HK1169992B

HK1169992B - Pyrrolidine derivatives as nk - 3 receptor antagonists

Info

Publication number: HK1169992B
Application number: HK12110830.9A
Authority: HK
Inventors: 亨纳．努斯特; 安德烈亚斯．克布雷特; 马蒂亚斯．内特科文; 哈萨内．拉特尼; 克劳斯．里默尔; 沃特．维凡
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2009-12-18
Filing date: 2010-12-14
Publication date: 2015-10-23

Description

Pyrrolidine derivatives as NK-3 receptor antagonists

The present application relates to compounds of the formula

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl or lower alkyl substituted by halogen;

n is 1, 2 or 3, and if n is 2 or 3, R¹May be different;

R²is C_2-7-alkyl or C_3-6-a cycloalkyl group;

R³is the following group

Wherein

X is CH or N;

R⁵is hydrogen, -C (O) -lower alkyl, -C (O) O-lower alkyl, S (O)₂-a lower alkyl group,

-C(O)CH₂o-lower alkyl, -C (O) -CH₂-CN, or

-C (O) -cycloalkyl, cycloalkyl or-CH₂-a cycloalkyl group,

wherein said cycloalkyl is optionally substituted by lower alkyl, -CH₂-O-lower alkyl, lower alkoxy, CF₃Halogen or cyano, or

-C (O) -heterocycloalkyl or heterocycloalkyl, or

-C (O) -heteroaryl, or is

-C (O) -aryl or aryl,

the heterocycloalkyl, heteroaryl or aryl group is optionally substituted with: halogen, lower alkyl, ═ O, lower alkoxy, halogen-substituted lower alkyl, hydroxy-substituted lower alkyl, -c (O) -CH₂N (di-lower alkyl), C (O) NH-lower alkyl, C (O) NH₂-O-C (O) -lower alkyl, S (O)₂-lower alkyl or cyano;

R⁴is aryl, which is optionally substituted by halogen, hydroxy, lower alkyl substituted by halogen, S (O)₂-lower alkyl, cyano or lower alkoxy;

or a pharmaceutically active salt thereof.

The present invention includes all stereoisomeric forms, including individual diastereomers and enantiomers of the compounds of formula (I) as well as racemic and non-racemic mixtures thereof.

It has been found that the compounds of the present invention are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and Attention Deficit Hyperactivity Disorder (ADHD).

Three major mammalian tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the neuropeptide family, which share Phe-X-Gly-Leu-Met-NH₂A common COOH-terminal pentapeptide sequence of (a). As neurotransmitters, these peptides exert their biological activity via three different Neurokinin (NK) receptors, called NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1 receptor, NKA binds preferentially to NK-2 and NKB binds preferentially to the NK-3 receptor.

The NK-3 receptor is characterized by a predominant expression in the CNS and has been shown to be involved in the regulation of the central monoaminergic system. These properties make the NK-3 receptor a potential target for central nervous system diseases such as anxiety, depression, bipolar disorder, Parkinson's disease, schizophrenia and pain (neurosci. letters, 2000, 283, 185-.

Schizophrenia is one of the major neuropsychiatric disorders characterized by severe and chronic mental damage. This devastating disease affects approximately 1% of the world population. Symptoms begin in early adulthood and are followed by periods of interpersonal and social dysfunction. Schizophrenia manifests as: auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted emotions, depression, anhedonia, speech deficits, memory and attention deficits, and social withdrawal (negative symptoms).

For decades, scientists and clinicians have made efforts to find ideal drugs for pharmacological treatment of schizophrenia. However, those efforts have been hampered by the complexity of the disease due to the numerous symptoms. There is no specific focal feature for the diagnosis of schizophrenia and there is no single symptom consistently present in all patients. Thus, schizophrenia has been discussed as a single disease or as a diagnosis of various diseases, but has not yet been addressed. The main difficulty in developing new drugs for schizophrenia lies in the lack of knowledge about the cause and nature of the disease. On the basis of pharmacological studies, in order to rationalize the development of corresponding treatments, several neurochemical hypotheses have been proposed: dopamine, 5-hydroxytryptamine and glutamate hypotheses. However, given the complexity of schizophrenia, appropriate multi-receptor affinity profiles may be required for efficacy against both positive and negative signs and symptoms. Furthermore, an ideal drug against schizophrenia would preferably have a low dose, allowing for a once-a-day dose due to the low adherence of schizophrenic patients.

In recent years, clinical studies using selective NK1 and NK2 receptor antagonists have emerged in the literature as indications of results for the treatment of emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2 and NK 1). The most exciting data was generated in chemotherapy-induced emesis, nausea and depression treated with NK1 and asthma treated with NK 2-receptor antagonists. In contrast, no clinical data for NK3 receptor antagonists appeared in the literature until 2000. Osanetant (Osanetant) (SR 142, 801) from Sanofi-synthiabo is the first non-peptide antagonist to be found that was identified as a potent and selective antagonist for NK3 tachykinin receptor for potential treatment of Schizophrenia, reported in the literature (Current Opinion in Investigational Drugs, 2001, 2(7), 950-. The proposed drug SR142, 801 has been shown in phase II trials to be active against positive symptoms of schizophrenia such as behavioral changes, delusions, hallucinations, extreme mood, excitatory motor activity and allophasic speech, but inactive in treating negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.

Neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, and in Schizophrenia, exp. opinion. Ther. patents (2000), 10(6), 939-.

Objects of the present invention are the novel compounds of formula I, their manufacture, medicaments based on the compounds according to the invention and their manufacture as well as the use of the compounds of formula I for the control or prevention of illnesses such as depression, pain, bipolar disorder, psychosis, parkinson's disease, schizophrenia, anxiety and Attention Deficit Hyperactivity Disorder (ADHD).

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

The following definitions of general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

As used herein, the term "C_2-7The "alkyl group" means a straight or branched alkyl group having 2 to 7 carbon atoms, for example, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Preferred lower alkyl groups are those having 2 to 4 carbon atoms.

As used herein, the term "lower alkoxy" refers to a straight or branched chain alkyl group as described above attached to an oxygen atom.

The term "halogen-substituted lower alkyl" refers to an alkyl group as defined above wherein at least one hydrogen atom is substituted by: halogen, e.g. -CF₃，-CHF₂，-CH₂F，-CH₂CF₃，-C(CH₃)₂CF₃，-CH(CH₃)CH₂CF₃，-CH(CH₃)CF₃，-CH₂CH₂CF₃，-CH₂CH₂CH₂CF₃，-CH₂CH₂CF₂CF₃，-CH₂CH₂CH₂CF₂CF₃，-CH₂CF₂CF₃And the like. Preferred halogen-substituted lower alkyl groups are those having 1 to 5 carbon atoms.

The term "halogen" refers to chlorine, iodine, fluorine and bromine.

The term "cycloalkyl" refers to a saturated carbocyclic ring containing 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "aryl" refers to a cyclic aromatic hydrocarbon radical consisting of one or more fused rings and containing from 6 to 14 carbon atoms, wherein at least one ring is aromatic in nature, such as phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, or indanyl. Preferred is phenyl.

The term "heteroaryl" refers to a cyclic aromatic hydrocarbon radical consisting of one or more fused rings, containing 5 to 14 ring atoms, preferably 5 to 10 ring atoms, wherein at least one ring is aromatic in nature and which contains at least one heteroatom selected from N, O or S, such as quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyrazolyl, 2, 4-dihydro-pyrazol-3-one, pyridinyl, iso-pyridinylAzolyl radical, benzo [1, 3 ]]Dioxoles, [1.3.4 ]]Thiadiazoles, pyridazinyl, pyrimidinyl, benzotriazole-5-yl, benzimidazol-5-yl, [1, 3, 4]-Oxadiazol-2-yl, [1, 2.4 ]]Triazol-1-yl, [1, 6 ]]Naphthyridin-2-yl, imidazo [4, 5-b)]Pyridin-6-yl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, imidazol-1-yl or benzofuryl. Preferred heteroaryl groups are pyridin-2, 3 or 4-yl.

The term "heterocycloalkyl" refers to an alkyl ring in which one or two carbon atoms are replaced by N, S or O, such as the following groups: tetrahydropyranyl, 1, 1-dioxo-hexahydro-1. lamda⁶Thio-pyranyl, 1, 1-dioxo-tetrahydro-1. lambda⁶Phenylthio, oxetanyl, morpholinyl, [1, 4 ]]Diazepam-1-yl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidin-4-yl or 1, 1-dioxo-lambda⁶-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 present invention is a compound of formula Ia

Wherein

R¹Is halogen;

n is 1, 2 or 3, and if n is 2 or 3, the halogens may be different;

R²is C_2-7-alkyl or C_3-6-a cycloalkyl group;

R³is the following group

Wherein

-C(O)-CH₂-CN, or

-C (O) -cycloalkyl,

-C (O) -heterocycloalkyl, or is

-C (O) -heteroaryl, or is

-C (O) -aryl,

the heterocycloalkyl, heteroaryl or aryl group is optionally substituted with: the halogen(s) are selected from the group consisting of,

lower alkyl, ═ O, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy,

-C(O)-CH₂n (di-lower alkyl), C (O) NH₂-O-C (O) -lower alkyl, C (O) -lower alkyl

Lower alkyl, S (O)₂-lower alkyl or cyano;

R⁴is aryl, optionally substituted by halogen,

or a pharmaceutically active salt thereof.

A preferred aryl group is phenyl.

The present invention includes the following compounds:

rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

Rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -isopropyl-carbamic acid 4-fluoro-phenyl ester

Rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -isobutyl-carbamic acid 4-fluoro-phenyl ester

Rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3R, 4S) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (4 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (4 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -isopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -isopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -isopropyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -isopropyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -isopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -isopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

Ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

4- { (3R, 4S) -3- (4-chloro-3-fluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino ] -pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (6 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (4 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-methyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (6 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 3' ] bipyridinyl-4-carbonyl) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (4 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (5 '-methyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl ] -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- [1- (5-cyano-pyrazin-2-yl) -piperidine-4-carbonyl ] -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (3-methyl-oxetane-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (3, 3-difluoro-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (1-cyclobutanecarbonyl-piperidine-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (1-trifluoromethyl-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (3-fluoro-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (2, 2-difluoro-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (1-trifluoromethyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (1-cyano-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (2, 2-dimethyl-tetrahydro-pyran-4-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (5-trifluoromethyl-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (5-fluoro-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (4-cyano-benzoyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (4-fluoro-benzoyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (5-trifluoromethyl-pyrazine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (6-cyano-pyridine-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (1-acetyl-piperidine-4-carbonyl) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (1-methanesulfonyl-piperidine-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (1-acetyl-piperidine-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [5 '- (1-hydroxy-1-methyl-ethyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3-methyl-oxetane-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 2-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-cyano-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 2-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-trifluoromethyl-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 2-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (1-cyclobutanecarbonyl-piperidine-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3-methyl-oxetane-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3-fluoro-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3, 3-difluoro-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3-methoxy-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-trifluoromethyl-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (2-cyano-acetyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-cyano-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-trifluoromethyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (2, 2-difluoro-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (tetrahydro-pyran-4-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (2, 2-dimethyl-tetrahydro-pyran-4-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-methoxymethyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (2, 2-dimethyl-cyclopropanecarbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-trifluoromethyl-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-fluoro-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (6-oxo-piperidine-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (1-isopropyl-6-oxo-piperidine-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (1-isopropyl-6-oxo-piperidine-3-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- [1- ((S) -4-oxo-azetidine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- [1- (6-oxo-piperidine-3-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [5 '- (1-hydroxy-ethyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-carbamoyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-carbamoyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-carbamoyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- ((S) -4-oxo-azetidine-2-carbonyl) -piperidine-4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- [5 '- (2-diethylamino-acetyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl ] -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester, or

Acetic acid 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino ] -pyrrolidine-1-carbonyl } -3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-5' -yl ester.

Particular embodiments of the present invention are the following compounds:

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester, or

One embodiment of the invention is a compound of the formula:

wherein

n is 1, 2 or 3, and if n is 2 or 3, R¹May be different;

R²is C_2-7-alkanesRadical or C_3-6-a cycloalkyl group;

R³is a non-aromatic heterocyclic radical

Wherein

X is CH;

y is-N (R)⁷’)-；

R⁶Is hydrogen;

o and m may be 0, 1 or 2 independently of each other;

p is 0 or 1;

R⁷' is hydrogen, -C (O) -lower alkyl, -C (O) O-lower alkyl, S (O)₂-lower alkyl, -C (O) CH₂O-lower alkyl, or

Cycloalkyl, -CH₂-cycloalkyl or-C (O) -cycloalkyl, wherein said cycloalkyl is optionally substituted by lower alkyl, CF₃Halogen or cyano, or

-c (o) -heterocycloalkyl or heterocycloalkyl, or-heteroaryl or-c (o) -heteroaryl, or-c (o) -aryl or aryl, said heterocycloalkyl, heteroaryl or aryl being optionally substituted with: halogen, lower alkyl, lower alkoxy, halogen-substituted lower alkyl, C (O) NH-lower alkyl, C (O) NH₂C (O) -lower alkyl, S (O)₂-lower alkyl or cyano;

z is-O-;

R⁴is (CH)₂)_qAryl or is (CH)₂)_q-heteroaryl, said aryl or heteroaryl ring being optionally substituted by halogen, hydroxy, lower alkyl substituted by halogen, S (O)₂-lower alkyl, cyano or lower alkoxy;

q is 0 or 1;

or a pharmaceutically active salt thereof.

The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by a process comprising:

a) reacting a compound of formula II

Coupling with a suitable carbamoyl chloride, acid chloride or carboxylic acid to provide a compound of formula I,

wherein the substituent R¹，R²，R³And R⁴As defined above, the above-mentioned,

and if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt;

or

b) Reacting a compound of formula III

With a mixture of the corresponding chloroformate, anhydride or triphosgene and the corresponding alcohol or amine to provide the compound of formula I,

and, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt.

The following schemes 1 and 2 describe in more detail the methods of preparing the compounds of formula I. The starting materials of formula II are known compounds and can be prepared according to methods known in the art.

Scheme 1

Wherein the substituent R¹，R²，R³And R⁴And X is as defined above.

According to scheme 1, the synthesis of N- (methoxymethyl) -N- (phenylmethyl) -N- (trimethylsilyl) methylamine V is carried out by reacting 2-nitrostyrene derivative IV with azomethine generated in situ from N- (methoxymethyl) -N- (phenylmethyl) -N- (trimethylsilyl) methylamine V in the presence of catalytic amounts of an acid such as TFAStereospecific 1, 3-dipolar cycloaddition between salts to prepare 3, 4-disubstituted pyrrolidines VI. Using standard conditions, e.g. SnCl₂.H₂O reduces the nitro moiety of VI to yield VII. The amino moiety of VII is subsequently alkylated to yield VIII. The reaction of VIII with a mixture of anhydride, chloroformate or triphosgene with an alcohol or amine in the presence of a base gives IX. Selective N-debenzylation to yield II is then carried out using several known methods compatible with the substitution pattern of the aromatic ring. Finally, derivative I is prepared via coupling of the appropriate carbamoyl chloride, acid chloride or carboxylic acid. Alternatively, pyrrolidine II is coupled with the corresponding acid to form a compound of formula IA, which may be deprotected to yield a piperidine of formula IB, which may be further derivatised to obtain the final compound of formula I.

Scheme 2

Wherein the substituent R¹，R²，R³And R⁴As defined above.

According to scheme 2, the secondary amine of intermediate VII can be protected, e.g., using a Boc group, to yield a compound of formula X, followed by selective debenzylation to yield XI. Thereafter, coupling with a suitable carbamoyl chloride, acid chloride or carboxylic acid gives XII. Deprotection with TFA gives the free amine XIII which, after reaction with an anhydride, chloroformate or a mixture of triphosgene and alcohol or amine in the presence of a base, gives the derivative of formula I.

Example 1

a) Rac- (3R, 4S) -1-benzyl-3- (3, 4-dichloro-phenyl) -4-nitro-pyrrolidine

At 0 ℃ over a period of 30 minutes will be in CH₂Cl₂A solution of N- (methoxymethyl) -N- (phenylmethyl) -N- (trimethylsilyl) methylamine (32.50g, 0.135mol) in (70mL) was added dropwise to CH₂Cl₂To a stirred solution of 1, 2-dichloro-4- ((E) -2-nitro-vinyl) -benzene (19.60g, 0.09mol) and trifluoroacetic acid (1.54mL, 0.013mol) in (160 mL). The ice bath was removed and the solution was stirred at 25 ℃ for an additional 48 h. It was then concentrated and purified by flash chromatography (SiO)₂EtOAc/H1: 6) purification yielded 25.0g (79%) of the title compound as a yellow oil. MS m/e: 351.0(M + H)⁺)。

b) Rac- (3S, 4R) -1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-ylamine

To a stirred solution of rac- (3R, 4S) -1-benzyl-3- (3, 4-dichloro-phenyl) -4-nitro-pyrrolidine (11.60g, 33.0mmol) in EtOAc (200mL) was added SnCl in one portion₂.2H₂O (37.26g, 0.165 mol). The reaction mixture was then heated at reflux for 4 hours, cooled to ambient temperature and NaHCO was added₃A saturated aqueous solution of (a). The salt was filtered off and the product was extracted with EtOAc. Then passing through Na₂SO₄The organic phase was dried and concentrated in vacuo to yield 5.7g (54%) of rac- (3S, 4R) -1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-ylamine as a yellow oil. The product was then used in the next step without further purification. ES-MS m/e: 321.2(M + H)⁺)。

c) Rac- (3S, 4R) - [ 1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl group Esters

To a solution of rac- (3S, 4R) -1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-ylamine (30.64g, 0.095mol) in dichloromethane (300mL) was added N, N-diisopropylamine (32.65mL, 0.191mol) and 4-dimethylaminopyridine (1.17g, 0.01 mol). The reaction mixture was cooled to 0 ℃ and di-tert-butyl dicarbonate (24.98g, 0.114mol) was added. After stirring at 0 ℃ for 2h and at ambient temperature for 18h, it was concentrated. By flash chromatography (SiO)₂EtOAc/heptane 1: 3) yielded 5.82g (14%) of the title compound as a yellow oil. ES-MS m/e: 421.1(M + H)⁺)。

d) Rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl ester

To a solution of rac- (3S, 4R) - [ 1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl ] -carbamic acid tert-butyl ester (5.59g, 0.013mol) and N, N-diisopropylamine (6.81mL, 0.017mol) in toluene (60mL) was added 1-chloroethyl formate (1.88mL, 0.017mol) at ambient temperature and the reaction mixture was stirred for 24 h. It was concentrated and the resulting residue was diluted in methanol (60mL) and stirred at ambient temperature for 3 h. Concentration yielded the crude title compound as a light brown solid (6.59g, 67% purity), which was used directly without further purification.

e) Rac- (3S, 4R) - {4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl Base of]-pyrrolidin-3-yl } -carbamic acid tert-butyl ester

To a solution of 1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carboxylic acid (4.48g, 0.02mol) in DMF (40ml) was added O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate (9.54g, 0.03 mol). After stirring for 10min at ambient temperature N, N-diisopropylethylamine (19.82ml, 0.116mol) and rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl in DMF (45ml) were added]-a solution of tert-butyl carbamate (6.39g, 67% purity, 0.013mol) and the reaction mixture was stirred at this temperature for 19 h. It was diluted with ethyl acetate (80mL) and the organic layer was washed with water (80mL), aqueous sodium carbonate (1M, 40mL) and brine (40 mL). The aqueous layer was extracted with ethyl acetate (160 mL). The combined organic layers were dried over sodium sulfate and concentrated. By flash chromatography (SiO)₂EtOAc/methanol 100: 0 to 80: 20) yields 5.84g (87%) of the title compound as a light brown foam. ES-MS m/e: 524.1(M + H)⁺)。

f) Rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl]- [1- (1-methyl-cyclopropane) Alkylcarbonyl) -piperidin-4-yl]-methanones

To rac- (3S, 4R) - {4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl in dichloromethane (55mL)]A solution of-pyrrolidin-3-yl } -carbamic acid tert-butyl ester (5.747g, 0.011mol) was added trifluoroacetic acid (8.39mL, 0.110mol) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was alkalinized by the addition of aqueous sodium carbonate (1M, 10 mL). The organic layer was washed with water (8mL) and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield 4.30g (92%) of the title compound as a light brown foam.ES-MS m/e：524.2(M+H⁺)。

g) Racemic- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-ethylamino-pyrrolidin-1-yl]- [1- (1-methyl- Cyclopropanecarbonyl) -piperidin-4-yl]-methanones

To rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl in ethanol (0.3mL)]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]To a solution of methanone (50mg, 0.12mmol) was added acetaldehyde (10uL, 0.18mmol) and sodium cyanoborohydride (15mg, 0.24mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was concentrated and the residue was separated between water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. By chromatography (SiO)₂Purification of dichloromethane: methanol 100: 0 to 95: 5) yielded the title compound as a pale yellow oil (30mg, 56%). MS m/e: 452.3[ M ]]⁺。

h) Racemic- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl Base of]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

To racemic- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-ethylamino-pyrrolidin-1-yl in dichloromethane (1mL)]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]To a solution of methanone (25mg, 0.06mmol) was added N, N-diisopropylethylamine (10uL, 0.06 mmol). It was cooled to 0 ℃ and 4-fluorophenyl chloroformate (8uL, 0.06mmol) was added and the reaction mixture was stirred at this temperature for 30min then at ambient temperature for 2 h. Concentration and chromatography (SiO)₂Ethyl acetate) yielded the title compound (17mg, 52%) as a colorless foam. MS m/e: 590.4[ M ]]⁺。

Example 2

a) Racemic- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-isopropylamino-pyrrolidin-1-yl]- [1- (1-methyl) Cyclopropyl carbonyl) -piperidin-4-yl]-methanones

To rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl in dichloromethane (1mL)]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]To a solution of-methanone (120mg, 0.28mmol) were added acetone (21uL, 0.28mmol) and sodium triacetoxyborohydride (72mg, 0.34mmol) and acetic acid (16uL, 0.28mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was diluted with dichloromethane and washed with aqueous sodium bicarbonate (1M). The organic layer was dried over sodium sulfate and concentrated to give the title compound as a pale yellow foam (95mg, 72%). MS m/e: 466.3[ M]⁺。

b) Racemic- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl Base of]-pyrrolidin-3-yl } -isopropyl-carbamic acid 4-fluoro-phenyl ester

Analogously to the procedure described for the synthesis of example 1 (step h), starting from rac- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-isopropylamino-pyrrolidin-1-yl]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]-methanone instead of rac- {4- [ (3S, 4R) -3- (3, 4-dichloro-phenyl) -4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl } - (1-methyl-cyclopropyl) -methanone using 4-fluorophenyl chloroformate to prepare and obtain the title compound rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl as a colorless foam]-pyrrolidin-3-yl } -isopropyl-carbamic acid 4-fluoro-phenyl ester. MS m/e: 604.3[ M ]]⁺。

Example 3

a) Racemic- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-isobutylamino-pyrrolidin-1-yl]- [1- (1-methyl) Cyclopropyl carbonyl) -piperidin-4-yl]-methanones

To rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl in dichloromethane (1mL)]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]To a solution of-methanone (150mg, 0.35mmol) were added isobutyraldehyde (39uL, 0.42mmol) and sodium cyanoborohydride (27mg, 0.42mmol) and acetic acid (51uL, 0.88mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was diluted with dichloromethane and washed with aqueous sodium bicarbonate (1M). The organic layer was dried over sodium sulfate and concentrated to give the title compound as a pale yellow oil (140mg, 82%). MS m/e: 480.3[ M ]]⁺。

b) Racemic- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl Base of]-pyrrolidin-3-yl } -isobutyl-carbamic acid 4-fluoro-phenyl ester

In analogy to the procedure described for the synthesis of example 1 (step h), starting from rac- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-isobutylamino-pyrrolidin-1-yl]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]-methanone instead of rac- {4- [ (3S, 4R) -3- (3, 4-dichloro-phenyl) -4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl } - (1-methyl-cyclopropyl) -methanone using 4-fluorophenyl chloroformate to prepare and obtain the title compound rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl as a colorless foam]-pyrrolidin-3-yl } -isobutyl-carbamic acid 4-fluoro-phenyl ester. MS m/e: 618.5[ M ]]⁺。

Example 4

a) Racemic- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-cyclopropylamino-pyrrolidin-1-yl]- [1- (1-methyl) Cyclopropyl carbonyl) -piperidin-4-yl]-methanones

To rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl in dichloromethane (1mL)]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]To a solution of-methanone (150mg, 0.35mmol) was added ((1-ethoxycyclopropyl) oxy) trimethylsilane (62uL, 0.35mmol) and sodium triacetoxyborohydride (90mg, 0.42mmol) and acetic acid (20uL, 0.35mmol) and the reaction mixture was stirred at ambient temperature for 20 h. It was diluted with dichloromethane and washed with aqueous sodium bicarbonate (1M). The organic layer was dried over sodium sulfate and concentrated. By chromatography (SiO)₂Purification of dichloromethane: methanol 100: 0 to 95: 5) yielded the title compound as a pale yellow oil (30mg, 18%). MS m/e: 464.3[ M ]]⁺。

b) Racemic- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl Base of]-pyrrolidin-3-yl } -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

In analogy to the procedure described for the synthesis of example 1 (step h), starting from rac- [ (3R, 4S) -3- (3, 4-dichloro-phenyl) -4-cyclopropylamino-pyrrolidin-1-yl]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]-methanone instead of rac- {4- [ (3S, 4R) -3- (3, 4-dichloro-phenyl) -4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl } - (1-methyl-cyclopropyl) -methanone prepared using 4-fluorophenyl chloroformate and obtained as a colorless foamThe title compound rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -cyclopropyl-carbamic acid 4-fluoro-phenyl ester. MS m/e: 602.3[ M ]]⁺。

Example 5

And

example 6

Reacting racemic- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester column chromatography of the chiral phase to yield { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl as a colorless foam]Pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (MS (M/e): 590.3[ M]⁺) And { (3R, 4S) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl as a colorless foam]Pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (MS (M/e): 590.3[ M]⁺)。

Example 7

a)Rac- (3R, 4S) -1-benzyl-3- (4-chloro-phenyl) -4-nitro-pyrrolidine

In analogy to the procedure described for the synthesis of rac- (3R, 4S) -1-benzyl-3- (3, 4-dichloro-phenyl) -4-nitro-pyrrolidine (example 1, step a) the title compound was prepared from (E) -1-chloro-4- (2-nitrovinyl) benzene and N- (methoxymethyl) -N- (phenylmethyl) -N- (trimethylsilyl) methylamine as light yellow viscous oil. MS m/e: 317.1[ M + H]⁺。

b) Rac- (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-ylamine

In analogy to the procedure described for the synthesis of rac- (3S, 4R) -1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-ylamine (example 1, step b) the title compound was prepared from rac- (3R, 4S) -1-benzyl-3- (4-chloro-phenyl) -4-nitro-pyrrolidine by reduction using SnCl2 as brown oil. MS m/e: 287.1[ M + H]⁺。

c) Racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-ethyl-carbamic acid Phenyl ester

A mixture of 2.14g (7.09mmol) rac- (3S, 4R) -1-benzyl-4- (4-chlorophenyl) -pyrrolidin-3-amine, 540uL (9.5mmol) acetaldehyde, 609uL (10.6mmol) acetic acid and 2.25g (10.6mmol) sodium triacetoxyborohydride was stirred at 20 ℃ overnight. Adding water and Na₂CO₃Aqueous solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄To dry and evaporate to dryness. The residue was dissolved in 60mL DCM. 1.15g of DIPEA (8.86mmol) and 43.3mg of DMAP (354. mu. mol) were added. The brown solution was cooled with an ice bath. A solution of 1.48g (8.51mmol) 4-fluorophenyl chloroformate in 15mL DCM was added dropwise and the mixture was stirred at 0-5 ℃ for 1 h. Adding Na₂CO₃Aqueous solution and the mixture was extracted with DCM. The combined organic layers were washed with brine, Na₂SO₄Dried and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from TBDME and heptane to yield after evaporation of the product containing fractions 1.62g (50%) of the title compound as yellow oil. MS m/e: 453.3[ M + H]⁺。

d) Rac-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-azoles Alkyl-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

A mixture of 1.62g (3.58mmol) rac-4-fluorophenyl (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-yl (ethyl) carbamate and 624mg (4.83mmol) DIPEA in 25mL toluene was cooled to 0-5 ℃. 690mg (4.83mmol) of 1-chloroethyl chloroformate are added and the mixture is stirred at ambient temperature overnight and evaporated to dryness. Drying the residue at 60-70 ℃ under high vacuum to give racemic- [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester. The residue was dissolved in 25mL of methanol, stirred for 90min and evaporated to dryness. The residue was dissolved in 25mL of DMF and 2.5g (19.3mmol) of DIPEA was added. A solution of 738mg (3.22mmol) of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 1.35g (3.54mmol) of HATU in 25ml of DMF was added and the mixture was stirred at room temperature for 30min and evaporated under high vacuum. The residue was dissolved in ethyl acetate and taken up with 10% Na₂CO₃Aqueous solution and brine. The aqueous layer was extracted with ethyl acetate and passed over Na₂SO₄The combined organic layers were dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 1.8g (97%) of the title compound as a light brown foam. MS m/e: 574.2[ M + H]⁺。

e)4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl Butyl-piperidine-1-carboxylate

Racemic-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. After evaporation of the product containing fractions, the title compound was obtained as a yellow viscous oil. MS m/e: 474.3[ M-Boc]⁺。

And

4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl Butyl-piperidine-1-carboxylate

Purification by chiral HPLC with isopropyl alcoholAlcohol/heptane elution to rac-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. After evaporation of the product containing fractions, the title compound was obtained as a yellow viscous oil. MS m/e: 474.3[ M-Boc]⁺。

f) (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro -phenyl ester

804mg (1.4mmol) of 4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino in 25mL DCM]A mixture of-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester and 1.6g (14mmol) TFA was stirred at room temperature for 5 h. Water and 2N aqueous NaOH were added and the mixture was extracted with DCM. Through Na₂SO₄The combined organic layers were dried, filtered and evaporated to yield 577mg (87%) of the title compound as a yellow foam. MS m/e: 474.3[ M + H]⁺。

g) { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidine-3- Phenyl-ethyl-carbamic acid 4-fluoro-ester

94.7mg (0.2mmol) of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl in 2.5mL of DMF]A mixture of 4-fluoro-phenyl ethyl-carbamate, 83.7mg (0.3mmol) 2-chloropyrimidine-5-carbonitrile and 129mg (1mmol) DIPEA was shaken at 65 ℃ for 22 h. The mixture was subjected to preparative HPLC purification on reversed phase using a column chromatography from acetonitrile, water and NEt₃The gradient formed elutes. The product containing fractions were evaporated to yield 58mg (51%) of the title compound as an off-white solid. MS m/e: 577.3[ M + H]⁺。

Example 8

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone to prepare the title compound as an off-white solid. MSm/e: 593.4[ M + H]⁺。

Example 9

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2-bromoisonicotinitrile (2-bromoisonicotinitrile) to prepare the title compound as an off-white solid. MS m/e: 576.3[ M + H]⁺。

Example 10

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2-bromo-5- (methylsulfonyl) pyridine to prepare the title compound as an off-white solid. MSm/e: 629.3[ M + H]⁺。

Example 11

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5-bromopyrazine-2-carbonitrile to prepare the title compound as an off-white solid. MS m/e: 577.3[ M + H]⁺。

Example 12

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 6-chloropyridazine-3-carbonitrile to prepare the title compound as an off-white solid. MS m/e: 577.3[ M + H]⁺。

Example 13

a) [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro -phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate analogous from 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the protecting group with TFA. The title compound was obtained as a yellow foam. MS m/e: 474.3[ M + H]⁺。

b) { (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidine-3- Phenyl-ethyl-carbamic acid 4-fluoro-ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 6-chloropyridazine-3-carbonitrile to prepare the title compound as an off-white solid. MS m/e: 577.3[ M + H]⁺。

Example 14

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone to prepare the title compound as an off-white solid. MSm/e: 593.4[ M + H]⁺。

Example 15

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2-bromoisonicotinic acid to prepare the title compound as an off-white solid. MS m/e: 576.3[ M + H]⁺。

Example 16

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2-bromo-5- (methylsulfonyl) pyridine to prepare the title compound as an off-white solid. MSm/e: 629.3[ M + H]⁺。

Example 17

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (pyrrolidin-3-yl) -ethyl-carbamate was analogous from [ (3S, 4R) -4- (4-chloro-phenyl)-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5-bromopyrazine-2-carbonitrile to prepare the title compound as an off-white solid. MS m/e: 577.3[ M + H]⁺。

Example 18

Example 19

And

example 20

a) Rac- [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyri Pyridine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

125mg (0.456mmol) of rac- [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl in 10mL of DMF]A mixture of 198mg (0.547mmol) of 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid, 208mg (0.547mmol) of HATU and 353mg (2.73mmol) of DIPEA was stirred at room temperature for 1 h. The mixture was concentrated and DMF and DIPEA were added and subjected to purification by preparative HPLC using on reversed phase a mixture of acetonitrile, water and NEt₃The gradient formed. The product containing fractions were evaporated to yield 187mg (66%) of the title compound as a light brown viscous oil. MS m/e: 619.4[ M + H]⁺。

The racemic material was separated using an isopropanol/heptane elution at CHIRALPAK AD. To give [ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 ' -trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' as a pale yellow solid ']Bipyridine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester. MS m/e: 619.4[ M + H]⁺And [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 ' -trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' is obtained as a pale yellow solid ']Bipyridine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester. MS m/e: 619.4[ M + H]⁺。

Example 21

And the same was used to synthesize [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate from rac- [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and 1- (5-cyanopyridin-2-yl) piperidine-4-carboxylic acid, followed by isolation via chiral chromatography on Chiralpak AD to prepare the title compound as an off-white solid. MS m/e: 576.3[ M + H]⁺。

Example 22

Example 23

a) Racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-isopropyl-carbamic acid Fluoro-phenyl ester

A mixture of 3.1g (10.8mmol) rac- (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-amine, 785mg (13.5mmol) acetone, 974mg (16.2mmol) acetic acid and 3.44g (16.2mmol) sodium triacetoxyborohydride in 50mL THF was stirred at room temperature for 4 h. Adding water and Na₂CO₃Aqueous solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. The residue was dissolved in 50mL DCM and 1.75g (13.5mmol) DIPEA and 13.2mg (0.1mmol) DMAP were added. The mixture was cooled to 0-5 ℃ and 2.08g (11.9mmol) of 4-fluorophenyl chloroformate in 20mL of DCM were added. The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 3.1g (61%) of the title compound as a pale yellow viscous oil. MS m/e: 467.2[ M + H]⁺。

b)4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino]-pyrrolidine-1- Carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And

4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ (4-fluoro-benzeneOxycarbonyl) -isopropyl-amino]-pyrrolidine-1-carbonyl Butyl-piperidine-1-carboxylate

And the use as described for the synthesis of rac-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]Procedure for-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester was analogous to that described for racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-isopropyl-carbamate, the title compound was prepared by cleavage of the benzyl group and subsequent coupling with 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. The resulting rac-4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino was eluted by chiral HPLC on CHIRALPAK AD with isopropanol/heptane]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. 4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino ] was obtained as a yellow viscous oil after evaporation of the product containing the fractions]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. MS m/e: 588.3[ M + H]⁺. 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino was obtained as a yellow viscous oil]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. MS m/e: 588.3[ M + H]⁺。

c) [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-isopropyl-carbamic acid Fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate analogous from 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester byThe title compound was prepared by cleavage of the protecting group with TFA. The title compound was obtained as an off-white foam. MS m/e: 488.3[ M + H]⁺。

d) [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) - Pyrrolidin-3-yl radical]-isopropyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 6-bromonicotinonitrile to prepare the title compound as an off-white solid. MS m/e: 590.4[ M + H]⁺。

Example 24

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone to prepare the title compound as an off-white solid. MS m/e: 607.3[ M + H]⁺。

Example 25

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 2-bromo-5- (trifluoromethyl) pyridine to prepare the title compound as an off-white solid. MS m/e: 633.4[ M + H]⁺。

Example 26

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 6-chloropyridazine-3-carbonitrile to prepare the title compound as a light brown solid. MS m/e: 591.3[ M + H]⁺。

Example 27

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 5-chloropyrazine-2-carbonitrile to prepare the title compound as a light brown solid. MS m/e: 591.3[ M + H]⁺。

Example 28

a) [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-isopropyl-carbamic acid Fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate analogous from 4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ (4-fluoro-phenoxycarbonyl) -isopropyl-amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the protecting group with TFA. The title compound was obtained as an off-white foam. MS m/e: 488.3[ M + H]⁺。

b) [ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Dipyridyl-4-carbonyl) - Pyrrolidin-3-yl radical]-isopropyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl isopropyl-carbamate and 6-bromonicotinonitrile to prepare the title compound as an off-white solid. MS m/e: 590.2[ M + H]⁺。

Example 29

a) Racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-cyclopropyl-amine

A mixture of 3.75g (13.1mmol) rac- (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-amine, 3.14g (52mmol) acetic acid and 2.62g (15mmol) (1-ethoxycyclopropoxy) trimethylsilane in 15mL methanol was stirred at room temperature for 1h and at reflux for 3h and evaporated to dryness. The residue is dissolved in 35mL of THF and added to a mixture of 989mg (26mmol) of sodium borohydride in 15mL of THF, which is treated with 3.7g (26mmol) of boron trifluoride etherate at 0-5 ℃ and stirred for 1 h. The mixture was stirred at room temperature overnight, water and 4n naoh aqueous solution were added and extracted with ethyl acetate. The organic layer was washed with brine, Na₂SO₄Drying, filtering and evaporating toAnd (5) drying. The residue was purified by flash column chromatography on silica with DCM, methanol and NEt₃The gradient formed elutes. The product containing fractions were evaporated to yield 2.27g (53%) of the title compound as a light brown oil. MS m/e: 327.1[ M + H]⁺。

b) Racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-cyclopropyl-carbamic acid Fluoro-phenyl ester

2.27g (6.94mmol) of rac- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl in 40mL DCM at 0 deg.C]A mixture of cyclopropyl-amine, 987mg (7.64mmol) of DIPEA, 8.48mg (0.07mmol) of DMAP and 1.27g (7.29mmol) of 4-fluorophenyl chloroformate was stirred at room temperature overnight and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 1.64g (51%) of the title compound as a colorless viscous oil. MS m/e: 465.1[ M + H]⁺。

c)4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1- Carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And

4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl Butyl-piperidine-1-carboxylate

And the use as described for the synthesis of rac-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]Procedure for-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester was analogous to that described for racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate, the title compound was prepared by cleavage of the benzyl group and subsequent coupling with 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. The resulting rac-4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino group was eluted by chiral HPLC on CHIRALPAK AD with isopropanol/heptane]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. 4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino ] as a light brown foam was obtained after evaporation of the product containing the fractions]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. MS m/e: 586.3[ M + H]⁺. Obtaining 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino as a yellow viscous oil]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester. MS m/e: 586.3[ M + H]⁺。

d) [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-cyclopropyl-carbamic acid Fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate analogous from 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the protecting group with TFA. The title compound was obtained as a pale yellow foam. MS m/e: 486.4[ M + H]⁺。

e) [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) - Azole compoundsAlk-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 6-bromonicotinonitrile to prepare the title compound as an off-white solid. MS m/e: 588.2[ M + H]⁺。

Example 30

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone to prepare the title compound as an off-white solid. MS m/e: 605.3[ M + H]⁺。

Example 31

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 2-bromo-5- (trifluoromethyl) pyridine to prepare the title compound as an off-white solid. MS m/e: 631.4[ M + H]⁺。

Example 32

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Procedure for 4-fluoro-phenyl (E) -pyrrolidin-3-yl } -ethyl-carbamate was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 6-chloropyridazine-3-carbonitrile to prepare the title compound as an off-white solid. MS m/e: 589.3[ M + H]⁺。

Example 33

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-benzeneThe procedure for the ester was analogous, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 5-chloropyrazine-2-carbonitrile to prepare the title compound as a pink solid. MS m/e: 589.3[ M + H]⁺。

Example 34

a) [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-cyclopropyl-carbamic acid Fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate analogous from 4- { (3S, 4R) -3- (4-chloro-phenyl) -4- [ cyclopropyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the protecting group with TFA. The title compound was obtained as a pale yellow foam. MS m/e: 486.4[ M + H]⁺。

b) [ (3R, 4S) -4- (4-chloro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) - Pyrrolidin-3-yl radical]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]Analogous procedure for 4-fluoro-phenyl (pyrrolidin-3-yl) -ethyl-carbamate, prepared from [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl cyclopropyl-carbamate and 6-bromonicotinonitrile to prepare the title compound as an off-white solid. MS m/e: 588.2[ M + H]⁺。

Example 35

a) Rac- (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-ylamine

With the described catalyst for the synthesis of rac- (3S, 4R) -1-benzyl-4- (3, 4-dichloro-phenyl) -pyrrolidin-3-ylamine (example 1, step a)&b) Analogously to the procedure of (1), the reduction of NO by N- (methoxymethyl) -N- (phenylmethyl) -N- (trimethylsilyl) methylamine and 1-fluoro-4- ((E) -2-nitro-vinyl) -benzene and subsequent use of tin chloride₂Function to prepare the title compound. MS m/e: 271.4[ M + H ]]⁺。

b) Racemic- [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-amine

38g (141mmol) of rac- (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-ylamine, 7.12g (162mmol) of acetaldehyde, 12.1mL of acetic acid and 44.7g (211mmol) of triacetoxyborohydride in 400mL of THFThe sodium chloride mixture was stirred at 0 ℃ for 3h and then warmed to room temperature. Adding water and Na₂CO₃Aqueous solution and ethyl acetate. The organic layer was washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica using a mixture of ethyl acetate, heptane and NEt₃The gradient formed proceeds with elution. The product containing fractions were evaporated to yield 18.5g (44%) of the title compound as a brown oil. MS m/e: 299.4[ M + H]⁺。

c) Racemic- [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-ethyl-carbamic acid Phenyl ester

And methods described for the synthesis of rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 1, step h) the procedure was analogous to that described for rac- [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-amine and 4-fluorophenyl chloroformate to prepare the title compound as a light brown viscous oil. MSm/e: 437.3[ M + H]⁺。

d) [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

Racemic- [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl eluted with hexane and isopropanol by column chromatography on Chiralpak AD]-ethyl-carbamic acid 4-fluoro-phenyl ester. The product containing fractions were evaporated to yield the title compound as a light brown viscous oil. MS m/e: 437.3[ M + H]⁺。

And

[ (3R, 4S) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

e) Ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-carbamic acid 4-fluoro-phenyl ester

And the process described for the synthesis of rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]Tert-butyl (carbamate) (example 1, step d) the procedure was analogous to that described for [ (3S, 4R) -1-benzyl-4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate, prepared by cleaving the benzyl protecting group the title compound as a brown foam. MS m/e: 347.1[ M + H]⁺。

f) (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) - Pyrrolidin-3-yl radical]-ethyl-carbamic acid 4-fluoro-phenyl ester

125mg (0.36mmol) of ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] in 4mL of DMF]4-fluoro-phenyl carbamate, 137mg (0.36mmol) HATU, 63uL (0.36mmol) DIPEA and 69.4mg (0.3mmol)5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']The mixture of bipyridine-4-carboxylic acid was shaken at room temperature for 2 h. The mixture was purified by preparative HPLC on reversed phaseFrom acetonitrile, water and NEt₃The gradient formed proceeds with elution. The product containing fractions were evaporated to yield 106mg (63%) of the title compound as an off-white solid. MS m/e: 560.2[ M + H]⁺。

Example 36

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate (example 35) from ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 569.3[ M + H]⁺。

Example 37

a)4- [ (3S, 4R) -3- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-4- (4-fluoro-phenyl) -pyrrolidine-1-carbonyl Base of]-piperidine-1-carboxylic acid tert-butyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate (example 35) from ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. MS m/e: 558.4[ M + H]⁺。

b) Ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-carbamic acid 4-fluoro -phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl-carbamic acid example 7, step f) the procedure was analogous to that described for 4- [ (3S, 4R) -3- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-4- (4-fluoro-phenyl) -pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the Boc group with TFA. MS m/e: 458.4[ M + H]⁺。

c) Ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -1- (5 '-methanesulfonyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine -4-carbonyl) -pyrrolidin-3-yl]-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl carbamate and 2-bromo-5- (methylsulfonyl) pyridine. MS m/e: 613.2[ M + H]⁺。

Example 38

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from ethyl- [ (3S, 4R) -4- (4-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl carbamate and 1- (6-bromopyridin-3-yl) ethanone. MS m/e: 577.3[ M + H]⁺。

Example 39

a) (4-chloro-3-fluoro-phenyl) -propiolic acid ethyl ester

To a mixture of 4-chloro-3-fluoroiodobenzene (74.27g, 284mmol) and cesium carbonate (185.0g, 568mmol) in tetrahydrofuran (730mL) was added cuprous iodide (2.16g, 11.4mmol) and bis (triphenylphosphine) palladium (II) chloride (3.98g, 5.7mmol) under argon. Ethyl propiolate (57.0g, 575mmol) was added dropwise over a period of 20 min. The resulting dark brown suspension is then suspended inStirring at 35 ℃ for 38h, then stirring atIt was filtered and the residue was washed with tetrahydrofuran (285 ml). The filtrate was evaporated and chromatographed (SiO)₂The residue was purified from heptane: ethyl acetate 90: 10) to yield the title compound (57.1g, 89%) as a yellow liquid. MS m/e: 226.0[ M ]]⁺。

b) 1-benzyl-4- (4-chloro-3-fluoro-phenyl) -2, 5-dihydro-1H-pyrrole-3-carboxylic acid

To a solution of (4-chloro-3-fluoro-phenyl) -propiolic acid ethyl ester (57.08g, 252mmol) in dichloromethane (240mL) was added trifluoroacetic acid (1.9mL, 25.2 mmol). The reaction mixture was cooled with a water bath at ambient temperature and a solution of N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (93.43g, 378mmol) in dichloromethane (185mL) was added dropwise over a period of 3 h. After stirring at ambient temperature for 20h, N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (15.6g, 63.0mmol) in dichloromethane (30mL) was added again and stirring continued for another 4 h. Removing the solvent and dissolving the residue in IIAlkane (540 mL). After addition of water (270mL) and aqueous sodium hydroxide (32%, 64.8mL, 700mmol), it was stirred at ambient temperature for 44 h. After concentration, the resulting residue was diluted with water (225mL) and extracted with tert-butyl methyl ether (225 mL). The organic layer was washed with water (225mL) and the aqueous layer was cooled to 5 ℃ and adjusted to pH 1.5 with aqueous hydrochloric acid (25%, 112 mL). After stirring at 5 ℃ for 1h, the resulting solid was filtered and washed with water (795mL) and ethanol (225 mL). Drying gave a pale yellow solid which was stirred with ethanol (4L) at 85 ℃ for 1 h. The resulting suspension was filtered and the filtrate was concentrated. Trituration with tert-butyl methyl ether (2L) gave a solid as off-whiteTitle compound of body (62.34g, 67%). MS m/e: 330.1[ M-H]^-。

c) (3R, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid

In a glove box under argon (O)₂Content < 2ppm) 1-benzyl-4- (4-chloro-3-fluoro-phenyl) -2, 5-dihydro-1H-pyrrole-3-carboxylic acid (1.00g, 3.01mmol), [ Ru (OAc)₂((S) -2-furyl-MeOBIPHEP)](9.18mg, 0.012mmol) (2-furyl-MeOBIPHEP ═ 6, 6 '-dimethoxydiphenyl-2, 2' -diyl) bis (di-2-furanylphosphine) and methanol (30mL) were charged to an autoclave and the asymmetric hydrogenation was carried out at 30 ℃ under 40bar of hydrogen for 20H after the pressure was released the grey suspension was evaporated to dryness to give the crude title compound MS M/e: 332.1[ M-H]。

d) (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid

A mixture of 48.8g (146mmol) of (3R, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid and 15.6mL of sulfuric acid in 400mL of methanol was heated to reflux for 21h and evaporated. The residue was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and heptane. The intermediate was dissolved in 500mL of methanol and 4.06mL of sodium methoxide (5.4N in methanol) was added and stirred at room temperature overnight. An additional 31.3mL of sodium methoxide (5.4N in methanol) was added and stirred at room temperature for 1 h. Water was added and the mixture was stirred at room temperature for 2 h. After evaporation of the methanol, water was added and the pH was adjusted to 6-7 with acetic acid. The product is precipitated and decantedAnd (3) mixing. The organic layer from the extraction with THF and ethyl acetate was washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. The residue was washed with hexane and diethyl ether and filtered to yield 44g (49%) of the title compound as a colorless solid after drying. MS m/e: 334.3[ M + H]⁺。

e) [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl ester

A mixture of 44g (132mmol) (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid, 25.3mL (145mmol) DIPEA and 45.3g (165mmol) diphenyl azide phosphate in 600mL tert-butanol was heated to reflux for 16 h. After cooling to room temperature, the mixture was evaporated to dryness. The residue was adsorbed on isolute HM-N and purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 25g (47%) of the title compound as a light brown solid. MS m/e: 405.4[ M + H]⁺。

f) (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-ylamine

And the process described for the synthesis of rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]The procedure for methanone (example 1, step f) was analogous to that of [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]-tert-butyl carbamate the title compound was prepared by cleavage of the Boc group with TFA. MS m/e: 305.2[ M + H]⁺。

g) [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-benzene Esters

And the process described for the synthesis of rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 1, step g)&h) The title compound was prepared analogously to (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-ylamine by reductive amination with acetaldehyde followed by reaction with 4-fluorophenyl chloroformate to yield the title compound as a light brown oil. MS m/e: 471.2[ M + H]⁺。

h) [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the process described for the synthesis of rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]Tert-butyl (carbamate) (example 1, step d) the procedure was analogous to that described for [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate, prepared by cleaving the benzyl group as the title compound in brown foam, which was used in the successive steps without further purification. MS m/e: 381.3[ M + H]⁺。

i)4- { (3R, 4S) -3- (4-chloro-3-fluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidines -1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]Preparation of 4-fluoro-phenyl (ethyl) -carbamate (example 35)Analogously, from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. MS m/e: 592.4[ M + H]⁺。

Example 40

a) [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid ester Acid 4-fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl-carbamic acid) ester (example 7, step f) analogous to that described by 4- { (3R, 4S) -3- (4-chloro-3-fluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the Boc group with TFA. MS m/e: 492.2[ M + H]⁺。

b) [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl Radical) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl)-1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-cyanopyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 594.3[ M + H]⁺。

EXAMPLE 41

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 603.2[ M + H]⁺。

Example 42

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl)Radical) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 637.3[ M + H]⁺。

Example 43

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 594.3[ M + H]⁺。

Example 44

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (1-methylcyclopropanecarbonyl) piperidine-4-carboxylic acid. MS m/e: 574.5[ M + H]⁺。

Example 45

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (4-cyanopyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 594.3[ M + H]⁺。

Example 46

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-amino4-fluoro-phenyl formate and 1- (5-fluoropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 587.2[ M + H]⁺。

Example 47

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-methylpyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 583.2[ M + H]⁺。

Example 48

a) (3, 4-difluoro-phenyl) -propiolic acid ethyl ester

And the use ofIn analogy to the procedure for the synthesis of (4-chloro-3-fluoro-phenyl) -propiolic acid ethyl ester (example 39, step a) the title compound was prepared from 3, 4-difluoroiodobenzene and ethyl propiolate as yellow liquid. MS m/e: 210[ M + H]⁺。

b) 1-benzyl-4- (3, 4-difluoro-phenyl) -2, 5-dihydro-1H-pyrrole-3-carboxylic acid

In analogy to the procedure described for the synthesis of 1-benzyl-4- (4-chloro-3-fluoro-phenyl) -2, 5-dihydro-1H-pyrrole-3-carboxylic acid (example 39, step b) the title compound was prepared from (3, 4-difluoro-phenyl) -propiolic acid ethyl ester and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine. MS m/e: 314.1[ M-H]^-。

c) (3R, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidine-3-carboxylic acid

In analogy to the procedure described for the synthesis of (3R, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid (example 39, step c) the title compound was prepared from 1-benzyl-4- (3, 4-difluoro-phenyl) -2, 5-dihydro-1H-pyrrole-3-carboxylic acid by asymmetric hydrogenation.

d) (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidine-3-carboxylic acid

Analogously to the procedure described for the synthesis of (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidine-3-carboxylic acid (example 39, step d), starting from (3R, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -Pyrrolidine-3-carboxylic acid to prepare the title compound as a white solid. MS m/e: 318.1[ M + H]⁺。

e) [ (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl ester

And the synthesis of [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]In analogy to the procedure for tert-butyl-carbamate (example 39, step e) the title compound was prepared from (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidine-3-carboxylic acid as off-white solid. MS m/e: 389.3[ M + H]⁺。

f) (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-ylamine

In analogy to the procedure described for the synthesis of (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-ylamine (example 39, step f) starting from [ (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]Tert-butyl carbamate to prepare the title compound as a brown oil. MS m/e: 289.2[ M + H]⁺。

g) [ (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-benzene Esters

And the synthesis of [ (3S, 4R) -1-benzyl-4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 39, step g) the procedure was analogous to that described for (3S)4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-ylamine to prepare the title compound as a light yellow oil. MS m/e: 455.3[ M + H]⁺。

h) [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate (example 39, step h) from [ (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate to prepare the title compound as a brown foam. MS m/e: 365.3[ M + H]⁺。

i) [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (3, 4-difluoro-benzene Radical) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]Analogous procedure for 4-fluoro-phenyl (ethyl-carbamic acid) ester (example 35) from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-cyanopyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 578.3[ M + H]⁺。

Example 49

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]Analogous procedure for 4-fluoro-phenyl (ethyl-carbamic acid) ester (example 35) from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 587.2[ M + H]⁺。

Example 50

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 612.4[ M + H]⁺。

Example 51

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (6-cyanopyridin-3-yl) piperidine-4-carboxylic acid. MSm/e: 578.3[ M + H]⁺。

Example 52

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (1-methylcyclopropanecarbonyl) piperidine-4-carboxylic acid. MSm/e: 558.3[ M + H]⁺。

Example 53

With said compounds for the synthesis of [ (3S, 4R)-1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (4-cyanopyridin-2-yl) piperidine-4-carboxylic acid. MSm/e: 578.4[ M + H ]]⁺。

Example 54

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-fluoropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 571.4[ M + H]⁺。

Example 55

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-methylpyridin-2-yl) piperidine-4-carboxylic acid. MSm/e: 567.4[ M + H]⁺。

Example 56

a)4- { (3R, 4S) -3- (4-chloro-3-fluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidines -1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. MS m/e: 592, 4[ M + H ]]⁺。

b) [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid ester Acid 4-fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]The procedure for 4-fluoro-phenyl-ethyl-carbamate (example 7, step f) was analogous to that described by 4- { (3R,4S) -3- (4-chloro-3-fluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester, the title compound was prepared by cleavage of the Boc group with TFA. MS m/e: 492.2[ M + H]⁺。

Example 57

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 6-chloropyridazine-3-carbonitrile on silica in acetonitrile gave the title compound as an off-white solid. MS m/e: 595.4[ M + H]⁺。

Example 58

a)4- { (3R, 4S) -3- (3, 4-difluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidines -1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. MS m/e: 576.3[ M + H]⁺。

b) [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl-carbamic acid) ester (example 7, step f) analogous to that described by 4- { (3R, 4S) -3- (3, 4-difluoro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidine-1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester the title compound was prepared by cleavage of the Boc group with TFA. MS m/e: 492.2[ M + H]⁺。

c) [ (3S, 4R) -1- [1- (6-cyano-pyridazin-3-yl) -piperidine-4-carbonyl]-4- (3, 4-difluoro-phenyl) -pyrrolidine -3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 6-chloropyridazine-3-carbonitrile on silica in acetonitrile gave the title compound as an off-white solid. MS m/e: 579.4[ M + H ]]⁺。

Example 59

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone on silica in acetonitrile gives the title compound as an off-white solid. MS m/e: 611.3[ M + H]⁺。

Example 60

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 1- (6-bromopyridin-3-yl) ethanone on silica in acetonitrile gives the title compound as an off-white solid. MS m/e: 595.4[M+H]⁺。

Example 61

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 5-bromopyrazine-2-carbonitrile on silica in acetonitrile gives the title compound as a dark brown solid. MS m/e: 595.4[ M + H]⁺。

Example 62

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 5-bromopyrazine-2-carbonitrile on silica in acetonitrile gives the title compound as a dark brown solid. MS m/e: 579.4[ M + H ]]⁺。

Example 63

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 2-bromo-5- (methylsulfonyl) pyridine on silica in acetonitrile yields the title compound as an off-white solid. MS m/e: 647.4[ M + H ]]⁺。

Example 64

And the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, step g) prepared from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Purification of 4-fluoro-phenyl-ethyl-carbamate and 2-bromo-5- (methylsulfonyl) pyridine on silica in acetonitrile to give as dark brown solidThe title compound. MS m/e: 631.4[ M + H]⁺。

Example 65

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3-methyloxetane-3-carboxylic acid. MS m/e: 590.3[ M + H]⁺。

Example 66

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3, 3-difluorocyclobutanecarboxylic acid. MS m/e: 610.2[ M + H]⁺。

Example 67

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and cyclobutanecarboxylic acid. MS m/e: 574.5[ M + H]⁺。

Example 68

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (trifluoromethyl) cyclobutanecarboxylic acid. MS m/e: 642.3[ M + H]⁺。

Example 69

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3-fluorocyclobutanecarboxylic acid. MSm/e: 592.4[ M + H]⁺。

Example 70

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2, 2-difluorocyclopropanecarboxylic acid. MS m/e: 596.3[ M + H]⁺。

Example 71

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (trifluoromethyl) cyclopropanecarboxylic acid. MS m/e: 628.4[ M + H]⁺。

Example 72

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1-cyanocyclopropanecarboxylic acid. MSm/e: 585.3[ M + H]⁺。

Example 73

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2, 2-dimethyltetrahydro-2H-pyran-4-carboxylic acid. MS m/e: 632.5[ M + H]⁺。

Example 74

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 5- (trifluoromethyl) picolinic acid. MS m/e: 665.2[ M + H]⁺。

Example 75

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5-fluoropicolinic acid. MS m/e: 615.2[ M + H]⁺。

Example 76

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 4-cyanobenzoic acid. MS m/e: 621.4[ M + H]⁺。

Example 77

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 4-fluorobenzoic acid. MS m/e: 614.2[ M + H]⁺。

Example 78

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5- (trifluoromethyl) pyrazine-2-carboxylic acid. MS m/e: 666.2[ M + H]⁺。

Example 79

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 6-cyanonicotinic acid. MS m/e: 622.4[ M + H]⁺。

Example 80

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and acetic acid. MS m/e: 534.2[ M + H]⁺。

Example 81

32mg (0.065mmol) of [ (3S,4R) -4- (4-chloro-3-fluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]A mixture of 4-fluoro-phenyl ethyl-carbamate, 57uL (0.325mmol) DIPEA and 11.2mg (0.097mmol) methanesulfonyl chloride was shaken at room temperature for 90 min. The mixture was purified by preparative HPLC on reversed phase from acetonitrile, water and NEt₃The gradient formed elutes. The product containing fractions were evaporated to yield 16mg (43%) of the title compound as an off-white solid. MS m/e: 570.4[ M + H]⁺。

Example 82

a) [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

From racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate (example 7, c) the title compound was prepared by chiral column chromatography on Chiralpak AD. MS m/e: 453.3[ M + H]⁺。

b)[ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the process described for the synthesis of d) rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl groupThe procedure for the ester (example 1, d) is analogous to that described for [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate to prepare the title compound as a light brown foam, which was used in the subsequent step without processing. MS m/e: 363.2[ M + H]⁺。

c)[ (3S, 4R) -1- (1-acetyl-piperidine-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-ammonia Benzoic acid 4-fluoro-phenyl ester

And the same was used to synthesize [ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-trifluoromethyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl) -carbamate (example 20) from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1-acetylpiperidine-4-carboxylic acid. MS m/e: 516.2[ M + H]⁺。

Example 83

142mg (0.23mmol) [ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]5mL of a mixture of 4-fluoro-phenyl (ethyl) -carbamate (example 59) and 0.097mL (0.29mmol) of methylmagnesium iodide (3M) was stirred over a period of 90min from 0 ℃ to 15 ℃ with NH₄Cl (aq) was quenched at 0 ℃. The mixture was extracted with ethyl acetate and Na₂SO₄The combined organic layers were dried and evaporated. The residue was purified by preparative HPLC on reversed phase from acetonitrile, water and NEt₃The gradient formed proceeds with elution. Subjecting to distillationThe product fractions were evaporated to yield 19mg (13%) of the title compound as a white solid. MS m/e: 627.2[ M + H]⁺。

Example 84

a) Racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 2-fluoro -phenyl ester

And the process described for the synthesis of racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]In analogy to the procedure for 4-fluoro-phenyl (ethyl-carbamate) (example 7, c) the title compound was prepared from rac- (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-ylamine by reductive amination with acetaldehyde followed by reaction with 2-fluorophenyl chloroformate as a light yellow oil. MS m/e: 453.1[ M + H]⁺。

b)[ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 2-fluoro-phenyl ester

From racemic- [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]The title compound was prepared by chiral column chromatography on Chiralpak AD. MS m/e: 453.1[ M + H]⁺。

c)[ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 2-fluoro-phenyl ester

And the process described for the synthesis of d) rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]Procedure for tert-butyl (carbamic acid ester (example 1, d)) from [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]Ethyl-carbamic acid 2-fluoro-phenyl ester to prepare the title compound as a light brown foam which is used in the subsequent step without processing. MS m/e: 363.3[ M + H]⁺.

d)[ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]2-ethyl-carbamic acid Fluoro-phenyl ester

And the synthesis of [ (3R, 4S) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]Procedure for 4-fluoro-phenyl (ethyl-carbamic acid) ester (example 7, f) from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]2-fluoro-phenyl-ethyl-carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (coupling according to example 7, d) and subsequent removal of the Boc-protecting group (example 7, e) gave the title compound as a pale yellow foam. MS m/e: 474.2[ M + H]⁺。

e){ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3-methyl-oxetane-3-carbonyl) -piperidine-4-carbonyl]- Pyrrolidin-3-yl } -ethyl-carbamic acid 2-fluoro-phenyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (realgar)EXAMPLE 35, procedure of step f) was analogous to that described for [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]2-fluoro-phenyl ethyl-carbamate and 1- (1-methylcyclopropanecarbonyl) piperidine-4-carboxylic acid. MS m/e: 572.2[ M + H]⁺。

Example 85

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]2-fluoro-phenyl ethyl-carbamate and 1-cyanocyclopropanecarboxylic acid. MS m/e: 567.3[ M + H ]]⁺。

Example 86

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl)) -pyrrolidin-3-yl]-ethyl-carbamic acid 2-fluoro-phenyl ester and 5- (trifluoromethyl) picolinic acid. MSm/e: 647.7[ M + H]⁺。

Example 87

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and cyclobutanecarboxylic acid. MS m/e: 556.2[ M + H]⁺。

Example 88

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3-methyloxetane-3-carboxylic acid. MS m/e：572.2[M+H]⁺。

Example 89

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3-fluorocyclobutanecarboxylic acid. MS m/e: 574.2[ M + H]⁺。

Example 90

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3, 3-difluorocyclobutanecarboxylic acid. MSm/e: 592.3[ M + H]⁺。

Example 91

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 3-methoxycyclobutanecarboxylic acid. MSm/e: 586.2[ M + H]⁺。

Example 92

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (trifluoromethyl) cyclobutanecarboxylic acid. MS m/e: 624.1[ M + H]⁺。

Example 93

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 2-cyanoacetic acid. MS m/e: 541.3[ M + H]⁺。

Example 94

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1-cyanocyclopropanecarboxylic acid. MS m/e: 567.3[ M + H ]]⁺。

Example 95

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (trifluoromethyl) cyclopropanecarboxylic acid. MS m/e: 610.2[ M + H]⁺。

Example 96

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2, 2-difluorocyclopropanecarboxylic acid. MSm/e: 578.3[ M + H]⁺。

Example 97

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and tetrahydro-2H-pyran-4-carboxylic acid. MSm/e: 586.3[ M + H]⁺。

Example 98

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2, 2-dimethyltetrahydro-2H-pyran-4-carboxylic acid. MS m/e: 614.2[ M + H]⁺。

Example 99

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (methoxymethyl) cyclopropanecarboxylic acid. MS m/e: 586.3[ M + H]⁺。

Example 100

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 2, 2-dimethylcyclopropanecarboxylic acid. MSm/e: 570.2[ M + H]⁺。

Example 101

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 5- (trifluoromethyl) picolinic acid. MSm/e: 647.3[ M + H]⁺。

Example 102

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5-fluoropicolinic acid. MS m/e: 597.2[ M + H]⁺。

Example 103

With the procedure described for the synthesis of [ (3S, 4R) -1- (5' -cyano-3, 4,5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 6-oxopiperidine-3-carboxylic acid. MS m/e: 599.2[ M + H]⁺。

Example 104

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1-isopropyl-6-oxopiperidine-3-carboxylic acid. MS m/e: 641.4[ M + H]⁺。

Example 105

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl radical4-fluoro-phenyl (carbamic acid example 35, step f) the procedure was analogous to that described for the preparation of (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl ester]4-fluoro-phenyl ethyl-carbamate (example 39, h) and 1-isopropyl-6-oxopiperidine-3-carboxylic acid. MS m/e: 548.3[ M + H]⁺。

Example 106

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate (example 58, b) and (S) -4-oxoazetidine-2-carboxylic acid. MS m/e: 573.2[ M + H]⁺。

Example 107

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (realgar)EXAMPLE 35, procedure of step f) was analogous, starting from [ (3S, 4R) -4- (3, 4-difluoro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate (example 58, b) and 6-oxopiperidine-3-carboxylic acid. MS m/e: 601.3[ M + H]⁺。

Example 108

62mg (0.1.5mmol) of [ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]A mixture of 4-fluoro-phenyl-ethyl-carbamate (example 14) and 3.95mg (0.105mmol) of sodium borohydride is stirred at room temperature for 45 minutes. Water was added and the mixture was extracted with ethyl acetate. With Na₂SO₄The combined organic layers were dried, filtered and evaporated to dryness to yield 58mg (93%) of the title compound as an off-white solid. MS m/e: 595.2[ M + H]⁺。

Example 109

And the synthesis of [ (3S, 4R) -1- (5' -cyano-3, 4, 5, 6-tetrahydro-2H)-[1，2′]Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate (example 39, h) and 1- [5- (aminocarbonyl) pyridin-2-yl]Piperidine-4-carboxylic acid. MS m/e: 612.3[ M + H]⁺。

Example 110

a) [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-carbamic acid tert-butyl ester

And the synthesis of [ (3S, 4R) -1-benzyl-4- (3, 4-difluoro-phenyl) -pyrrolidin-3-yl]In analogy to the procedure for tert-butyl-carbamate (example 48, e) the title compound was prepared following the sequence as described in example 48, b to e starting from ethyl 3- (4-chlorophenyl) propiolate and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine as off-white solid. MS m/e: 387.3[ M + H]⁺。

b)[ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl]-Ethyl-carbamic acid tert-butyl ester

4.2g (10.9mmol) of [ (3S, 4R) -1-benzyl-4- (4-chloro-phenyl) -pyrrolidin-3-yl in 40mL of DMF]A mixture of tert-butyl carbamate, 521mg (13mmol) NaH (60%) and 2.54g (16.3mmol) iodoethane was stirred at 60 ℃ for 1h and evaporated to dryness. The residue was dissolved in ethyl acetate and water and further extracted with ethyl acetate. The combined organic layers were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.5g (55%) of the title compound as a pale yellow viscous oil. MSm/e: 415.3[ M + H]⁺。

c)[ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the use as described for rac- (3S, 4R) - [ 3-amino-4- (3, 4-dichloro-phenyl) -pyrrolidin-1-yl]- [1- (1-methyl-cyclopropanecarbonyl) -piperidin-4-yl group]The procedure for methanones (example 1, f) was analogous to removal of the Boc protecting group. And the process described for the synthesis of rac- { (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- [1- (1-methyl-cyclopropanecarbonyl) -piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 1, h) the procedure was analogous to reacting the liberated amine to the corresponding carbamate. And the use as described for rac- (3S, 4R) - [4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]Method of tert-butyl carbamate (example 1, d) the benzyl protecting group was removed analogously, yielding the title compound as an amorphous crude brown foam. MS m/e: 363.3[ M + H]⁺。

d)[ (3S, 4R) -4- (4-chloro-phenyl) -1- (5 '-chloro-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -pyridine Pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the placeThe synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 585.2[ M + H]⁺。

Example 111

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) carbamate and 1- [5- (aminocarbonyl) pyridin-2-yl]Piperidine-4-carboxylic acid. MSm/e: 594.3[ M + H]⁺。

Example 112

a)[ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]-ethyl-ammoniaBenzoic acid 4-fluoro-phenyl ester

In analogy to the procedure described for the synthesis of [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester (example 110, c) the title compound was prepared following the same sequence of transformations described in example 110 starting from ethyl 3- (3, 4-dichlorophenyl) propiolate and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine as amorphous crude brown foam.

b)[ (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl Radical) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-fluoropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 603.2[ M + H]⁺。

Example 113

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 619.3[ M + H]⁺。

Example 114

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 653.2[ M + H]⁺。

Example 115

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-benzeneThe procedure for the ester (example 35, step f) was analogous to that described for [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-carbamoylpyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 628.4[ M + H]⁺。

Example 116

a)4- { (3R, 4S) -3- (3, 4-dichloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino]-pyrrolidines -1-carbonyl } -piperidine-1-carboxylic acid tert-butyl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. MS m/e: 608.0[ M + H]⁺。

b)[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (3, 4-dichloro- Phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

After removal of the Boc-protecting group under acidic conditions, with the procedure described for the synthesis of { (3R, 4S) -4- (4-chloro-phenyl) -1- [1- (5-cyano-pyrimidin-2-yl) -Piperidine-4-carbonyl]-pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, g) prepared from [ (3S, 4R) -4- (3, 4-dichloro-phenyl) -1- (piperidine-4-carbonyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 5-acetyl-2-bromopyridine to prepare the title compound as an off-white foam. MS m/e: 627.3[ M + H]⁺。

Example 117

a)[ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

In analogy to the procedure described for the synthesis of [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester (example 110, c) the title compound was prepared from (3-chloro-4-fluoro-phenyl) -propiolic acid ethyl ester (prepared in analogy to (4-chloro-3-fluoro-phenyl) -propiolic acid ethyl ester (example 39, step a)) and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine following the same conversion sequence described in example 110 as amorphous crude brown solid.

b)[ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -1- (5 '-fluoro-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl Radical) -pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester

And the synthesis of [ (3S, 4R) -1- (5' -cyano-3, 4, 5, 6-tetrahydro-2-)H-[1，2′]Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-fluoropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 587.1[ M + H]⁺。

Example 118

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-chloropyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 603.2[ M + H]⁺。

Example 119

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrroleAlk-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5- (trifluoromethyl) pyridin-2-yl) piperidine-4-carboxylic acid. MS m/e: 637.3[ M + H]⁺。

Example 120

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was prepared analogously to [ (3S, 4R) -4- (3-chloro-4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-acetylpyridin-2-yl) piperidine-4-carboxylic acid. MSm/e: 611.3[ M + H]⁺。

Example 121

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl-ethyl-carbamate (example)35, step f) analogously to the procedure, starting from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and (S) -4-oxoazetidine-2-carboxylic acid. MS m/e: 571.2[ M + H]⁺。

Example 122

[ (3S, 4R) -1- [5 '- (2-diethylamino-acetyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl ] -4- (4-fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

Will be in the range of 10mL two0.17g (0.285mmol) of [ (3S, 4R) -1- (5 ' -acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' in a alkane ']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]A mixture of 4-fluoro-phenyl (ethyl-carbamate) (example 38) and 84.3mg (0.295mmol) of 5, 5-dibromobarbituric acid is heated to 85 ℃ for 40 h. 0.216g (2.95mmol) diethylamine was added at room temperature and heated to 45 ℃ for 2h and evaporated. The residue was dissolved in methanol and purified by preparative HPLC on reversed phase using a solvent selected from acetonitrile, water and NEt₃The gradient formed proceeds with elution. The product containing fractions were evaporated to yield 49mg (26%) of the title compound as a light brown solid. MS m/e: 648.3[ M + H]⁺。

Example 123

Acetic acid 4- { (3R, 4S) -3- (4-chloro-phenyl) -4- [ ethyl- (4-fluoro-phenoxycarbonyl) -amino ] -pyrrolidine-1-carbonyl } -3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-5' -yl ester

And the same was used for the synthesis of [ (3S, 4R) -1- (5 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridine-4-carbonyl) -4- (4-fluoro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl (ethyl) -carbamate (example 35, step f) was synthesized in analogy to the procedure from [ (3S, 4R) -4- (4-chloro-phenyl) -pyrrolidin-3-yl]4-fluoro-phenyl ethyl-carbamate and 1- (5-hydroxypyridin-2-yl) piperidine-4-carboxylic acid. Thereafter, acetyl chloride was added and stirring was continued at room temperature for 30 min. The mixture was purified directly by preparative HPLC on reversed phase from acetonitrile, water and NEt₃The gradient formed proceeds with elution. The product containing fractions were evaporated to yield the title compound as an off-white solid. MS m/e: 608.2[ M + H]⁺。

Experimental procedures

The compounds were studied according to the tests given below.

[³H]SR142801 competitive binding assay

Use of³H]SR142801 (catalog number TRK1035, specific activity: 74.0Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membranes isolated from HEK293 cells transiently expressing recombinant human NK3 receptor were subjected to hNK3 receptor binding experiments. After thawing, the membrane homogenate was centrifuged at 48,000X g for 10min at 4 ℃ and the pellet resuspended in 50mM Tris-HCl, 4mM MnCl₂mu.M phosphoramidon, in 0.1% BSA binding buffer at pH 7.4 to a final assay concentration of 5. mu.g protein/well. For the inhibition experiment, the membrane was used³H]SR142801 equal to radioligand K_DThe concentration of values and 10 inhibitory compound concentrations (0.0003-10. mu.M) (in a total reaction volume of 500. mu.l) were incubated for 75min at Room Temperature (RT). At the end of the incubation, the membrane was filtered to a unit filter (unitfilter) (96-well white microplate with bound GF/C filter, preincubated for 1h in 0.3% PEI + 0.3% BSA using a Filtermate 196 harvester (Packard BioScience), Packard BioScience, Meriden, CT) and washed 4 times with ice-cold 50mM Tris-HCl, pH 7.4 buffer. For both radioligands, nonspecific binding was measured in the presence of 10 μ M SB 222200. After addition of 45. mu.l microscint 40(Canberra Packard S.A., Z rich, Switzerland) and shaking for 1h, the radioactivity on the filter was counted (5min) on a Packard Top-count microplate scintillation counter with correction for quenching. Using Excel-fit 4 software (Microsoft), according to Hill (Hill) equation: y is 100/(1+ (x/IC)₅₀)^nH) Fitting an inhibition curve, wherein n_HSlope factor. Obtaining IC from the inhibition Curve₅₀Values and using Cheng-Prussoff equation K_i＝IC₅₀/(1+[L]/K_D) Calculation of affinity constant (K)_i) Wherein [ L ]]Is the concentration of the radioligand, and K_DIs derived from the saturation isotherm, which is the dissociation constant at the receptor. All experiments were performed in duplicate and a single K was calculated_iMean ± Standard Error (SEM) of values.

The results (in μ M) for all specific compounds with hNK-3 receptor affinity are shown in Table 1 below.

TABLE 1

Example data K_i[μM]Example data K_i[μM]
	1 0.001 63 0.0007
2 0.046 64 0.005
	3 0.276 65 0.003
4 0.01 66 0.001
	5 0.002 67 0.002
6 0.062 68 0.002
	7 0.089 69 0.002
8 0.055 70 0.004
	9 0.138 71 0.004
10 0.065 72 0.002
	11 0.036 73 0.003
12 0.023 74 0.012
	13 0.008 75 0.003
14 0.003 76 0.017
	15 0.008 77 0.004
16 0.002 78 0.005
	17 0.002 79 0.008
18 0.002 80 0.002
	19 0.088 81 0.029
20 0.003 82 0.0082
	21 0.002 83 0.0038
22 0.025 84 0.0298
	23 0.021 85 0.0233
24 0.062 86 0.0707
	25 0.112 87 0.0021

26 0.046 88 0.0056
	27 0.047 89 0.0033
28 0.05 90 0.0024
	29 0.012 91 0.0065
30 0.035 92 0.0066
	31 0.057 93 0.0071
32 0.052 94 0.0078
	33 0.048 95 0.0061
34 0.116 96 0.0034
	35 0.004 97 0.0044
36 0.01 98 0.0047
	37 0.008 99 0.0047
38 0.007 100 0.0036
	39 0.004 101 0.0425
40 0.0007 102 0.0082
	41 0.0006 103 0.0326
42 0.002 104 0.0176
	43 0.0003 105 0.0312
44 0.002 106 0.066
	45 0.003 107 0.1312
46 0.001 108 0.0047
	47 0.002 109 0.0017
48 0.002 110 0.0048
	49 0.005 111 0.0074
50 0.009 112 0.0008
	51 0.002 113 0.0005
52 0.015 114 0.0016
	53 0.016 115 0.0009
54 0.007 116 0.0005

55 0.009 117 0.0033
	56 0.267 118 0.0018
57 0.0007 119 0.0037
	58 0.005 120 0.0017
59 0.0005 121 0.0169
	60 0.004 122 0.0696
61 0.0008 123 0.006
	62 0.006

The compounds of formula I and their pharmaceutically acceptable acid addition salts 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 and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients and are used for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such excipients, for example for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable excipients 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.

The dosage may vary within wide limits and will of course be fitted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 10 to 1000mg of a compound of formula I per person will be appropriate, although the above upper limits may also be exceeded if desired.

Example A

Tablets of the following composition were manufactured in the usual manner:

example B

Capsules of the following composition were made:

the active substances, lactose and corn starch are first mixed in a mixer and then in a mill. The mixture was returned to the mixer, talc was added thereto and thoroughly mixed. The mixture is machine filled into hard gelatin capsules.

Example C

Suppositories of the following composition were made:

the suppository material was melted in a glass or steel container, mixed thoroughly and cooled to 45 deg.f. C. Then, the fine powder of the active substance is added thereto and stirred until it is completely dispersed. The mixture is poured into suppository molds of appropriate size, left to cool, and the suppositories are then removed from the molds and individually packaged in wax paper or metal foil.

Claims

1. A compound of formula I

Wherein

R¹Is hydrogen, halogen, cyano, C_2-4Alkyl or halogen substituted C_1-5An alkyl group;

n is 1, 2 or 3, and if n is 2 or 3, R¹May be different;

R²is C_2-7-alkyl or C_3-6-a cycloalkyl group;

R³is the following group

Wherein

X is CH;

R⁵is hydrogen, -C (O) -C_2-4Alkyl, -C (O) O-C_2-4Alkyl, S (O)₂-C_2-4Alkyl, -C (O) CH₂O-C_2-4Alkyl, -C (O) -CH₂-CN, or

-C (O) -cycloalkyl, cycloalkyl or-CH₂-a cycloalkyl group,

wherein said cycloalkyl is optionally substituted by C_2-4Alkyl, -CH₂-O-C_2-4Alkyl radical, C_2-4Alkoxy radical, CF₃Halogen or cyano, or

-C (O) -heterocycloalkyl or heterocycloalkyl, or

-C (O) -heteroaryl, or is

-C (O) -aryl,

the heterocycloalkyl, heteroaryl or aryl group is optionally substituted with: halogen, C_2-4Alkyl, ═ O, C_2-4Alkoxy, halogen substituted C_1-5Alkyl, hydroxy-substituted C_2-4Alkyl, -C (O) -CH₂-N (di-C)_2-4Alkyl group, C (O) NH-C_2-4Alkyl, C (O) NH₂，-O-C(O)-C_2-4Alkyl radical, C (O) -C_2-4Alkyl, S (O)₂-C_2-4Alkyl or cyano;

R⁴is aryl substituted by halogen;

wherein "cycloalkyl" refers to a saturated carbocyclic ring containing 3 to 6 carbon atoms,

the term "aryl" is intended to mean a phenyl group,

"heteroaryl" is pyrazinyl, pyridinyl, pyridazinyl or pyrimidinyl,

"Heterocycloalkyl" means an alkyl ring in which one or two carbon atoms are replaced by N, S or O,

or a pharmaceutically active salt thereof.

2. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,

wherein

R¹Is halogen;

n is 1, 2 or 3, and if n is 2 or 3, the halogens may be different;

R²is C_2-7-alkyl or C_3-6-a cycloalkyl group;

R³is the following group

Wherein

R⁵Is hydrogen, -C (O) -C_2-4Alkyl, -C (O) O-C_2-4Alkyl, S (O)₂-C_2-4An alkyl group, a carboxyl group,

-C(O)-CH₂-CN, or

-C (O) -cycloalkyl,

wherein said cycloalkyl is optionally substituted by C_2-4Alkyl, -CH₂-O-C_2-4Alkyl radical, C_2-4Alkoxy radical

Basic group, CF₃Halogen or cyano, or

-C (O) -heterocycloalkyl, or is

-C (O) -heteroaryl, or is

-C (O) -aryl,

the heterocycloalkyl, heteroaryl or aryl group is optionally substituted with: halogen, C_2-4Alkyl, ═ O, halogen substituted C_1-5Alkyl, hydroxy-substituted C_2-4Alkyl, -C (O) -CH₂-N (di-C)_2-4Alkyl group, C (O) NH₂，-O-C(O)-C_2-4Alkyl radical, C (O) -C_2-4Alkyl, S (O)₂-C_2-4Alkyl or cyano;

R⁴is an aryl group substituted by a halogen, or a salt thereof,

or a pharmaceutically active salt thereof.

3. A compound which is:

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (4-chloro-benzene 4- - > yl) -pyrrolidin-3-yl ] -cyclopropyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (4 '-cyano-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-5- - > carbonyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3, 4-bis 6- - > fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (2, 2-dimethyl-tetrahydro-pyran-4-carbonyl) -piperidine 4-carbonyl ] -pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- [1- (5-fluoro-pyridine-2-carbonyl) -piperidine-4-carbonyl ] -py τ ridin 7- - > pyrrolidin-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

{ (3S, 4R) -4- (4-chloro-phenyl) -1- [1- (3, 3-difluoro-cyclobutanecarbonyl) -piperidine-4-carbonyl ] -pyrrole 8- - > alk-3-yl } -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -4- (4-chloro-3-fluoro-phenyl) -1- (1-isopropyl-6-oxo-piperidine-3-carbonyl) -pyrrolidine 9- - > -3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

[ (3S, 4R) -1- (5 '-acetyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-carbonyl) -4- (3-chloro-4-10- - > fluoro-phenyl) -pyrrolidin-3-yl ] -ethyl-carbamic acid 4-fluoro-phenyl ester

4. A process for the preparation of a compound as defined in claim 1, which process comprises:

a) reacting a compound of formula II

wherein the substituent R¹，R²，R³And R⁴As defined in claim 1, the method further comprising the step of,

or

b) Reacting a compound of formula III

5. A medicament containing one or more compounds according to any one of claims 1-3 and pharmaceutically acceptable excipients.

6. A medicament according to claim 5 for the treatment of depression, pain, psychosis, Parkinson's disease, anxiety and Attention Deficit Hyperactivity Disorder (ADHD).

7. A medicament according to claim 5 for the treatment of schizophrenia.

8. The use of a compound according to any one of claims 1-3 for the manufacture of medicaments for the treatment of depression, pain, psychosis, parkinson's disease, anxiety and Attention Deficit Hyperactivity Disorder (ADHD).

9. Use of a compound according to any one of claims 1-3 for the manufacture of a medicament for the treatment of schizophrenia.