using (RS) -ketoprofen (CAS 22071-15-4) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 399.2(M + H)]⁺)。

Example 65

(RS) -2- (3-methoxy-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -acetamide hydrochloride

The title compound was obtained in analogy to example 29 using 3-methoxy-phenylacetic acid instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 311.2(M + H)]⁺)。

Example 66

(RS) -2- (3-cyano-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -acetamide

The title compound was obtained in analogy to example 29 using 3-cyano-phenylacetic acid instead of (R) -2-phenylpropionic acid. A colorless oil. Ms (isp): 306.2(M + H)]⁺)。

Example 67

(RS) -2- (3-methoxy-phenyl) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using 2- (3-methoxy-phenyl) -propionic acid (CAS 3146-60-9) instead of (R) -2-phenylpropionic acid. A yellow oil. Ms (isp): 325.2(M + H)]⁺)。

Example 68

(RS) -2- (3-cyano-phenyl) -N- ((RS) -4-pyrrolidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29 using 2- (3-cyano-phenyl) -propionic acid instead of (R) -2-phenylpropionic acid. A yellow oil. Ms (isp): 320.2(M + H)]⁺)。

Example 69

4-chloro-N- [4- ((3RS, 4RS) -4-fluoro-pyrrolidin-3-yl) -phenyl ] -benzamide hydrochloride

a) (3RS,4RS) -3- [4- (4-chloro-benzoylamino) -phenyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

To (3RS, 4SR) -3- [4- (4-chloro-benzoylamino) -phenyl]A stirred suspension of tert-butyl-4-hydroxy-pyrrolidine-1-carboxylate (730mg, example 63(b)) in dichloroethane (15ml) and acetonitrile (15ml) was added dropwise to diethylaminosulfur trifluoride (0.46ml) at 0 ℃ and the mixture was stirred at room temperature for 1 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (3RS,4RS) -3- [4- (4-chloro-benzoylamino) -phenyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (112mg, 15%) as a white solid. Ms (isp): 438.4([{³⁷Cl}M+NH₄]⁺)，436.3([{³⁵Cl}M+NH₄]⁺)，365.1([{³⁷Cl}M+H-C₄H₈]⁺)，363.0([{³⁵Cl}M+H-C₄H₈]⁺)。

b) 4-chloro-N- [4- ((3RS, 4RS) -4-fluoro-pyrrolidin-3-yl) -phenyl]-benzamide hydrochloride

To (3RS,4RS) -3- [4- (4-chloro-benzoylamino) -phenyl]Stirred solution of tert-butyl (4-fluoro-pyrrolidine-1-carboxylate (110mg) in THF (2ml)Adding hydrogen chloride dropwise into the solutionA solution in alkane (0.98ml, 4M solution), and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and diluted with ethyl acetate. The resulting crystals were collected by filtration, washed twice with ethyl acetate and twice with diethyl ether, then dried under vacuum at 60 ℃ to give 4-chloro-N- [4- ((3RS, 4RS) -4-fluoro-pyrrolidin-3-yl) -phenyl]Benzamide hydrochloride (81mg, 87%) as a white crystalline solid. Ms (isp): 321.1([{³⁷Cl}M+H]⁺)，319.1([{³⁵Cl}M+H]⁺)。

Example 70

(RS) -4-chloro-N- [3- (pyrrolidin-3-yloxy) -phenyl ] -benzamide

The title compound was obtained in analogy to example 39 using 3-iodoaniline instead of 4-iodoaniline. Light yellow gum. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 71

(RS) -4-chloro-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride

In analogy to example 29, tert-butyl (RS) -2- (4-aminophenyl) morpholine-4-carboxylate (CAS1002726-96-6) was used instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-Benzoic acid instead of (R) -2-phenylpropionic acid the title compound was obtained. A white solid. Ms (isp): 319.0([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 72

(RS) -4-chloro-N- (3-morpholin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -2- (3-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-benzoic acid instead of (R) -2-phenylpropionic acid. A colorless amorphous solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 73

(RS) -6-pyrazol-1-yl-N- (4-pyrrolidin-3-yl-phenyl) -nicotinamide hydrochloride

The title compound was obtained in analogy to example 29 using 6-pyrazol-1-ylnicotinic acid (CAS 253315-22-9) instead of (R) -2-phenylpropionic acid. Light brown solid. Ms (isp): 334.2(M + H)]⁺)。

Example 74

(RS) -6-chloro-N- (4-piperidin-3-yl-phenyl) -nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6-chloro-nicotinic acid (CAS5326-23-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 318.2([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 75

(RS) -3, 5-difluoro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 3, 5-difluoropicolinic acid (CAS 745784-04-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 304.1(M + H)]⁺)。

Example 76

(RS) -1H-benzimidazole-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 1H-benzimidazole-2-carboxylic acid (CAS 2849-93-6) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 307.2(M + H)]⁺)。

Example 77

(RS) -4-chloro-2-fluoro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 4-chloro-2-fluoro-benzoic acid instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 321.1([{³⁷Cl}M+H]⁺)，319.1([{³⁵Cl}M+H]⁺)。

Example 78

(RS) -5-chloro-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-picolinic acid (CAS 86873-60-1) instead of (R) -2-phenylpropionic acid. Light yellow solid. Ms (isp): 318.3([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 79

(RS) -1- (6-chloro-pyridin-3-yl) -3- (4-piperidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-5-isocyanatopyridine (CAS 125117-96-6) instead of phenyl isocyanate. Off-white solid. Ms (isp): 333.1([{³⁷Cl}M+H]⁺)，331.1([{³⁵Cl}M+H]⁺)。

Example 80

(RS) -4-chloro-N- [4- (4-methyl-morpholin-2-yl) -phenyl ] -benzamide

The title compound was obtained in analogy to example 32, using 4-chloro-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride (example 71) instead of (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride. A white solid. Ms (isp): 333.2([{³⁷Cl}M+H]⁺)，331.1([{³⁵Cl}M+H]⁺)。

Example 81

(RS) -1- (4-pyrrolidin-3-yl-phenyl) -3-quinolin-8-yl-urea

The title compound was obtained in analogy to example 6, using 8-aminoquinoline (CAS 578-66-5) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and (RS) -3- (4-isocyanato-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (example 45a) instead of phenyl isocyanate. Ash ofA white solid. Ms (isp): 333.2([ M + H)]⁺)。

Example 82

(RS) -3-fluoro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 3-fluoro-pyridine-2-carboxylic acid (CAS 152126-31-3) instead of (R) -2-phenylpropionic acid. Light yellow solid. Ms (isp): 286.2([ M + H)]⁺)。

Example 83

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-piperidin-3-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 6, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-2-isocyanatopyridine (CAS 95735-68-5) instead of phenyl isocyanate. Off-white solid. Ms (isp): 333.3([{³⁷Cl}M+H]⁺)，331.2([{³⁵Cl}M+H]⁺)。

Example 84

(RS) -quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using quinaldinic acid (CAS 93-10-7) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 318.2([ M + H)]⁺)。

Example 85

(RS) -isoquinoline-1-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 1-isoquinolinecarboxylic acid (CAS 486-73-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 318.2([ M + H)]⁺)。

Example 86

(RS) -4-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 4-chloropicolinic acid (CAS 5470-22-4) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 304.1([{³⁷Cl}M+H]⁺)，302.1([{³⁵Cl}M+H]⁺)。

Example 87

(RS) -5-bromo-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 5-bromo-pyridine-2-carboxylic acid (CAS 30766-11-1) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 348.2([{⁸¹Br}M+H]⁺)，346.0([{⁷⁹Br}M+H]⁺)。

Example 88

(RS) -2-fluoro-4-methoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 using 2-fluoro-4-methoxy-benzoic acid (CAS 394-42-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 315.1([ M + H)]⁺)。

Example 89

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -6- (2, 2, 2-trifluoro-ethoxy) -nicotinamide hydrochloride

The title compound was obtained in analogy to example 29 using 6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (CAS175204-90-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 366.2([ M + H)]⁺)。

Example 90

(RS) -4-methoxy-quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 4-methoxy-2-quinolinecarboxylic acid (CAS 15733-83-2) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 348.2([ M + H)]⁺)。

Example 91

(RS) -6-methoxy-quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 6-methoxy-quinoline-2-carboxylic acid (CAS 75433-99-7) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 348.2([ M + H)]⁺)。

Example 92

(RS) -3-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

In analogy to example 29, (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) was used instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3-chloro-benzoic acid (CA)S535-80-8) instead of (R) -2-phenylpropionic acid to obtain the title compound. A white solid. Ms (isp): 317.2([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 93

(RS) -thieno [2, 3-c ] pyridine-7-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

Thieno [2, 3-c ] is used in analogy to example 29]Pyridine-7-carboxylic acid (CAS 852532-64-0) instead of (R) -2-phenylpropionic acid gave the title compound. Yellow solid. Ms (isp): 324.2([ M + H)]⁺)。

Example 94

(RS) -5-methoxy-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 5-methoxy-pyridine-2-carboxylic acid (CAS 29082-92-6) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 298.2([ M + H)]⁺)。

Example 95

(RS) -2, 6-dimethoxy-N- (4-pyrrolidin-3-yl-phenyl) -nicotinamide

The title compound was obtained in analogy to example 29 using 2, 6-dimethoxy-nicotinic acid (CAS 16727-43-8) instead of (R) -2-phenylpropionic acid. Light yellow oil. Ms (isp): 328.2([ M + H)]⁺)。

Example 96

(RS) -3, 4-dichloro-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 4-dichloro-benzoic acid (CAS 51-44-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 353.2([{³⁷Cl}M+H]⁺)，351.3([{³⁷Cl³⁵Cl}M+H]⁺)，349.2([{³⁵Cl}M+H]⁺)。

Example 97

(RS) -4-ethoxy-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-ethoxy-benzoic acid (CAS 619-86-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 325.4([ M + H)]⁺)。

Example 98

(RS) -N- (4-piperidin-3-yl-phenyl) -4-trifluoromethyl-benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-trifluoromethyl-benzoic acid (CAS 455-24-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 349.2([ M + H)]⁺)。

Example 99

(RS) -2, 4-dichloro-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2, 4-dichloro-benzoic acid (CAS 50-84-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 353.2([{³⁷Cl}M+H]⁺)，351.3([{³⁷Cl³⁵Cl}M+H]⁺)，349.2([{³⁵Cl}M+H]⁺)。

Example 100

(RS) -4-chloro-2-fluoro-N- (4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-2-fluoro-benzoic acid (CAS 446-30-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 335.3([{³⁷Cl}M+H]⁺)，333.3([{³⁵Cl}M+H]⁺)。

Example 101

(RS) -3- (4-chloro-phenyl) -N- (4-piperidin-3-yl-phenyl) -propionamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3- (4-chloro-phenyl) -propionic acid (CAS 2019-34-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 345.2([{³⁷Cl}M+H]⁺)，343.2([{³⁵Cl}M+H]⁺)。

Example 102

(RS) -2- (4-chloro-phenyl) -N- (4-piperidin-3-yl-phenyl) -acetamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3- (4-chloro-phenyl) -acetic acid (CAS 1878-66-6) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 331.2([{³⁷Cl}M+H]⁺)，329.3([{³⁵Cl}M+H]⁺)。

Example 103

(RS) -2- (4-chloro-phenyl) -N- ((RS) -4-piperidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2- (4-chloro-phenyl) -propionic acid (CAS 938-95-4) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 345.2([{³⁷Cl}M+H]⁺)，343.3([{³⁵Cl}M+H]⁺)。

Example 104

(RS) -N- ((RS) -4-piperidin-3-yl-phenyl) -2- (3-trifluoromethyl-phenyl) -propionamide

In analogy to example 29, the title was obtained using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2- (3-trifluoromethyl-phenyl) -propionic acid (CAS68718-08-1) instead of (R) -2-phenylpropionic acidThe title compound. A white solid. Ms (isp): 377.4([ M + H)]⁺)。

Example 105

(RS) -N- ((RS) -4-piperidin-3-yl-phenyl) -2- (3-trifluoromethoxy-phenyl) -propionamide

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2- (3-trifluoromethoxy-phenyl) -propionic acid instead of (R) -2-phenylpropionic acid. A colorless gum. Ms (isp): 393.2([ M + H)]⁺)。

Example 106

(RS) -3, 5-difluoro-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 5-difluoropyridine-2-carboxylic acid (CAS 745784-04-7) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 318.3([ M + H)]⁺)。

Example 107

(RS) -4-chloro-N- (4-pyrrolidin-2-ylmethyl-phenyl) -benzamide hydrochloride

a) (RS) -2- (4-bromo-benzyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-bromo-benzyl) -pyrrolidine (1.00g, CAS 383127-68-2) in 1, 2-dichloroethane (10ml) were added N, N-diisopropylethylamine (0.79ml) and di-tert-butyl dicarbonate (1.02g) successively and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane and washed successively with water, dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated in vacuo to give (RS) -2- (4-bromo-benzyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (1.41g, quant.) as a light yellow viscous oil. Ms (isp): 342.1([{⁸¹Br}M+H]⁺)，340.2([{⁷⁹Br}M+H]⁺)，286.1([{⁸¹Br}M+H-C₄H₈]⁺)，284.2([{⁷⁹Br}M+H-C₄H₈]⁺)。

b) (RS) -2- [4- (4-chloro-benzoylamino) -benzyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

(RS) -2- (4-bromo-benzyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (400mg), 4-chlorobenzamide (280mg), cesium carbonate (766mg), N, N' -dimethylethylenediamine (0.04ml) and copper (I) iodide (23mg) in dioxaneA stirred suspension in an alkane (3ml) was heated at 120 ℃ for 18h in a sealed tube under an argon atmosphere. The mixture was then cooled to room temperature, filtered through celite and the filtrate concentrated in vacuo. The residue was poured into ethyl acetate, and the resulting solution was successively washed with water and with saturated brine. The organic phase is then separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to obtainTo (RS) -2- [4- (4-chloro-benzoylamino) -benzyl]Tert-butyl-pyrrolidine-1-carboxylate (19mg, 4%) as a pale yellow gum. Ms (isp): 417.3([{³⁷Cl}M+H]⁺)，415.3([{³⁵Cl}M+H]⁺)，361.1([{³⁷Cl}M+H-C₄H₈]⁺)，359.1([{³⁵Cl}M+H-C₄H₈]⁺)。

c) (RS) -4-chloro-N- (4-pyrrolidin-2-ylmethyl-phenyl) -benzamide hydrochloride

To (RS) -2- [4- (4-chloro-benzoylamino) -benzyl]A stirred solution of tert-butyl-pyrrolidine-1-carboxylate (16mg) in THF (1.5ml) was added dropwise to hydrogen chloride in diethyl etherA solution in alkane (0.14ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed once with ethyl acetate and once with diethyl ether and dried under vacuum at 60 ℃ to give (RS) -4-chloro-N- (4-pyrrolidin-2-ylmethyl-phenyl) -benzamide hydrochloride (3mg, 22%) as an off-white crystalline solid. Ms (isp): 317.1([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 108

(RS) -1-chloro-isoquinoline-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using 1-chloro-isoquinoline-3-carboxylic acid (CAS 1049606-80-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 354.2([{³⁷Cl}M+H]⁺)，352.2([{³⁵Cl}M+H]⁺)。

Example 109

(RS) -4-chloro-N- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -benzamide hydrochloride

a) (RS) -3- [ (E) -2- (4-Nitro-phenyl) -vinyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of N, N-diisopropylamine (3.36ml) in tetrahydrofuran (20ml) was added dropwise a solution of N-butyllithium (14.9ml, 1.6M in hexane) at-78 deg.C, and the reaction mixture was then warmed to 0 deg.C for 15 min. After cooling again to-78 ℃, a solution of diethyl phosphonate (4-nitrobenzyl ester) (5.00g, CAS 2609-49-6) in tetrahydrofuran (10ml) was added dropwise. The mixture was stirred at-78 ℃ for 60min, then a solution of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.01g, CAS 59379-02-1) in tetrahydrofuran (10ml) was added dropwise over 30 min. The mixture was then allowed to warm to room temperature and stirring was continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and acidified to pH 6 by addition of aqueous hydrochloric acid (1N). The mixture was washed successively with water and with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield (RS) -3- [ (E) -2- (4-nitro-phenyl) -vinyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (3.39g, 58%) as a yellow oil.

b) (RS) -3- [2- (4-amino-phenyl) -ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.39g) in methanol (250ml) was added palladium on charcoal (10%, 340 mg). The mixture was stirred vigorously under a hydrogen atmosphere for 7 hours. The catalyst was filtered off and the filtrate was evaporated. The crude product was purified by column chromatography (SiO2, heptane/EtO)Ac gradient) to obtain (RS) -3- [2- (4-amino-phenyl) -ethyl]Tert-butyl-pyrrolidine-1-carboxylate (2.44g, 79%) as a yellow oil. Ms (isp): 291.2([ M + H)]⁺)。

c) (RS) -3- {2- [4- (4-chloro-benzoylamino) -phenyl]-Ethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester

To (RS) -3- [2- (4-amino-phenyl) -ethyl]A stirred suspension of tert-butyl-pyrrolidine-1-carboxylate (100mg) in THF (5ml) was successively added N-methylmorpholine (0.15ml), TBTU (221mg) and 4-chloro-benzoic acid (70mg), and the mixture was heated at 50 ℃ for 18 h. The mixture is then concentrated in vacuo and the residue is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- {2- [4- (4-chloro-benzoylamino) -phenyl]-ethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (131mg, 89%) as a white solid. Ms (isp): ): 431.3([{³⁷Cl}M+H]⁺)，429.3([{³⁵Cl}M+H]⁺)，375.5([{³⁷Cl}M+H-C₄H₈]⁺)，373.2([{³⁵Cl}M+H-C₄H₈]⁺)。

d) (RS) -4-chloro-N- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl]-benzamide hydrochloride

To (RS) -3- {2- [4- (4-chloro-benzoylamino) -phenyl]A stirred solution of-ethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (130mg) in THF (3ml) was added dropwise hydrogen chloride in diethyl etherA solution in alkane (1.14ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed with ethyl acetate and dried under vacuum at 60 ℃ to give (RS) -4-chloro-N- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl]Benzamide hydrochloride (111mg, quant.) as an off-white crystalline solid. Ms (isp): 331.3([{³⁷Cl}M+H]⁺)，329.1([{³⁵Cl}M+H]⁺)。

Example 110

(RS) -4-chloro-N- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. Off-white solid. Ms (isp): 345.2([{³⁷Cl}M+H]⁺)，343.2([{³⁵Cl}M+H]⁺)。

Example 111

(RS) -2- (3-chloro-phenyl) -N- ((RS) -4-piperidin-3-yl-phenyl) -propionamide

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 2- (3-chloro-phenyl) -propionic acid (14161-84-3) instead of (R) -2-phenylpropionic acid. A colorless gum. Ms (isp): 345.2([{³⁷Cl}M+H]⁺)，343.2([{³⁵Cl}M+H]⁺)。

Example 112

4-chloro-N- ((S) -4-piperidin-3-yl-phenyl) -benzamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chlorobenzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 317.3([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 113

4-chloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chlorobenzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 317.3([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 114

(RS) -1- (5-chloro-pyridin-2-yl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -urea hydrochloride

a) (RS) -3- (2- {4- [3- (5-chloro-pyridin-2-yl) -ureido ] -2]-phenyl } -ethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester Esters

To (RS) -3- [2- (4-amino-phenyl) -ethyl]A stirred suspension of tert-butyl-pyrrolidine-1-carboxylate (100mg, example 109(b)) in dichloroethane (3ml) was successively added triethylamine (0.10ml) and triphosgene (38mg), and the mixture was heated at 80 ℃ for 30 min. To the resulting mixture was added 2-amino-5-chloropyridine (44mg, CAS 1072-98-6), and the mixture was heated at 80 ℃ for 18 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- (2- {4- [3- (5-chloro-pyridin-2-yl) -ureido)]-phenyl } -ethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (89mg, 58%) as a white solid. Ms (isp): 447.4([{³⁷Cl}M+H]⁺)，445.4([{³⁵Cl}M+H]⁺)，391.2([{³⁷Cl}M+H-C₄H₈]⁺)，389.1([{³⁵Cl}M+H-C₄H₈]⁺)。

b) (RS) -1- (5-chloro-pyridin-2-yl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl]-urea hydrochloride

To (RS) -3- (2- {4- [3- (5-chloro-pyridin-2-yl) -ureido ] -2]A stirred solution of-phenyl } -ethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (85mg) in THF (2ml) was added hydrogen chloride dropwise to the solution in hydrogen chlorideA solution in alkane (0.72ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed twice with ethyl acetate and dried under vacuum at 60 ℃ to give (RS) -1- (5-chloro-pyridin-2-yl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl]Urea hydrochloride (74mg, quant.) as a white crystalline solid. Ms (isp): 347.2([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 115

(RS) -1- (5-chloro-pyridin-2-yl) -3- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -urea hydrochloride

The title compound was obtained in analogy to example 109 step (b) and example 114, using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 361.2([{³⁷Cl}M+H]⁺)，359.2([{³⁵Cl}M+H]⁺)。

Example 116

(RS) -1- (4-chloro-phenyl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -urea hydrochloride

The title compound was obtained in analogy to example 114, using 4-chloro-aniline (CAS 106-47-8) instead of 2-amino-5-chloropyridine. A white solid. Ms (isp): 346.1([{³⁷Cl}M+H]⁺)，344.2([{³⁵Cl}M+H]⁺)。

Example 117

(RS) -5-chloro-pyridine-2-carboxylic acid [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109, using 5-chloro-pyridine-2-carboxylic acid (CAS 86873-60-1) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 332.2([{³⁷Cl}M+H]⁺)，330.2([{³⁵Cl}M+H]⁺)。

Example 118

(RS) -5-chloro-pyridine-2-carboxylic acid [4- (2-piperidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyridine-2-carboxylic acid (CAS 86873-60-1) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 346.1([{³⁷Cl}M+H]⁺)，344.2([{³⁵Cl}M+H]⁺)。

Example 119

(RS) -1- (4-chloro-phenyl) -3- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -urea hydrochloride

The title compound was obtained in analogy to example 109 step (b) and example 114, using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-aniline (CAS 106-47-8) instead of 2-amino-5-chloropyridine. A white solid. Ms (isp): 360.2([{³⁷Cl}M+H]⁺)，358.2([{³⁵Cl}M+H]⁺)。

Example 120

a) (RS) -3- {4- [2- (4-chloro-phenyl) -ethoxycarbonylamino]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (100mg, CAS908334-28-1) in dichloroethane (4ml) were added successively triethylamine (0.62ml) and triphosgene (44mg) and the mixture was heated at 80 ℃ for 1 h. To the resulting mixture was added 4-chlorophenethanol (0.06ml, CAS 1875-88-3) and the mixture was heated at 100 ℃ for 18 h. The mixture was then cooled to room temperature and diluted with dichloromethane. The mixture was washed with water, then the phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- {4- [2- (4-chloro-phenyl) -ethoxycarbonylamino]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (104mg, 63%) as an orange solid. Ms (isp): 464.3([{³⁷Cl}M+NH₄]⁺)，462.3([{³⁵Cl}M+NH₄]⁺)。391.2([{³⁷Cl}M+H-C₄H₈]⁺)，389.2([{³⁵Cl}M+H-C₄H₈]⁺)。

b) (RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-chloro-phenyl) -ethyl ester

To (RS) -3- {4- [2- (4-chloro-phenyl) -ethoxycarbonylamino]A stirred solution of tert-butyl (100mg) of-phenyl } -pyrrolidine-1-carboxylate in THF (2ml) was added dropwise hydrogen chloride in diethyl etherA solution in alkane (0.84ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and washed with water by adding 1M hydrogen hydroxideThe aqueous sodium solution was made alkaline. The mixture was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Flash-NH₂From Separtis; gradient: heptane/ethyl acetate/methanol) gave (RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 2- (4-chloro-phenyl) -ethyl ester (38mg, 49%) as a colorless gum. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 121

The title compound was obtained in analogy to example 120 using 3-chlorophenethanol instead of 4-chlorophenethanol. A colorless gum. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 122

The title compound was obtained in analogy to example 120 using 4- (trifluoromethyl) phenethyl alcohol instead of 4-chlorophenethyl alcohol. A colorless gum. Ms (isp): 379.3([ M + H)]⁺)。

Example 123

The title compound was obtained in analogy to example 120 using 3- (trifluoromethyl) phenethyl alcohol instead of 4-chlorophenethyl alcohol. A colorless gum. Ms (isp): 379.3([ M + H)]⁺)。

Example 124

The title compound was obtained in analogy to example 120 using 2, 5-difluoro-phenethyl alcohol instead of 4-chlorophenethyl alcohol. A colorless gum. Ms (isp): 347.2([ M + H)]⁺)。

Example 125

The title compound was obtained in analogy to example 120 using 4- (trifluoromethoxy) -phenethyl alcohol instead of 4-chlorophenethyl alcohol. Light yellow gum. MS(ISP)：395.2([M+H]⁺)。

Example 126

The title compound was obtained in analogy to example 120 using 3, 4-dichlorophenethyl alcohol instead of 4-chlorobenzenethanol. Orange glue. Ms (isp): 383.1([{³⁷Cl}M+H]⁺)，381.2([{³⁷Cl³⁵Cl}M+H]⁺)，379.3([{³⁵Cl}M+H]⁺)。

Example 127

The title compound was obtained in analogy to example 120 using 3-chlorophenethanol instead of 4-chlorophenethanol. Amorphous colorless solid. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 128

The title compound was obtained in analogy to example 120 using 3- (4-chlorophenyl) propan-1-ol instead of 4-chlorophenethanol. Off-white solid. Ms (isp): 361.2([{³⁷Cl}M+H]⁺)，359.2([{³⁵Cl}M+H]⁺)。

Example 129

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid indan-2-yl ester

The title compound was obtained in analogy to example 120 using 2-indanol instead of 4-chlorophenylethanol. Off-white solid. Ms (isp): 323.3([ M + H)]⁺)。

Example 130

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid (RS) -1- (4-chloro-phenyl) -2, 2, 2-trifluoro-ethyl ester

The title compound was obtained in analogy to example 120 using 1- (4-chlorophenyl) -2, 2, 2-trifluoroethanol instead of 4-chlorophenethanol. Off-white solid. Ms (isp): 401.2([{³⁷Cl}M+H]⁺)，399.2([{³⁵Cl}M+H]⁺)。

Example 131

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid (RS) -3, 3, 3-trifluoro-1-methyl-propyl ester

The title compound was obtained in analogy to example 120 using 4, 4, 4-trifluoro-2-butanol instead of 4-chlorophenethanol. Amorphous brown solid. Ms (isp): 317.3([ M + H)]⁺)。

Example 132

(RS) -3-fluoro-pyridine-2-carboxylic acid [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109 using 3-fluoro-pyridine-2-carboxylic acid (CAS 152126-31-3) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 314.1([ M + H)]⁺)。

Example 133

(RS) -3, 5-difluoro-pyridine-2-carboxylic acid [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109 using 3, 5-difluoro-pyridine-2-carboxylic acid (CAS 745784-04-7) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 332.2([ M + H)]⁺)。

Example 134

(RS) -3-fluoro-pyridine-2-carboxylic acid [4- (2-piperidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109 using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-fluoro-pyridine-2-carboxylic acid (CAS 152126-31-3) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 328.3([ M + H)]⁺)。

Example 135

(RS) -3, 5-difluoro-pyridine-2-carboxylic acid [4- (2-piperidin-3-yl-ethyl) -phenyl ] -amide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -3-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS118156-93-7) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 5-difluoro-pyridine-2-carboxylic acid (CAS 745784-04-7) instead of 4-chloro-benzoic acid. Yellow solid. Ms (isp): 346.1([ M + H)]⁺)。

Example 136

(RS) -4-chloro-N- [4- (pyrrolidine-3-carbonyl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 141 using (RS) -3- (4-bromo-benzoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (CAS 960402-23-7) instead of (RS) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester and 4-chloro-benzamide (CAS619-56-7) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. Light brown solid. Ms (isp): 331.2([{³⁷Cl}M+H]⁺)，329.3([{³⁵Cl}M+H]⁺)。

Example 137

(RS) -N- (4-piperidin-3-yl-phenyl) -4-propyl-benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-n-propyl-benzoic acid (CAS 2438-05-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 323.2([ M + H)]⁺)。

Example 138

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-trifluoromethyl-2-pyridine-carboxylic acid (CAS 80194-69-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 350.2([ M + H)]⁺)。

Example 139

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29 using 5-trifluoromethyl-2-pyridine-carboxylic acid (CAS 80194-69-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 336.2([ M + H)]⁺)。

Example 140

(RS) -4-chloro-N- (6-pyrrolidin-3-yl-pyridin-3-yl) -benzamide

(a) (RS) -2- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]-5-nitro-pyridine

To a stirred solution of 5-nitro-2-vinyl-pyridine (400mg, CAS 119836-85-0) and (4-methoxy-benzyl) -methoxymethyl-trimethylsilylmethyl-amine (1.43g, CAS 433289-59-9) in dichloromethane was added a solution of trifluoroacetic acid (0.02ml) in dichloromethane (0.3ml) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was then washed successively with saturated aqueous sodium bicarbonate solution and with saturated brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, heptane/EtOAc gradient) to yield (RS) -2- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]-5-nitro-pyridine (592mg, 71%) as orange viscous oil. Ms (isp): 314.2([ M + H)]⁺)。

(b) (RS) -6- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]-pyridin-3-ylamine

To (RS) -2- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]A solution of-5-nitro-pyridine (586mg) in methanol (2ml) was added palladium on charcoal (10%, 99 mg). The mixture was stirred under hydrogen atmosphere for 1 hour. The mixture was filtered through celite to remove the catalyst, the filter was washed with dichloromethane, and the filtrate was concentrated in vacuo to give (RS) -6- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]Pyridin-3-ylamine (532mg, quant.) as a red viscous oil. Ms (isp): 284.3([ M + H)]⁺)。

(c) (RS) -4-chloro-N- {6- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]-pyridin-3-yl } -benzamide

In analogy to example 29 step (a), (RS) -6- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl]-pyridin-3-ylamine instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chlorobenzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid the title compound was obtained. Orange glue. Ms (isp): 424.2([{³⁷Cl}M+H]⁺)，422.2([{³⁵Cl}M+H]⁺)。

(d) (RS) -4-chloro-N- (6-pyrrolidin-3-yl-pyridin-3-yl) -benzamide

To (RS) -4-chloro-N- {6- [1- (4-methoxy-benzyl) -pyrrolidin-3-yl at 0 deg.C]A stirred solution of-pyridin-3-yl } -benzamide in dichloromethane (10ml) was added successively pyridine (0.24ml) and triphosgene (455mg) and the resulting mixture was allowed to warm to room temperature while stirring was continued overnight. The mixture was then concentrated in vacuo and the residue was charged to twoAlkane (5ml) and water (5 ml). Two drops of concentrated hydrochloric acid were added and the resulting mixture was then heated at 70 ℃ for 18 h. The reaction mixture was then cooled to room temperature and quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted twice with ethyl acetate andthe combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Flash-NH₂From Separtis; gradient: Heptane/EtOAc/MeOH 100: 0 to 0: 80: 20) yielded (RS) -4-chloro-N- (6-pyrrolidin-3-yl-pyridin-3-yl) -benzamide (18mg, 8%) as an orange gum. Ms (isp): 304.1([{³⁷Cl}M+H]⁺)，302.1([{³⁵Cl}M+H]⁺)。

Example 141

(RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide hydrochloride

a) (RS) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-bromo-phenyl) -morpholine (1.00g, CAS 83555-73-1) in THF (12ml) were added N, N-diisopropylethylamine (0.84ml) and di-tert-butyl dicarbonate (1.08g) successively, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) yielded (RS) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (1.30g, 92%) as a colorless oil. Ms (isp): 344.2([{⁸1Br}M+H]⁺)，342.2([{⁷⁹Br}M+H]⁺)，288.1([{⁸¹Br}M+H-C₄H₈]⁺)，286.1([{⁷⁹Br}M+H-C₄H₈]⁺)。

b) (RS) -2- {4- [ (5-trifluoromethyl-pyridine-2-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester

(RS)-tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (500mg), 5-trifluoromethyl-pyridine-2-carboxylate amide (389mg, CAS 22245-86-9), cesium carbonate (952mg), N, N' -dimethylethylenediamine (0.04ml) and copper (I) iodide (28mg) in dioxaneA stirred suspension in an alkane (10ml) was heated in a sealed tube under an argon atmosphere at 180 ℃ for 2h in a microwave oven. The mixture was then cooled to room temperature, filtered through celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -2- {4- [ (5-trifluoromethyl-pyridine-2-carbonyl) -amino group]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (366mg, 55%) as a white solid. Ms (isp): 469.2([ M + NH ]₄]⁺)，396.0([M+H-C₄H₈]⁺)。

c) (RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide hydrochloride

To (RS) -2- {4- [ (5-trifluoromethyl-pyridine-2-carbonyl) -amino]A stirred solution of tert-butyl (360mg) of-phenyl } -morpholine-4-carboxylate in THF (3ml) was added dropwise hydrogen chloride in diethyl etherA solution in alkane (2.99ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed twice with ethyl acetate and dried under vacuum at 60 ℃ to give (RS) -5-trifluoromethyl-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide hydrochloride (263mg, 85%) as a white crystalline solid. Ms (isp): 352.3([ M + H)]⁺)。

Example 142

(RS) -4-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. Off-white solid. Ms (isp): 331.1([{³⁷Cl}M+H]⁺)，329.3([{³⁵Cl}M+H]⁺)。

Example 143

4-chloro-N- (R) -4-morpholin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 141 using (R) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 207b) instead of tert-butyl (RS) -2- (4-bromophenyl) morpholine-4-carboxylate and 4-chloro-benzamide (CAS619-56-7) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 144

4-chloro-N- ((S) -4-morpholin-2-yl-phenyl) -benzamide hydrochloride

In analogy to example 141, (S) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 208b) was used instead of tert-butyl (RS) -2- (4-bromophenyl) morpholine-4-carboxylate and 4-chloro-benzamide (CAS619-56-7) instead of 5-tris-benzoateFluoromethyl-pyridine-2-carboxylic acid amide to give the title compound. A white solid. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 145

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxymethyl) -phenyl ] -benzamide hydrochloride

(a) (RS) -3- (4-amino-benzyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (RS) -3- (4-nitro-benzyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester (70mg, CAS1121634-39-6) in methanol (5ml) was added palladium on charcoal (10%, 12 mg). The mixture was stirred vigorously under a hydrogen atmosphere for 18 hours. The catalyst was filtered off and the filtrate was evaporated. The crude product was purified by column chromatography (SiO2, heptane/EtOAc gradient) to give (RS) -3- (4-amino-benzyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester (33mg, 52%) as a light yellow viscous oil. Ms (isp): 315.2([ M + Na ]]⁺)。

(b) (RS) -4-chloro-N- [4- (pyrrolidin-3-yloxymethyl) -phenyl]-benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-amino-benzyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chlorobenzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 333.1([{³⁷Cl}M+H]⁺)，331.1([{³⁵Cl}M+H]⁺)。

Example 146

(RS) -4-chloro-2-fluoro-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 4-chloro-2-fluoro-benzamide (CAS 104326-93-4) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 337.3([{³⁷Cl}M+H]⁺)，335.3([{³⁵Cl}M+H]⁺)。

Example 147

(RS) -3, 4-dichloro-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 3, 4-dichloro-benzamide (CAS 2670-38-4) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 355.3([{³⁷Cl}M+H]⁺)，353.2([{³⁷Cl³⁵Cl}M+H]⁺)，351.3([{³⁵Cl}M+H]⁺)。

Example 148

(RS) -5-chloro-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide hydrochloride

In analogy to example 141, 5-chloro-pyridine-2-carboxylic acid amide (CAS) was used370104-72-6) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide to give the title compound. Off-white solid. Ms (isp): 320.1([{³⁷Cl}M+H]⁺)，318.2([{³⁵Cl}M+H]⁺)。

Example 149

(RS) -4-chloro-N- (4-pyrrolidin-3-ylmethyl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 107 using (RS) -3- (4-bromo-benzyl) -pyrrolidine (CAS 1158764-56-7) instead of (RS) -2- (4-bromo-benzyl) -pyrrolidine. Light brown solid. Ms (isp): 317.2([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 150

3, 4-dichloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide hydrochloride

(a) (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester&(S) -3- (4-aminophenyl) piperidine-1-carboxylic acid methyl ester Tert-butyl ester

Separation of the enantiomer of (RS) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (6.00g, CAS875798-79-1) using chiral HPLC (column: Chiralpak AD, 5X50 cm; eluent: 10% ethanol/heptane; pressure: 15 bar; flow rate: 35ml/min) gave:

(+) - (R) -3- (4-aminophenyl) piperidine-1-Carboxylic acid tert-butyl ester(2.72g, white solid) retention time 62min

(-) - (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester(2.65g, white solid) retention time 88min

(b)3, 4-dichloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 4-dichlorobenzoic acid (CAS 51-44-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 353.2([{³⁷Cl}M+H]⁺)，351.3([{³⁷Cl³⁵Cl}M+H]⁺)，349.2([{³⁵Cl}M+H]⁺)。

Example 151

(R) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3-chlorobenzoic acid (CAS535-80-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 317.3([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 152

3, 4-dichloro-N- ((S) -4-piperidin-3-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3, 4-dichlorobenzoic acid (CAS 51-44-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 353.2([{³⁷Cl}M+H]⁺)，351.3([{³⁷Cl³⁵Cl}M+H]⁺)，349.2([{³⁵Cl}M+H]⁺)。

Example 153

(S) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3-chlorobenzoic acid (CAS535-80-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 317.2([{³⁷Cl}M+H]⁺)，315.2([{³⁵Cl}M+H]⁺)。

Example 154

(RS) -3, 4-dichloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide hydrochloride

Similar to realityEXAMPLE 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 4-dichlorobenzoic acid (CAS 51-44-5) instead of 4-chlorobenzoic acid, the title compound was obtained. Off-white solid. Ms (isp): 367.1([{³⁷Cl}M+H]⁺)，365.2([{³⁷Cl³⁵Cl}M+H]⁺)，363.2([{³⁵Cl}M+H]⁺)。

Example 155

(RS) -N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -4-trifluoromethyl-benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- (trifluoromethyl) benzoic acid (CAS 455-24-3) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 363.3([ M + H)]⁺)。

Example 156

(RS) -4-fluoro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-fluorobenzoic acid (CAS456-22-4) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 313.3([ M + H)]⁺)。

Example 157

(RS) -3-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-chlorobenzoic acid (CAS535-80-8) instead of 4-chlorobenzoic acid. Off-white solid. Ms (isp): 331.2([{³⁷Cl}M+H]⁺)，329.3([{³⁵Cl}M+H]⁺)。

Example 158

(RS) -4-ethoxy-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-ethoxybenzoic acid (CAS 619-86-3) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 313.3([ M + H)]⁺)。

Example 159

(RS) -4-chloro-N- (4-piperidin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) -1-piperidinecarboxylate (CAS908334-26-9) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chlorobenzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 317.2([{³⁷Cl}M+H]⁺)，315.1([{³⁵Cl}M+H]⁺)。

Example 160

(RS) -5-chloro-pyrazine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 161

(R) -6-chloro-N- (4- (piperidin-3-yl) phenyl) nicotinamide hydrochloride

In analogy to example 29, (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) was used instead of (RS) -3- (4-amino)Phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6-chloro-nicotinic acid (CAS5326-23-8) instead of (R) -2-phenylpropionic acid the title compound was obtained. A white solid. Ms (isp): 318.2([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 162

(S) -6-chloro-N- (4- (piperidin-3-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6-chloro-nicotinic acid (CAS5326-23-8) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 318.2([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 163

(RS) -5-chloro-N- (4- (pyrrolidin-3-yl) phenyl) pyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 29 using 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 305.2([{³⁷Cl}M+H]⁺)，303.3([{³⁵Cl}M+H]⁺)。

Example 164

(RS) -5-chloro-N- (4- (2- (pyrrolidin-2-yl) ethyl) phenyl) pyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 333.3([{³⁷Cl}M+H]⁺)，331.2([{³⁵Cl}M+H]⁺)。

Example 165

(RS) -5-cyano-N- (4- (pyrrolidin-3-yl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 29 using 5-cyanopicolinic acid (CAS 53234-55-2) instead of (R) -2-phenylpropionic acid. Light brown solid. Ms (isp): 293.2([ M + H)]⁺)。

Example 166

(RS) -5-fluoro-N- (4- (2- (pyrrolidin-2-yl) ethyl) phenyl) picolinamide hydrochloride

In analogy to example 109, use was made of (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-fluoro-pyridine-2-carboxylic acid (CAS 107504-08-5) instead of 4-chlorobenzoic acid. Yellow solid. Ms (isp): 314.2([ M + H)]⁺)。

Example 167

(R) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-picolinic acid (CAS 86873-60-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 318.2([{³⁷Cl}M+H]⁺)，316.1([{³⁵Cl}M+H]⁺)。

Example 168

(S) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 5-chloro-picolinic acid (CAS 86873-60-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 318.2([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 169

(RS) -4-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 345.2([{³⁷Cl}M+H]⁺)，343.2([{³⁵Cl}M+H]⁺)。

Example 170

(RS) -4-fluoro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-fluorobenzoic acid (CAS456-22-4) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 327.2([ M + H)]⁺)。

Example 171

(RS) -5-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyridine-2-carboxylic acid (CAS 86873-60-1) instead of 4-chlorobenzoic acid. Yellow solid. Ms (isp): 346.1([{³⁷Cl}M+H]⁺)，344.2([{³⁵Cl}M+H]⁺)。

Example 172

(RS) -5-ethoxy-N- (4- (2- (pyrrolidin-2-yl) ethyl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS117625-90-8) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-ethoxy-pyridine-2-carboxylic acid (CAS 98353-08-3) instead of 4-chlorobenzoic acid. Light yellow solid. Ms (isp): 340.2([ M + H)]⁺)。

Example 173

(RS) -6-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 6-chloro-pyridine-3-carboxylic acid (CAS5326-23-8) instead of 4-chlorobenzoic acid. Yellow solid. Ms (isp): 346.2([{³⁷Cl}M+H]⁺)，344.2([{³⁵Cl}M+H]⁺)。

Example 174

(RS) -5-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) pyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.1([{³⁵Cl}M+H]⁺)。

Example 175

(RS) -N- (4- (2- (piperidin-2-yl) ethyl) phenyl) -4- (trifluoromethyl) benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- (trifluoromethyl) benzoic acid (CAS 455-24-3) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 377.2([ M + H)]⁺)。

Example 176

(RS) -3, 4-dichloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 4-dichlorobenzoic acid (CAS 51-44-5) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 381.1([{³⁷Cl}M+H]⁺)，379.1([{³⁷Cl³⁵Cl}M+H]⁺)，377.1([{³⁵Cl}M+H]⁺)。

Example 177

(RS) -4-ethynyl-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 109, using (RS) -2-formyl-piperidine-1-carboxylic acid tert-butyl ester (CAS157634-02-1) instead of (RS) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- (ethynyl) benzoic acid (CAS 10602-00-3) instead of 4-chlorobenzoic acid. A white solid. Ms (isp): 333.2([ M + H)]⁺)。

Example 178

(RS) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

Similar to the implementationExample 29 the title compound was obtained using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6- (2, 2, 2-trifluoro-ethoxy) -nicotinic acid (CAS175204-90-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 380.3([ M + H)]⁺)。

Example 179

(RS) -5-ethoxy-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide; hydrochloride salt

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-ethoxy-pyridine-2-carboxylic acid (CAS 98353-08-3) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 326.3([ M + H)]⁺)。

Example 180

(RS) -5-fluoro-N- (4- (piperidin-3-yl) phenyl) picolinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-fluoro-pyridine-2-carboxylic acid (CAS 107504-08-5) instead of (R) -2-phenylpropionic acid. Light yellow solid. Ms (isp): 300.3([ M + H)]⁺)。

Example 181

(RS) -4-chloro-N- (5- (pyrrolidin-3-yl) pyridin-2-yl) benzamide hydrochloride

(a)3- (6-Aminopyridin-3-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

To a solution of 3-trifluoromethanesulfonyloxy-2, 5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (395mg, CAS 630121-86-7) in THF (10ml) at room temperature under an argon atmosphere was added potassium carbonate (434mg), 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (329mg, CAS 827614-64-2), tetrakis (triphenylphosphine) palladium (0) (14.4mg) and water (200 μ l). The reaction mixture was heated to 70 ℃ and stirred for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with ether. The phases were separated and the organic layer was washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (Flash-NH₂From Separtis; gradient: 0% to 100% EtOAc in heptane, then 0% to 10% MeOH in EtOAc) yielded 3- (6-aminopyridin-3-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (325mg, 46%) as a light yellow solid. Ms (isp): 262.2([ M + H)]⁺)，206.1([M+H-C₄H₈]⁺)。

(b) (RS) -3- (6-Aminopyridin-3-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3- (6-aminopyridin-3-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (145mg) in methanol (12ml) was added palladium on charcoal (10%, 12 mg). The mixture was stirred vigorously under a hydrogen atmosphere for 48 hours. The catalyst was filtered off and the filtrate was evaporatedTert-butyl (RS) -3- (6-aminopyridin-3-yl) pyrrolidine-1-carboxylate (167mg, quant.) was obtained as a pale yellow solid. Ms (isp): 264.2([ M + H)]⁺)，208.2([M+H-C₄H₈]⁺)。

(c) (RS) -4-chloro-N- (5- (pyrrolidin-3-yl) pyridin-2-yl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (6-aminopyridin-3-yl) pyrrolidine-1-carboxylic acid tert-butyl ester instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-benzoic acid (CAS74-11-3) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 304.2([{³⁷Cl}M+H]⁺)，302.3([{³⁵Cl}M+H]⁺)。

Example 182

(RS) -4-methyl-N- (4- (pyrrolidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using 4-methylbenzoic acid (CAS 99-94-5) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 281.3([ M + H)]⁺)。

Example 183

(RS) -4-methoxy-N- (4- (pyrrolidin-3-yl) phenyl) benzamide hydrochloride

4-Methoxybenzoic acid (CAS 100-09-4) is used in analogy to example 29The title compound was obtained for (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 297.4([ M + H)]⁺)。

Example 184

(RS) -N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and benzoic acid (CAS65-85-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 281.3([ M + H)]⁺)。

Example 185

(RS) -4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-methylbenzoic acid (CAS 99-94-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 295.3([ M + H)]⁺)。

Example 186

(RS) -4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4-methoxybenzoic acid (CAS 100-09-4) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 311.3([ M + H)]⁺)。

Example 187

(RS) -4-chloro-N- (5- (piperidin-3-yl) pyridin-2-yl) benzamide hydrochloride

The title compound was obtained in analogy to example 181, using 5-trifluoromethanesulfonyloxy-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (CAS 180691-65-0) instead of 3-trifluoromethanesulfonyloxy-2, 5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester. Off-white solid. Ms (isp): 318.3([{³⁷Cl}M+H]⁺)，316.2([{³⁵Cl}M+H]⁺)。

Example 188

(RS) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141, using benzamide (CAS 55-21-0) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 283.3([M+H]⁺)。

Example 189

(RS) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 4-methyl-benzamide (CAS619-55-6) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 297.4([ M + H)]⁺)。

Example 190

(RS) -4-methoxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 4-methoxy-benzamide (CAS 3424-93-9) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 313.3([ M + H)]⁺)。

Example 191

(RS) -N- (4- (piperidin-3-yl) phenyl) -5- (2, 2, 2-trifluoroethoxy) picolinamide hydrochloride

Similar to the implementationExample 29 the title compound was obtained using (RS) -3- (4-aminophenyl) -1-piperidinecarboxylic acid tert-butyl ester (CAS875798-79-1) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5- (2, 2, 2-trifluoro-ethoxy) -pyridine-2-carboxylic acid (CAS 881409-53-6) instead of (R) -2-phenylpropionic acid. Light yellow solid. Ms (isp): 380.3([ M + H)]⁺)。

Example 192

(RS) -4- (benzyloxy) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 4-benzyloxy-benzamide (CAS-56442-43-4) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 389.3([ M + H)]⁺)。

Example 193

(RS) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 141, using 6-chloronicotinamide (CAS-6271-78-9) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 318.0([ M + H)]⁺)。

Example 194

(RS) -2- (4- (6-cyanonicotinamido) phenyl) morpholine-4-chloride

The title compound was obtained in analogy to example 141, using 6-cyano-nicotinamide (CAS-14178-45-1) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. Off-white solid. Ms (isp): 309.2([ M + H)]⁺)。

Example 195

(R) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141 using (R) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 207b) instead of tert-butyl (RS) -2- (4-bromophenyl) morpholine-4-carboxylate and 4-methyl-benzamide (CAS619-55-6) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 297.3([ M + H)]⁺)。

Example 196

(S) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

In analogy to example 141, (S) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 208b) was used instead of (RS) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylateAnd 4-methyl-benzamide (CAS619-55-6) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide to obtain the title compound. A white solid. Ms (isp): 297.3([ M + H)]⁺)。

Example 197

(RS) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141, using 4-ethoxy-benzamide (CAS-55836-71-0) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 327.3([ M + H)]⁺)。

Example 198

(RS) -4-Ethyl-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141 using 4-ethyl-benzamide (CAS-33695-58-8) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 311.3([ M + H)]⁺)。

Example 199

(RS) -4-hydroxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

a) (RS) -2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester

(RS) -tert-butyl 2- (4- (4- (benzyloxy) benzoylamino) phenyl) morpholine-4-carboxylate (31mg, 63. mu. mol, intermediate from example 192) was dissolved in methanol (15ml) and treated with 10% Pd/C (10mg) and hydrogenated at room temperature for 1.5 h. The catalyst was then removed by filtration and the solvent removed in vacuo to give 25mg of tert-butyl 2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylate (MS (ISP): 343.2([ M + H)]⁺) Which is used directly in the next step.

b) (RS) -4-hydroxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

(RS) -2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester (24mg, 60.2. mu. mol) was dissolved in THF (0.85ml) and washed with di4M HCl in alkane (0.23ml, 0.9 mmol). After stirring at 60 ℃ for 3.5h, the mixture was cooled to room temperature, diluted with ethyl acetate and the resulting crystals were collected by filtration, washed with ethyl acetate and diethyl ether and dried under high vacuum to give (RS) -4-hydroxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride (19mg, 94%) as a white crystalline solid. Ms (isp): 299.3([ M + H)]⁺)。

Example 200

(R) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

Analogously to example 29The title compound was obtained by substituting (R) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) for tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-3-methoxybenzoic acid (CAS 85740-98-3) for (R) -2-phenylpropionic acid. A white solid. Ms (isp): 347.2([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 201

(S) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-3-methoxybenzoic acid (CAS 85740-98-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 202

(R) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3-chloro-4-methoxybenzoic acid (CAS 37908-96-6) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 347.2([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 203

(S) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3-chloro-4-methoxybenzoic acid (CAS 37908-96-6) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 347.3([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 204

(R) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

a) (RS) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1- (iv) Carboxylic acid tert-butyl ester

The title compound was obtained in analogy to example 29 step (a) using 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS175204-90-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 466.2([ M + H)]⁺)，410.2([M+H-C₄H₈]⁺)。

b) (R) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1- (iv) Carboxylic acid tert-butyl ester&(S) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -substituted benzene Pyrrolidine-1-carboxylic acid tert-butyl ester

Separation of the enantiomer of (RS) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl ] -amino } -phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (310mg) using chiral HPLC (column: Chiralpak AD, 5X50 cm; eluent: 25% isopropanol/heptane; pressure: 15 bar; flow rate: 35ml/min) gave:

(+) - (R) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1- (iv) Carboxylic acid tert-butyl ester(139mg, white solid)

Retention time 60min

(-) - (S) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1- (iv) Carboxylic acid tert-butyl ester(138mg, white solid)

Retention time 81min

c) (R) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

To (R) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (135mg, example 204b) in THF (3ml) as a stirred solution was added hydrogen chloride in di-tert-butyl acetate dropwiseA solution in alkane (1.09ml, 4M solution) and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃ and the resulting crystals were collected by filtration, washed twice with ethyl acetate and dried under vacuum at 60 ℃ to give (R) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride (113mg, 97%) as a white crystalline solid. Ms (isp): 366.1([M+H]⁺)。

Example 205

(S) -N- (4- (pyrrolidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

In analogy to example 204 step (c), (S) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl was used]-amino } -phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (example 204b) instead of (R) -3- (4- { [6- (2, 2, 2-trifluoro-ethoxy) -pyridine-3-carbonyl]-amino } -phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester to obtain the title compound. A white solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 206

(RS) -4- (4-chlorophenoxy) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

a)4- (4-chlorophenoxy) benzamide

4- (4-chlorophenoxy) benzoic acid (CAS-21120-67-2) (500mg, 2.01mmol) and 1, 1-carbonyldiimidazole (504mg, 3.02mmol) were dissolved in DMF (5ml) and stirred at 50 ℃ for 1 h. After cooling to room temperature, 25% aqueous ammonium hydroxide (4.51g, 4.96ml, 32.2mmol) was added dropwise. After stirring for 3h, the suspension was filtered, the solid was washed with ethyl acetate and diethyl ether and dried under high vacuum to give 500mg of a white solid, ms (isp): 248.1([ M + H)]⁺)。

b)(RS) -4- (4-chlorophenoxy) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141 using 4- (4-chlorophenoxy) benzamide instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 409.2([ M + H)]⁺)。

Example 207

(R) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

a) (R) -2- (4-bromophenyl) morpholine:

the enantiomer of (RS) -2- (4-bromo-phenyl) -morpholine (2.27g, CAS-1131220-82-0) was separated using chiral HPLC (column: Chiralpak IA, 8X32 cm; eluent: n-heptane/ethanol (1: 11) containing 0.1% DEA) to give:

(S) -2- (4-bromo-phenyl) -morpholine: collected from 7.6min to 9.4min. yield 0.97g (42.9%), 97.4% ee

(R) -2- (4-bromo-phenyl) -morpholine: yield 0.99g (43.6%), 97.4% ee from 9.8min to 13.9min was collected

b) (R) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester

(R) -2- (4-bromophenyl) morpholine (6g, 24.8mmol) and N, N-diisopropylethylamine (3.84g, 5.19ml, 29.7mmol) in THF (60ml) were treated with di-tert-butyl dicarbonate (6.49g, 29.7 mmol). The reaction mixture was stirred at room temperature for 17h, concentrated in vacuo, diluted with ethyl acetate, washed with 1M aqueous citric acid, dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization of the crude material from heptane/ethyl acetate yielded 8.48g (87%) of tert-butyl (R) -2- (4-bromophenyl) morpholine-4-carboxylate as a white solidAnd (3) a body. Ms (isp): 344.1([ M + H)]⁺)。

c) (R) -2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester

(R) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (5.4g, 15.8mmol), diphenylazomethine (3.43g, 3.17ml, 18.9mmol), BINAP (737mg, 1.18mmol) and Pd2(dba)3(361mg, 0.39mmol) were dissolved in anhydrous and degassed toluene (108ml) under argon and treated with sodium tert-butoxide (2.12g, 22.1 mmol). The dark brown mixture was stirred at 90 ℃ for 18 h. The yellow/brown reaction mixture was diluted with toluene (100ml), cooled to room temperature and extracted twice with water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was diluted with 50ml of hexane, stirred for 1h and filtered to give a yellow solid (7.4g) which was purified by column chromatography (50g silica gel, 5% to 15% ethyl acetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17h, filtered off and dried in high vacuum to yield 6.15g (86%) of a yellow solid. Ms (isp): 443.4([ M + H)]⁺)。

d) (R) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester

A suspension of (R) -tert-butyl 2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylate (6g, 13.6mmol), ammonium formate (12.8g, 203mmol) and Pd/C5% (721mg, 0.339mmol) in methanol (103ml) was stirred at 60 ℃ for 2 h. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5M HCl. The combined aqueous phases were basified with 2M-NaOH and extracted twice with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and dried in vacuo to give 3.04g of an off-white solid. Ms (isp): 279.1([ M + H)]⁺)。

e) (R) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

In analogy to example 29, tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate was used instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6-chloro-nicotinic acid (CAS-53)26-23-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) the title compound was obtained. A white solid. Ms (isp): 318.1([ M + H)]⁺)。

Example 208

(S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

a) (S) -2- (4-bromophenyl) morpholine:

(S) -2- (4-bromo-phenyl) -morpholine: collecting from 7.6min to 9.4min.

Yield 0.97g (42.9%), 97.4% ee

(R) -2- (4-bromo-phenyl) -morpholine: collecting from 9.8min to 13.9min

Yield 0.99g (43.6%), 97.4% ee

b) (S) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester:

(S) -2- (4-bromo-phenyl) -morpholine (36.3g, 150mmol) and N, N-diisopropylethylamine (23.3g, 31.4ml, 180mmol) in THF (360ml) were treated with di-tert-butyl dicarbonate (39.3g, 180 mmol). The reaction mixture was stirred at room temperature for 17h, concentrated in vacuo, diluted with ethyl acetate, washed with 1M aqueous citric acid (2 × 100ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was crystallized from hexane to yield 47.1g (92%) of tert-butyl (S) -2- (4-bromophenyl) morpholine-4-carboxylate as an off-white solid. Ms (isp): 344.1([ M + H)]⁺)。

c) (S) -2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (S) -2- (4-bromophenyl) morpholine-4-carboxylate (47g, 137mmol), diphenylmethanimine (29.9g, 27.6m, 165mmol), BINAP (6.41g, 10.3mmol) and Pd2(dba)3(3.14g, 3.43mmol) were dissolved in anhydrous and degassed toluene (940ml) under argon and treated with sodium tert-butoxide (18.5g, 192 mmol). The dark brown mixture was stirred at 90 ℃ for 18 h. The yellow/brown reaction mixture was diluted with toluene (700ml), cooled to room temperature and extracted twice with water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was diluted with 300ml of hexane, stirred for 1h and filtered off to give an orange solid (68g) which was purified by column chromatography (1.3kg silica gel, 20% ethyl acetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17h, filtered off and dried in high vacuum to give 54.1g (89%) of a yellow solid. Ms (isp): 443.3([ M + H)]⁺)。

d) (S) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester:

a suspension of (S) -tert-butyl 2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylate (54.1g, 122mmol), ammonium formate (116g, 1.83mol) and Pd/C5% (6.5g, 3.06mmol) in methanol (930ml) was stirred at 60 ℃ for 2 h. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5M aqueous HCl. The combined aqueous phases were basified with 2M aqueous NaOH and extracted twice with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and dried in vacuo to yield 31.95g of an off-white solid. Ms (isp): 279.1([ M + H)]⁺)。

e) (S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

In analogy to example 29, (S) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS-1002726-96-6) was used instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 6-chloro-nicotinic acid (CA)S-5326-23-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) the title compound was obtained. A white solid. Ms (isp): 318.1([ M + H)]⁺)。

Example 209

(RS) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 3-chloro-benzoic acid instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 317.1([ M + H)]⁺)。

Example 210

(RS) -5-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 5-chloronicotinic acid instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 318.1([ M + H)]⁺)。

Example 211

(RS) -4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoic acid methyl ester hydrochloride

a)(RS) -2- (4- (4- (4- (methoxycarbonyl) benzyloxy) benzoylamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester Butyl ester:

tert-butyl (RS) -2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylate (100mg, 0.25mmol, example 199a), methyl 4- (bromomethyl) benzoate (129mg, 0.565mmol), potassium carbonate (78mg, 0.565mmol) and potassium iodide (6.2mg, 0.037mmol) were combined with acetone (6ml) to give a light brown suspension. The reaction mixture was stirred at 60 ℃ for 17 h. The crude reaction mixture was concentrated in vacuo, mixed with water and extracted with dichloromethane (3 ×). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was mixed with methanol (15ml), stirred at reflux for 15 minutes, cooled to room temperature and filtered off to give 99mg of a white solid. Ms (isp): 547.2([ M + H)]⁺)。

b)(RS) -4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoic acid methyl ester salt Acid salt:

the title compound was obtained in analogy to example 29 (step b), starting from (RS) -tert-butyl 2- (4- (4- (4- (methoxycarbonyl) benzyloxy) benzoylamino) phenyl) morpholine-4-carboxylate.

A white solid. Ms (isp): 447.2([ M + H)]⁺)。

Example 212

(RS) -4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoic acid hydrochloride

Methyl (RS) -4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoate hydrochloride (40mg, 0.083mmol, example 211) was suspended in THF (1ml) and methanol (0.25ml) and 1M aqueous LiOH (0.207ml, 0.207mmol) was added. The solution was stirred at room temperature for 17h, concentrated in vacuo, suspended in water (2ml) and acidified with 1M aqueous HCl. The precipitate was filtered off and dried under high vacuum to give 30mg of a white solid. Ms (isp): 433.2([ M + H)]⁺)。

Example 213

(RS) -2-chloro-4- (4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) benzoic acid methyl ester hydrochloride

a)(RS) -2- (4- (4- (3-chloro-4- (methoxycarbonyl) phenoxy) benzoylamino) phenyl) morpholine-4-carboxylic acid methyl ester Tert-butyl ester:

tert-butyl (RS) -2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylate (150mg, 1.13mmol, example 199a), 3-chloro-4- (methoxycarbonyl) phenylboronic acid (CAS-603122-82-3) (242mg, 1.13mmol), copper (II) acetate (205mg, 1.13mmol) and pyridine (149mg, 1.88mmol) were combined with dichloromethane (3ml) to give a blue suspension. The reaction mixture was stirred for 40h, filtered through celite and concentrated. The residue was dissolved in dichloromethane and adsorbed on SiO₂Chromatography (20g of silica gel, 10 to 35% ethyl acetate in heptane, gives 70mg of a colourless, amorphous solid MS (ISP): 567.3([ M + H)]⁺)。

b)(RS) -2-chloro-4- (4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) benzoic acid methyl ester hydrochloride Salt:

the title compound was obtained in analogy to example 29 (step b) starting from (RS) -tert-butyl 2- (4- (4- (3-chloro-4- (methoxycarbonyl) phenoxy) benzoylamino) phenyl) morpholine-4-carboxylate.

A white solid. Ms (isp): 467.3([ M + H ]]⁺)。

Example 214

(RS) -4-Cyclopropylmethoxy-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride

a) (RS) -2- (4- (4- (cyclopropylmethoxy) benzoylamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (RS) -2- (4- (4-hydroxybenzoylamino) phenyl) morpholine-4-carboxylate (60mg, 0.15mmol, example 199a), (bromomethyl) cyclopropane (47mg, 0.339mmol), potassium carbonate (47mg, 0.339mmol) and potassium iodide (3.7mg, 0.023mmol) were mixed with acetone (4ml) to give a light brown suspension. The reaction mixture was stirred at 60 ℃ for 17 h. The crude reaction mixture was concentrated in vacuo, mixed with water and extracted with dichloromethane (3 ×). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was mixed with methanol (5ml), stirred for 15 minutes and filtered off to give 48mg of a white solid. Ms (isp): 453.3([ M + H)]⁺)。

b) (RS) -4-Cyclopropylmethoxy-N- (4-morpholin-2-yl-phenyl) -benzamide hydrochloride

The title compound was obtained in analogy to example 29 (step b) starting from (RS) -2- (4- (4- (cyclopropylmethoxy) benzoylamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester.

A white solid. Ms (isp): 353.3([ M + H)]⁺)。

Example 215

(RS) -2-chloro-4- (4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) benzoic acid hydrochloride

The title compound was obtained in analogy to example 212 using (RS) -methyl 4- ((4- (4- (morpholin-2-yl) phenylcarbamoyl) phenoxy) methyl) benzoate hydrochloride. A white solid. Ms (isp): 453.2([ M + H)]⁺)。

Example 216

(RS) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4- (methylthio) benzoic acid instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 329.1([ M + H)]⁺)。

Example 217

(RS) -2-methyl-N- (4- (morpholin-2-yl) phenyl) thiazole-4-carboxamide hydrochloride

The title compound was obtained in analogy to example 141 using 2-methylthiazole-4-carboxamide (CAS-31825-95-3) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide.

Yellow solid. Ms (isp): 304.2([ M + H)]⁺)。

Example 218

(RS) -2-chloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-chloroisonicotinic acid instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 318.1([ M + H)]⁺)。

Example 219

(RS) -5, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 5, 6-dichloronicotinic acid instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 352.1([ M + H)]⁺)。

Example 220

The title compound was obtained in analogy to example 214, using 3-bromomethyl-3-methyloxetane (CAS-78385-26-9) instead of (bromomethyl) cyclopropane. A white solid. Ms (isp): 419.2([ M + H)]⁺)。

Example 221

(RS) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2, 6-dichloroisonicotinic acid (CAS-5398-44-7) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU. A white solid. Ms (isp): 352.3([ M + H)]⁺)。

Example 222

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

Similar toExample 29 using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS-159783-29-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) the title compound was obtained. A white solid. Ms (isp): 382.4([ M + H)]⁺)。

Example 223

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS175204-90-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 380.3([ M + H)]⁺)。

Example 224

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS175204-90-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 380.3([ M + H)]⁺)。

Example 225

(S) -3-chloro-4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3-chloro-4-methyl-benzoic acid (CAS 5162-82-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 331.3([{³⁷Cl}M+H]⁺)，329.4([{³⁵Cl}M+H]⁺)。

Example 226

(S) -4-chloro-3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4-chloro-3-methyl-benzoic acid (CAS 7697-29-2) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 331.3([{³⁷Cl}M+H]⁺)，329.4([{³⁵Cl}M+H]⁺)。

Example 227

(S) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3, 4-dimethyl-benzoic acid (CAS 619-04-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 309.4([ M + H)]⁺)。

Example 228

(RS) -4- ((3-Methylooxetan-3-yl) methoxy) -N- (4- (morpholin-2-yl) phenyl) benzamide

The title compound was obtained in analogy to example 214, using 3-bromomethyl-3-methyloxetane (CAS-78385-26-9) instead of (bromomethyl) cyclopropane and performing the deprotection step using 10 equivalents of TFA at-10 ℃ in dichloromethane (17 h). A white solid. Ms (isp): 383.2([ M + H)]⁺)。

Example 229

(R) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

In analogy to example 141, (R) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 207b) was used instead of (RS) -2- (4-bromophenyl) morpholineTert-butyl-4-carboxylate and 4-chloro-2-fluoro-benzamide (CAS 104326-93-4) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide to obtain the title compound. A white solid. Ms (isp): 337.1([{³⁷Cl}M+H]⁺)，335.1([{³⁵Cl}M+H]⁺)。

Example 230

(S) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 141 using (S) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 208b) instead of (RS) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate and 4-chloro-2-fluoro-benzamide (CAS 104326-93-4) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 320.1([{³⁷Cl}M+H]⁺)，318.2([{³⁵Cl}M+H]⁺)。

Example 231

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-5-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-phenyl-thiazole-5-carboxylic acid (CAS-10058-38-5) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Yellow solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 232

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (tetrahydro-2H-pyran-4-yloxy) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (tetrahydro-2H-pyran-4-yloxy) nicotinic acid (CAS-886851-55-4) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17H at room temperature). A white solid. Ms (isp): 384.2([ M + H)]⁺)。

Example 233

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-4-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-phenylthiazole-4-carboxylic acid (CAS-7113-10-2) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 366.2([ M + H)]⁺)。

Example 234

(S) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3- (trifluoromethyl) benzoic acid (CAS 454-92-2) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 349.3([ M + H)]⁺)。

Example 235

(S) -2- (4-chlorophenoxy) -N- (4- (piperidin-3-yl) phenyl) acetamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 2- (4-chlorophenoxy) acetic acid (CAS 122-88-3) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 347.2([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 236

(S) -4- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

In analogy to example 29, use is made of (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (exampleExample 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 4- (methylthio) benzoic acid (CAS 13205-48-6) instead of (R) -2-phenylpropionic acid the title compound was obtained. Off-white solid. Ms (isp): 327.3([ M + H)]⁺)。

Example 237

(S) -4- (ethylsulfanyl) -N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 4- (ethylthio) benzoic acid (CAS 13205-49-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 341.3([ M + H)]⁺)。

Example 238

5-chloro-pyrazine-2-carboxylic acid ((S) -4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 239

5-chloro-pyrazine-2-carboxylic acid ((R) -4-piperidin-3-yl-phenyl) -amide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-chloro-pyrazine-2-carboxylic acid (CAS 36070-80-1) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 319.2([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

Example 240

(S) -4- (piperidin-3-yl) phenylcarbamic acid 4-chlorobenzyl ester hydrochloride

The title compound was obtained in analogy to example 120, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and (4-chlorophenyl) methanol (CAS 873-76-7) instead of 4-chlorophenethanol. Off-white solid. Ms (isp): 347.1([{³⁷Cl}M+H]⁺)，345.2([{³⁵Cl}M+H]⁺)。

Example 241

(RS) -N- (4- (morpholin-2-yl) phenyl) -6-morpholinonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6-morpholinonicotinic acid (CAS-120800-52-4) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 369.1([ M + H)]⁺)。

Example 242

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6- (trifluoromethyl) nicotinic acid (CAS 231291-22-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 350.4([ M + H)]⁺)。

Example 243

(S) -6-methyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide hydrochloride

The title compound is obtained in analogy to example 29, using (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6-methylnicotinic acid (CAS3222-47-7) instead of (R) -2-phenylpropionic acidA compound (I) is provided. A white solid. Ms (isp): 296.4([ M + H)]⁺)。

Example 244

(S) -6- (methylthio) -N- (4- (piperidin-3-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6- (methylthio) nicotinic acid (CAS 74470-25-0) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 328.4([ M + H)]⁺)。

Example 245

(RS) -6-ethoxy-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6-ethoxynicotinic acid (CAS-97455-65-7) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 328.3([ M + H)]⁺)。

Example 246

(S) -3- (ethylsulfanyl) -N- (4- (piperidin-3-yl) phenyl) benzamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3- (ethylthio) benzoic acid (CAS 5537-74-6) instead of (R) -2-phenylpropionic acid. A colorless gum. Ms (isp): 341.1([ M + H)]⁺)。

Example 247

(S) -5-methyl-N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 5-methyl-pyrazine-2-carboxylic acid (CAS 5521-55-1) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 297.4([ M + H)]⁺)。

Example 248

(S) -N- (4- (piperidin-3-yl) phenyl) -5- (trifluoromethyl) pyrazine-2-carboxamide hydrochloride

In analogy to example 29, (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) was used instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5- (tris-phenyl) pyrrolidine-1-carboxylic acid tert-butyl esterFluoromethyl) pyrazine-2-carboxylic acid (CAS 1060814-50-7) instead of (R) -2-phenylpropionic acid the title compound was obtained. A white solid. Ms (isp): 351.4([ M + H)]⁺)。

Example 249

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenyl

Azole-4-carboxamide hydrochloride

In analogy to example 29, (RS) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS-1002726-96-6) was used instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 2-phenylOxazole-4-carboxylic acid (CAS-23012-16-0) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) gave the title compound. A white solid. Ms (isp): 350.1([ M + H)]⁺)。

Example 250

(S) -N- (4- (piperidin-3-yl) phenyl) -5- (2, 2, 2-trifluoroethoxy) pyrazine-2-carboxamide hydrochloride

In analogy to example 29, (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) was used instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5- (2, 2)-trifluoroethoxy) pyrazine-2-carboxylic acid (CAS 1174323-36-4) instead of (R) -2-phenylpropionic acid the title compound was obtained. A white solid. Ms (isp): 381.4([ M + H)]⁺)。

Example 251

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 5-bromo-pyrazine-2-carboxylic acid (CAS 876161-05-6) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 363.2([{⁸¹Br}M+H]⁺)，361.2([{⁷⁹Br}M+H]⁺)。

Example 252

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6-bromo-nicotinic acid (CAS6311-35-9) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 362.2([{⁸¹Br}M+H]⁺)，360.2([{⁷⁹Br}M+H]⁺)。

Example 253

(S) -3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3-methylbenzoic acid (CAS99-04-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 295.2([ M + H)]⁺)。

Example 254

Cis- (RS) -4-methoxy-N- (4- (morpholin-2-yl) phenyl) cyclohexanecarboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4-methoxycyclohexanecarboxylic acid cis/trans mixture (CAS-95233-12-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). The cis/trans isomer was isolated by chromatography using silica gel (heptane/ethyl acetate 1: 1). Light brown solid. Ms (isp): 319.2([ M + H)]⁺)。

Example 255

Trans- (RS) -4-methoxy-N- (4- (morpholin-2-yl) phenyl) cyclohexanecarboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4-methoxycyclohexanecarboxylic acid cis/trans mixture (CAS-95233-12-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). The cis/trans isomer was isolated by chromatography using silica gel (heptane/ethyl acetate 1: 1). A white solid. Ms (isp): 319.2([ M + H)]⁺)。

Example 256

(S) -6-ethoxy-N- (4- (piperidin-3-yl) phenyl) nicotinamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6-ethoxy-nicotinic acid (CAS 97455-65-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 326.4([ M + H)]⁺)。

Example 257

(S) -5- (methylthio) -N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide

In analogy to example 29, use is made of (S) -3- (4-aminophenyl) piperidine-1-carboxylic acidTert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5- (methylthio) -pyrazine-2-carboxylic acid (CAS 1174322-69-0) instead of (R) -2-phenylpropionic acid the title compound was obtained. A white solid. Ms (isp): 329.4([ M + H)]⁺)。

Example 258

(S) -4- (piperidin-3-yl) phenylcarbamic acid (2, 3-dihydro-1H-inden-2-yl) ester 2, 2, 2-trifluoroacetate salt

The title compound was obtained in analogy to example 120, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate and 2-indanol (CAS4254-29-9) instead of 4-chlorophenethanol. Off-white solid. Ms (isp): 337.5([ M + H)]⁺)。

Example 259

(S) -3- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 3- (methylthio) -benzoic acid (CAS 825-99-0) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 327.3([ M + H)]⁺)。

Example 260

(R) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3, 4-dimethylbenzoic acid (CAS 619-04-5) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 309.5([ M + H)]⁺)。

Example 261

(R) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 3- (trifluoromethyl) benzoic acid (CAS 454-92-2) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 349.3([ M + H)]⁺)。

Example 262

(R) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared as in example 207-steps a-d) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 3-chlorobenzoic acid (CAS-535-80-8) instead of (R) -2-phenylpropionic acid, and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 317.1([ M + H)]⁺)。

Example 263

(S) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 3-chlorobenzoic acid (CAS-535-80-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Off-white solid. Ms (isp): 317.1([ M + H)]⁺)。

Example 264

(R) -6-methyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6-methylnicotinic acid (CAS3222-47-7) instead of (R) -2-phenylpropionic acid. Off-white solid. Ms (isp): 296.4([ M + H)]⁺)。

Example 265

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 6- (trifluoromethyl) nicotinic acid (CAS 231291-22-8) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 350.4([ M + H)]⁺)。

Example 266

(R) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4- (methylthio) benzoic acid (CAS-13205-48-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU. A white solid. Ms (isp): 329.1([ M + H)]⁺)。

Example 267

(S) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4- (methylthio) benzoic acid (CAS-13205-48-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature).

A white solid. Ms (isp): 329.1([ M + H)]⁺)。

Example 268

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS-159783-29-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 382.1([ M + H)]⁺)。

Example 269

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

Similar to realityExample 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS-159783-29-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU, the title compound was obtained. A white solid. Ms (isp): 382.1([ M + H)]⁺)。

Example 270

(R) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2, 6-dichloroisonicotinic acid (CAS-5398-44-7) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 352.1([ M + H)]⁺)。

Example 271

(S) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2, 6-dichloroisonicotinic acid (CAS-5398-44-7) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). White solid。MS(ISP)：352.1([M+H]⁺)。

Example 272

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (trifluoromethyl) nicotinic acid (CAS-158063-66-2) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 352.2([ M + H)]⁺)。

Example 273

(RS) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-chloro-6-methylpyridine-4-carboxylic acid (CAS-25462-85-5) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 332.3([ M + H)]⁺)。

Example 274

(S) -5-Ethyl-N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-ethyl-pyrazine-2-carboxylic acid (CAS 13534-75-3) instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 311.4([ M + H)]⁺)。

Example 275

(R) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4-ethoxybenzoic acid (CAS-619-86-3) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 327.2([ M + H)]⁺)。

Example 276

(S) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

In analogy to example 29, use is made of (S) -2- (4-aminophenyl) morpholine-4-carbaTert-butyl ester (prepared in example 208-steps a-d) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 4-ethoxybenzoic acid (CAS-619-86-3) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) the title compound was obtained. A white solid. Ms (isp): 327.2([ M + H)]⁺)。

Example 277

(RS) -3-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 3-methylbenzoic acid (CAS-99-04-7) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 297.2([ M + H)]⁺)。

Example 278

(S) -N- (4- (piperidin-3-yl) phenyl) -5-propylpyrazine-2-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -3- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (example 150a) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and 5-propyl-pyrazine-2-carboxylic acid instead of (R) -2-phenylpropionic acid. Yellow solid. Ms (isp): 325.4([ M + H)]⁺)。

Example 279

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (pyrrolidin-1-yl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 6-pyrrolidin-1-yl-nicotinic acid (CAS-210963-95-4) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 353.2([ M + H ]]⁺)。

Example 280

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2- (trifluoromethyl) isonicotinic acid (CAS-131747-41-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 353.2([ M + H ]]⁺)。

Example 281

(S) -2, 6-dichloro-N- (4- (piperidin-3-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 2, 6-dichloroisonicotinic acid (CAS 5398-44-7) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 354.3([{³⁷Cl}M+H]⁺)，352.3([{³⁷Cl³⁵Cl}M+H]⁺)，350.3([{³⁵Cl}M+H]⁺)。

Example 282

(S) -2-chloro-6-methyl-N- (4- (piperidin-3-yl) phenyl) isonicotinamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 2-chloro-6-methylisonicotinic acid (CAS 25462-85-5) instead of (R) -2-phenylpropionic acid. Light yellow solid. Ms (isp): 332.2([{³⁷Cl}M+H]⁺)，330.3([{³⁵Cl}M+H]⁺)。

Example 283

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide hydrochloride

In analogy to example 29, using (R) -2- (4-aminophenyl) morpholine-Tert-butyl 4-carboxylate (prepared in example 207-steps a-d) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (trifluoromethyl) nicotinic acid (CAS-158063-66-2) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) gave the title compound. A white solid. Ms (isp): 352.2([ M + H)]⁺)。

Example 284

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 6- (trifluoromethyl) nicotinic acid (CAS-158063-66-2) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 352.2([ M + H)]⁺)。

Example 285

(R) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 2-chloro-6-methylpyridine-4-carboxylic acid (CAS-25462-85-5) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 332.1([ M + H)]⁺)。

Example 286

(S) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-chloro-6-methylpyridine-4-carboxylic acid (CAS-25462-85-5) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). A white solid. Ms (isp): 332.1([ M + H)]⁺)。

Example 287

(RS) -N- (4- (morpholin-2-yl) phenyl) -1- (pyrimidin-4-yl) piperidine-4-carboxamide dihydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 1- (pyrimidin-4-yl) piperidine-4-carboxylic acid hydrochloride (CAS-712261-81-9) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Off-white solid. Ms (isp): 368.2([ M + H)]⁺)。

Example 288

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (pyrazin-2-yl) thiazole-4-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2- (pyrazin-2-yl) thiazole-4-carboxylic acid (CAS-115311-44-9) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Yellow solid. Ms (isp): 368.2([ M + H)]⁺)。

Example 289

(S) -N- (4- (piperidin-3-yl) phenyl) -6-propylnicotinamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6-propylnicotinic acid (CAS847046-96-2) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 324.4([ M + H)]⁺)。

Example 290

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (pyrimidin-2-yl) thiazole-4-carboxamide hydrochloride

In analogy to example 29, use is made of (RS) -2- (4-amino)Phenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 2- (pyrimidin-2-yl) thiazole-4-carboxylic acid (CAS-1014631-26-5) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature) gave the title compound. Light brown solid. Ms (isp): 368.2([ M + H)]⁺)。

Example 291

(RS) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea hydrochloride

a)(RS) -2- (4- (3- (4- (trifluoromethyl) phenyl) ureido) phenyl) morpholine-4-carboxylic acid tert-butyl ester

(RS) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS-1002726-96-6) (400 mg; 1.44mmol), 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6) (336 mg; 1.8mmol) and triethylamine (182 mg; 1.8mmol) were dissolved in DMF (13.3ml) and stirred at 70 ℃ for 17 h. After cooling to room temperature, the reaction mixture was poured into water, extracted twice with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (90g silica; heptane/ethyl acetate 1: 1) to yield 433mg of a pale yellow solid. Ms (isp): 410.2mg ([ M + H ]]⁺A tertiary butyl group).

b)(RS) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea hydrochloride

(RS) -2- (4- (3- (4- (trifluoromethyl) phenyl) ureido) phenyl) morpholine-4-carboxylic acid tert-butyl ester (167 mg; 0.359mmol) was dissolved in di (tert-butyl) acetateIn alkane (1ml), used in twoTreated with 4M HCl in an alkane (1.35 ml; 5.4mmol) and stirred at room temperature for 2 h. The resulting suspension was filtered and washed with diethyl ether to yield 74mg of a white solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 292

(RS) -1- (4-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using 4-chlorophenyl isocyanate (CAS-104-12-1) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). Light brown solid. Ms (isp): 332.2([ M + H)]⁺)。

Example 293

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-p-tolylurea hydrochloride

The title compound was obtained in analogy to example 291, using p-tolylisocyanate (CAS-374675-64-6) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). A white solid. Ms (isp): 312.1([ M + H)]⁺)。

Example 294

(RS) -2-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide dihydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-methylisonicotinic acid (CAS-4021-11-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Light yellow solid. Ms (isp): 298.4([ M + H ]]⁺)。

Example 295

(RS) -2, 6-dimethyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide dihydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2, 6-dimethylisonicotinic acid (CAS-54221-93-1) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Yellow solid. Ms (isp): 312.4([ M + H)]⁺)。

Example 296

(RS) -2- (1-methyl-1H-pyrazol-4-yl) -N- (4- (morpholin-2-yl) phenyl) thiazole-4-carboxamide hydrochloride

In analogy to example 29, (RS) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester (CAS-1002726-96-6) was used instead of (RS) -3- (96-6)4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester, 2- (1-methyl-1H-pyrazol-4-yl) thiazole-4-carboxylic acid (CAS-1152605-07-6) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17H at room temperature) gave the title compound. A white solid. Ms (isp): 370.2([ M + H)]⁺)。

Example 297

(S) -6-ethyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 3- (4-aminophenyl) piperidine-1-carboxylate (example 150a) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate and 6-ethylnicotinic acid (CAS802828-81-5) instead of (R) -2-phenylpropionic acid. A white solid. Ms (isp): 310.4([ M + H)]⁺)。

Example 298

(RS) -4-methyl-N- (4- (morpholin-2-yl) phenyl) -2- (pyrazin-2-yl) thiazole-5-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4-methyl-2- (pyrazin-2-yl) thiazole-5-carboxylic acid (CAS-216959-92-1) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Yellow solid. Ms (isp): 382.4([ M + H)]⁺)。

Example 299

(RS) -N- (4- (morpholin-2-yl) phenyl) -1-phenyl-1H-pyrazole-3-carboxamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 1-phenyl-1H-pyrazole-3-carboxylic acid (CAS-4747-46-0) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17H at room temperature). Off-white solid. Ms (isp): 349.2([ M + H)]⁺)。

Example 300

(RS) -2-ethoxy-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

The title compound was obtained in analogy to example 29, using (RS) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6) instead of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 2-ethoxyisonicotinic acid (CAS-91940-86-2) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU (17h at room temperature). Light yellow solid. Ms (isp): 328.2([ M + H)]⁺)。

Example 301

(S) -4-chloro-2-iodo-N- (4- (morpholin-2-yl) phenyl) benzamide

The title compound was obtained in analogy to example 141 using (S) -tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate (example 208b) instead of tert-butyl (RS) -2- (4-bromophenyl) morpholine-4-carboxylate and 4-chloro-2-iodo-benzamide (CAS 942319-20-2) instead of 5-trifluoromethyl-pyridine-2-carboxylic acid amide. A white solid. Ms (isp): 445.0([{³⁷Cl}M+H]⁺)，443.0([{³⁵Cl}M+H]⁺)。

Example 302

(RS) -1- (6-Chloropyridin-3-yl) -3- (4- (morpholin-2-yl) phenyl) Urea hydrochloride

The title compound was obtained in analogy to example 291, using 2-chloro-5-isocyanatopyridine (CAS-125117-96-6) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). An orange solid. Ms (isp): 333.3([ M + H)]⁺)。

Example 303

(RS) -1- (3-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using 3-chlorophenyl isocyanate (CAS-2909-38-8) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). Light grey solid. Ms (isp): 332.1([ M + H)]⁺)。

Example 304

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-m-tolylurea hydrochloride

The title compound was obtained in analogy to example 291, using m-toluyl isocyanate (CAS-621-29-4) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). Light grey solid. Ms (isp): 312.4([ M + H)]⁺)。

Example 305

(RS) -1- (2-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using 2-chlorophenyl isocyanate (CAS-3320-83-0) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). Light grey solid. Ms (isp): 332.2([ M + H)]⁺)。

Example 306

(RS) -1- (4-methylbenzyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

In analogy to example 291, 4-methylbenzyl isocyanate (CAS-56651-57-1) was used instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6)The title compound was obtained. Light brown solid. Ms (isp): 326.3([ M + H)]⁺)。

Example 307

(RS) -1-cyclohexyl-3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using cyclohexyl isocyanate (CAS-3173-53-3) instead of 4- (trifluoromethyl) phenyl isocyanate (CAS-1548-13-6). Off-white solid. Ms (isp): 304.3([ M + H)]⁺)。

Example 308

(S) -N- (4- (1, 4-oxazepan-2-yl) phenyl) -3-chlorobenzamide hydrochloride

a) (S) -3- (2-hydroxy-2- (4-nitrophenyl) ethylamino) propan-1-ol

(S) -2- (4-Nitrophenyl) oxirane (5g, 30.3mmol, CAS 78038-42-3) was mixed with isopropanol (2.33ml) and 3-aminopropan-1-ol (2.27g, 2.3ml, 30.3mmol) was added. The yellow suspension was stirred at room temperature for 17 hours. The reaction mixture was quenched by addition of 150ml brine. A mixture of dichloromethane and methanol (9: 1, 200ml) was added, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane/methanol (9: 1). The organic layer was MgSO₄Drying and evaporation gave a brown solid which was recrystallized from ethyl acetate/heptane/TBME to give (S) -3- (2-hydroxy-2- (4-nitrophenyl) ethylamino) propan-1-ol (2.74g, 38%) as a light yellow solid, ms (isp): 241.2([ M + H)]⁺)。

b) (S) -2-hydroxy-2- (4-nitrophenyl) ethyl (3-hydroxypropyl) carbamic acid tert-butyl ester

(S) -3- (2-hydroxy-2- (4-nitrophenyl) ethylamino) propan-1-ol (2.4g, 10mmol) was suspended in 8ml dichloromethane. A solution of di-tert-butyl dicarbonate (2.18g, 10mmol) in 5ml of dichloromethane is added dropwise and the reaction mixture is stirred at room temperature for 2 hours. The mixture was washed with water, the organic layer was washed with brine, over MgSO₄Dried and evaporated. The solid was stirred in a mixture of heptane and ethyl acetate and filtered off to give tert-butyl (S) -2-hydroxy-2- (4-nitrophenyl) ethyl (3-hydroxypropyl) carbamate (2.1g, 62%) as a pale yellow solid, ms (isp): 241.3 (100%, [ M-BOC + H ]]⁺)，341.1(20％，[M+H]⁺)。

c) (S) -2- (4-Nitrophenyl) -1, 4-oxazepane-4-carboxylic acid tert-butyl ester

(S) -tert-butyl 2-hydroxy-2- (4-nitrophenyl) ethyl (3-hydroxypropyl) carbamate (2g, 5.88mmol) was dissolved in TBME (8.2ml) and triphenylphosphine (1.85g, 7.05mmol) was added. A thick white suspension was obtained. Diisopropyl diazodicarboxylate (DIAD, 1.52g, 1.46ml, 7.05mmol) (solid dissolved) was added slowly and the mixture was stirred at room temperature for 17 h. The white solid formed during the reaction was filtered and the filtrate was evaporated. The crude material was purified by flash chromatography (silica gel, heptane/ethyl acetate gradient 90: 10 to 80: 20) to give tert-butyl (S) -2- (4-nitrophenyl) -1, 4-oxazepan-4-carboxylate (369mg, 20%) as a pale yellow oil, which was used directly in the next step.

d) (S) -2- (4-aminophenyl) -1, 4-oxazepane-4-carboxylic acid tert-butyl ester

(S) -2- (4-Nitrophenyl) -1, 4-oxazepane-4-carboxylic acid tert-butyl ester (0.36g, 1.12mmol) was dissolved in methanol (4ml), andpalladium on charcoal (10%, 35.7mg, 33.5. mu. mol) was added. After degassing, the reaction mixture was stirred at room temperature for 45min under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated to give tert-butyl (S) -2- (4-aminophenyl) -1, 4-oxazepane-4-carboxylate (288mg, 88%) as a pale yellow oil. Ms (isp): 193.3 (100%, [ M-BOC + H)]⁺)，293.3(3％，[M+H]⁺)。

e) (S) -2- (4- (3-chlorobenzoylamino) phenyl) -1, 4-oxazepane-4-carboxylic acid tert-butyl ester

In a 250ml round bottom flask, (S) -tert-butyl 2- (4-aminophenyl) -1, 4-oxazepane-4-carboxylate (106mg, 0.36mmol), 3-chlorobenzoic acid (74mg, 0.47mmol), N-methylmorpholine (110mg, 120. mu.l, 1.09mmol) and HBTU (206mg, 0.544mmol) were combined with tetrahydrofuran (5ml) to give a pale yellow suspension. The reaction mixture was stirred at room temperature for 17 h. The reaction suspension was poured into water (100ml) and extracted twice with ethyl acetate. The organic layer was dried (MgSO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give tert-butyl (S) -2- (4- (3-chlorobenzoylamino) phenyl) -1, 4-oxazepane-4-carboxylate (143mg, 92%) as a pale brown gum. Ms (isp): 431.3([{³⁵Cl}M+H]⁺)，433.3([{³⁷Cl}M+H]⁺)。

f) (S) -N- (4- (1, 4-oxazepan-2-yl) phenyl) -3-chlorobenzamide hydrochloride

(S) -2- (4- (3-chlorobenzoylamino) phenyl) -1, 4-oxazepane-4-carboxylic acid tert-butyl ester (0.14g, 0.325mmol) was dissolved in diTo an alkane (5ml) and HCl added in bisSolution in alkane (4M, 1.22ml, 4.87 mmol). The reaction mixture was stirred at 60 ℃ overnight. Evaporating the solvent and removing the residueThe residue was dissolved in ethanol. After sonication and heating, a pale yellow suspension was obtained. The solid was filtered and dried in vacuo at 60 ℃ to give (S) -N- (4- (1, 4-oxazepan-2-yl) phenyl) -3-chlorobenzamide hydrochloride (119mg) as a pale yellow solid. Ms (isp): 331.2([{³⁵Cl}M+H]⁺)，333.3([{³⁷Cl}M+H]⁺)。

Example 309

3-chloro-N- (4- ((2S, 6S) -6-methylmorpholin-2-yl) phenyl) benzamide hydrochloride

The title compound was obtained in analogy to example 308, using (R) -1-aminopropan-2-ol instead of 3-aminopropanol in step a). Off-white solid. Ms (isp): 331.2([{³⁵Cl}M+H]⁺)，333.3([{³⁷Cl}M+H]⁺)。

Example 310

6-chloro-N- (4- ((2S, 6R) -6-methylmorpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 308, using (S) -1-aminopropan-2-ol instead of 3-aminopropanol in step a). Off-white solid. Ms (isp): 332.2([{³⁵Cl}M+H]⁺)，334.3([{³⁷Cl}M+H]⁺)。

Example 311

(R) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 207-steps a-d) instead of tert-butyl (RS) -2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6). Off-white solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 312

(S) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 291, using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (prepared in example 208-steps a-d) instead of tert-butyl (RS) -2- (4-aminophenyl) morpholine-4-carboxylate (CAS-1002726-96-6). Off-white solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 313

(R) -3-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

a) (R) -2- (4-formylphenyl) morpholine-4-carboxylic acid tert-butyl esterEster:

tert-butyl (R) -2- (4-bromophenyl) morpholine-4-carboxylate (342mg, 1mmol, example 207 step b) in THF (3ml) was cooled to-74 ℃ and treated dropwise with n-BuLi (0.938ml, 1.5mmol, 1.6M solution in hexane) and stirred at-74 ℃ for 30 min. DMF (0.5ml, 1mmol) was added dropwise and the mixture was stirred at-74 ℃ for 2h, then allowed to warm to-10 ℃. The mixture was then quenched with saturated aqueous ammonium chloride (2ml) and water (2ml) and the resulting mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (20g SILICYCLE-silica gel, heptane/ethyl acetate (Ethal acetate) 4: 1) to yield 160mg of an off-white solid. Ms (isp): 292.3([ M + H)]⁺)。

b) (R, E) -2- (4- ((hydroxyimino) methyl) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (R) -2- (4-formylphenyl) morpholine-4-carboxylate (155mg, 0.532mmol) was dissolved in ethanol (0.9 ml). Molecular sieves 0.3nm were added followed by hydroxylamine hydrochloride (74mg, 1.06 mmol). The reaction mixture was refluxed for 2h, cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 159mg of an off-white solid, which was used in the next step without further purification.

c) (R) -2- (4- (aminomethyl) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (R, E) -2- (4- ((hydroxyimino) methyl) phenyl) morpholine-4-carboxylate (138mg, 0.45mmol) was dissolved in methanol (8.2ml) and hydrogenated over 5% Pd/C (41mg) for 1 h. The reaction mixture was filtered off and concentrated in vacuo, dissolved in ethyl acetate and extracted with 0.5M aqueous HCl (2 × 1.2ml). The combined aqueous layers were basified to pH 10 with 1M aqueous NaOH and extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo to give 63mg of a colorless oil. Ms (isp): 293.2([ M + H)]⁺)。

d) (R) -3-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (R) -tert-butyl 2- (4- (aminomethyl) phenyl) morpholine-4-carboxylate instead of (RS) -tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate, 3-chlorobenzoic acid (CAS-535-80-8) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU, at 60 ℃ (17h) in DMF instead of THF.

A colorless amorphous solid. Ms (isp): 331.1([ M + H)]⁺)。

Example 314

(R) -4-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

The title compound was obtained in analogy to example 313 using 4-chlorobenzoic acid (CAS-74-11-3) instead of 3-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 331.1([ M + H)]⁺)。

Example 315

(R) -6-chloro-N- (4- (morpholin-2-yl) benzyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 313, using 6-chloronicotinic acid (CAS-5326-23-8) instead of 3-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 332.2([ M + H)]⁺)。

Example 316

(R) -N- (4- (morpholin-2-yl) benzyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

The title compound was obtained in analogy to example 313, using 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (CAS-159783-29-6) instead of 3-chlorobenzoic acid.

A colorless amorphous solid. Ms (isp): 396.3([ M + H)]⁺)。

Example 317

(S) -4-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

Step a) tert-butyl 2- (4-formylphenyl) morpholine-4-carboxylate:

tert-butyl (S) -2- (4-bromophenyl) morpholine-4-carboxylate (5g, 14.6mmol, example 208b) in THF (40ml) was cooled to-74 deg.C and treated dropwise with n-BuLi (13.7ml, 21.9mmol, 1.6M solution in hexanes) and stirred at-74 deg.C for 30 min. DMF (7.3ml, 14.6mmol) was added dropwise (15min) and the mixture was stirred at-74 ℃ for 2h, then allowed to warm to-10 ℃. The mixture was then quenched with saturated aqueous ammonium chloride (30ml) and water (30ml), and the resulting mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4.7g of crude product. Ms (isp): 292.3([ M + H)]⁺)。

b) (S, E) -2- (4- ((hydroxyimino) methyl) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (S) -2- (4-formylphenyl) morpholine-4-carboxylate (2.2g, 7.55mmol) was dissolved in ethanol (13 ml). Molecular sieves (0.3nm) were added followed by hydroxylamine hydrochloride (1.05, 15.1 mmol). The reaction mixture was refluxed for 2h, cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 1.72g of an off-white solid which was used in the next step without further purification. Ms (isp): 207.2([ M + H)]⁺-BOC)。

c) (S) -2- (4- (aminomethyl) phenyl) morpholine-4-carboxylic acid tert-butyl ester:

tert-butyl (S, E) -2- (4- ((hydroxyimino) methyl) phenyl) morpholine-4-carboxylate (1.63g, 5.32mmol) was dissolved in methanol (25ml) and hydrogenated over 5% Pd/C (543mg, 0.255mmol) for 1 h. The reaction mixture was filtered off and concentrated in vacuo, dissolved in ethyl acetate and extracted with 0.5M aqueous HCl (2 × 10 ml). The combined aqueous layers were basified to pH 10 with 1M aqueous NaOH and extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo to yield 991mg of a pale yellow viscous oil. Ms (isp): 293.2([ M + H)]⁺)。

d) (S) -4-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

The title compound was obtained in analogy to example 29, using (S) -tert-butyl 2- (4- (aminomethyl) phenyl) morpholine-4-carboxylate instead of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate, 4-chlorobenzoic acid (CAS-74-11-3) instead of (R) -2-phenylpropionic acid and HBTU instead of TBTU, at 60 ℃ (4h) in DMF instead of THF. A white solid. Ms (isp): 331.2([ M + H)]⁺)。

Example 318

(S) -3-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide hydrochloride

The title compound was obtained in analogy to example 317, using 3-chlorobenzoic acid (CAS-535-80-8) instead of 4-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 331.2([ M + H)]⁺)。

Example 319

(S) -6-chloro-N- (4- (morpholin-2-yl) benzyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 317, using 6-chloronicotinic acid (CAS-5326-23-8) instead of 4-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 332.1([ M + H)]⁺)。

Example 320

(S) -N- (4- (morpholin-2-yl) benzyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 317, using 6- (trifluoromethyl) nicotinic acid (CAS-158063-66-2) instead of 4-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 366.2([ M + H)]⁺)。

Example 321

(R) -N- (4- (morpholin-2-yl) benzyl) -6- (trifluoromethyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example 313, using 6- (trifluoromethyl) nicotinic acid (CAS-158063-66-2) instead of 3-chlorobenzoic acid. A colorless amorphous solid. Ms (isp): 366.1([ M + H)]⁺)。

Example 322

3-chloro-N- [4- ((2S, 5S) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 308, using (S) -2-aminopropanol instead of 3-aminopropanol in step a). Off-white solid. Ms (isp): 331.2([{³⁵Cl}M+H]⁺)，333.3([{³⁷Cl}M+H]⁺)。

Example 323

3-chloro-N- [4- ((2S, 5R) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide hydrochloride

The title compound was obtained in analogy to example 308, using (R) -2-aminopropanol instead of 3-aminopropanol in step a). Off-white solid. Ms (isp): 331.2([{³⁵Cl}M+H]⁺)，333.4([{³⁷Cl}M+H]⁺)。

The compounds of formula I and their pharmaceutically useful addition salts possess valuable pharmacological properties. In particular, it has been found that the compounds of the invention have a good affinity for Trace Amine Associated Receptors (TAARs), especially TAAR 1.

These compounds were investigated according to the tests given hereinafter.

Materials and methods

Construction of TAAR expression plasmids and stably transfected cell lines

For constructing 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 PCR products were cloned into pCR2.1-TOPO cloning vector (Invitrogen) using an extended High Fidelity PCR System (Roche Diagnostics) and following the manufacturer's instructions. The PCR product was subcloned into pIRESneo2 vector (BD Clontech, PaloAlto, California) and the expression vector was sequence verified prior to introduction into the cell line.

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, granulated at 1' 000rpm at 4 ℃ for 5min, frozen and stored at-80 ℃. The frozen pellets were suspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 10mM EDTA 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, pH7.4) 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 (Kd) was determined by saturation curve. TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine (described in WO 2008/098857) is used at a concentration equivalent to the calculated Kd value, which is typically about 2.3nM, 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 unlabelled 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 96-deep well plates (Treffl)ab) and adding 180. mu.l of MgCl-containing solution₂(10mM) and CaCl₂(2mM) HEPES-NaOH (20mM, pH7.4) (binding buffer), 300. mu.l radioligand at a concentration of 3.3xKd in nM³[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, granulated at 1' 000rpm at 4 ℃ for 5min, frozen and stored at-80 ℃. The frozen pellets were suspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 10mM EDTA 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 containing 0.1mM EDTA (20mM, pH7.4) 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 of the membrane portion will beAliquots were stored at-80 ℃. For each new membrane batch, the dissociation constant (Kd) was determined by saturation curve. TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamine (described in WO 2008/098857) is used at a concentration equivalent to the calculated Kd value, which is typically about 0.7nM, 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 unlabelled 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, pH7.4) (binding buffer), 300. mu.l radioligand at a concentration of 3.3xKd in nM³[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 (PerkinElmer) 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).

As shown in the table below, preferred compounds show Ki values (μ M) in the range of < 0.01 μ M for TAAR1 in mice or rats.

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 the treatment or prevention of depression, psychotic disorders, parkinson's disease, anxiety disorders and Attention Deficit Hyperactivity Disorder (ADHD).

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 the formula I,

wherein

R is hydrogen or lower alkyl;

R¹is- (CH)₂)_n-(O)_o-heterocycloalkyl or-c (o) -heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by lower alkyl, hydroxy, halogen or by- (CH)₂)_p-aryl substitution;

n is 0, 1 or 2;

o is 0 or 1;

p is 0, 1 or 2;

x is a bond, -NR' -, -CH₂NH-，-CHR”，-(CHR”)_q-O-，-O-(CHR”)_q-or- (CH)₂)₂-；

Y is a bond or-CH₂-；

R' is hydrogen or lower alkyl,

r' is hydrogen, lower alkyl, CF₃A lower alkoxy group,

q is 0, 1, 2 or 3;

or a pharmaceutically suitable acid addition salt thereof.

2. A compound of formula I according to claim 1, wherein X is NR 'and R' is hydrogen.

3. A compound of formula I according to claim 2, wherein the compound is:

(RS) -1- (4-butyl-2-methyl-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

1- (3, 4-dichloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl ] -urea

(RS) -1- (3, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (4-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1-phenyl-3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (2, 4-dichloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (3-chloro-phenyl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (4-pyrrolidin-3-yl-phenyl) -3- (4-trifluoromethyl-phenyl) -urea

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (6-chloro-pyridin-3-yl) -3- (4-piperidin-3-yl-phenyl) -urea

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-piperidin-3-yl-phenyl) -urea

(RS) -1- (4-chloro-phenyl) -3- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -urea

(RS) -1- (4-chloro-phenyl) -3- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea

(RS) -1- (4-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-p-tolylurea

(RS) -1- (6-Chloropyridin-3-yl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (3-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4- (morpholin-2-yl) phenyl) -3-m-tolylurea

(RS) -1- (2-chlorophenyl) -3- (4- (morpholin-2-yl) phenyl) urea

(RS) -1- (4-methylbenzyl) -3- (4- (morpholin-2-yl) phenyl) urea

(R) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea or

(S) -1- (4- (morpholin-2-yl) phenyl) -3- (4- (trifluoromethyl) phenyl) urea.

4. A compound of formula I according to claim 1, wherein X is a bond.

5. A compound of formula I according to claim 4, wherein the compound is:

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -N- (4-pyrrolidin-3-yl-phenyl) -4-trifluoromethyl-benzamide

(RS) -2, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -3-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- [4- (1-methyl-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (1-ethyl-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxy) -phenyl ] -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -6-chloro-pyridine-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-ethoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-propyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-ethynyl-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -4-cyano-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

4-chloro-N- (4-piperidin-4-yl-phenyl) -benzamides

(RS) -4-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide

4-chloro-N- (4-piperazin-1-yl-phenyl) -benzamide

4-chloro-N- [4- ((3RS, 4RS) -4-fluoro-pyrrolidin-3-yl) -phenyl ] -benzamide

(RS) -4-chloro-N- [3- (pyrrolidin-3-yloxy) -phenyl ] -benzamide

(RS) -6-pyrazol-1-yl-N- (4-pyrrolidin-3-yl-phenyl) -nicotinamide

(RS) -6-chloro-N- (4-piperidin-3-yl-phenyl) -nicotinamide

(RS) -4-chloro-2-fluoro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(RS) -4-chloro-N- [4- (4-methyl-morpholin-2-yl) -phenyl ] -benzamide

(RS) -quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -isoquinoline-1-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -5-bromo-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -2-fluoro-4-methoxy-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

(RS) -6-methoxy-quinoline-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -3-chloro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -4-ethoxy-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -N- (4-piperidin-3-yl-phenyl) -4-trifluoromethyl-benzamide

(RS) -4-chloro-2-fluoro-N- (4-piperidin-3-yl-phenyl) -benzamide

(RS) -4-chloro-N- (4-pyrrolidin-2-ylmethyl-phenyl) -benzamide

(RS) -1-chloro-isoquinoline-3-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

(RS) -4-chloro-N- [4- (2-pyrrolidin-3-yl-ethyl) -phenyl ] -benzamide

(RS) -4-chloro-N- [4- (2-piperidin-3-yl-ethyl) -phenyl ] -benzamide

4-chloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide

(RS) -N- (4-piperidin-3-yl-phenyl) -4-propyl-benzamide

(RS) -4-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

4-chloro-N- ((R) -4-morpholin-2-yl-phenyl) -benzamide

4-chloro-N- ((S) -4-morpholin-2-yl-phenyl) -benzamide

(RS) -4-chloro-N- [4- (pyrrolidin-3-yloxymethyl) -phenyl ] -benzamide

(RS) -4-chloro-2-fluoro-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -3, 4-dichloro-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -5-chloro-pyridine-2-carboxylic acid (4-morpholin-2-yl-phenyl) -amide

(RS) -4-chloro-N- (4-pyrrolidin-3-ylmethyl-phenyl) -benzamide

3, 4-dichloro-N- ((R) -4-piperidin-3-yl-phenyl) -benzamide

(R) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide

3, 4-dichloro-N- ((S) -4-piperidin-3-yl-phenyl) -benzamide

(S) -3-chloro-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -3, 4-dichloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -4-trifluoromethyl-benzamide

(RS) -4-fluoro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -3-chloro-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -4-ethoxy-N- [4- (2-pyrrolidin-2-yl-ethyl) -phenyl ] -benzamide

(RS) -5-chloro-pyrazine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(S) -6-chloro-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(R) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide

(S) -5-chloro-N- (4- (piperidin-3-yl) phenyl) picolinamide

(RS) -4-chloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -5-ethoxy-N- (4- (2- (pyrrolidin-2-yl) ethyl) phenyl) picolinamide

(RS) -3, 4-dichloro-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -4-ethynyl-N- (4- (2- (piperidin-2-yl) ethyl) phenyl) benzamide

(RS) -5-ethoxy-pyridine-2-carboxylic acid (4-piperidin-3-yl-phenyl) -amide

(RS) -4-methyl-N- (4- (pyrrolidin-3-yl) phenyl) benzamide

(RS) -4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-methoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4- (benzyloxy) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -2- (4- (6-cyanonicotinamido) phenyl) morpholine-4-chloride

(R) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -4-ethyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4-chloro-3-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -3-chloro-4-methoxy-N- (4- (piperidin-3-yl) phenyl) benzamide

(RS) -4- (4-chlorophenoxy) -N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -5-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -4-Cyclopropylmethoxy-N- (4-morpholin-2-yl-phenyl) -benzamide

(RS) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -2-chloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -5, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -3-chloro-4-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4-chloro-3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-chloro-2-fluoro-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-5-carboxamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylthiazole-4-carboxamide

(S) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide

(S) -4- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -4- (ethylsulfanyl) -N- (4- (piperidin-3-yl) phenyl) benzamide

5-chloro-pyrazine-2-carboxylic acid ((S) -4-piperidin-3-yl-phenyl) -amide

5-chloro-pyrazine-2-carboxylic acid ((R) -4-piperidin-3-yl-phenyl) -amide

(S) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(S) -6-methyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(S) -6- (methylthio) -N- (4- (piperidin-3-yl) phenyl) nicotinamide

(RS) -6-ethoxy-N- (4- (morpholin-2-yl) phenyl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2-phenylAzole-4-carboxamides

(S) -3-methyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(S) -5- (methylthio) -N- (4- (piperidin-3-yl) phenyl) pyrazine-2-carboxamide

(S) -3- (methylthio) -N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -3, 4-dimethyl-N- (4- (piperidin-3-yl) phenyl) benzamide

(R) -N- (4- (piperidin-3-yl) phenyl) -3- (trifluoromethyl) benzamide

(R) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -3-chloro-N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -N- (4- (piperidin-3-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(R) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4- (methylthio) -N- (4- (morpholin-2-yl) phenyl) benzamide

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

(R) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -2, 6-dichloro-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(R) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -4-ethoxy-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -3-methyl-N- (4- (morpholin-2-yl) phenyl) benzamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -6- (pyrrolidin-1-yl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

(S) -2, 6-dichloro-N- (4- (piperidin-3-yl) phenyl) isonicotinamide

(S) -2-chloro-6-methyl-N- (4- (piperidin-3-yl) phenyl) isonicotinamide

(R) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (trifluoromethyl) nicotinamide

(R) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -2- (pyrazin-2-yl) thiazole-4-carboxamide

(S) -N- (4- (piperidin-3-yl) phenyl) -6-propylnicotinamide

(S) -6-ethyl-N- (4- (piperidin-3-yl) phenyl) nicotinamide

(RS) -N- (4- (morpholin-2-yl) phenyl) -1-phenyl-1H-pyrazole-3-carboxamide

(RS) -2-ethoxy-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -4-chloro-2-iodo-N- (4- (morpholin-2-yl) phenyl) benzamide

(S) -N- (4- (1, 4-oxazepan-2-yl) phenyl) -3-chlorobenzamide

3-chloro-N- (4- ((2S, 6S) -6-methylmorpholin-2-yl) phenyl) benzamide

(R) -4-chloro-N- (4- (morpholin-2-yl) benzyl) benzamide

(R) -6-chloro-N- (4- (morpholin-2-yl) benzyl) nicotinamide

3-chloro-N- [4- ((2S, 5S) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide or

3-chloro-N- [4- ((2S, 5R) -5-methyl-morpholin-2-yl) -phenyl ] -benzamide.

6. A compound of formula I according to claim 1, wherein X is- (CH)₂)_q-O-。

7. A compound of formula I according to claim 6, wherein the compound is:

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-chloro-phenyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid 4-fluoro-benzyl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid indan-2-yl ester

(RS) - (4-pyrrolidin-3-yl-phenyl) -carbamic acid (RS) -1- (4-chloro-phenyl) -2, 2, 2-trifluoro-ethyl ester or

8. Compounds of formula I according to claim 1, wherein X is-O (CHR ")_q-。

9. A compound of formula I according to claim 8, wherein the compound is:

(S) -2- (4-chlorophenoxy) -N- (4- (piperidin-3-yl) phenyl) acetamide or

(S) - (4-chlorobenzyl) 4- (piperidin-3-yl) phenylcarbamate.

10. A compound of formula I according to claim 1, wherein X is-CHR "-.

11. A compound of formula I according to claim 10, wherein the compound is:

(RS) -2- (4-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -acetamide

12. A compound of formula I according to claim 1, wherein X is-CH₂CH₂-。

13. A compound of formula I according to claim 12, wherein the compound is:

(RS) -3- (2-chloro-phenyl) -N- (4-pyrrolidin-3-yl-phenyl) -propionamide or

(RS) -3- (4-chloro-phenyl) -N- (4-piperidin-3-yl-phenyl) -propionamide.

14. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 13, which process comprises:

a) cleaving off the N-protecting group from the compound of the formula,

to obtain a compound of the following formula,

b) Reacting a compound of the formula

With a compound of the formula,

to obtain a compound of the following formula,

wherein X is a bond or-CH₂-and the other definitions are as defined in claim 1, or

c) Reacting a compound of the formula

With a compound of the formula,

to obtain a compound of the following formula,

wherein is defined as in claim 1, and

15. A compound according to any one of claims 1-13, when manufactured by a process according to claim 14.

16. A pharmaceutical composition comprising a compound according to any one of claims 1-13 and a pharmaceutically acceptable carrier and/or adjuvant.

17. A pharmaceutical composition comprising a compound according to any one of claims 1-13 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.

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

19. A compound according to any one of claims 1-13 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.

20. The use of a compound according to any one of claims 1-13 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.

21. The invention as hereinbefore described.