CN100378092C

CN100378092C - Biphenyl derivatives

Info

Publication number: CN100378092C
Application number: CNB2004800065284A
Authority: CN
Inventors: M·玛曼; S·邓纳姆; A·休斯; 李泰源; C·休斯菲尔德; E·斯坦格兰德; 陈燕
Original assignee: SHIWAN PHARMACEUTICALS Inc
Current assignee: Theravance Biopharma R&D IP LLC
Priority date: 2003-02-14
Filing date: 2004-02-13
Publication date: 2008-04-02
Anticipated expiration: 2024-02-13
Also published as: CN101239969A; ES2351392T3; CN101239970B; CN1759108A; CN101239971A; CN101239971B; CN101239970A; ZA200506215B; CN101239969B; CN101239968B; AR098785A2; CN101239968A

Abstract

This invention provides biphenyl derivatives of formula I: wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Description

Biphenyl derivatives

Background of invention

Invention field

The present invention relates to be applicable to the new biphenyl derivatives of treatment tuberculosis.The present invention also relates to comprise the pharmaceutical composition of this class biphenyl derivatives, prepare the method and the intermediate of this class biphenyl derivatives, and the method for using this class biphenyl derivatives treatment tuberculosis.

Technology status

Usually treat tuberculosis with bronchodilator, for example asthma and chronic obstructive pulmonary disease (COPD).One class bronchodilator of widespread use is by β ₂Adrenergic receptor (adrenoceptor) agonist, for example salbutamol, formoterol and Salmeterol are formed.These compounds pass through inhalation usually.Another kind of bronchodilator is by muscarinic receptor antagonist (anticholinergic compound), and for example ipratropium and tiotropium form.These compounds also pass through inhalation usually.

The β that comprises that is used for the treatment of tuberculosis ₂The pharmaceutical composition of 3 adrenergic receptor agonists and muscarinic receptor antagonist also is known in the art.For example, U.S. Patent No. 6433027 discloses and has comprised muscarinic receptor antagonist for example tiotropium bromide and β ₂3 adrenergic receptor agonists is the pharmaceutical composition of Formoterol Fumarate for example.

Though have β ₂The compound of 3 adrenergic receptor agonists or muscarinic receptor antagonist activity is known, but the previous unexposed β that has ₂Two kinds of active compounds of 3 adrenergic receptor agonists and muscarinic receptor antagonist.Have β ₂Two kinds of active compounds of 3 adrenergic receptor agonists and muscarinic receptor antagonist are very desirable, because this class dual-function compound can by two kinds independently binding mode bronchiectasis is provided, and only have single molecular medicine kinetics.

Summary of the invention

The invention provides the new biphenyl derivatives that is applicable to treatment tuberculosis.Except other character, The compounds of this invention has been found and has had β ₂Two kinds of activity of 3 adrenergic receptor agonists and muscarinic receptor antagonist.

Therefore, it composition aspect one of, the present invention relates to formula I compound:

Wherein

A is 0 or the integer of 1-3;

R ¹Each be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^1a,-C (O) OR ^1b,-SR ^1c,-S (O) R ^1d,-S (O) ₂R ^1eAnd NR ^1fR ^1g

R ^1a, R ^1b, R ^1c, R ^1d, R ^1e, R ^1fAnd R ^1gEach is the alkyl of hydrogen, (1-4C) alkyl or phenyl-(1-4C) independently;

B is 0 or the integer of 1-3;

R ²Each be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^2a,-C (O) OR ^2b,-SR ^2c,-S (O) R ^2d,-S (O) 2R ^2eWith-NR ^2fR ^2g

R ^2a, R ^2b, R ^2c, R ^2d, R ^2e, R ^2fAnd R ^2gEach is the alkyl of hydrogen, (1-4C) alkyl or phenyl-(1-4C) independently;

W with link to each other with respect to the 3-of nitrogen-atoms in the piperidine ring or 4-position and represent O or NW ^a

W ^aBe hydrogen or (1-4C) alkyl;

C is 0 or the integer of 1-4;

R ³Each be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^3a,-C (O) OR ^3b,-SR ^3c,-S (O) R ^3d,-S (O) ₂R ^3eWith-NR ^3fR ^3gOr two R ³The group combination is to form (1-3C) alkylidene group, (2-3C) alkenylene or oxyethane-2,3-two bases;

R ^3a, R ^3b, R ^3c, R ^3d, R ^3e, R ^3fAnd R ^3gBe hydrogen or (1-4C) alkyl independently;

R ⁴Be the divalent group of following formula:

-(R ^4a) _d-(A ¹) _e-(R ^4b) _f-Q-(R ^4c) _g-(A ²) _h-(R ^4d) _i-

Wherein

D, e, f, g, h and i are selected from 0 and 1 independently of one another;

R ^4a, R ^4b, R ^4cAnd R ^4dBe selected from (1-10C) alkylidene group, (2-10C) alkenylene and (2-10C) alkynylene independently of one another, wherein each alkylidene group, alkenylene or alkynylene group are unsubstituted or are independently selected from (1-4C) alkyl, fluorine, hydroxyl, phenyl and phenyl-(1-4C) 1-5 substituting group replacement of alkyl;

A ¹And A ²Be selected from (3-7C) cycloalkylidene independently of one another, (6-10C) arylidene,-O-(6-10C) arylidene, (6-10C) arylidene-O-, (2-9C) inferior heteroaryl,-O-(2-9C) inferior heteroaryl, (2-9C) inferior heteroaryl-O-and (3-6C) inferior heterocyclic radical, wherein each cycloalkylidene is unsubstituted or 1-4 substituting group being independently selected from (1-4C) alkyl replaces, and each arylidene, inferior heteroaryl or inferior heterocyclic radical group are unsubstituted or are independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group,-S-(1-4C) alkyl,-S (O)-(1-4C) alkyl,-S (O) ₂-(1-4C) alkyl ,-1-4 substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replace;

Q be selected from key ,-O-,-C (O) O-,-OC (O)-,-S-,-S (O)-,-S (O) ₂-,-N (Q ^a) C (O)-,-C (O) N (Q ^b)-,-N (Q ^c) S (O) ₂-,-S (O) ₂N (Q ^d)-,-N (Q ^e) C (O) N (Q ^f)-,-N (Q ^g) S (O) ₂N (Q ^h)-,-OC (O) N (Q ⁱ)-,-N (Q ^j) C (O) O-and-N (Q ^k);

Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱ, Q ^jAnd Q ^kBe selected from hydrogen, (1-6C) alkyl, A independently of one another ³(1-4C) alkylidene group-A ⁴, wherein alkyl group is unsubstituted or is independently selected from fluorine, hydroxyl and (1-4C) 1-3 substituting group replacement of alkoxyl group; Perhaps nitrogen-atoms that is connected with them and radicals R ^4bOr R ^4cForm the inferior azocycloalkyl group of 4-6 unit together;

A ³And A ⁴Be selected from (3-6C) cycloalkyl, (6-10C) aryl, (2-9C) heteroaryl and (3-6C) heterocyclic radical independently of one another, wherein each cycloalkyl is unsubstituted or 1-4 substituting group being independently selected from (1-4C) alkyl replaces, and each aryl, heteroaryl or heterocyclic radical group are unsubstituted or are independently selected from halogen, (1-4C) alkyl and (1-4C) 1-4 substituting group replacement of alkoxyl group;

Condition is R ⁴On the short chain between two nitrogen-atoms that connect in abutting connection with atom number in the 4-16 scope;

R ⁵Represent hydrogen or (1-4C) alkyl;

R ⁶Be-NR ^6aCR ^6b(O) or-CR ^6CR ^6dOR ^6eAnd R ⁷Be hydrogen; Perhaps R ⁶And R ⁷Formation-NR together ^7aC (O)-CR ^7b=CR ^7c-,-CR ^7d=CR ^7e-C (O)-NR ^7f-,-NR ^7gC (O)-CR ^7hR ⁷ⁱ-CR ^7jR ^7k-or-CR ^7lR ^7m-CR ⁷ⁿR ^7o-C (O)-NR ^7p-;

R ^6a, R ^6b, R ^6C, R ^6dAnd R ^6eEach is hydrogen or (1-4C) alkyl independently; And

R ^7a, R ^7b, R ^7c, R ^7d, R ^7e, R ^7f, R ^7g, R ^7h, R ⁷ⁱ, R ^7j, R ^7k, R ^7l, R ^7m, R ⁷ⁿ, R ^7oAnd R ^7pEach is hydrogen or (1-4C) alkyl independently;

Or its pharmacy acceptable salt or solvate or steric isomer.

It Composition Aspects on the other hand, the present invention relates to formula II compound:

Wherein

R ⁴(comprise any specific or embodiment preferred) as defined herein;

W represents O or NH;

Or its pharmacy acceptable salt or solvate or steric isomer.

It Composition Aspects also on the other hand, the present invention relates to the formula III compound:

Wherein

R ⁴(comprise any specific or embodiment preferred) as defined herein;

W represents O or NH;

Or its pharmacy acceptable salt or solvate or steric isomer.

It Composition Aspects also on the other hand, the present invention relates to formula IV compound:

Wherein

R ⁴(comprise any specific or embodiment preferred) as defined herein;

W represents O or NH;

Or its pharmacy acceptable salt or solvate or steric isomer.

It Composition Aspects on the other hand, the present invention relates to comprise pharmaceutically acceptable carrier and the formula I compound of treatment significant quantity or the pharmaceutical composition of its pharmacy acceptable salt or solvate or steric isomer.This class pharmaceutical composition can randomly comprise other therapeutical agent.Therefore, in one embodiment, the present invention relates to a kind of like this pharmaceutical composition, wherein said composition further comprises the steroidal anti-inflammatory medicine for the treatment of significant quantity, for example reflunomide.

The compounds of this invention has β ₂Two kinds of activity of 3 adrenergic receptor agonists and muscarinic receptor antagonist.Therefore, formula I compound is applicable to treatment tuberculosis, for example asthma and chronic obstructive pulmonary disease.

Therefore, one of aspect its method, the present invention relates to treat the method for tuberculosis, this method comprises formula I compound or its pharmacy acceptable salt or the solvate or the steric isomer of the patient treatment significant quantity that needs treatment.

In addition, aspect its method on the other hand, the present invention relates to provide in the patient bronchiectasic method, this method comprises needs the formula I of bronchiectasic patient treatment significant quantity compound or its pharmacy acceptable salt or solvate or steric isomer.

The present invention also relates to treat the method for chronic obstructive pulmonary disease or asthma, this method comprises formula I compound or its pharmacy acceptable salt or the solvate or the steric isomer of the patient treatment significant quantity that needs treatment.

Because The compounds of this invention has β ₂Two kinds of activity of 3 adrenergic receptor agonists and muscarinic receptor antagonist are made research tool so this compounds also is suitable for.Therefore, also another aspect aspect its method the present invention relates to use formula I compound or its pharmacy acceptable salt or solvate or steric isomer and studies biosystem or sample as research tool, perhaps finds to have β ₂The method of 2-adrenergic agonist components and two kinds of active new chemical compounds of muscarinic receptor antagonist.

The present invention also relates to be applicable to preparation I compound or the method for its pharmacy acceptable salt or solvate or steric isomer and new intermediate.Therefore, on the other hand, the present invention relates to the method for preparation I compound aspect its method, this method comprises:

(a) make formula 1Compound or its salt and formula 2The compound reaction;

(b) make formula 3Compound or its salt and formula 4The compound reaction;

(c) make formula 5Compound and formula 6The compound coupling;

(d) for R wherein ⁵Represent the formula I compound of hydrogen atom, in the presence of reductive agent, make formula 3Compound and formula 7Compound or its hydrate reaction;

(e) in the presence of reductive agent, make formula 1Compound and formula 8Compound or its hydrate reaction;

(f) make formula 9Compound and formula 10The compound reaction; Perhaps

(g) in the presence of reductive agent, make formula 11Compound or its hydrate and formula 10The compound reaction;

Remove any blocking group then to form formula I compound; Its Chinese style 1- 11Compound as defined herein.

In one embodiment, aforesaid method further comprises the step of the pharmacy acceptable salt that forms formula I compound.In another embodiment, the present invention relates to other method described herein; And relate to product by any method preparation described herein.

The present invention also relates to formula I compound or its pharmacy acceptable salt or solvate or steric isomer, be used for the treatment of or as medicine.

In addition, the present invention relates to the purposes that formula I compound or its pharmacy acceptable salt or solvate or steric isomer are used to prepare medicine; The medicine that is used for the treatment of tuberculosis especially for preparation.

Detailed Description Of The Invention

In its one of Composition Aspects, the present invention relates to new biphenyl derivatives or its pharmacy acceptable salt or solvate or the steric isomer of formula I.These compounds comprise one or more chiral centres, therefore unless otherwise noted, the present invention relates to racemic mixture; Pure stereoisomers (being enantiomer or diastereomer); Be rich in the mixture of steric isomer etc.Unless otherwise noted, when this paper shows or names particular stereoisomer, it will be appreciated by those skilled in the art that a spot of other steric isomer may reside in the composition of the present invention, condition is that composition availability is not as a whole eliminated by the existence of this other isomer of class.

Especially, the carbon atom place that pointed out by symbol * in following formula of formula I compound comprises chiral centre:

In one embodiment of the invention, has (R) configuration by the specified carbon atom of symbol *.In this embodiment, preferred formula I compound has (R) configuration or enrichment is the stereoisomer form that has (R) configuration at this carbon atom at the specified carbon atom of symbol *.In another embodiment of the present invention, the specified carbon atom of symbol * has (S) configuration.In this embodiment, preferred formula I compound has (S) configuration or enrichment is the stereoisomer form that has (S) configuration at this carbon atom at the specified carbon atom of symbol *.In some cases, in order to optimize the β of The compounds of this invention ₂The 2-adrenergic agonist components activity, the preferred specified carbon atom of symbol * has (R) configuration.

Formula I compound also comprises a plurality of basic groups (for example amino group), so formula I compound can be used as free alkali or exists with various salt forms.All these class salt forms all are included in the scope of the present invention.In addition, the solvate of formula I compound or its salt comprise within the scope of the invention.

In addition, unless otherwise noted, when applicable, all of formula I compound are suitable-and anti-or E/Z isomer (geometrical isomer), tautomeric form and topoisomerase form comprise within the scope of the invention.

The nomenclature in order to name The compounds of this invention and intermediate thereof that this paper adopts generally is to utilize the commercial AutoNom software of buying (MDL, San Leandro California) derive from.Usually, wherein W is the ester derivative that the formula I compound of O is named as biphenyl-2-aminocarbamic acid; And wherein W is NW ^aFormula I compound named as urea derivatives.

Representative embodiment

Following substituting group and value are for the representational example of each side of the present invention and embodiment is provided.These representational values are in order further to define and illustrate these aspects and embodiment, are not in order to get rid of other embodiment or to limit the scope of the invention.At this on the one hand, unless specifically note, preferred particular value or substituent statement are not in order to get rid of other value or substituting group from the present invention by any way.

In the particular of formula I compound, a and b are 0,1 or 2 independently; Comprise 0 or 1.In one embodiment, a and b are 0.

When existing, R ¹Each can be in 2,3,4,5 or 6-position of coupled phenyl ring.In one embodiment, R ¹Each be independently selected from (1-4C) alkyl, halogen ,-OR ^1aWith-NR ^1fR ^1gFor example methyl, fluorine, chlorine, bromine, hydroxyl, methoxyl group, amino, methylamino, dimethylamino etc.R ¹Particular value be fluorine or chlorine.

When existing, R ²Each can be in 3,4,5 or 6-position of coupled phenylene (carbon atom on inferior phenyl ring that is connected with nitrogen-atoms is position 1).In one embodiment, R ²Each be independently selected from (1-4C) alkyl, halogen ,-OR ^2aWith-NR ^2fR ^2gFor example methyl, fluorine, chlorine, bromine, hydroxyl, methoxyl group, amino, methylamino, dimethylamino etc.R ²Particular value be fluorine or chlorine.

R ^1a, R ^1b, R ^1c, R ^1d, R ^1e, R ^1fAnd R ^1gAnd R ^2a, R ^2b, R ^2c, R ^2d, R ^2e, R ^2fAnd R ^2gEach ought be respectively at R ¹And R ²In when using, be the alkyl of hydrogen, (1-4C) alkyl or phenyl-(1-4C) independently; For example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl or benzyl.In one embodiment, these groups are hydrogen or (1-3C) alkyl independently.In another embodiment, these groups are hydrogen, methyl or ethyl independently.

In one embodiment of the invention, W is O.In another embodiment, W is NW ^a

Generally speaking, have been found that wherein W represents the compound of O for muscarine and β ₂Adrenergic receptor shows especially high affinity.Therefore, in particular of the present invention, W preferably represents O.

When mentioning W, can mention the compound that W wherein is connected with piperidine ring in the 4-position with respect to the piperidine ring nitrogen-atoms especially.

When W is NW ^aThe time, W ^aBe hydrogen or (1-4C) alkyl; For example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.In one embodiment, W ^aBe hydrogen or (1-3C) alkyl.In another embodiment, W ^aBe hydrogen, methyl or ethyl; For example hydrogen or methyl.In another embodiment, W ^aBe hydrogen and NW ^aBe NH.

In the particular of formula I compound, c is 0,1 or 2; Comprise 0 or 1.In one embodiment, c is 0.

In one embodiment, each R ³In 3,4 or 5-position of piperidine ring (wherein the nitrogen-atoms of piperidine ring is 1).In another embodiment, R ³4-position at piperidine ring.In the particular aspects of these embodiments, each R ³Be independently selected from (1-4C) alkyl; For example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.On the other hand, each R ³Be methyl or ethyl independently.

In another embodiment, R ³In the 1-position of piperidine ring, promptly on the nitrogen-atoms of piperidine ring, therefore form quaternary ammonium salt.At a particular aspects of this embodiment, each R ³Be independently selected from (1-4C) alkyl; For example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.On the other hand, each R ³Be methyl or ethyl independently.

In going back another embodiment, two R ³Group is in conjunction with to form (1-3C) alkylidene group or (2-3C) alkenylene group.For example, on piperidine ring 2 and two R of 6-position ³Group can be in conjunction with (being piperidine ring and R to form ethylene bridge ³Group forms 8-azabicyclo [3.2.1] octane ring); Perhaps on piperidine ring 1 and two R of 4-position ³Group can be in conjunction with (being piperidine ring and R to form ethylene bridge ³Group forms 1-azabicyclo [2.2.2] octane ring).In this embodiment, also can there be other R as herein defined ³Group.

In going back another embodiment, two R ³The group combination is to form oxyethane-2,3-two groups.For example, on piperidine ring 2 and two R of 6-position ³Group can be in conjunction with to form 3-oxatricyclo [3.3.1.0 ^2,4] the nonane ring).In this embodiment, also can there be other R as herein defined ³Group.

R ^3a, R ^3b, R ^3c, R ^3d, R ^3e, R ^3fAnd R ^3gEach is worked as at R ³In be hydrogen or (1-4C) alkyl independently when using; For example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.In one embodiment, these groups are hydrogen or (1-3C) alkyl independently.In another embodiment, these groups are hydrogen, methyl or ethyl independently.

In an embodiment of formula I compound, R ⁵Be hydrogen or (1-4C) alkyl; For example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.In another embodiment, each R ⁵Be hydrogen, methyl or ethyl independently.In specific embodiments, R ⁵Be hydrogen.

In one embodiment of the invention, R ⁶Be-NR ^6aCR ^6b(O) and R ⁷Be hydrogen, R wherein ^6aAnd R ^6bEach is hydrogen or (1-4C) alkyl, for example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl independently.In one embodiment, these groups are hydrogen or (1-3C) alkyl independently.In another embodiment, these groups are hydrogen, methyl or ethyl independently.In this embodiment, R ⁶Particular value be-NHCHO.

In another embodiment, R ⁶And R ⁷Formation-NR together ^7aC (O)-CR ^7b=CR ^7c-,-CR ^7d=CR ^7e-C (O)-NR ^7f-,-NR ^7gC (O)-CR ^7hR ⁷ⁱ-CR ^7jR ^7k-or-CR ^7lR ^7m-CR ⁷ⁿR ^7o-C (O)-NR ^7p-; R wherein ^7a, R ^7b, R ^7c, R ^7d, R ^7e, R ^7f, R ^7g, R ^7h, R ⁷ⁱ, R ^7j, R ^7k, R ^7l, R ^7m, R ⁷ⁿ, R ^7oAnd R ^7PEach is hydrogen or (1-4C) alkyl independently; For example hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.In one embodiment, these groups are hydrogen or (1-3C) alkyl independently.In another embodiment, these groups are hydrogen, methyl or ethyl independently.In this embodiment, R ⁶And R ⁷Particular value be R ⁶And R ⁷Together formation-NHC (O)-CH=CH-,-CH=CH-C (O)-NH-,-CH ₂-CH ₂-C (O) NH-or-NHC (O)-CH ₂-CH ₂-; Comprise wherein R ⁶And R ⁷Together formation-NHC (O)-CH=CH-or-CH=CH-C (O)-NH-; Especially, R wherein ⁶And R ⁷Formation-NHC (O)-CH=CH-(is that nitrogen-atoms is connected R together ⁶And carbon atom is connected R ⁷, with R ⁶And R ⁷The hydroxyl phenyl ring that connects forms 8-hydroxyl-2-oxygen-1 together, 2-dihydroquinoline-5-base group).

In formula I compound, R ⁴Be the divalent group of following formula:

-(R ^4a) _d-(A ¹) _e-(R ^4b) _f-Q-(R ^4c) _g-(A ²) _h-(R ^4d) _i-

R wherein ^4a, A ¹, R ^4b, Q, R ^4c, A ², R ^4d, d, e, f, g, h and i be as defined herein.In compound of the present invention, select component R ^4a, A ¹, R ^4b, Q, R ^4c, A ²And R ^4dThe value of each, like this with R ⁴Between two nitrogen-atoms that link to each other on the short chain number of adjacent atom be in the 4-16 scope, (especially, 4,5,6,7,8,9,10,11,12,13,14,15 or 16); Comprise 8,9,10,11,12,13 or 14; For example 8,9,10 or 11; Or 9 or 10.When being R ⁴In each Variables Selection value the time, it will be appreciated by those skilled in the art that should selective value to make and form the chemically stable group.

When measuring and R ⁴Between two nitrogen-atoms that connect on the short chain during, from the R of the nitrogen of contiguous piperidine ring in abutting connection with the number of atom ⁴First atom of group begins, and arrives the R of the nitrogen of contiguous amino hydroxyethyl groups ⁴Last atom on the group finishes, and each on the counting chain is in abutting connection with atom continuously.When two or more chains be possible the time, use short chain to measure number in abutting connection with atom.As follows, for example, work as R ⁴Be-(CH ₂) ₂-NHC (O)-CH ₂-(benzene-1,4-subunit)-CH ₂-time, the R of the nitrogen from contiguous piperidine ring as follows ⁴First atom in the group begins, and arrives the R of the nitrogen of contiguous amino hydroxyethyl groups ⁴Last atom in the group finishes, and has 10 in abutting connection with atom on the short chain of continuous counter:

At R ⁴An embodiment in, R ^4aBe selected from (1-10C) alkylidene group, (2-10C) alkenylene and (2-10C) alkynylene, wherein alkylidene group is unsubstituted or 1 or 2 substituting group being independently selected from (1-4C) alkyl, hydroxyl and phenyl replaces.R ^4aThe representational example of particular value is-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-,-(CH ₂) ₆-,-(CH ₂) ₇-,-(CH ₂) ₈-,-(CH ₂) ₉-,-(CH ₂) ₁₀-,-(CH ₂) CH (CH ₃)-,-(CH ₂) C (CH ₃) ₂-and-(CH ₂) ₂C (phenyl) ₂-.On the other hand, R ^4aBe-(CH ₂) C (=CH ₂)-.

In one embodiment, d is 1.

In one embodiment, A ¹It is (3-7C) cycloalkylidene group that randomly replaces; Comprise the cyclohexylidene group, hexamethylene-1 for example, 4-subunit and hexamethylene-1,3-subunit; With the cyclopentylidene group, for example encircle penta-1, the 3-subunit.

In another embodiment, A ¹Be (6-10C) arylene group that randomly replaces, comprise phenylene group, benzene-1 for example, 4-subunit, benzene-1,3-subunit and benzene-1,2-subunit; With the naphthylidene group, naphthalene-1 for example, 4-subunit and naphthalene-1,5-subunit.

In another embodiment of the invention, A ¹Randomly be (2-9C) inferior heteroaryl group that replaces, comprise the pyridylidene group, pyridine-1 for example, 4-subunit; The furylidene group, furans-2 for example, 5-subunit and furans-2,4-subunit; Inferior thienyl group, thiophene-2 for example, 5-subunit and thiophene-2,4-subunit; With inferior pyrryl, pyrroles-2 for example, 5-subunit and pyrroles-2, the 4-subunit.

In another embodiment, A ¹Be (3-6C) the inferior heterocyclic radical group that randomly replaces, comprise the piperidylidene group, piperidines-1 for example, 4-subunit; With the pyrrolidinylidene group, tetramethyleneimine-2 for example, 5-subunit.

In specific embodiments, A ¹Be the phenylene that randomly replaces, inferior thienyl, cyclopentylidene, cyclohexylidene or piperidylidene.

In one embodiment, e is 0.

In specific embodiments, R ^4bIt is (1-5C) alkylidene group.R ^4bThe representational example of particular value be-CH ₂-,-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-; Comprise methylene radical, ethylidene and propylidene.

In one embodiment, f is 0.

In a particular, Q be selected from key ,-N (Q ^a) C (O)-,-C (O) N (Q ^b)-,-N (Q ^c) S (O) ₂-,-S (O) ₂N (Q ^d)-,-N (Q ^e) C (O) N (Q ^f)-,-OC (O) N (Q ⁱ)-,-N (Q ^j) C (O) O-or-N (Q ^k); For example wherein Q be key ,-N (Q ^a) C (O)-or-C (O) N (Q ^b)-.The representational example of the particular value of Q be key, O, NH ,-C (O) NH-,-C (O) N (CH ₃)-,-NHC (O)-,-N (CH ₃) C (O)-,-S (O) ₂NH-,-S (O) ₂N (CH ₃)-,-NHS (O) ₂-,-N (CH ₃) S (O) ₂-and-NHC (O) NH-.Another example of the value of Q is and R ^4cBe-C (O) (piperidines-1,4-subunit) together.

In one embodiment, Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱ, Q ^jAnd Q ^kBe selected from hydrogen and (1-6C) alkyl independently of one another, wherein alkyl group be replace or be independently selected from fluorine, hydroxyl and (1-4C) 1-3 substituting group replacement of alkoxyl group.For example, Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱ, Q ^jAnd Q ^kBe selected from hydrogen and (1-3C) alkyl independently of one another, comprise hydrogen, methyl, ethyl, n-propyl and sec.-propyl.Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱ, Q ^jAnd Q ^kThe example of the value of each is a hydrogen.

In another embodiment, Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱ, Q ^jAnd Q ^kNitrogen-atoms that is connected with them and R ^4bOr R ^4cForm the inferior azocycloalkyl group of 4-6 unit together.For example, Q ^aAnd Q ^bNitrogen-atoms that is connected with them and R ^4bOr R ^4cForm piperidines-4-subunit group together.Via explanation, as Q representative-N (Q ^a) C (O)-and Q ^aNitrogen-atoms that is connected with it and radicals R ^4bWhen forming piperidines-4-subunit group together, R ⁴Be the group of following formula:

Similarly, as Q representative-C (O) N (Q ^b)-and Q ^bNitrogen-atoms that is connected with it and radicals R ^4cWhen forming piperidines-4-subunit together, R ⁴Be the group of following formula:

In a particular, R ^4cIt is (1-5C) alkylidene group.R ⁴The representational example of particular value be-CH ₂-,-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-; Comprise methylene radical, ethylidene and propylidene.

In one embodiment, A ²It is (3-7C) cycloalkylidene group that randomly replaces; Comprise the cyclohexylidene group, hexamethylene-1 for example, 4-subunit and hexamethylene-1,3-subunit; With the cyclopentylidene group, for example encircle penta 1,3-subunit.

In another embodiment, A ²Be (6-10C) arylene group that randomly replaces, comprise phenylene group, benzene-1 for example, 4-subunit, benzene-1,3-subunit and benzene-1,2-subunit; With the naphthylidene group, naphthalene-1 for example, 4-subunit and naphthalene-1,5-subunit.

In another embodiment, A ²Randomly be (2-9C) inferior heteroaryl group that replaces, comprise the pyridylidene group, pyridine-1 for example, 4-subunit; The furylidene group, furans-2 for example, 5-subunit and furans-2,4-subunit; Inferior thienyl group, thiophene-2 for example, 5-subunit and thiophene-2,4-subunit; With inferior pyrryl, pyrroles-2 for example, 5-subunit and pyrroles-2, the 4-subunit.

In going back another embodiment, A ²Be (3-6C) the inferior heterocyclic radical group that randomly replaces, comprise the piperidylidene group, piperidines-1 for example, 4-subunit; With the pyrrolidinylidene group, tetramethyleneimine-2 for example, 5-subunit.

In specific embodiments, A ²Be the phenylene that randomly replaces, inferior thienyl, cyclopentylidene, cyclohexylidene or piperidylidene.

Via explanation, A ¹Or A ²Each or both can be phenylenes, benzene-1 for example, 4-subunit or benzene-1, the 3-subunit, wherein phenylene group be unsubstituted or be independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group ,-S-(1-4C) alkyl ,-S (O)-(1-4C) alkyl ,-S (O) ₂-(1-4C) alkyl ,-1-4 substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replace.Representational example comprises benzene-1, the 3-subunit, benzene-1, the 4-subunit, 4-chloro-benzene-1, the 3-subunit, 6-chloro-benzene-1, the 3-subunit, 4-methyl-benzene-1, the 3-subunit, 2-fluoro-benzene-1, the 4-subunit, 2-chloro-benzene-1, the 4-subunit, 2-bromo-benzene-1, the 4-subunit, 2-iodo-benzene-1, the 4-subunit, 2-methylbenzene-1, the 4-subunit, 2-anisole-1, the 4-subunit, 2-Trifluoromethyl phenyl ether-1, the 4-subunit, 3-oil of mirbane-1, the 4-subunit, 3-chlorobenzene-1, the 4-subunit, 2,5-two fluorobenzene-1,4-subunit, 2,6-dichlorobenzene-1, the 4-subunit, 2,6-two iodo-benzene 1,4-subunit, 2-chloro-6-methylbenzene-1, the 4-subunit, 2-chloro-5-methoxyl group-benzene 1, the 4-subunit, 2,3,5,6-tetra fluoro benzene-1, the 4-subunit.

Perhaps, A ¹Or A ²Or both can be cyclopentylidene or cyclohexylidene; Wherein cyclopentylidene or cyclohexylidene group are unsubstituted or the replacement of quilt (1-4C) alkyl.That representational example comprises is suitable-ring penta-1, and 3-subunit, anti--ring penta-1,3-subunit, suitable-hexamethylene-1,4-subunit and anti--Ya hexamethylene-1,4-base.A ¹Or A ²Or both also can be inferior thienyl or the piperidylidenes that randomly replaces, for example, and thiophene-2,5-subunit or piperidines-1,4-subunit.

In one embodiment, R ^4dBe selected from (1-10C) alkylidene group, (2-10C) alkenylene and (2-10C) alkynylene, wherein alkylidene group is unsubstituted or 1 or 2 substituting group being independently selected from (1-4C) alkyl, hydroxyl and phenyl replaces.R ^4dThe representational example of particular value be-(CH ₂)-,-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-,-(CH ₂) ₆-,-(CH ₂) ₇-,-(CH ₂) ₈-,-(CH ₂) ₉-,-(CH ₂) ₁₀-and-(CH ₂) CH (CH ₃)-(CH ₂)-C (CH ₃) ₂-(CH ₂) ₂-.

In a particular, R ⁴Be the divalent group of following formula :-(R ^4a) _d-R wherein ^4aIt is (4-10C) alkylidene group.Aspect of this embodiment, R ⁴Be the divalent group of following formula :-(CH ₂) _j-, wherein j is 8,9 or 10.R in this embodiment ⁴The example of particular value be-(CH ₂) ₄-,-(CH ₂) ₅-,-(CH ₂) ₆-,-(CH ₂) ₇-,-(CH ₂) ₈-,-(CH ₂) ₉-and-(CH ₂) ₁₀-; Comprise--(CH ₂) ₈-,-(CH ₂) ₉-and-(CH ₂) ₁₀-.

In another special embodiment, R ⁴Be the divalent group of following formula:

-(R ^4a) _d-(A ²) _h-(R ^4d) _i-

R wherein ^4aBe (1-10C) alkylidene group, for example-(CH ₂)-,-(CH ₂) ₂-,-(CH ₂) ₃-; A ²Be (6-10C) arylidene, benzene-1 for example, 4-subunit or benzene-1,3-subunit, or (2-9C) inferior heteroaryl, thiophene-2 for example, 5-subunit or thiophene-2,4-subunit; And R ^4dBe (1-10C) alkylidene group, for example-(CH ₂)-,-(CH ₂) ₂-,-(CH ₂) ₃-.R in this embodiment ⁴The example of particular value be-(CH ₂)-(benzene-1, the 4-subunit)-(CH ₂)-;-(CH ₂)-(benzene-1, the 4-subunit)-(CH ₂) ₂-;-(CH ₂)-(benzene-1, the 4-subunit)-(CH ₂) ₃-;-(CH ₂) ₂-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₂-(benzene-1,4-subunit)-(CH ₂) ₂-;-(CH ₂) ₂-(benzene-1,4-subunit)-(CH ₂) ₃-;-(CH ₂) ₃-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₃-(benzene-1,4-subunit)-(CH ₂) ₂-;-(CH ₂) ₃-(benzene-1,4-subunit)-(CH ₂) ₃-,-(CH ₂) ₄-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₄-(benzene-1,4-subunit)-(CH ₂) ₂-and-(CH ₂) ₄-(benzene-1,4-subunit)-(CH ₂) ₃-.

In going back another special embodiment, R ⁴Be the divalent group of following formula:

-(R ^4a) _d-Q-(A ²) _h-(R ^4d) _i-

Wherein Q be-O-or-N (Q ^k)-; Q ^kBe hydrogen or (1-3C) alkyl, for example methyl or ethyl; R ^4aBe (1-10C) alkylidene group, for example-(CH ₂)-,-(CH ₂) ₂-,-(CH ₂) ₃-; A ²Be (6-10C) arylidene, benzene-1 for example, 4-subunit or benzene-1,3-subunit, or (2-9 C) inferior heteroaryl, thiophene-2 for example, 5-subunit or thiophene-2,4-subunit; And R ^4dBe (1-10C) alkylidene group, for example-(CH ₂)-,-(CH ₂) ₂-,-(CH ₂) ₃-.R in this embodiment ⁴The example of particular value be-(CH ₂) ₂-O-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₂-O-(benzene-1,4-subunit)-(CH ₂) ₂-;-(CH ₂) ₂-O-(benzene-1,4-subunit)-(CH ₂) ₃-;-(CH ₂) ₃-O-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₃-O-(benzene-1,4-subunit)-(CH ₂) ₂-;-(CH ₂) ₃-O-(benzene-1,4-subunit)-(CH ₂) ₃-;-(CH ₂) ₂-NH-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₂-NH-(benzene-1,4-subunit)-(CH ₂) ₂-;-(CH ₂) ₂-NH-(benzene-1,4-subunit)-(CH ₂) ₃-;-(CH ₂) ₃-NH-(benzene-1,4-subunit)-(CH ₂)-;-(CH ₂) ₃-NH-(benzene-1,4-subunit)-(CH ₂) ₂-and-(CH ₂) ₃-NH-(benzene-1,4-subunit)-(CH ₂) ₃-.

-(R ^4a) _d-(A ¹) _e(R ^4b)-Q-(R ^4c) _g-(A ²) _h-(R ^4d) _i-

Wherein Q is-N (Q ^a) C (O)-or-C (O) N (Q ^b)-.In this embodiment, R ⁴Special value be following formula:

Wherein m is the integer of 2-10; And n is the integer of 2-10; Condition is that m+n is the integer of 4-12.At R ⁴This same form in, d and g be 1 and e, f, h and i be 0; And R ^4aBe-(CH ₂) _m-, R ^4cBe-(CH ₂) _n-with Q be-C (O) NH-.The particular value of m is 2 or 3; With the particular value of n be 4,5 or 6.

R ⁴Another special value be following formula:

Wherein o is the integer of 2-7; With p be the integer of 1-6; Condition is that o+p is the integer of 3-8.At R ⁴This same form in, d, h and i be 1 and e, f and g be 0; And R ^4aBe-(CH ₂) o-, A ²Be benzene-1,4-subunit, R ^4dBe-(CH ₂) _p-with Q be-C (O) NH-.The particular value of o is 2 or 3; With the particular value of p be 1 or 2.In this embodiment, benzene-1,4-subunit group can be randomly as this paper to A ²Being substituted of definition.

R ⁴Another special value be following formula:

Wherein q is the integer of 2-6; R is the integer of 1-5; With s be the integer of 1-5; Condition is that q+r+s is the integer of 4-8.At R ⁴This same form in, d, g, h and i be 1 and e and f be 0; And R ^4aBe-(CH ₂) _q-, R ^4cBe-(CH ₂) _r-, A ²Be 1,4-phenylene, R ^4dBe-(CH ₂) _s-with Q be-C (O) NH-.The particular value of q is 2 or 3; The particular value of r is 1 or 2; And the particular value of s is 1 or 2.In this embodiment, benzene-1,4-subunit group can be randomly as this paper to A ²Being substituted of definition.

R ⁴Another special value be following formula:

Wherein t is the integer of 2-10; With u be the integer of 2-10; Condition is that t+u is the integer of 4-12.At R ⁴This same form in, d and g be 1 and e, f, h and i be 0; And R ^4aBe-(CH ₂) _t-, R ^4cBe-(CH ₂) _u-with Q be-NHC (O)-.The particular value of t is 2 or 3; With the particular value of u be 4,5 or 6.

R ⁴Another special value be following formula:

Wherein v is the integer of 2-7; With w be the integer of 1-6; Condition is that v+w is the integer of 3-8.At R ⁴This same form in, d, h and i be 1 and e, f and g be 0; And R ^4aBe-(CH ₂) v-, A ²Be 1,4-phenylene, R ^4dBe-(CH ₂) _w-with Q be-NHC (O)-.The particular value of v is 2 or 3; With the particular value of w be 1 or 2.In this embodiment, benzene-1,4-subunit group can be randomly as this paper to A ²Being substituted of definition.

R ⁴Another special value be following formula:

Wherein x is the integer of 2-6; Y is the integer of 1-5; With z be the integer of 1-5; Condition is that x+y+z is the integer of 4-8.At R ⁴This same form in, d, g, h and i be 1 and e and f be 0; And R ^4aBe-(CH ₂) _x-, R ^4cBe-(CH ₂) _y-, A ²Be 1,4-phenylene, R ^4dBe-(CH ₂) _z-and Q be-NHC (O)-.The particular value of X is 2 or 3; The particular value of y is 1 or 2; With the particular value of z be 1 or 2.In this embodiment, benzene-1,4-subunit group can be randomly as this paper to A ²Being substituted of definition.

Via further specifying R ⁴Can be selected from:

-(CH ₂) ₇-；

-(CH ₂) ₈-；

-(CH ₂) ₉-；

-(CH ₂) ₁₀-；

-(CH ₂) ₁₁-；

-(CH ₂) ₂C(O)NH(CH ₂) ₅-；

-(CH ₂) ₂N(CH ₃)C(O)(CH ₂) ₅-；

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC(O)NH(CH ₂) ₅-；

-(CH ₂) ₃NHC(O)NH(CH ₂) ₅-；

-(CH ₂) ₂C (O) NHCH ₂(hexamethylene-1,3-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (ring penta-1,3-subunit)-;

-(CH ₂) ₂NHC (O) NH (benzene-1,4-subunit) (CH ₂) ₂-;

1-[-(CH ₂) ₂C (O)] (piperidin-4-yl) (CH ₂) ₂-;

-(CH ₂) ₂NHC (O) (anti--hexamethylene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-;

-(CH ₂) NH (benzene-1,4-subunit) (CH ₂) ₂-;

1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl) (CH ₂) ₂-;

-CH ₂(benzene-1,4-subunit) NH (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(pyridine-2,6-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (suitable-hexamethylene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (anti--hexamethylene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₂NH C (O) (suitable-ring penta-1, the 3-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (anti--hexamethylene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) C*H (CH ₃)-((S)-isomer);

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) C*H (CH ₃)-((R)-isomer);

2-[(S)-(CH ₂-] (tetramethyleneimine-1-yl) C (O) (CH ₂) ₄-;

2-[(S)-(CH ₂-] (tetramethyleneimine-1-yl) C (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (4-chlorobenzene-1,3-subunit) CH ₂-;

-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (4-methylbenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (6-chlorobenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chlorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2,6-dichlorobenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) NHCH ₂(benzene-1,3-subunit) CH ₂-;

4-[-CH ₂-] (piperidines-1-yl) C (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) N (CH ₂CH ₃) (benzene-1,4-subunit) CH ₂-;

1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl)-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂NHC (O) (thiophene-2,5-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (3-oil of mirbane-1,4-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (anti--hexamethylene-1, the 4-subunit)-;

1-[-CH ₂-(2-fluorobenzene-1,3-subunit) CH ₂] (piperidin-4-yl)-;

5-[-(CH ₂) ₂NHC (O)] (pyridine-2-yl) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₃(thiophene-2,5-subunit) (CH ₂) ₃-;

-(CH ₂) ₂(benzene-1,4-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-CH ₂(benzene-1,2-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidin-4-yl) (CH ₂) ₂-;

1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidin-4-yl) CH ₂-;

-(CH ₂) ₂C (O) NH (3-chlorobenzene-1,4-subunit) CH ₂-;

-(CH2) ₂C (O) NH (2-(CF ₃O-) benzene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₃(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂S(O) ₂NH(CH ₂) ₅-；

-CH ₂(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (2-iodobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chloro-5-anisole-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chloro-6-methylbenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C(O)NH(CH ₂) ₅-；

-(CH ₂) ₂N (CH ₃) S (O) ₂(benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-bromobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₃(benzene-1,4-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₃(benzene-1,2-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidin-4-yl) (CH ₂) ₃-;

-(CH ₂) ₂C (O) NH (2-anisole-1,4-subunit) CH ₂-;

-(CH ₂) ₅NH (benzene-1,4-subunit) (CH ₂) ₂-;

4-[-(CH ₂) ₂-] (piperidines-1-yl) (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH (CH ₃) CH ₂-;

-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (2-fluorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (2,5-two fluorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) (CH ₂) ₂-;

1-[-CH ₂(pyridine-2,6-subunit) CH ₂] (piperidin-4-yl) CH ₂-;

-(CH ₂) ₃NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂NH (naphthalene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₃O (benzene-1,4-subunit) CH ₂-;

1-[-(CH ₂) ₃] (piperidin-4-yl) CH ₂-;

4-[-(CH ₂) ₂-] (piperidines-1-yl) C (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₃(benzene-1,4-subunit) NHC (O) (CH ₂) ₂-;

-(CH ₂) ₃O (benzene-1,4-subunit) (CH ₂) ₂-;

2-[-(CH ₂) ₂] (benzoglyoxaline-5-yl) CH ₂-;

-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₂-;

-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₄-;

-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₅-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₂-;

-(CH ₂) ₂NHC (O) NH (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) (CH ₂) ₂(suitable-hexamethylene-1,4-subunit)-;

-(CH ₂) ₂C (O) NH (2,3,5,6-tetra fluoro benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2,6-diiodo-benzene-1,4-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₃-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₄-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₅-;

-(CH ₂) ₂C (O) NH CH ₂(benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) NHCH ₂(benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-methylbenzene-1,4-subunit) CH ₂-;

1-[-(CH ₂) ₃O (benzene-1,4-subunit) (CH ₂) ₂] (piperidin-4-yl) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(benzene-1,3-subunit) (CH ₂) ₂-;

-(CH ₂) ₂O (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) CH ₂O (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) CH ₂O (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (furans-2,5-subunit) CH ₂-;

-(CH ₂) ₂N (CH ₃) C (O) (thiophene-2,5-subunit) CH ₂-;

-(CH ₂) ₂O (benzene-1,4-subunit) OCH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,2-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (furans-2,5-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (thiophene-2,5-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,2-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,3-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,4-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (furans-2,5-subunit) CH ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (thiophene-2,5-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) CH ₂O (benzene-1,2-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) CH ₂O (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) CH ₂O (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (furans-2,5-subunit) CH ₂-;

-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (thiophene-2,5-subunit) CH ₂-;

-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₃O (benzene-1,3-subunit) CH ₂-;

-CH ₂CH (OH) CH ₂NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₄NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂NHC (O) CH ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂NHC (O) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(anti--hexamethylene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₂NHC(O)(CH ₂) ₅-；

-(CH ₂) ₂O (benzene-1,3-subunit) OCH ₂-;

-(CH ₂) ₂O (benzene-1,2-subunit) OCH ₂-;

-CH ₂(benzene-1,2-subunit) O (benzene-1,2-subunit) CH ₂-;

-(CH ₂) ₂C(O)NH(CH ₂) ₆-；

-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₃-;

-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₄(benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₃(furans-2,5-subunit) (CH ₂) ₃-;

-(CH ₂) ₂N (CH ₃) C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-;

4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₃(benzene-1,3-subunit) (CH ₂) ₃-;

-(CH ₂) ₃(tetrahydrofuran (THF)-2,5-subunit) (CH ₂) ₃-; With

-(CH ₂) ₂O (benzene-1,4-subunit) C (O) (CH ₂) ₂-.

Representational subgenus group

Following subgenus formula and group are for the representational example of each side of the present invention and embodiment is provided, and unless otherwise noted, they are not got rid of other embodiment or do not limit the scope of the invention.

The formula I compound of a particular group is those disclosed in the U.S. Provisional Application of submitting on February 14th, 2,003 60/447,843.This group comprises formula I compound; Wherein:

A is 0 or the integer of 1-3;

R ¹Each be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^1a,-C (O) OR ^1b, SR ^1c,-S (O) R ^1d,-S (O) ₂R ^1eWith-NR ^1fR ^1g

R ^1a, R ^1b, R ^1c, R ^1d, R ^1e, R ^1fAnd R ^1gEach is hydrogen or (1-4C) alkyl independently;

B is 0 or the integer of 1-3;

R ²Each be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^2a,-C (O) OR ^2b, SR ^2c,-S (O) R ^2d,-S (O) ₂R ^2eAnd NR ^2fR ^2g

R ^2a, R ^2b, R ^2c, R ^2d, R ^2e, R ^2fAnd R ^2gEach is hydrogen or (1-4C) alkyl independently;

W is connected to respect to the 3-of nitrogen-atoms on the piperidine ring or 4-position, and represents O or NW ^a

W ^aBe hydrogen or (1-4C) alkyl;

C is 0 or the integer of 1-4;

R ³Each is the substituting group on carbon, be independently selected from (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, cyano group, halogen ,-OR ^3a,-C (O) OR ^3b, SR ^3c,-S (O) R ^3d,-S (O) ₂R ^3eAnd NR ^3fR ^3g

R ^3a, R ^3b, R ^3c, R ^3d, R ^3e, R ^3fAnd R ^3gEach is hydrogen or (1-4C) alkyl independently;

R ⁴Be the divalent group of following formula:

-(R ^4a) _d-(A ¹) _e-(R ^4b) _f-Q-(R ^4c) _g-(A ²) _h-(R ^4d) _i-

Wherein

D, e, f, g, h and i are selected from 0 and 1 independently of one another;

R ^4a, R ^4b, R ^4cAnd R ^4dBe selected from (1-10C) alkylidene group, (2-10C) alkenylene and (2-10C) alkynylene independently of one another, wherein each alkylidene group, alkenylene or alkynylene group are unsubstituted or are independently selected from 1-5 substituting group replacement of (1-4C) alkyl, fluorine, hydroxyl, phenyl and phenyl (1-4C)-alkyl;

A ¹And A ²Be selected from (3-7C) cycloalkylidene, (6-10C) arylidene, (2-9C) inferior heteroaryl and (3-6C) inferior heterocyclic radical independently of one another; Wherein each cycloalkylidene is unsubstituted or 1-4 substituting group being independently selected from (1-4C) alkyl replaces and each arylidene, inferior heteroaryl or inferior heterocyclic radical group are unsubstituted or are independently selected from halogen, (1-4C) alkyl and (1-4C) 1-4 substituting group replacement of alkoxyl group;

Q be selected from key ,-O-,-C (O) O ,-OC (O)-,-S-,-S (O)-,-S (O) ₂-,-N (Q ^a) C (O)-,-C (O) N (Q ^b)-,-N (Q ^c) S (O) ₂-,-S (O) ₂N (Q ^d)-,-N (Q ^e) C (O) N (Q ^f)-,-N (Q ^g) S (O) ₂N (Q ^h)-,-OC (O) N (Q ⁱ)-and-N (Q ^j) C (O) O-;

Q ^a, Q ^b, Q ^c, Q ^d, Q ^e, Q ^f, Q ^g, Q ^h, Q ⁱAnd Q ^jBe selected from hydrogen, (1-6C) alkyl, A independently of one another ³(1-4C) alkylidene group-A ⁴Wherein alkyl group is unsubstituted or is independently selected from fluorine, hydroxyl and (1-4C) 1-3 substituting group replacement of alkoxyl group; Or nitrogen-atoms that is connected with them and radicals R ^4bOr R ^4cForm the inferior azocycloalkyl group of 4-6 unit together;

A ³And A ⁴Be selected from (3-6C) cycloalkyl, (6-10C) aryl, (2-9C) heteroaryl and (3-6C) heterocyclic radical independently of one another; Wherein each cycloalkyl is unsubstituted or 1-4 substituting group being independently selected from (1-4C) alkyl replaces and each aryl, heteroaryl or heterocyclic radical group are unsubstituted or are independently selected from halogen, (1-4C) alkyl and (1-4C) 1-4 substituting group replacement of alkoxyl group;

Condition is R ⁴Between two nitrogen-atoms that connect in the short chain in abutting connection with the number of atom in the 8-14 scope;

R ⁵Represent hydrogen or (1-4C) alkyl;

R ⁶Be-NR ^6aCR ^6b(O) and R ⁷Be hydrogen, perhaps R ⁶And R ⁷Formation-NR together ^7aC (O)-CR ^7b=CR ^7c-,-CR ^7d=CR ^7e-C (O)-NR ^7f-,-NR ^7gC (O)-CR ^7hR ⁷ⁱ-CR ^7jR ^7k-or-CR ⁷¹R ^7m-CR ⁷ⁿR ^7o-C (O)-NR ^7p-;

R ^6aAnd R ^6bEach is hydrogen or (1-4C) alkyl independently; With

Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is those disclosed in the U.S. Provisional Application of submitting on May 1st, 2,003 60/467,035.This group compound comprises formula I compound; Wherein:

A is 0 or the integer of 1-3;

B is 0 or the integer of 1-3;

W ^aBe hydrogen or (1-4C) alkyl;

C is 0 or the integer of 1--4;

R ⁴Be the divalent group of following formula:

-(R ^4a) _d-(A ¹) _e-(R ^4b) _f-Q-(R ^4c) _g-(A ²) _h-(R ^4d) _i-

Wherein

D, e, f, g, h and i are selected from 0 and 1 independently of one another;

Condition is R ⁴Between two nitrogen-atoms that connect in the short chain in abutting connection with the number of atom in the 4-14 scope;

R ⁵Represent hydrogen or (1-4C) alkyl;

R ⁶Be-NR ^6aCR ^6b(O) or CR ^6cR ^6dOR ^6eAnd R ⁷Be hydrogen, perhaps R ⁶And R ⁷Formation-NR together ^7aC (O)-CR ^7b=CR ^7c-,-CR ^7d=CR ^7e-C (O)-NR ^7f-,-NR ^7gC (O)-CR ^7hR ⁷ⁱ-CR ^7jR ^7k-or-CR ^7lR ^7m-CR ⁷ⁿR ^7o-C (O)-NR ^7p-;

R ^6a, R ^6b, R ^6c, R ^6dAnd R ^6eBe hydrogen or (1-4C) alkyl independently; With

Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is O; W is connected the 4-position of piperidine ring; R ⁵Be hydrogen; And R ⁴, R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is NH; W is connected the 4-position of piperidine ring; R ⁵Be hydrogen; And R ⁴, R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

Also the formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is O; W is connected the 4-position of piperidine ring; R ⁴Be-(CH ₂) _j-, wherein j is 8,9 or 10; R ⁵Be hydrogen; And R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is NH; W is connected the 4-position of piperidine ring; R ⁴Be-(CH ₂) _j-, wherein j is 8,9 or 10; R ⁵Be hydrogen; And R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

Also the formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is O; W is connected the 4-position of piperidine ring; R ⁴Be-(CH ₂) ₂-C (O) NH-(CH ₂) ₅R ⁵Be hydrogen; And R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is those, and wherein: a is 0; B is 0; C is 0; W is NH; W is connected the 4-position of piperidine ring; R ⁴Be-(CH ₂) ₂-C (O) NH-(CH ₂) ₅R ⁵Be hydrogen; And R ⁶And R ⁷As defined herein; Or its pharmacy acceptable salt or solvate or steric isomer.

Another particular group of formula I compound is those of formula II as herein defined; Or its pharmacy acceptable salt or solvate or steric isomer.

Another particular group of formula I compound is those of formula III as herein defined; Or its pharmacy acceptable salt or solvate or steric isomer.

Another particular group of formula I compound is those of formula IV as herein defined, or its pharmacy acceptable salt or solvate or steric isomer.

Another particular group of formula I compound is those of formula II, III or IV as herein defined, and wherein piperidine ring is replaced by methyl group in the 4-position; Or its pharmacy acceptable salt or solvate or steric isomer.

The formula I compound of another particular group is a formula V compound:

Wherein W, R ⁴, R ⁶And R ⁷Be as defined in Table 1; Or its pharmacy acceptable salt or solvate.

Table 1

Embodiment	W	R ⁴	R ⁶	R ⁷
Embodiment	W	R ⁴	R ⁶	R ⁷	1	NH	-(CH ₂) ₉-(racemic) ¹	-NHC(O)CH＝CH- ²

2	O	-(CH2) 9-(racemic)	-NHC(O)CH＝CH-
2	O	-(CH2) 9-(racemic)	-NHC(O)CH＝CH-		3	O	-(CH2)9-	-NHC(O)CH＝CH-
4	O	-(CH ₂) ₉-	-NHC(O)H	H	3	O	-(CH2)9-	-NHC(O)CH＝CH-
4	O	-(CH ₂) ₉-	-NHC(O)H	H	5	O	-(CH ₂) ₉-	-NHC(O)CH ₂CH ₂-
6	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-		5	O	-(CH ₂) ₉-	-NHC(O)CH ₂CH ₂-
6	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-		7	O	-(CH ₂) ₂N(CH ₃)C(O)(CH ₂) ₅-	-NHC(O)CH＝CH-
8	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		7	O	-(CH ₂) ₂N(CH ₃)C(O)(CH ₂) ₅-	-NHC(O)CH＝CH-
8	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		9	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
10	O	-(CH ₂) ₂NHC(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-		9	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
10	O	-(CH ₂) ₂NHC(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-		11	O	-(CH ₂) ₃NHC(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-
12	O	-(CH ₂) ₉-	-CH ₂OH	H	11	O	-(CH ₂) ₃NHC(O)NH(CH ₂) ₅-	-NHC(O)CH＝CH-
12	O	-(CH ₂) ₉-	-CH ₂OH	H	13	NH	-(CH ₂) ₉-	-CH ₂OH	H
14	O	-(CH ₂) ₂C(O)NHCH ₂(hexamethylene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		13	NH	-(CH ₂) ₉-	-CH ₂OH	H
14	O	-(CH ₂) ₂C(O)NHCH ₂(hexamethylene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		15	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-	-NHC(O)CH ₂CH ₂-
16	O	-(CH ₂) ₂C (O) NH (2-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		15	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-	-NHC(O)CH ₂CH ₂-
16	O	-(CH ₂) ₂C (O) NH (2-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		17	O	-(CH ₂) ₂S(O) ₂NH(CH ₂) ₅-	-NHC(O)CH＝CH-
18	O	-(CH ₂) ₂N(CH ₃)S(O) ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		17	O	-(CH ₂) ₂S(O) ₂NH(CH ₂) ₅-	-NHC(O)CH＝CH-
18	O	-(CH ₂) ₂N(CH ₃)S(O) ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		19	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
2O	O	-(CH ₂) ₃(benzene-1,4-subunit) NH (benzene-1,2-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		19	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
2O	O		-NHC(O)CH＝CH-		21	O	1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidines-4-yl) CH ₂-	-NHC(O)CH＝CH-
22	O	-(CH ₂) ₃O (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		21	O		-NHC(O)CH＝CH-
22	O	-(CH ₂) ₃O (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		23	O	-(CH ₂) ₂(benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-

24	O	-(CH ₂) ₃(thiophene-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-
24	O	-(CH ₂) ₃(thiophene-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-		25	O	-(CH ₂) ₂C (O) NH (2-chloro-5-anisole-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
26	O	-(CH ₂) ₇-	-NHC(O)CH＝CH-		25	O	-(CH ₂) ₂C (O) NH (2-chloro-5-anisole-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
26	O	-(CH ₂) ₇-	-NHC(O)CH＝CH-		27	O	-(CH ₂) ₈-	-NHC(O)CH＝CH-
28	O	-(CH ₂) ₂NHC (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		27	O	-(CH ₂) ₈-	-NHC(O)CH＝CH-
28	O	-(CH ₂) ₂NHC (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		29	O	1-[-(CH ₂) ₂C (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-
30	O	-(CH ₂) ₂NHC (O) (anti--hexamethylene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-		29	O	1-[-(CH ₂) ₂C (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-
30	O		-NHC(O)CH＝CH-		31	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-	-NHC(O)CH＝CH-
32	O	-(CH ₂) ₂NHC(O)NH(CH ₂) ₅-	-NHC(O)H	H	31	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-	-NHC(O)CH＝CH-
32	O	-(CH ₂) ₂NHC(O)NH(CH ₂) ₅-	-NHC(O)H	H	33	O	-(CH ₂) ₂NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
34	O	-(CH ₂) ₃NHC(O)NH(CH ₂) ₅-	-NHC(O)H	H	33	O	-(CH ₂) ₂NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
34	O	-(CH ₂) ₃NHC(O)NH(CH ₂) ₅-	-NHC(O)H	H	35	O	1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-
36	O	-CH ₂(benzene-1,4-subunit) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		35	O	1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-
36	O	-CH ₂(benzene-1,4-subunit) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		37	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
38	NH	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		37	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
38	NH	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		39	O	-(CH ₂) ₂C(O)NHCH ₂(pyridine-2,6-subunit) CH ₂-	-NHC(O)CH＝CH-
40	O	-(CH ₂) ₂C (O) NH (suitable-hexamethylene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		39	O	-(CH ₂) ₂C(O)NHCH ₂(pyridine-2,6-subunit) CH ₂-	-NHC(O)CH＝CH-
40	O		-NHC(O)CH＝CH-		41	O	-(CH ₂) ₂C (O) NH (anti--hexamethylene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-
42	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit) CH ₂-	-NHC(O)CH＝CH-		41	O		-NHC(O)CH＝CH-
42	O		-NHC(O)CH＝CH-		43	O	-(CH ₂) ₂N(CH ₃) CO (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
44	O	-(CH ₂) ₂N(CH ₃) CO (anti--hexamethylene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-		43	O	-(CH ₂) ₂N(CH ₃) CO (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
44	O		-NHC(O)CH＝CH-		45	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-(racemic)	-NHC(O)CH＝CH-

46	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) C*H (CH ₃)-((S)-isomer)	-NHC(O)CH＝CH-
46	O		-NHC(O)CH＝CH-		47	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) C*H (CH ₃)-((R)-isomer)	-NHC(O)CH＝CH-
48	O	2-[(S)-(-CH ₂-] (tetramethyleneimine-1-yl) C (O) (CH ₂) ₄-	-NHC(O)CH＝CH-		47	O		-NHC(O)CH＝CH-
48	O	2-[(S)-(-CH ₂-] (tetramethyleneimine-1-yl) C (O) (CH ₂) ₄-	-NHC(O)CH＝CH-		49	O	2-[(S)-(-CH ₂-] (tetramethyleneimine-1-yl) C (O) benzene-1,4-subunit CH ₂-	-NHC(O)CH＝CH-
50	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H	49	O		-NHC(O)CH＝CH-
50	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H	51	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) C*H (CH ₃)-((R)-isomer)	-NHC(O)H	H
52	O	-(CH ₂) ₂C (O) NH (4-chlorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		51	O		-NHC(O)H	H
52	O	-(CH ₂) ₂C (O) NH (4-chlorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		53	NH	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
54	NH	1-[-(CH ₂) ₂C (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-		53	NH	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
54	NH	1-[-(CH ₂) ₂C (O)] (piperidin-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-		55	NH	-(CH ₂) ₂C(O)NH CH ₂(benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
56	O	-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		55	NH	-(CH ₂) ₂C(O)NH CH ₂(benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
56	O	-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		57	O	-(CH ₂) ₂C (O) NH (4-methylbenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
58	O	-(CH ₂) ₂C (O) NH (6-chlorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		57	O	-(CH ₂) ₂C (O) NH (4-methylbenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
58	O	-(CH ₂) ₂C (O) NH (6-chlorobenzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-		59	O	-(CH ₂) ₂C (O) NH (2,6-dichlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
60	O	4-[-CH ₂-] (piperidines-1-yl) C (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		59	O	-(CH ₂) ₂C (O) NH (2,6-dichlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
60	O		-NHC(O)CH＝CH-		61	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
62	O	-(CH ₂) ₂C(O)N(CH ₂CH ₃) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		61	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
62	O	-(CH ₂) ₂C(O)N(CH ₂CH ₃) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		63	O	1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl)-	-NHC(O)CH＝CH-
64	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		63	O	1-[-(CH ₂) ₂NHC (O)] (piperidin-4-yl)-	-NHC(O)CH＝CH-
64	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		65	O	-(CH ₂) ₂NHC (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-

66	O	-(CH ₂) ₂N(CH ₃) C (O) (3-oil of mirbane-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
66	O	-(CH ₂) ₂N(CH ₃) C (O) (3-oil of mirbane-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		67	O	-(CH ₂) ₂C (O) NH (anti--hexamethylene-1, the 4-subunit) CH ₂-	-NHC(O)H	H
68	O	-(CH ₂) ₂N(CH ₃) C (O) (anti--hexamethylene-1, the 4-subunit)-	-NHC(O)CH＝CH-		67	O		-NHC(O)H	H
68	O		-NHC(O)CH＝CH-		69	O	1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidines-4-yl)-	-NHC(O)CH＝CH-
70	O	5-[-(CH ₂) ₂NH C (O)] (pyridine-2-yl) CH ₂-	-NHC(O)CH＝CH-		69	O		-NHC(O)CH＝CH-
70	O	5-[-(CH ₂) ₂NH C (O)] (pyridine-2-yl) CH ₂-	-NHC(O)CH＝CH-		71	O	1-[-(CH ₂) ₃] (pyridin-4-yl) CH ₂-	-NHC(O)CH＝CH-
72	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)H	H	71	O	1-[-(CH ₂) ₃] (pyridin-4-yl) CH ₂-	-NHC(O)CH＝CH-
72	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)H	H	73	O	-CH ₂(benzene-1,2-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
74	O	1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidines-4-yl) (CH ₂) ₂-	-NHC(O)CH＝CH-		73	O		-NHC(O)CH＝CH-
74	O		-NHC(O)CH＝CH-		75	O	-(CH ₂) ₃NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
76	O	-(CH ₂) ₂C (O) NH (3-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		75	O	-(CH ₂) ₃NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
76	O	-(CH ₂) ₂C (O) NH (3-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		77	O	-(CH ₂) ₂C(O)NH(2-(CF ₃O) benzene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-
78	O	-(CH ₂) ₃(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		77	O	-(CH ₂) ₂C(O)NH(2-(CF ₃O) benzene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-
78	O		-NHC(O)CH＝CH-		79	O	-CH ₂(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
80	O	-(CH ₂) ₂C (O) NH (2-iodobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		79	O		-NHC(O)CH＝CH-
80	O	-(CH ₂) ₂C (O) NH (2-iodobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		81	O	-(CH ₂) ₂C (O) NH (2-chloro-6-methylbenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
82	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-(racemic)	-NHC(O)CH＝CH-		81	O		-NHC(O)CH＝CH-
82	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-(racemic)	-NHC(O)CH＝CH-		83	O	-(CH ₂) ₂C (O) NH (2-bromobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
84	O	-(CH ₂) ₃(benzene-1,2-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-		83	O	-(CH ₂) ₂C (O) NH (2-bromobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-

85	O	1-[-CH ₂(2-fluorobenzene-1,3-subunit) CH ₂] (piperidines-4-yl) (CH ₂) ₃-	-NHC(O)CH＝CH-
85	O		-NHC(O)CH＝CH-	86	O	-(CH ₂) ₂C (O) NH (2-anisole-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
87	O	-(CH ₂) ₅NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	86	O	-(CH ₂) ₂C (O) NH (2-anisole-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
87	O	-(CH ₂) ₅NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	88	O	4-[-(CH ₂) ₂-] (piperidines-1-yl) (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
89	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH (CH ₃)CH ₂-	-NHC(O)CH＝CH-	88	O		-NHC(O)CH＝CH-
89	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH (CH ₃)CH ₂-	-NHC(O)CH＝CH-	90	O	-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
91	O	-(CH ₂) ₂C (O) NH (2-fluorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	90	O		-NHC(O)CH＝CH-
91	O	-(CH ₂) ₂C (O) NH (2-fluorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	92	O	-(CH ₂) ₂(benzene-1,3-subunit) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
93	O	-(CH ₂) ₂C (O) NH (2,5-two fluorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	92	O		-NHC(O)CH＝CH-
93	O	-(CH ₂) ₂C (O) NH (2,5-two fluorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	94	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
95	O	1-[-CH ₂(pyridine-2,6-subunit) CH ₂] (piperidines-1-yl) CH ₂-	-NHC(O)CH＝CH-	94	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
95	O		-NHC(O)CH＝CH-	96	O	-(CH ₂) ₂NH (naphthalene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
97	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	96	O	-(CH ₂) ₂NH (naphthalene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
97	O		-NHC(O)CH＝CH-	98	O	-(CH ₂) ₃(benzene-1,4-subunit) NHC (O) (CH ₂) ₂-	-NHC(O)CH＝CH-
99	O	-(CH ₂) ₃O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	98	O	-(CH ₂) ₃(benzene-1,4-subunit) NHC (O) (CH ₂) ₂-	-NHC(O)CH＝CH-
99	O	-(CH ₂) ₃O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	100	O	2-[-(CH ₂) ₂] (benzoglyoxaline-5-yl) CH ₂-	-NHC(O)CH＝CH-
101	O	-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₂-	-NHC(O)CH＝CH-	100	O	2-[-(CH ₂) ₂] (benzoglyoxaline-5-yl) CH ₂-	-NHC(O)CH＝CH-
101	O		-NHC(O)CH＝CH-	102	O	-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₄-	-NHC(O)CH＝CH-
103	O	-(CH ₂) ₂-(anti--hexamethylene-1, the 4-subunit) NHC (O) (CH ₂) ₅-	-NHC(O)CH＝CH-	102	O		-NHC(O)CH＝CH-

104	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₂-	-NHC(O)CH＝CH-
104	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₂-	-NHC(O)CH＝CH-	105	O	-(CH ₂) ₂NH C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
106	O	-(CH ₂) ₂N-(CH ₃)(CH ₂) ₂(suitable-hexamethylene-1,4-subunit)-	-NHC(O)CH＝CH-	105	O	-(CH ₂) ₂NH C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
106	O		-NHC(O)CH＝CH-	107	O	-(CH ₂) ₂C (O) NH (2,3,5,6-tetra fluoro benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
1O8	O	-(CH ₂) ₂C (O) NH (2,6-diiodo-benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	107	O		-NHC(O)CH＝CH-
1O8	O	-(CH ₂) ₂C (O) NH (2,6-diiodo-benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	1O9	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₃-	-NHC(O)CH＝CH-
110	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₄-	-NHC(O)CH＝CH-	1O9	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₃-	-NHC(O)CH＝CH-
110	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₄-	-NHC(O)CH＝CH-	111	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₅-	-NHC(O)CH＝CH-
112	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	111	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (CH ₂) ₅-	-NHC(O)CH＝CH-
112	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	113	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
114	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	113	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
114	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	115	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
116	O	-(CH ₂) ₂C (O) NH (2-methylbenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	115	O	-(CH ₂) ₂NHC(O)NHCH ₂(benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
116	O	-(CH ₂) ₂C (O) NH (2-methylbenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	117	O	1-[-(CH ₂) ₃O (benzene-1,4-subunit) (CH ₂) ₂-] (piperidin-4-yl) CH ₂-	-NHC(O)CH＝CH-
118	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,3-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	117	O		-NHC(O)CH＝CH-
118	O	-(CH ₂) ₂C(O)NHCH ₂(benzene-1,3-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	119	O	-(CH ₂) ₂O (benzene-1,3-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
120	O	-(CH ₂) ₂N(CH ₃)C(O)CH ₂O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	119	O	-(CH ₂) ₂O (benzene-1,3-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
120	O	-(CH ₂) ₂N(CH ₃)C(O)CH ₂O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	121	O	-(CH ₂) ₂N(CH ₃)C(O)CH ₂O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
122	O	-(CH ₂) ₂N(CH ₃) C (O) (furans-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-	121	O	-(CH ₂) ₂N(CH ₃)C(O)CH ₂O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
122	O	-(CH ₂) ₂N(CH ₃) C (O) (furans-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-	123	O	-(CH ₂) ₂N(CH ₃) C (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-
124	O	-(CH ₂) ₂O (benzene-1,4-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-	123	O	-(CH ₂) ₂N(CH ₃) C (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-
124	O	-(CH ₂) ₂O (benzene-1,4-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-	125	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NH C (O) (benzene	-NHC(O)CH＝CH-

		-1, the 4-subunit) CH ₂-
		-1, the 4-subunit) CH ₂-		126	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,2-subunit) CH ₂-	-NHC(O)CH＝CH-
127	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-	126	O		-NHC(O)CH＝CH-
127	O		-NHC(O)CH＝CH-	128	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) CH ₂O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
129	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (furans-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-	128	O		-NHC(O)CH＝CH-
129	O		-NHC(O)CH＝CH-	130	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-
131	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,2-subunit) CH ₂-	-NHC(O)CH＝CH-	130	O		-NHC(O)CH＝CH-
131	O		-NHC(O)CH＝CH-	132	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
133	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) CH ₂O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	132	O		-NHC(O)CH＝CH-
133	O		-NHC(O)CH＝CH-	134	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (furans-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-
135	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-	134	O		-NHC(O)CH＝CH-
135	O		-NHC(O)CH＝CH-	136	O	-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
137	O	-(CH ₂) ₂(benzene-1,4-subunit) NH C (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	136	O		-NHC(O)CH＝CH-
137	O		-NHC(O)CH＝CH-	138	O	-(CH ₂) ₂(benzene-1,4-subunit) NH C (O) CH ₂O (benzene-1,2-	-NHC(O)CH＝CH-

		Subunit) CH ₂-
		Subunit) CH ₂-		139	O	-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) CH ₂O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
140	O	-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) CH ₂O (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-	139	O		-NHC(O)CH＝CH-
140	O		-NHC(O)CH＝CH-	141	O	-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (furans-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-
142	O	-(CH ₂) ₂(benzene-1,4-subunit) NHC (O) (thiophene-2,5-subunit) CH ₂-	-NHC(O)CH＝CH-	141	O		-NHC(O)CH＝CH-
142	O		-NHC(O)CH＝CH-	143	O	-(CH ₂) ₂(anti--hexamethylene-1, the 4-subunit) NHC (O) (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-
144	O	-(CH ₂) ₃O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-	143	O		-NHC(O)CH＝CH-
144	O	-(CH ₂) ₃O (benzene-1,3-subunit) CH ₂-	-NHC(O)CH＝CH-	145	O	-CH ₂CH(OH)CH ₂NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
146	O	-(CH ₂) ₄NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	145	O	-CH ₂CH(OH)CH ₂NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
146	O	-(CH ₂) ₄NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	147	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂NHC(O) CH ₂-	-NHC(O)CH＝CH-
148	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂NHC(O) CH ₂-	-NHC(O)CH＝CH-	147	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂NHC(O) CH ₂-	-NHC(O)CH＝CH-
148	O		-NHC(O)CH＝CH-	149	O	-(CH ₂) ₂C(O)NHCH ₂(anti--hexamethylene-1, the 4-subunit) CH ₂-	-NHC(O)CH＝CH-
150	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)CH＝CH-	149	O		-NHC(O)CH＝CH-
150	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)CH＝CH-	151	O	-(CH ₂) ₂O (benzene-1,3-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-
152	O	-(CH ₂) ₂O (benzene-1,2-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-	151	O	-(CH ₂) ₂O (benzene-1,3-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-
152	O	-(CH ₂) ₂O (benzene-1,2-subunit) O (CH ₂) ₂-	-NHC(O)CH＝CH-	153	O	-CH ₂(benzene-1,2-subunit) O (benzene-1,2-subunit) CH ₂-	-NHC(O)CH＝CH-
154	O	-(CH ₂) ₂C(O)NH(CH ₂) ₆-	-NHC(O)CH＝CH-	153	O	-CH ₂(benzene-1,2-subunit) O (benzene-1,2-subunit) CH ₂-	-NHC(O)CH＝CH-
154	O	-(CH ₂) ₂C(O)NH(CH ₂) ₆-	-NHC(O)CH＝CH-	155	O	-(CH ₂) ₂NHC (O) (suitable-ring penta-1, the 3-subunit)-	-NHC(O)CH＝CH-

156	O	-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-
156	O	-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-	157	O	-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
158	O	-(CH ₂) ₄(benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	157	O	-(CH ₂) ₃(benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
158	O	-(CH ₂) ₄(benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	159	O	-(CH ₂) ₃(furans-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-
160	O	-(CH ₂) ₂N(CH ₃) C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	159	O	-(CH ₂) ₃(furans-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-
160	O	-(CH ₂) ₂N(CH ₃) C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-	161	O	4-[-(CH ₂) ₂] (piperidines-1-yl) C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-	-NHC(O)CH＝CH-
162	O	-(CH ₂) ₃(benzene-1,3-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-	161	O		-NHC(O)CH＝CH-
162	O	-(CH ₂) ₃(benzene-1,3-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-	163	O	-(CH ₂) ₃(tetrahydrofuran (THF)-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-
164	O	-(CH ₂) ₂O (benzene-1,4-subunit) C (O) (CH ₂) ₂-	-NHC(O)CH＝CH-	163	O	-(CH ₂) ₃(tetrahydrofuran (THF)-2,5-subunit) (CH ₂) ₃-	-NHC(O)CH＝CH-

1 in Table I-III, and " (racemic) " refers to that compound has an oh group in formula V, VI or VII chiral carbon place is racemic.

2 for this group, nitrogen-atoms and R ⁶Connect carbon atom and R ⁷Connect.

The formula I compound of another special group is a formula VI compound:

Wherein W, R ^1A, R ^1B, R ^1C, R ^2A, R ^2B, R ⁴, R ⁶And R ⁷Be such as in the Table II definition; Or its pharmacy acceptable salt or solvate.

Table II

Embodiment	W	R ^1A	R ^1B	R ^1C	R ^2A	R ^2B	R ⁴	R ⁶	R ⁷
Embodiment	W	R ^1A	R ^1B	R ^1C	R ^2A	R ^2B	R ⁴	R ⁶	R ⁷	165	O	H	H	H	Br	H	-(CH ₂) ₉-(racemic)	-NHC(O)CH＝CH-
166	O	F	H	H	H	H	-(CH ₂) ₉-	-NHC(O)CH＝CH-		165	O	H	H	H	Br	H	-(CH ₂) ₉-(racemic)	-NHC(O)CH＝CH-
166	O	F	H	H	H	H	-(CH ₂) ₉-	-NHC(O)CH＝CH-		167	O	H	Cl	H	F	F	-(CH ₂) ₉-	-NHC(O)CH＝CH-
168	O	H	Cl	Cl	F	F	-(CH ₂) ₉-	-NHC(O)CH＝CH-		167	O	H	Cl	H	F	F	-(CH ₂) ₉-	-NHC(O)CH＝CH-
168	O	H	Cl	Cl	F	F	-(CH ₂) ₉-	-NHC(O)CH＝CH-		169	O	H	H	H	F	F	-(CH ₂) ₉-	-NHC(O)CH＝CH-

The formula I compound of another particular group is a formula VII compound:

Wherein W, R ⁴, R ⁶And R ⁷Be as defined in the Table III; Or its pharmacy acceptable salt or solvate.

Table III

Embodiment	W	R ⁴	R ⁶	R ⁷
Embodiment	W	R ⁴	R ⁶	R ⁷	170	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
171	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H	170	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
171	O	-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H	172	O	-(CH ₂) ₉-	-NHC(O)CH＝CH-
173	O	-(CH ₂) ₉-	-NHC(O)H	H	172	O	-(CH ₂) ₉-	-NHC(O)CH＝CH-

174	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)	CH ₂CH ₂-
174	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)	CH ₂CH ₂-	175	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)H	H
176	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)CH＝CH-		175	O	-(CH ₂) ₂C(O)NH(CH ₂) ₅-	-NHC(O)H	H
176	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)CH＝CH-		177	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)H	H
178	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		177	O	-(CH ₂) ₂NHC(O)(CH ₂) ₅-	-NHC(O)H	H
178	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		179	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
180	O	-(CH ₂) ₃(benzene-1,4-subunit) NH (benzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		179	O	-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-	-NHC(O)H	H
180	O		-NHC(O)CH＝CH-		181	O	-(CH ₂) ₂NHC (O) (2-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-
182	O	-(CH ₂) ₂NHC (O) (2-chloro-5-anisole-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-		181	O	-(CH ₂) ₂NHC (O) (2-chlorobenzene-1,4-subunit) CH ₂-	-NHC(O)CH＝CH-

Definition

When describing compound of the present invention, composition, method and process, unless otherwise noted, following term has following implication.

Term " alkyl " refers to it may is the univalent saturated hydrocarbon radical of straight or branched.Unless otherwise defined, this alkyl group comprises 1-10 carbon atom usually.Representational alkyl group comprises, by way of example, and methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl etc.

Term " alkylidene group " refers to it may is the divalent saturated hydrocarbon base of straight or branched.Unless otherwise defined, this alkylidene group comprises 1-10 carbon atom usually.Representational alkylidene group comprises, by way of example, and methylene radical, ethane-1,2-two bases (" ethylidene "), propane-1,2-two bases, propane-1,3-two bases, butane-1,4-two bases, pentane-1,5-two bases etc.

Term " alkoxyl group " refers to the univalent perssad of formula (alkyl)-O-, and wherein alkyl as defined herein.Representational alkoxy base comprises, by way of example, and methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert.-butoxy etc.

Term " thiazolinyl " refers to it may is the univalent unsaturated hydrocarbon radical of straight or branched, and it has at least 1, and 1,2 or 3 carbon-carbon double bond is arranged usually.Unless otherwise defined, this alkenyl group comprises 2-10 carbon atom usually.Representational alkenyl group comprises, by way of example, vinyl, positive propenyl, pseudoallyl, positive but-2-ene base, just oneself-3-thiazolinyl etc. term " alkenylene " refers to the divalence alkenyl group.

Term " alkynyl " refers to it may is the univalent unsaturated hydrocarbon radical of straight or branched, and it has at least 1, and 1,2 or 3 carbon carbon triple bond is arranged usually.Unless otherwise defined, this alkynyl group comprises 0 carbon atom of 2-1 usually.Representational alkynyl group comprises, by way of example, ethynyl, positive proyl, positive fourth-2-alkynyl, just oneself-3-alkynyl etc.Term " alkynylene " refers to the divalence alkynyl group.

The monovalence aromatic hydrocarbon of term " aryl " refers to have monocycle (being phenyl) or fused rings (being naphthalene).Unless otherwise defined, this aromatic yl group comprises 6-10 carboatomic ring atom usually.Representational aromatic yl group comprises, by way of example, and phenyl and naphthalene-1-base, naphthalene-2-base etc.Term " arylidene " refers to the divalent aryl group.

Term " azacycloalkyl " refers to comprise the monovalence heterocycle of a nitrogen-atoms, i.e. the group of naphthene base that replaced by nitrogen-atoms of one of them carbon atom.Unless otherwise defined, this azocycloalkyl group comprises 2-9 carbon atom usually.The representational example of azocycloalkyl group is pyrrolidyl and piperidyl group.Term " inferior azacycloalkyl " refers to the divalence azocycloalkyl group.The representational example of inferior azocycloalkyl group is pyrrolidinylidene and piperidylidene group.

Term " cycloalkyl " refers to the carbocyclic ring alkyl that monovalence is saturated.Unless otherwise defined, this group of naphthene base comprises 3-10 carbon atom usually.Representational group of naphthene base comprises, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Term " ring alkylidene group " refers to the divalent cycloalkyl group.

Term " halogen " refers to fluorine, chlorine, bromine and iodine.

Term " heteroaryl " refers to have monocycle or two fused rings and comprise the heteroatomic monovalence aryl that at least one (1-3 heteroatoms usually) is selected from nitrogen, oxygen or sulphur in ring.Unless otherwise defined, this heteroaryl groups comprises 5-10 total annular atoms usually.Representational heteroaryl groups comprises, by way of example, and the pyrroles of monovalence class, imidazoles, thiazole, the  azoles, furans, thiophene, triazole, pyrazoles, different  azoles, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indoles, cumarone, thionaphthene, benzoglyoxaline, benzothiazole, quinoline, isoquinoline 99.9, quinazoline, quinoline  quinoline etc., wherein tie point is at any available carbon or azo-cycle atom.Term " inferior heteroaryl " refers to the divalence heteroaryl groups.

Term " heterocyclic radical " or " heterocycle " refer to have monocycle or many fused rings and comprise monovalence saturated or unsaturated (non-fragrance) group of at least one heteroatoms that is selected from nitrogen, oxygen or sulphur (1-3 heteroatoms usually) in rings.Unless otherwise defined, this heterocyclic group comprises 2-9 total ring carbon atom usually.Representational heterocyclic group comprises, by way of example, the tetramethyleneimine of monovalence class, imidazolidine, pyrazolidine, piperidines, 1,4-two  alkane, morpholine, thiomorpholine, piperazine, 3-pyrroline etc., wherein tie point is at any available carbon or azo-cycle atom.Term " inferior heterocyclic radical " refers to divalent heterocycle or heterocyclic group.

The particular term that adopts about this paper shows carbon atom number in the bracket before term when meaning the given number of carbon atom.For example, term " (1-4C) alkyl " refers to have the alkyl group of 1-4 carbon atom.

Term " pharmacy acceptable salt " refers to be accepted and is used for giving for example mammiferous salt of patient (salt that for example has acceptable mammalian safety for given dosage).This salt can be derived from pharmaceutically acceptable inorganic or organic bases with derived from pharmaceutically acceptable inorganic or organic acid.Salt derived from pharmaceutically acceptable mineral alkali comprises ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganic, bivalent manganese, potassium, sodium, zinc etc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.Salt derived from pharmaceutically acceptable organic bases comprises primary amine salt, what tertiary ammonium salt of secondary amine salt, the amine that comprises replacement, cyclammonium, the amine of natural formation etc., for example arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl ethylene diamine, diethylamide, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, ethylene diamine, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperidines (piperadine), piperazine, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine, tripropylamine, Trometamol etc.Salt from pharmaceutically acceptable acid comprises acetate, ascorbate salt, benzene sulfonate, benzoate, camsilate, Citrate trianion, esilate, ethanedisulphonate, fumarate, gentisate, gluconate, glucuronate, glutaminate, hippurate, hydrobromate, hydrochloride, isethionate, lactic acid salt, Lactobionate, maleate, malate, mandelate, mesylate, the mucus hydrochlorate, naphthalenesulfonate, naphthalene-1, the 5-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate, naphthalene-2, the 6-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate, the nicotine hydrochlorate, nitrate, Orotate, embonate, pantothenate, phosphoric acid salt, succinate, vitriol, tartrate, right-tosylate, xinafoate etc.Particularly preferably be Citrate trianion, hydrobromate, hydrochloride, isethionate, maleate, naphthalene-1,5-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate, phosphoric acid salt, vitriol and tartrate.

Term " its salt " refers to that for example metallic cation or organic cation etc. replace the compound that forms by positively charged ion when a kind of hydrogen of acid.Preferably, this salt is pharmacy acceptable salt, but for not being do not need like this patient's the salt of midbody compound to give.

Term " solvate " refers to that by a kind of solute be mixture or the aggregate that one or more molecules of one or more molecules of formula I compound or its pharmacy acceptable salt and a kind of solvent form.This " solvate " normally has the solute of fixed molar ratio and the crystalline solid of solvent in fact.Representational solvent comprises, by way of example, and water, methyl alcohol, ethanol, Virahol, acetic acid etc.When solvent was water, the solvate of formation was a hydrate.

To understand, term " or its pharmacy acceptable salt or solvate or steric isomer " refers to comprise all displacement, for example solvates of the pharmacy acceptable salt of the steric isomer of formula I compound of salt, solvate and steric isomer.

Term " treatment significant quantity " refers to be enough to realize the amount for the treatment of when needing the patient of treatment.

The term that this paper adopts " treatment (gerund) " or " treatment (noun) " refer to treat patient for example disease or the medical condition (for example COPD) of Mammals (especially people), and this comprises:

(a) preventing disease or medical condition take place, i.e. the prophylactic treatment patient;

(b) improve disease or medical condition, promptly in the patient, eliminate or disease or medical condition are disappeared;

(c) containment disease or medical condition promptly delay or stop the development of disease or medical condition in the patient; Perhaps

(d) in the patient, palliate a disease or the symptom of medical condition.

Functional group that term " leavings group " refers to for example can be replaced by another functional group or atom in the nucleophilic substitution reaction in substitution reaction or atom.By way of example, representational leavings group comprises chlorine, bromine and iodine group; Sulfonate ester group, for example methanesulfonates, tosylate, brosylate, p-nitrophenyl sulphonate etc.; With the acyloxy group, acetoxyl group for example, trifluoroacetyl oxygen base etc.

Term " its shielded derivative " refers to that one or more functional groups of compound are wherein avoided participating in the derivative of the specific compound of unwanted reaction with protection or capping group protection.Can protected functional group comprise, by way of example, hydroxy-acid group, amino group, oh group, thiol group, carbonyl group etc.The representational blocking group of carboxylic acid comprises ester class (for example to the methoxy-benzyl ester), amides and hydrazides class; For amino group, amino formate (for example uncle-butoxy carbonyl) and amides; For oh group, ethers and ester class; For the thiol group, thioether class and thioesters class; For carbonyl group, acetals and ketal class; Or the like.These blocking groups are known for those skilled in the art, and for example at T.W.Greene and G.M.Wuts, Protecting groups in OrganicSynthesis; Third Edition; Wiley, New York, 1999 and the reference wherein quoted in description is arranged.

Term " amino-blocking group " refers to be suitable for preventing at amino group the blocking group of unwanted reaction.Representational amino-blocking group comprises; but be not limited to tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenyl methoxy carbonyl (Fmoc), formyl radical, trimethyl silyl (TMS), tert-butyl dimetylsilyl (TBS) etc.

Term " carboxyl-blocking group " refers to be suitable for preventing at carboxylic group the blocking group of unwanted reaction.Representational carboxyl-blocking group comprises; but be not limited to; ester, for example methyl, ethyl, the tertiary butyl, benzyl (Bn), to methoxy-benzyl (PMB), 9-fluorenyl methyl (Fm), trimethyl silyl (TMS), tert-butyl dimetylsilyl (TBS), diphenyl methyl (diphenyl-methyl, DPM) etc.

Term " hydroxyl-blocking group " refers to be suitable for preventing at oh group the blocking group of unwanted reaction.Representational hydroxyl-blocking group includes, but not limited to silyl-group, comprises three (1-6C) alkyl silyl-group, for example trimethyl silyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS) etc.; Ester class (carboxyl groups) comprises (1-6C) alkyloyl group, formyl radical for example, ethanoyl etc.; The arylmethyl group, for example benzyl (Bn), to methoxy-benzyl (PMB), 9-fluorenyl methyl (Fm), diphenyl methyl (diphenyl-methyl, DPM) etc.In addition, it is protected that two oh groups also can be used as an alkylidene group, third-2-subunit (ylidine) for example, for example by with ketone for example the acetone reaction form.

General synthetic method

Biphenyl derivatives of the present invention can or pass through to use the out of Memory preparation that obtains easily to those skilled in the art from following general method of the prepared using of easy acquisition and step.Though this paper can show or describe particular of the present invention, those skilled in the art will recognize that all embodiments of the present invention or aspect utilize method described herein to prepare or also can prepare by using known for those skilled in the art other method, reagent and raw material.In addition statement also will be understood that, unless when providing general or preferable methods condition (being the mol ratio, solvent, pressure etc. of temperature of reaction, time, reactant), also can be used other method condition.Though optimum reaction condition can easily determine these conditions by optimization routine program those skilled in the art along with the specific reactants or the solvent change that adopt.

In addition, it is evident that the GPF (General Protection False group can be that the particular functional group that prevents who must or need carries out undesirable reaction for those of ordinary skills.Known in the art for being chosen in of the conditions suitable of the protection of particular functional group's appropriate protection group and this functional group and deprotection.Can adopt if desired except that in step described herein, illustrate those blocking group.For example, a large amount of blocking group and their introducings and remove; at T.W.Greene and G.M.Wuts, Protecting groups in OrganicSynthesis, Third Edition; Wiley, New York, 1999 and the reference wherein quoted in description is arranged.

By explanation, biphenyl derivatives of the present invention can be by a kind of method preparation, and this method comprises:

(a) make formula 1Compound:

Or its salt; With formula 2The compound reaction:

X wherein ¹Represent leavings group, P ¹And P ²Represent hydrogen atom or hydroxyl-blocking group independently of one another;

(b) make formula 3Compound

Or its salt; With formula 4The compound reaction:

X wherein ²Represent leavings group, P ³And P ⁴Represent hydrogen atom or hydroxyl-blocking group independently of one another;

(c) make formula 5Compound

With formula 6The compound coupling:

X wherein ^QaAnd X ^QbRepresent coupling to form the functional group of group Q, p independently of one another ^5aRepresent hydrogen atom or amino-blocking group; And p ^5bAnd p ⁶Represent hydrogen atom or hydroxyl-blocking group independently of one another;

(d) for R wherein ⁵Represent the formula I compound of hydrogen atom, in the presence of reductive agent, make formula 3Compound and formula 7Compound:

Or its hydrate (for example oxalic dialdehyde) reaction, wherein P ⁷Represent hydrogen atom or hydroxyl-blocking group;

(e) in the presence of reductive agent, make formula 1Compound and formula 8Compound:

Or its hydrate reaction, wherein p ⁸And P ⁹Represent hydrogen atom or hydroxyl-blocking group independently of one another, p ¹⁰Represent hydrogen atom or amino-blocking group, and R ⁴' represent residue, the connected carbon of this residue provides radicals R together when reaction is finished ⁴

(f) make formula 9Compound:

X wherein ³Represent leavings group, with formula 10The compound reaction:

P wherein ¹¹And p ¹²Represent hydrogen atom or hydroxyl-blocking group independently of one another, and p ¹³Represent hydrogen atom or amino-blocking group; Or

(g) in the presence of reductive agent, make formula 11Compound:

Or its hydrate; R wherein ⁴' represent residue, the connected carbon of this residue provides radicals R together when reaction is finished ⁴With formula 10The compound reaction; And then

Remove any blocking group P ¹, p ², P ³, P ⁴, P ^5a, P ^5b, P ⁶, P ⁷, P ⁸, P ⁹, P ¹⁰, P ¹¹, P ¹²Or P ¹³So that formula I to be provided compound; Randomly, form its pharmacy acceptable salt.

Usually, if the salt of one of raw material is used in the aforesaid method, acid salt for example, then this salt is neutralized before reaction or in the process usually.This neutralization reaction is normally finished by described salt is contacted with alkali for a molar equivalent of every molar equivalent acid salt.

In method (a), i.e. formula 1With 2Reaction between the compound is by X ¹The leavings group of representative for example can be a halogen, for example chlorine, bromine or iodine, or sulfonate ester group, for example methanesulfonates or tosylate.Group P ¹And P ²For example can be respectively trimethyl silyl and benzyl.This reaction is carried out in inert diluent usually, and acetonitrile for example is in the presence of alkali.For example, this reaction can be at tertiary amine, and for example diisopropylethylamine carries out under existing.Usually, this is reflected at and carries out in 0 ℃-100 ℃ the temperature range finishing in fact up to reaction.Utilize the ordinary method reaction product isolated then, for example extraction, recrystallization, chromatography etc.

Formula IThe normally known in the art known steps of maybe can utilizing of compound is from commercial feedstock production of buying.For example, formula 1Compound can pass through the deprotection formula 12Compound prepares:

P wherein ¹⁴Represent amino-blocking group, for example benzyl group.By explanation, benzyl group can easily be removed by reduction, uses for example hydrogen or ammonium formiate and the VIII of family metal catalyst, for example carries palladium at carbon.When W represents NW ^aThe time, utilizing Pearlman ' s catalyzer (is Pd (OH) ₂) carry out hydrogenation easily.

Formula 12Compound can be by making formula 13Isocyanate compound:

With formula 14Compound reaction be prepared:

Formula 2Compound can prepare by the whole bag of tricks described herein or by known method for those skilled in the art.For example, utilize the following formula of known reagent and method 23The oh group of compound can easily be converted into leavings group.By explanation, utilize mineral acid halogenide for example thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride etc., or haloid acid Hydrogen bromide for example, oh group can be converted to halogen group.

In method (b), i.e. formula 3Compound and formula 4The reaction of compound, X ²The leavings group of expression for example can be a halogen, for example chlorine, bromine or iodine, or sulfonate ester group, for example methanesulfonates or tosylate.Group P ³And P ⁴For example can be respectively t-butyldimethylsilyl and benzyl.This reaction is normally carried out in the presence of alkali, for example sodium bicarbonate and alkaline metal iodide, for example sodium iodide.Usually, this is reflected in the inert diluent and carries out, and for example tetrahydrofuran (THF) under 25 ℃-100 ℃ temperature, is finished in fact up to reaction.Utilize the ordinary method reaction product isolated then, for example extraction, recrystallization, chromatography etc.

By the deprotection formula 15The compound formula 3Compound:

P wherein ¹⁵And P ¹⁶One or both represent blocking group, for example tert-butoxycarbonyl, and any remaining representative hydrogen atom independently.For example can remove the tert-butoxycarbonyl group by handle protected compound with trifluoroacetic acid.

Formula 15Compound can be by making formula 1Compound and formula 16Compound reacts and prepares:

X ³-R ⁴-NP ¹⁵P ¹⁶

16

X wherein ³Represent for example halogen of leavings group, for example chlorine, bromine or iodine, or sulfonate ester group, for example methanesulfonates or tosylate.This reaction is usually by making formula in inert diluent 1Compound and formula 16Compound reacts and carries out, for example acetonitrile, DMF or their mixture, about 0 ℃ to about 100 ℃ temperature range, finish in fact up to reaction.

Perhaps, formula 3Compound can through type 11The reductive amination of compound obtains.This reductive amination can make formula by carrying in the presence of the palladium at carbon 11Compound carries out with for example benzyl amine and H-H reaction.

Formula 11Compound can be by utilizing suitable oxygenant, and for example sulfur trioxide pyridine complex and dimethyl sulfoxide (DMSO) are passed through oxidation-type 17Corresponding alcohol prepare.

This oxidizing reaction is carried out in inert solvent usually, and for example there is tertiary amine in methylene dichloride, and for example diisopropylethylamine is being made an appointment with-20 ℃ to about 25 ℃ temperature.

Formula 17Compound can be by making formula 1Compound and formula 18Compound reacts and prepares:

X ⁴-R ⁴-OH

18

X wherein ⁴Represent for example halogen of leavings group, for example chlorine, bromine or iodine, or sulfonate ester group, for example methanesulfonates or tosylate.

Formula 4Compound can pass through formula 19Compound:

With reductive agent for example borane reaction be prepared.If desired, this reduction can be carried out in the presence of chiral catalyst, so that the formula of chirality form to be provided 4Compound.For example, formula 19Compound can be from (R)-(+)-α, and α-biphenyl-2-pyrrolidine carbinol and trimethyl-boron oxygen six rings form; Perhaps, under existing, the chiral catalyst that α-biphenyl-2-pyrrolidine carbinol and trimethyl-boron oxygen six rings form is reduced from (S)-(-)-α.Can use hydroxy-protective group-P then ³Protect the oh group that obtains, for example by reacting with t-butyldimethylsilyl trifluoromethayl sulfonic acid ester.

X wherein ²Represent the formula of bromine atoms 19Compound can by Lewis acid for example boron trifluoride Anaesthetie Ether compound have the formula of ordering 20Compound:

Be prepared with bromine reaction.Formula 20Compound be known in the art and can utilize commercial raw material of buying and reagent to prepare by known method.

Refer to method (c), i.e. formula 5Compound and formula 6The reaction of compound will be understood, and should select radicals X ^QaAnd X ^QbSo that the group Q that needs is provided when reaction is finished.For example, when the group Q of needs be amide group promptly-N (Q ^a) C (O)-or-C (O) N (Q ^b) time, X ^QaAnd X ^QbIn one can be amino group (that is ,-NHQ ^aOr-NHQ ^b) and another can be carboxylic group (that is ,-COOH) or their response derivative (for example carboxylic acid halides, for example acyl chlorides or acylbromide).Group P ^5a, P ^5bAnd P ⁶For example can be respectively benzyl, trimethyl silyl and benzyl.When Q was amide group, reaction can be carried out under conventional acid amides coupling condition.Similarly, when the group Q of needs be sulphonamide promptly-N (Q ^c) S (O) ₂-or-S (O) ₂N (Q ^d)-time, X ^QaAnd X ^QbIn one can be amino group ,-NHQ ^cOr NHQ ^dAnd another can be alkylsulfonyl halide group (for example SULPHURYL CHLORIDE or a sulfuryl bromide).

Formula 5Compound can be by making formula 1Compound and formula 21Compound reacts and prepares:

X ⁵-(R ^4a) _d-(A ¹) _e-(R _4b) _f-X ^Qa’

21

X wherein ⁵Expression comprises for example chlorine, bromine or iodine and the sulphonate leavings group of methanesulfonates or tosylate for example of halogen; And X ^Qa' represent X ^Qa, for example carboxylic group or amino group NHQ ^a, or their shielded derivative, for example (1-6C) alkoxycarbonyl amino group or tert-butoxycarbonyl amino group.This reaction normally by be used for preparation formula 3The similar approach of compound is carried out, and removes X then ^Qa' in any blocking group.

Formula 6Compound can be by making formula 4Compound and formula 22Compound reacts and prepares:

X ^Qb′-(R ^4c) _g-(A ²) _h-(R ^4d) _i-X ⁶

22

X wherein ⁶Representative comprises for example chlorine, bromine or iodine and the sulphonate leavings group of methanesulfonates or tosylate for example of halogen; And X ^Qb' represent X ^Qb, for example carboxylic group or amino group NHQ ^b, or their shielded derivative, for example (1-6C) alkoxycarbonyl amino group or tert-butoxycarbonyl amino group.This reaction normally by be used for preparation formula 3The similar approach of compound is carried out, and removes X then ^Qb' in any blocking group.

Refer to method (d), i.e. formula 3Compound and formula 7The reaction of compound can be adopted any appropriate reductant in this reaction.For example, reductive agent can make at the group VIII metal catalyst, and for example carbon carries the hydrogen under the palladium existence; Or metal hydride reagent, for example triacetyl oxygen base sodium borohydride.Group P ⁷It for example can be benzyl.This reaction normally, is carried out under 0 ℃-100 ℃ temperature range for example in ethylene dichloride and the methanol mixture at inert diluent and protonic solvent, finishes in fact up to reaction.

The formula of hydrate forms 7Compound can prepare by ordinary method, for example by the dibrominated formula 19Compound (X in the case wherein ²Also can be hydrogen), the dibromide that obtains of hydrolysis then forms its oxalic dialdehyde or hydrate.For example, formula 19Compound can with reaction of hydrogen bromide, water hydrolysis then forms corresponding glyoxal hydrate.

Refer to method (e), i.e. formula 1Compound and formula 8The reaction of compound can be adopted any appropriate reductant in this reaction.For example, reductive agent can be at the group VIII metal catalyst, and for example carbon carries the hydrogen under the palladium existence; Or metal hydride reagent, for example triacetyl oxygen base sodium borohydride.Group P ⁸, P ⁹And P ¹⁰For example can be respectively trimethyl silyl, benzyl and benzyl.This reaction normally, is carried out under 0 ℃-100 ℃ temperature range for example in ethylene dichloride and the methyl alcohol at inert diluent and protonic solvent, finishes in fact up to reaction.

Formula 8Compound can be by utilizing any suitable oxygenant for example sulfur trioxide pyridine complex and dimethyl sulfoxide (DMSO) oxidation-type 23Compound prepare.

This reaction is usually at tertiary amine for example in the presence of the diisopropylethylamine, approximately-20 ℃ extremely carry out under about 25 ℃ temperature range, finish in fact up to oxidation.

Formula 23Compound can be by making formula 10Compound and formula 24Compound react and prepare:

HO-R ⁴-X ⁷

24

X wherein ⁷Representative comprises for example chlorine, bromine or iodine and the sulphonate leavings group of methanesulfonates or tosylate for example of halogen.

Refer to method (f), i.e. formula 9Compound and formula 10The reaction of compound is by X ³The leavings group of representative for example can be for example chlorine, a bromine or iodine of halogen, perhaps for example methanesulfonates or tosylate of sulfonate ester group.Group P ¹¹, P ¹²And P ¹³For example can be respectively trimethyl silyl, benzyl and benzyl.This reaction normally, is carried out in the presence of suitable alkali for example in the acetonitrile at inert diluent.For example this reaction is for example carried out in the presence of the diisopropylethylamine at tertiary amine usually.Usually, this is reflected at and carries out under 0 ℃-100 ℃ the temperature range, finishes in fact up to reaction.

Formula 9Compound can be from formula 1Compound is initial by preparing with the similar step of this paper method (a)-(e).In addition, formula 10Compound can be from formula 4Compound by with formula P ¹³NH ₂Amine react and prepare.

Refer to method (g), i.e. formula 11Compound and formula 10The reaction of compound can be adopted any appropriate reductant in this reaction.For example, reductive agent can be at the group VIII metal catalyst, and for example carbon carries the hydrogen under the palladium existence; Or metal hydride reagent, for example triacetyl oxygen base sodium borohydride.Group P ¹¹, P ¹²And P ¹³For example can be respectively t-butyldimethylsilyl, benzyl and benzyl.This reaction normally, is carried out under 0 ℃-100 ℃ temperature range for example in ethylene dichloride and the methyl alcohol at inert diluent and protonic solvent, finishes in fact up to reaction.

By the corresponding alcohol of oxidation or the corresponding acetal of hydrolysis preparation formula easily 11Compound.In this reaction, can use any suitable oxygenant that aldehyde is provided, for example sulfur trioxide pyridine complex and dimethyl sulfoxide (DMSO).This acetal can utilize the aqueous acids hydrolysis so that aldehyde to be provided under normal condition.

In specific embodiments, some specific compound of formula I is prepared by the following method, and this method comprises:

(h) deprotection formula 25Compound:

P wherein ¹⁷Represent hydrogen atom or amino-blocking group; P ¹⁸, P ¹⁹And P ²⁰Represent hydrogen atom or hydroxyl-blocking group independently of one another; Condition is P ¹⁷, P ¹⁸, P ¹⁹Or P ²⁰In at least one be blocking group;

(i) deprotection formula 26Compound:

P wherein ²¹Represent hydrogen atom or amino-blocking group; And P ²²And P ²³Represent hydrogen atom or hydroxyl-blocking group independently of one another; Condition is P ²¹, P ²²Or p ²³In at least one be blocking group; Or

(j) deprotection formula 27Compound:

P wherein ²⁴Represent hydrogen atom or amino-blocking group; And P ²⁵And P ²⁶Represent hydrogen atom or hydroxyl-blocking group independently of one another; Condition is P ²⁴, P ²⁵Or p ²⁶In at least one be blocking group.

Formula I compound is provided and randomly forms formula I compound pharmacy acceptable salt.

Refer to method (h), P ¹⁷, P ¹⁸, P ¹⁹And P ²⁰The example of particular value be: P ¹⁷Be hydrogen or benzyl; P ¹⁸Be hydrogen or t-butyldimethylsilyl; P ¹⁹And P ²⁰Be hydrogen or benzyl, or be propylidene (propylidine) together.In the method, the benzyl protection group by the group VIII metal catalyst for example carbon carry in the presence of the palladium and removed easily by catalytic hydrogenation; T-butyldimethylsilyl group by with hydrofluoride for example triethylamine three hydrofluorides handle and to be removed easily; Propylidene group by with acid for example trifluoroacetic acid handle and to be removed easily.

Formula 25Compound can be by method described herein, for example by method (a)-(g) preparation.Perhaps, formula 25Compound can be by making formula 28Compound:

R wherein ⁸Representative-CH ₂OP ¹⁹,-CHO ,-COOH or-C (O) O (1-6C) alkoxyl group, methoxycarbonyl for example, R ⁹Representative-OP ¹⁸And R ¹⁰Represent hydrogen atom, or R ⁹And R ¹⁰Representative=O together reacts with reductive agent and to prepare.This reaction can be adopted any appropriate reductant, comprises, by way of example, metal hydride reducing agent, for example sodium borohydride, lithium aluminum hydride etc.

R wherein ⁹And R ¹⁰The formula of representative=O group together 28Compound can be easily by making formula 29Compound

Or its salt and formula 30Compound reaction be prepared:

X wherein ⁸Represent leavings group, for example bromine.

Refer to method (i), P ²¹, P ²²And P ²³The example of particular value be: P ²¹Be hydrogen or benzyl; P ²²Be hydrogen or t-butyldimethylsilyl; P ²²Be hydrogen or benzyl.In the method, the benzyl protection group by the group VIII metal catalyst for example carbon carry in the presence of the palladium and removed easily by catalytic hydrogenation; T-butyldimethylsilyl group by with hydrofluoride for example triethylamine three hydrofluorides handle and to be removed easily.Formula 26Compound can be produced by method described herein, for example by method (a)-(g).

Refer to method (j), P ²⁴, P ²⁵And P ²⁶The example of particular value be: P ²⁴Be hydrogen or benzyl; P ²⁵Be hydrogen or t-butyldimethylsilyl; P ²⁶Be hydrogen or benzyl.In the method, the benzyl protection group by the group VIII metal catalyst for example carbon carry in the presence of the palladium and removed easily by catalytic hydrogenation; T-butyldimethylsilyl group by with hydrofluoride for example triethylamine three hydrofluorides handle and to be removed easily.Formula 27Compound can be produced by method described herein, for example by method (a)-(g).

In addition, R wherein ⁶And R ⁷Formation-NR together ^7gC (O)-CR ^7hR ⁷ⁱ-CR ^7jR ^7k-or-CR ⁷¹R ^7m-CR ⁷ⁿR ^7o-C (O)-NR ^7p-formula I compound can be by reducing wherein R ⁶And R ⁷Formation-NR together ^7aC (O)-CR ^7b=CR ^7c-or-CR ^7d=CR ^7e-C (O)-NR ^7f-corresponding formula I compound prepare catalytic hydrogenation for example by describing among the embodiment 6 hereinafter.

The further details for preparing other method of the representative compound of the present invention or its intermediate about concrete reaction conditions and being used to is described in the following embodiments.

Pharmaceutical composition and preparation

Biphenyl derivatives of the present invention normally is given the patient with pharmaceutical composition or dosage form.This class pharmaceutical composition can be given the patient by any acceptable route of administration, includes but not limited to, suction, oral, nose with, local (comprising transdermal) and administered parenterally mode.Should be appreciated that any form (being free alkali, pharmacy acceptable salt, solvate or the like) that is suitable for the The compounds of this invention of specific administration pattern can be used in the pharmaceutical composition of this paper discussion.

One of therefore, aspect the present composition, the present invention relates to comprise pharmaceutically acceptable carrier or the formula I compound of vehicle and treatment significant quantity or the pharmaceutical composition of its pharmacy acceptable salt.Randomly, if desired, this pharmaceutical composition can comprise other therapeutical agent and/or preparation material.

Pharmaceutical composition of the present invention comprises compound of the present invention or its pharmacy acceptable salt for the treatment of significant quantity usually.Usually, this pharmaceutical composition will comprise about 0.01 promoting agent to about 95% weight; Comprise about 0.01 to about 30% weight; For example about 0.01 promoting agent to about 10% weight.

Any conventional carrier or vehicle can be used in the present composition.The selection of the composition of specific support or vehicle or carrier or vehicle will be depended on the type of the mode of administration or medical condition or the morbid state that are used to treat particular patient.In this, be used for the preparation of suitable pharmaceutical compositions of specific administration pattern fully in pharmaceutical field technician's scope.In addition, the composition that is used for this composition is commercial buying, for example available from Sigma, and P.0.Box 14508, St.Louis, MO 63178.By further specifying, the conventional formulation technology is at Remington:The Science and Practice of Pharmacy, the 20th edition, Lippincott Williams ﹠amp; White, Baltimore, Maryland (2000); With H.C.Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, the 7th edition, Lippincott Williams ﹠amp; White, Baltimore describes among the Maryland (1999) to some extent.

The representational example that can be used as pharmaceutically acceptable carrier includes, but not limited to following: (1) sugar, for example lactose, dextrose plus saccharose; (2) starch, for example W-Gum and yam starch; (3) Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum powder; (8) vehicle, for example cocoa butter and suppository wax class; (9) oil, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) glycol, for example propylene glycol; (11) polyvalent alcohol, for example glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; (12) ester, for example ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent, for example magnesium hydroxide and aluminium hydroxide; (15) Lalgine; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline buffer; (21) compression propelling gas, for example Chlorofluorocarbons and hydrogen fluorine carbon; (22) other is used in the nontoxic compatible material in the pharmaceutical composition.

The present composition is normally by mixing up hill and dale and nearly or fusion compound of the present invention and pharmaceutically acceptable carrier and the preparation of one or more optional ingredients.If essential or need, the mixed uniformly mixture that obtains can utilize ordinary method and equipment by moulding or be loaded in tablet, capsule, pill, jar, the cartridge case etc.

In one embodiment, pharmaceutical composition of the present invention is suitable for inhalation.The suitable pharmaceutical composition that is used for inhalation is aerosol or powder type normally.This composition utilizes known doser administration usually, for example spraying gun sucker, metered-dose inhaler (MDI), Diskus (DPI) or similar doser.

In particular of the present invention, the pharmaceutical composition that comprises promoting agent utilizes the spraying gun sucker by inhalation.This atomizer arrangement produces high velocity air usually, and it makes the pharmaceutical composition that comprises promoting agent be sprayed into patient's respiratory tract as mist.Therefore, when being produced when being used for the spraying gun sucker, promoting agent is dissolved in the suitable carriers usually to form solution.Perhaps, promoting agent can by micronization and with suitable carriers combination forming the suspension of the micronized particle that can suck size, micronization be generally defined as about 90% or more particles have diameter less than about 10 μ m.Suitable atomizer arrangement is provided by commercial, for example by PARI GmbH (Starnberg, Germany).Other atomizing comprises Respimat (Boehringer Ingelheim) and those for example in U.S. Patent No. 6,123 along device, 068 and WO 97/12687 in disclosed.

The representational pharmaceutical composition that is used for the spraying gun sucker comprises and comprises the isotonic aqueous solution of about 0.05 μ g/mL to about 10mg/mL formula I compound or its pharmacy acceptable salt or solvate or its steric isomer.

In another particular of the present invention, the pharmaceutical composition that comprises promoting agent utilizes Diskus to pass through inhalation.The common administration of this Diskus is dispersed in the promoting agent of the free flowing powder form in patient's air-flow during sucking.For the flowing powder that gains freedom, with suitable vehicle for example prepare usually by lactose or starch for promoting agent.

The example that is used for the representational pharmaceutical composition of Diskus comprises the dried lactose of granular size between about 1 μ m and about 100 μ m and the micronized particle of formula I compound or its pharmacy acceptable salt or solvate or steric isomer.

This dry powder formulations is passable, and for example by lactose and promoting agent are mixed, the dry blending component prepares then.Perhaps, if desired, promoting agent can be prepared without vehicle.Usually in the dry powder dispenser of pharmaceutical composition being packed into then, or the suction cartridge case or the capsule of packing into and using with the dry powder doser.

The example of Diskus doser comprises that (GlaxoSmithKline, Research Triangle Park NC) (for example see U.S. Patent No. 5,035,237) to Diskhaler; Diskus (GlaxoSmithKline) (for example sees U.S. Patent No. 6,378,519; (AstraZeneca, Wilmington DE) (for example see U.S. Patent No. 4,524,769) to Turbuhaler; Rotahaler (GlaxoSmithKline) (for example seeing U.S. Patent No. 4,353,365) and Handihaler (Boehringer Ingelheim).The other example of suitable DPI device is at United States Patent(USP) Nos. 5,415,162,5,239,993 and 5,715,810 and the reference wherein quoted in description is arranged.

In also another particular of the present invention, the pharmaceutical composition that comprises promoting agent utilizes metered-dose inhaler to pass through inhalation.This metered-dose inhaler utilizes the compression propelling gas to emit promoting agent or its pharmacy acceptable salt of measured quantity usually.Therefore, utilize the pharmaceutical composition of metered-dose inhaler administration to be generally comprised within solution or suspension in the liquefied propellant.Can adopt any suitable liquefied propellant, comprise chlorofluorocarbon, for example CCl ₃F and hydro fluorocarbons (HFAs), for example 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-fluoro-in heptan just-propane, (HFA 227).Owing to relate to the chlorofluorocarbon that influences ozonosphere, preferably comprise the preparation of HFAs usually.The other optional ingredients of HFA preparation comprises cosolvent, for example ethanol or pentane and tensio-active agent, for example Sorbitan Trioleate, oleic acid, Yelkin TTS and glycerine.For example see U.S. Patent No. 5,225,183, EP 0717987 A2 and WO 92/22286.

The representational pharmaceutical composition that is used for metered-dose inhaler comprises formula I compound or its pharmacy acceptable salt or the solvate or the steric isomer of about 5% weight of about 0.01%-; The ethanol of about 2% weight of about 0%-; Tensio-active agent with about 5% weight of about 0%-; Remaining is the HFA propelling agent.

This composition is prepared by add hydro fluorocarbons ice-cold or pressurization in the suitable containers that comprises promoting agent, ethanol (if existence) and tensio-active agent (if existence) usually.Be the preparation suspension, with the promoting agent micronization then with propellant mixing.The aerosol container of then said preparation being packed into, it forms the part of metered-dose inhaler device.Be in particular with the HFA propelling agent use and the example of the metered-dose inhaler device developed at United States Patent(USP) Nos. 6,006, provide in 745 and 6,143,277.Or this mixed suspension preparation can prepare by the tensio-active agent dressing of spraying drying on the promoting agent micronized particle.For example see WO99/53901 and WO 00/61108.

Can suck the particulate method and formulation and be applicable to that other example of the device of inhalation sees United States Patent(USP) Nos. 6,268 as for preparation, 533,5,983,956,5,874,063 and 6,221,398 and WO 99/55319 and WO 00/30614.

In another embodiment, pharmaceutical composition of the present invention is suitable for oral administration.The suitable pharmaceutical compositions that is used for oral administration can be capsule, tablet, pill, lozenge, cachet, drageeing, pulvis, granule form; Or as solution or suspension in moisture or anhydrous liq; Or as oil-in-water or water-in-oil emulsion; Or as elixir or syrup etc.; Each comprises the compound of the present invention as activeconstituents of predetermined amount.

When being used to be solid dosage (promptly as capsule, tablet, pill etc.) oral administration, pharmaceutical composition of the present invention will comprise usually as the compound of the present invention of activeconstituents and one or more pharmaceutically acceptable carriers, for example Trisodium Citrate or Lin Suanergai.Randomly or selectively, this solid dosage also can comprise: (1) weighting agent or extender, for example starch, lactose, sucrose, glucose, N.F,USP MANNITOL and/or silicic acid; (2) tackiness agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) wetting agent, for example glycerine; (4) disintegrating agent, for example agar-agar, lime carbonate, potato or tapioca (flour), alginic acid, specific silicate and/or yellow soda ash; (5) solution retarding agent, for example paraffin; (6) absorb accelerator, for example quaternary ammonium compound; (7) wetting agent, for example hexadecanol and/or glyceryl monostearate; (8) absorption agent, for example kaolin and/or wilkinite; (9) lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and/or their mixture; (10) tinting material; (11) buffer reagent.

Releasing agent, wetting agent, Drug coating, sweeting agent, seasonings and flavouring agent, sanitas and antioxidant also may reside in the pharmaceutical composition of the present invention.Pharmaceutically acceptable examples of antioxidants comprises: (1) water soluble antioxidant, for example xitix, cysteine hydrochloride, sodium pyrosulfate, sodium metabisulphate, S-WAT etc.; (2) oil-soluble inhibitor, for example ascorbyl palmitate, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), Yelkin TTS, propyl gallate ester, alpha-tocopherol etc.; (3) metal chelator, for example citric acid, ethylenediamine tetraacetic acid (EDTA) (EDTA), sorbyl alcohol, tartrate, phosphoric acid etc.The Drug coating that is used for tablet, capsule, pill etc. comprises that those are used for enteric coating, for example vinegar peptide fiber element (CAP), Vinyl acetate phthalate polymer (PVAP), hydroxypropyl methylcellulose phthalate, methacrylic acid-alkylmethacrylate polymer, acetate-1,2,4-benzenetricarboxylic acid Mierocrystalline cellulose (CAT), carboxymethylethylcellulose (CMEC), SA-M (HPMCAS) etc.

If desired, pharmaceutical composition of the present invention also can by way of example, utilize the HPMC of different ratios by preparation so that the slow or sustained release of activeconstituents to be provided; Or other polymeric matrix, liposome and/or microballoon.

In addition, pharmaceutical composition of the present invention can randomly comprise opalizer and can be by preparation, makes them only or preferentially at GI specific part release of active ingredients, randomly, and in the mode that postpones.Example that can adopted embedding composition comprises polymeric material and wax.Activeconstituents also can be the microencapsulation form, if suitable, with one or more above-mentioned excipient.

The suitable liquid dosage form that is used for oral administration comprises, by way of example, and pharmaceutically acceptable emulsion, micro emulsion, solution, suspension, syrup and elixir.This liquid dosage form comprises activeconstituents and inert diluent usually, for example water or other solvent, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture.Except that activeconstituents, suspension can comprise suspensoid for example different hard ester alcohol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar-agar and the tragakanta and their mixture of ethoxylation.

When wanting to be used for oral administration, pharmaceutical composition of the present invention preferably is packaged as presented in unit dosage form.Term " presented in unit dosage form " refers to be suitable for administration patient's physically discrete unit, and promptly each unit comprises the promoting agent that is calculated separately or combine the predetermined amount of the result of treatment that produces needs with one or more other unit.For example, this unit dosage form can be capsule, tablet, pill etc.

Compound of the present invention also can utilize known transdermal drug delivery system and vehicle transdermal administration.For example, compound of the present invention can mix with penetration enhancer, for example propylene glycol, polyethylene glycol monolaurate, azacycloalkyl-2-ketone etc., and be added into paster or similar drug delivery system.If desired, can in this transdermal composition, use other vehicle to comprise jelling agent, emulsifying agent and buffer reagent.

Pharmaceutical composition of the present invention also can comprise other and formula I compound or other therapeutical agent of its pharmacologically acceptable salt or solvate or steric isomer co-administered.For example, pharmaceutical composition of the present invention can further comprise one or more and is selected from other bronchodilator (PDE for example ₃Inhibitor, the modified and β of adenosine 2b ₂Adrenoceptor agonists); Anti-inflammatory agent (for example steroidal anti-inflammatory agents, for example cortical steroid; Non-steroidal anti-inflammatory agent (NSAIDs) and PDE ₄Inhibitor); Other muscarinic receptor antagonist (being anticholinergic); Anti-infection agent (for example Gram-positive and Gram-negative microbiotic or antiviral drug); Antihistaminic; Proteinase inhibitor; With import retarding agent (D for example into ₂Agonist and neurokinin are modified) therapeutical agent.Other therapeutical agent can be used with pharmaceutically acceptable salt or solvate forms.In addition, if suitable, other therapeutical agent can be used as the optical purity steric isomer and uses.

Can comprise with (except that The compounds of this invention) representational beta 2 adrenoreceptor agonists that The compounds of this invention is used in combination, but be not limited to Salmeterol, salbutamol, formoterol, Salmefamol, Partusisten, terbutaline, salbutamol, Isoetarine, Orciprenaline, bitolterol, pirbuterol, levosalbutamol etc., or their pharmacy acceptable salt.Other β that can be used in combination with The compounds of this invention ₂Adrenoceptor agonists include but not limited to 3-(4-{[6-({ (2R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxymethyl)-phenyl] ethyl } amino)-hexyl] oxygen } butyl) benzsulfamide and 3-(3-{[7-({ (2 R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxymethyl) phenyl] ethyl }-amino) heptyl] oxygen }-propyl group) benzsulfamide and disclosed related compound in the WO02/066422 that announced on August 29th, 2002; 3-[3-(4-{[6-([(2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(hydroxymethyl) phenyl] ethyl] amino) hexyl] oxygen } butyl)-phenyl] imidazolidine-2,4-diketone and disclosed related compound in the WO 02/070490 that announced on September 12nd, 2002; 3-(4-{[6-((2R)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino) hexyl] oxygen } butyl)-benzsulfamide; 3-(4-{[6-((2S)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino) hexyl] oxygen } butyl)-benzsulfamide, 3-(4-{[6-((2R/S)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino) hexyl] oxygen } butyl)-benzsulfamide, N-(tertiary butyl)-3-(4-{[6-((2R)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino) hexyl]-oxygen } butyl) benzsulfamide, N-(tertiary butyl)-3-(4-{[6-((2S)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino)-hexyl] oxygen } butyl)-benzsulfamide, N-(tert-butyl)-3-(4-{[6-((2R/S)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl } amino) hexyl]-oxygen } butyl) benzsulfamide and disclosed related compound in the WO 02/076933 that announced on October 3rd, 2002; 4-{ (1R)-2-[(6-{2-[(2, the 6-dichloro benzyl) oxygen] oxyethyl group } hexyl) amino]-the 1-hydroxyethyl }-2-(methylol) phenol and disclosed related compound in the WO 03/024439 that announced on March 27th, 2003; With their pharmacy acceptable salt.When using, β ₂-adrenoreceptor agonists will be present in the pharmaceutical composition with the treatment significant quantity.Usually, β ₂-adrenoceptor agonists is to be enough to the providing amount of the about 500 μ g of the about 0.05 μ g-of every dosage to exist.

Can comprise with the representational steroidal anti-inflammatory agents that The compounds of this invention is used in combination, but be not limited to, methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, 6,9-two fluoro-17-[(2-furyl carbonyls) oxygen]-11-hydroxyl-16-methyl-3-oxygen androstane-1,4-diene-17-carbothioic acid carbothiolic acid S-methyl fluoride ester, 6,9-two fluoro-11-hydroxyls-16-methyl-3-oxygen-17-propionyloxy-androstane-1,4-diene-17-carbothioic acid carbothiolic acid S-(2-oxygen-tetrahydrofuran (THF)-3S-yl) ester, beclomethasone ester (17-propionic ester or 17 for example, the 21-dipropionate), budesonide, flunisolide, Mometasone ester (for example furoate), triamcinolone, Rofleponide, ciclesonide, the Butixocort propionic ester, RPR-106541, ST-126 etc., or their pharmacy acceptable salt.When using, steroidal anti-inflammatory agents will be present in the pharmaceutical composition with the treatment significant quantity.Usually, steroidal anti-inflammatory agents will be to be enough to the providing amount of the about 500 μ g of the about 0.05 μ g-of every dosage to exist.

Other suitable combination comprises, other anti-inflammatory agent for example, for example NSAIDs (Sodium Cromoglicate for example; Sodium nedocromil; Phosphodiesterase (PDE) inhibitor (for example theophylline, PDE4 inhibitor or blended PDE3/PDE4 inhibitor); Leukotriene antagonist (for example Singulair); Leukotrienes synthetic inhibitor; The iNOS inhibitor; Proteinase inhibitor, for example tryptase and elastatinal; Beta 2 integrin antagonist and adenosine receptor agonist or antagonist (for example adenosine 2a agonist); Cytokine antagonist (chemokine antagonists interleukins-8 antibody (IL antibody) for example for example, especially, IL-4 therapy, IL-13 therapy or their combination); Or cytokine synthetic inhibitor.

For example, can comprise with representational phosphodiesterase-4 (PDE4) inhibitor or the blended PDE 3/PDE4 inhibitor that The compounds of this invention is used in combination, but be not limited to cis 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) hexanaphthene-1-carboxylic acid, 2-methoxycarbonyl-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexanaphthene-1-ketone; Suitable-[4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexanaphthene-1-alcohol]; Suitable-4-cyano group-4-[3-(cyclopentyloxy)-4-p-methoxy-phenyl] hexanaphthene-1-carboxylic acid etc., or their pharmacy acceptable salt.Other representational PDE4 or blended PDE4/PDE3 inhibitor comprise AWD-12-281 (elbion); NCS-613 (INSERM); D-4418 (Chiroseience and Schering-Plough); CI-1018 or PD-168787 (Pfizer); Disclosed benzo benzodioxol compound in WO 99/16766 (Kyowa Hakko); K-34 (Kyowa Hakko); V-11294A (Napp); Roflumilast (Byk-Gulden); Disclosed pthalazinone compound in WO 99/47505 (Byk-Gulden); Pumafentrine (Byk-Gulden, now Altana); Arofylline (Almirall-Prodesfarma); VM554/UM565 (Vernalis); T-440 (Tanabe Seiyaku); And T2585 (Tanabe Seiyaku).

Can comprise with (except compound of the present invention) representational muscarine antagonist (being anticholinergic) that The compounds of this invention is used in combination, but be not limited to coromegine, Tropintran, Genatropine, the methyl atropine nitrate, homatropine hydrobromide, hyoscyamine hydrobromide (d, l), scopolamine hydrobromide, ipratropium bromide, oxitropium bromide, tiotropium bromide, methantheline bromide, the Propanthelinium bromide, the Anisotropine MB, clidinium bromide, copyrrolate (Tarodyn), isopropamide iodide, mepenzolate bromide, Tridihexethyl Chloride (Pathilone), hexocyclium metilsulfate, cyclopentolate HCL 99, tropicamide, Benzhexol HCL, pirenzepine, telenzepine, AF-DX 116 and Methoctramine etc., or their pharmacy acceptable salt; Perhaps, those compounds of listing are as salt, their interchangeable pharmacy acceptable salt.

Can include, but not limited to ethanolamines, for example carbinoxamine maleate, clemastine fumarate, Vena and umine with the representational antihistaminic (being the H1-receptor antagonist) that The compounds of this invention is used in combination; Ethylenediamines, for example toxilic acid (amleate) Pyrilamine, pyribenzamine hydrochloride and citric acid Pyribenzamine; Alkyl amine, for example chlorphenamine and acrivastine; Piperazines, for example hydroxyzine hydrochloride, Paxistil, cyclizine chloride, cyclizine lactate, meclozine hydrochloride and cetirizine hydrochloride; Piperidines, for example astemizole, levocabastine hydrochloride, Loratadine or its descarbo oxyethyl group analogue, terfenadine and fexofenadine hydrochloride; Azelastine etc., or their pharmacy acceptable salt; Perhaps, those compounds of listing are as salt, their interchangeable pharmacy acceptable salt.

With the suitable dosage of other therapeutical agent of The compounds of this invention combination medicine-feeding about every day 0.05g to about 100mg scope every day.

Following preparation illustrates representational pharmaceutical composition of the present invention:

Example of formulations A

Be prepared as follows dry powder by inhalation:

Become component

The compounds of this invention 0.2mg

Lactose 25mg

Representational method: with the The compounds of this invention micronization, mix with lactose then.This blended mixture gelatin of packing into is sucked cartridge case.Utilize powder inhalator administration cartridge content.

Example of formulations B

Be prepared as follows the dry powder formulations that is used in the powder inhaler:

Representational method:The ratio for preparing micronized compound of the present invention and lactose mixed preparation is 1: 200 a pharmaceutical composition.Said composition every dosage of packing into can be transmitted the powder inhaler of about 10 μ g to 100 μ g The compounds of this invention.

Example of formulations C

Be prepared as follows in metered-dose inhaler dry powder by inhalation:

Representational method:By being dispersed in by being dissolved in less than the The compounds of this invention that is the micronized particle form of 10 μ m, the 10g median size prepares the suspension that comprises 5wt% The compounds of this invention and 0.1wt% Yelkin TTS in the solution that 0.2g Yelkin TTS forms in the 200mL softening water.Change into the particle of mean diameter with this suspension spraying drying and with the material micro mist that obtains less than 1.5 μ m.Particle is incorporated with 1,1,1 of pressurization, in the cartridge case of 2-Tetrafluoroethane.

Example of formulations D

Be prepared as follows the pharmaceutical composition that is used for metered-dose inhaler:

Representational method:By being dispersed in to be dissolved in by 0.5g trehalose and 0.5g Yelkin TTS less than the activeconstituents that is the micronized particle form of 10 μ m, the 5g median size prepares the suspension that comprises 5% The compounds of this invention, 0.5% Yelkin TTS and 0.5% trehalose in the colloidal solution that forms in the 100mL softening water.Change into the particle of mean diameter with this suspension spraying drying and with the material micro mist that obtains less than 1.5 μ m.Particle is incorporated with 1,1,1 of pressurization, in the filling of 2-Tetrafluoroethane.

Example of formulations E

Be prepared as follows the pharmaceutical composition that is used for the spraying gun sucker:

Representational method: the aqueous aerosol preparations that is used for spraying gun is to be prepared by the sodium chloride solution that the 0.1mg The compounds of this invention is dissolved in the 1mL0.9% of citric acid acidifying.Stirring also, ultrasonic mixture dissolves up to activeconstituents.By slow dropping NaOH the pH of solution is adjusted to value in the 3-8 scope.

Example of formulations F

Be prepared as follows the hard gelatin capsule that is used for oral administration:

Become component

The compounds of this invention 250mg

Lactose (spraying drying) 200mg

Magnesium Stearate 10mg

Representational method: composition is thoroughly mixed the hard gelatin capsule of packing into then (each capsule 460mg composition).

Example of formulations G

Be prepared as follows the suspension that is used for oral administration:

Become component

The compounds of this invention 1.0g

Fumaric acid 0.5g

Sodium-chlor 2.0g

Methyl p-hydroxybenzoate 0.15g

Propylparaben 0.05g

Granulated sugar 25.5g

Sorbyl alcohol (70% solution) 12.85g

Veegum k(Vanderbilt Co.) 1.0g

Seasonings 0.035mL

Tinting material 0.5mg

Distilled water is in right amount to 100mL

Representational method: composition is mixed to form the suspension that every 10mL suspension comprises the 100mg activeconstituents.

Example of formulations H

Be prepared as follows injectable formulation:

Become component

The compounds of this invention 0.2g

Sodium acetate buffer solution (0.4M) 2.0mL

HCl (0.5N) or NaOH (0.5N) are in right amount to pH4

Water (distillatory, aseptic) is in right amount to 20mL

Representational method: mix mentioned component, pH is adjusted to 4 ± 0.5 with 0.5N HCl or 0.5N NaOH.

Practicality

Biphenyl derivatives of the present invention has β ₂Two kinds of activity of 3 adrenergic receptor agonists and muscarinic receptor antagonist, therefore, this compound is applicable to that treatment is by β ₂The medical conditions of adrenergic receptor or M-ChR mediation is promptly by using β ₂The medical condition that 3 adrenergic receptor agonists or muscarinic receptor antagonist can be alleviated.This medical condition comprises, by way of example, and lung disorder or the disease relevant, for example chronic obstructive pulmonary disease (for example chronic and stridulate bronchitis and pulmonary emphysema), asthma, pulmonary fibrosis etc. with the reversible obstruction of the air passage.Other situation that can be treated (for example comprises premature labor, depression, congestive heart failure, tetter, inflammatory, supersensitivity, psoriasis and proliferative skin disorders), the situation that reduces digestion acidity is desirable (for example digestion and stomach ulcer) and disease of muscular dystrophy.

Therefore, in one embodiment, the present invention relates to treat the method for tuberculosis, this method comprises formula I compound or its pharmacy acceptable salt or the solvate or the steric isomer of the patient's significant quantity that needs treatment.When being used for the treatment of tuberculosis, The compounds of this invention usually by with every day multiple doses, every day single dose or weekly single dose suck by administration.Usually, the dosage that is used for the treatment of tuberculosis is about 10 μ g/ days to about 200 μ g/ days.

When by inhalation, the bronchiectasic effect that provides is provided The compounds of this invention usually.Therefore, aspect its method on the other hand, the present invention relates to provide in the patient bronchiectasic method, this method comprises needs the formula I of bronchiectasic patient treatment significant quantity compound or its pharmacy acceptable salt or solvate or steric isomer.Usually, provide the bronchiectasic dosage will be in about 10 μ g/ days to about 200 μ g/ days scope.

In one embodiment, the present invention relates to treat the method for chronic obstructive pulmonary disease or asthma, this method comprises formula I compound or its pharmacy acceptable salt or the solvate or the steric isomer of the patient treatment significant quantity that needs treatment.When being used for treating COPD or asthma, The compounds of this invention will be usually by with every day multiple doses or every day the single dose inhalation.Usually, the dosage of treatment COPD or asthma will be in 10 μ g/ days to 200 μ g/ days scope.

When this paper uses, COPD comprises chronic obstructive bronchitis and pulmonary emphysema (for example seeing Barnes, Chronic Obstructive Pulmonary disease, N Engl J Med2000:343:269-78).

When being used for the treatment of tuberculosis, The compounds of this invention randomly with other therapeutical agent combination medicine-feeding.Especially make up The compounds of this invention and steroidal anti-inflammatory agents (for example reflunomide), pharmaceutical composition of the present invention only just can provide triple treatments, i.e. β with two kinds of activeconstituentss ₂3 adrenergic receptor agonists, muscarinic receptor antagonist and anti-inflammatory activity.Owing to compare with comprising three kinds of composition of active components, comprise easier usually being produced of pharmaceutical composition of two kinds of activeconstituentss, so this two-component composition significantly is better than comprising the composition of three kinds of active ingredients.Therefore, in specific embodiments, pharmaceutical composition of the present invention and method further comprise the steroidal anti-inflammatory agents for the treatment of significant quantity.

Compound exhibits muscarinic receptor antagonist of the present invention and β ₂Two kinds of activity of 3 adrenergic receptor agonists.Therefore, except other character, special compound of interest is that proof is at M ₃The M-ChR bonded suppresses constant K _iValue and β ₂The active EC of 3 adrenergic receptor agonists ₅₀Value is less than about 100nM; Especially less than those of 10nM.Except these compounds, special compound of interest comprises when measuring with in vitro tests described herein or with similar test, is used in M ₃The muscarine activity that the M-ChR bonded suppresses constant K i expression approximates greatly with the maximum effective concentration EC of half ₅₀The β of the compound of expressing ₂2-adrenergic agonist components active those.For example, special compound of interest is at M ₃The M-ChR bonded suppresses constant K i and β ₂The EC of adrenergic receptor ₅₀Ratio be about 30: 1 to about 1: 30; Comprise about 20: 1 to about 1: 20; For example about 10: 1 to about 1: 10 those.

An aspect aspect its method, the present invention also provides the method for treatment tuberculosis, this method comprise needs the patient treatment significant quantity for the treatment of have muscarinic receptor antagonist and a β ₂Two kinds of active compounds of 3 adrenergic receptor agonists.In the particular of this method, the M of the compound of administration ₃The inhibition constant K of M-ChR _iLess than about 100nM, β ₂The maximum effective concentration EC of half that adrenergic receptor kinase 1 is moving ₅₀Less than about 100nM.In another embodiment, the method for treatment tuberculosis comprises the compound of drug treatment significant quantity, and it is to M ₃The inhibition constant K of M-ChR _iWith β ₂The EC that adrenergic receptor kinase 1 is moving ₅₀Ratio be about 30: 1 to about 1: 30.

Because compound of the present invention had both had β ₂The 2-adrenergic agonist components activity also has muscarinic receptor antagonist activity, and this compound also is suitable for to investigate or study has β ₂The biosystem of adrenergic receptor or M-ChR or the research tool of sample, or as finding both to have had β ₂The 3 adrenergic receptor agonists activity also has the research tool of the new compound of muscarinic receptor antagonist activity.This biosystem or sample can comprise β ₂Adrenergic receptor and/or M-ChR.Any suitable β that has ₂The biosystem of adrenergic and/or M-ChR or sample can be used in this research, and it can carry out in external or body.The representational biosystem or the sample that are applicable to this research include, but are not limited to cell, cell extract, plasma membrane, tissue samples, Mammals (for example mouse, rat, cavy, rabbit, dog, pig etc.) etc.

In this embodiment, make to comprise β ₂The biosystem of adrenergic receptor or M-ChR or sample and β ₂The compound of the present invention of adrenergic receptor kinase 1 momentum or M-ChR antagonism amount contacts.Utilize ordinary method and measuring apparatus effect then, for example radioligand binding assay and function test.This function test comprises the variation of cAMP (cAMP) in the cell of aglucon mediation, the active variation of enzyme adenylate cyclase (its synthetic cAMP) of aglucon mediation, the aglucon mediation via acceptor catalytic [ ³⁵S] GTP S to the exchange of GDP with guanosine 5 '-O-(sulfo-) triguaiacyl phosphate ([ ³⁵S] GTP S) introduce isolating film variation, the calcium ion variation (is for example used the Devices from Molecular, fluorescence joint imaging card reader or the FLIPR of Inc. in the free cell of aglucon mediation ^Measure).The compounds of this invention is with excitement or cause β ₂The activation of adrenergic receptor and in the test of the above-mentioned any function test listed or similarity antagonism or reduce the activation of M-ChR.The amount of the compound that in these researchs, adopts will be usually at about 0.1 nmole to the scope of about 100 nmoles.

In addition, compound of the present invention can be used as and finds to have β ₂The research tool of 3 adrenergic receptor agonists and two kinds of active new compounds of muscarinic receptor antagonist.In this embodiment, with the β of test compound or test compound group ₂The β of adrenergic receptor and M-ChR binding data (for example, by external beam radiotherapy aglucon displacement test determination) and The compounds of this invention ₂Adrenergic receptor and M-ChR binding data are compared, and differentiate that those have approximately identical or better β ₂Adrenergic receptor and/or those test compounds of M-ChR bonded, if any.Of the present invention this comprises that on the one hand as independent embodiment, interested test compound is identified in the analysis that produces comparative data (utilizing suitable test) and testing data.

In some cases, compound of the present invention may have weak muscarinic receptor antagonist activity or weak β ₂The 3 adrenergic receptor agonists activity.In these cases, it will be recognized by those of ordinary skills respectively mainly as β ₂3 adrenergic receptor agonists or muscarinic receptor antagonist, such compound still has practicality.

The character of The compounds of this invention and practicality can utilize known for those skilled in the art various external and in vivo test to prove.For example, representational test has been described in further detail in the following embodiments.

Embodiment

Provide following preparation and embodiment to illustrate particular of the present invention.Yet, unless otherwise indicated, the scope that these particular do not limit the present invention in any way.

Unless otherwise noted, following abbreviation has following implication, and any other abbreviation that undefined this paper adopts has their standard implication:

The AC adenylate cyclase

The Ach vagusstoff

The ATCC American type culture collection

The BSA bovine serum albumin

CAMP3 '-5 ' 3'5'-AMP

The CHO Chinese hamster ovary

CM ₅Clone's chimpanzee M5 acceptor

DCM methylene dichloride (being methylene chloride)

DIPEAN, the N-diisopropylethylamine

DPBS Dulbecco phosphate buffered saline (PBS)

DMEM Dulbecco improvement Iger (family name) substratum

The DMSO dimethyl sulfoxide (DMSO)

The EDTA ethylenediamine tetraacetic acid (EDTA)

The Emax maximum efficiency

The EtOAc ethyl acetate

EtOH ethanol

The FBS foetal calf serum

FLIPR fluorometric assay imaging plate reader

The Gly glycine

HATU O-(7-azepine benzo triazol-1-yl-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

HBSS Hank ' s buffer salt solution

The HEK HEKC

HEPES4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid

HM ₁Clone's people M ₁Acceptor

HM ₂Clone's people M ₂Acceptor

HM ₃Clone's people M ₃Acceptor

HM ₄Clone's people M ₄Acceptor

HM ₅Clone's people M ₅Acceptor

The HPLC high performance liquid chromatography

The IBMX 3-isobutyl-1-methylxanthine

%Eff percentage effect

The PBS phosphate buffered saline (PBS)

PyBOP benzotriazole-1-base oxygen tripyrrole alkane phosphorus hexafluorophosphate

The rpm rotations per minute

The TFA trifluoracetic acid

The THF tetrahydrofuran (THF)

Tris three (methylol) aminomethane

Unless otherwise noted, reagent, raw material and solvent are available from commodity provider (for example Aldrich, Fluka, Sigma etc.) and use and need not to be further purified.

In the following embodiments, (Palo Alto, CA) Series 1100 instruments carry out the HPLC analysis to utilize the Agilent that Zorbax Bonus RP 2.1x50mm post (C14 post) is arranged that has 3.5 micron particle sizes and provided by Agilent.Detection is to absorb by the UV at the 214nm place.Obtain HPLC 10-70 data through 6 minutes flow velocitys with 0.5mL/ minute 10%-70%B.Mobile phase A is 2%-98%-0.1%ACN-water-TFA; Mobile phase B is 90%-10%-0.1%CAN-water-TFA.Use above-mentioned mobile phase A and B, obtain HPLC 5-35 data and HPLC 10-90 data with 5 minutes gradients.

(Foster City, CA) type API-150EX instrument obtains liquid chromatography mass (LCMS) data with Applied Biosystems.Obtain LCMS 10-90 data with the 10%-90% Mobile phase B through 5 minutes gradients.

Be used to carry out small scale purification from the API of Applied Biosystems 150EX Prep workstation system.Moving phase is A: water+0.05%v/v TFA; And B: acetonitrile+0.05%v/vTFA.Adopt following condition: 20mL/ minute flow velocity as for arranging (sample size that about usually 3-50mg reclaims); 15 minutes gradients and have 5 micron particle 20mmx50mm Prism RP post (Thermo Hypersil-Keystone, Bellefonte, PA).As for large scale purification (usually greater than the rough sample of 100mg) more, adopt following condition: 60ml/ minute flow velocity; 30 minutes gradients and have 10 micron particle 41.4mmx250mm Microsorb BDS post (Varian, Palo Alto, CA).

The specific optical rotation that has the Jasco polarimeter (model P-1010) of tungsten halogen light source and 589nm strainer to measure chipal compounds 20 ℃ of utilizations (is called [α] ²⁰ _D).

Preparation 1

N-1,1 '-xenyl-2-base-N '-4-(1-benzyl) piperidyl urea

(50g 256mmol) is dissolved in the acetonitrile (400mL) with xenyl-2-isocyanate in room temperature.After being cooled to 0 ℃, added 4-amino-N-benzyl piepridine (48.8g, 256mmol) solution in acetonitrile (400mL) through 5 minutes.Observe precipitation immediately.After 15 minutes, add acetonitrile (600mL), the viscous mixture 12h that obtains 35 ℃ of stirrings.Filter out solid then also with cold acetonitrile washing, vacuum-drying then obtains title compound (100g, productive rate 98%).C ₂₅H ₂₇N ₃The MS m/z:[M+H of O ⁺] calculated value is 386.22; Measured value is 386.3.

Preparation 2

N-1,1 '-xenyl-2-base-N '-4-piperidyl urea

(20g, (3:1 is in mixture 800mL) 52mmol) to be dissolved in anhydrous methanol and dry DMF with preparation 1 product.(0.75mL 37% strong solution 7.6mmol) and acutely fed nitrogen 20 minutes to add aqueous hydrochloric acid in solution.Under nitrogen atmosphere (balloon), before the placement reaction mixture, under nitrogen gas stream, add PearlmanShi catalyzer (Pd (OH) ₂, 5g).Stirred reaction mixture 4 days, make then its twice by Celite pad to remove catalyzer.Under reduced pressure remove to desolvate then and obtain title compound (13g, productive rate 85%).C ₁₈H ₂₁N ₃The MS m/z:[M+H of O ⁺] calculated value is 296.17; Measured value is 296.0.

Perhaps, by 70 ℃ heat together xenyl-2-isocyanate (50g, 256mmol) and 4-amino-N-benzyl piepridine (51.1g, 269mmol) 12h synthesizes N-1,1 '-xenyl-2-base-N '-4-piperidyl urea (by the LCMS monitoring reaction).Reaction mixture is cooled to 50 ℃, and adds ethanol (500mL), slowly add 6M hydrochloric acid (95mL) then.Reaction mixture is cooled to room temperature.(10g) preceding (48.4g 768mmol) adds reaction mixture, and violently in solution feeds nitrogen 20 minutes with ammonium formiate adding palladium (10wt.% (butt) is on gac).At 40 ℃ of this reaction mixture of heating 12h, filter through Celite pad then, and under reduced pressure remove and desolvate.In rough residue, add 1M hydrochloric acid (20mL) and 10N sodium hydroxide to regulate pH to 12.Extract the waterbearing stratum with ethyl acetate (2x80mL), dry (sal epsom) and under reduced pressure except that desolvating obtains being solid title compound (71.7g, productive rate 95%).C ₁₈H ₂₁N ₃The MS m/z:[M+H of O ⁺] calculated value is 296.17;

Measured value is 296.0.

Preparation 3

N-1,1 '-xenyl-2-base-N '-4-[1-(9-hydroxyl nonyl)] piperidyl urea

50 ℃ with 9-bromo-1 nonyl alcohol (4.84g, 21.7mmol) join preparation 2 product (5.8g, 19.7mmol) and diisopropylethylamine (10.29mL, 59.1mmol) in acetonitrile (99mL) in the solution of stirring.At 50 ℃ of reacting by heating mixture 8h.The reaction mixture cooling is also under reduced pressure removed desolvates.Residue is dissolved in the methylene dichloride (100mL), with saturated aqueous carbonic acid hydrogen sodium (2 * 50ml) washings and dry (sal epsom).Under reduced pressure remove and desolvate.(methylene dichloride: methyl alcohol: ammonia system) purifying crude product obtains title compound (7.1g, 16.2mmol, productive rate 82%) by hurried chromatography.

Preparation 4

N-1,1 '-xenyl-2-base-N '-4-[1-(9-oxygen nonyl)] piperidyl urea

(49 μ L 6.9mmol), follow by diisopropylethylamine that (324 μ L, (500mg is 1.15mmol) in the solution in methylene dichloride (11.5mL) 3.45mmol) to join preparation 3 product with dimethyl sulfoxide (DMSO) at-10 ℃ under nitrogen atmosphere.-15 ℃ of stirred reaction mixtures 15 minutes, add then in batches sulfur trioxide pyridine complex (5 49mg, 3.45mmol).At-15 ℃ of stirred reaction mixture 1h, add entry (10mL) then.Separate organic phase then, water (10mL) washing, and dry (sodium sulfate).Under reduced pressure remove and desolvate, obtain title compound (475mg, 1.09mmol, productive rate 95%).HPLC(10-70)Rt＝3.39。

Preparation 5

N-1,1 '-xenyl-2-base-N '-4-[1-(the amino nonyl of 9-)] piperidyl urea

With palladium (10wt.% (butt) is on gac) (1.5g) join preparation 4 product (1.58g, 3.63mmol) and benzyl amine (516 μ L are 4.72mmol) in the solution through stirring in methyl alcohol (36.3mL).Under nitrogen atmosphere, place reaction mixture.After stirring 12h, reaction mixture is filtered by Celite pad and wash with methyl alcohol (10mL).Under reduced pressure remove and desolvate, obtain title compound (1.50g, 3.45mmol, productive rate 95%).HPLC (10-70) R _t=2.35; C ₂₇H ₄₀N ₄O ₁MS m/z:[M+H ⁺] calculated value is 437.06;

Measured value is 437.5.

Preparation 6

8-benzyloxy-5-(2,2-dihydroxyl ethanoyl)-1H-quinoline-2-one-

(a) 8-acetoxyl group-1H-quinoline-2-one-

Can be commercial available from Aldrich, Milwaukee, the oxine of WI-N-oxide compound (160.0g, 1.0mol) and acetic anhydride (800mL 8.4mol) heats 3h at 100 ℃, cools off in ice then.On B, collect product, obtain being solid 8-acetoxyl group-1H-quinoline-2-one-(144g) with acetic anhydride (2x100mL) washing and drying under reduced pressure.

(b) 5-ethanoyl-8-hydroxyl-1H-quinoline-2-one-

In ice, cool off aluminum chloride (85.7g, 640mmol) 1, the slurries in the 2-ethylene dichloride (280mL), and add step (a) product (56.8g, 280mmol).This mixture is warmed to room temperature, then 85 ℃ of heating.After 30 minutes, add Acetyl Chloride 98Min. (1.5mL, 21mmol) and this mixture of reheat 60 minutes.Reaction mixture then, and it is added 1N hydrochloric acid (3L) with well being stirred in 0 ℃.After stirring 2h, on B, collect solid, wash (3x250mL) and drying under reduced pressure with water.Merging is from a plurality of batches of isolating crude products (135g), and grinds 6h with methylene dichloride (4L).Collection product and drying under reduced pressure obtain 5-ethanoyl-8-hydroxyl-2 (1H)-quinolinone (121g) on B.

(c) 5-ethanoyl-8-benzyloxy-1H-quinoline-2-one-

To the product of step (b) (37.7g adds N in 186mmol), dinethylformamide (200mL) and salt of wormwood (34.5g, 250mmol), add subsequently bromotoluene (31.8g, 186mmol).In this mixture of stirring at room 2.25 hours, be poured into saturated sodium-chlor (3.5L) and stirred 1 hour at 0 ℃ then.Collect product and on B dry 1 hour, the solid that obtains is dissolved in the methylene dichloride (2L), and through this mixture of dried over sodium sulfate.Filter this solution through Celite pad, use methylene dichloride (5x200mL) washing then.Concentrate the filtrate that merges then and extremely do, use ether (500mL) to grind the solid 2h that obtains then.On B, collect product, obtain being the 5-ethanoyl-8-benzyloxy-1H-quinoline-2-one-(44g) of powder with ether (2x250mL) washing and drying under reduced pressure.

(d) 8-benzyloxy-5-(2,2-dihydroxyl ethanoyl)-1H-quinoline-2-one-

To step (c) (10.0g, add in the slurries of product 34.1mmol) in DMSO (60mL) the 48%w/w hydrobromic acid solution (11.8mL, 102.3mmol).This mixture is warmed to 60 ℃ of 16h, makes it to be cooled to room temperature then.Before being cooled to 0 ℃, the slurries 0.5h that adds entry (100mL) and obtain in stirring at room.Collect product on B, drying under reduced pressure obtains being solid 8-benzyloxy-5-(2,2-dihydroxyl ethanoyl)-1H-quinoline-2-one-(12.2g) then.

Preparation 7

1-(1-{9-[2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] nonyl } piperidin-4-yl)-3-xenyl-2-base urea

Room temperature will prepare 5 product (183mg, 0.42mmol) and the product of preparation 6 (149mg, 0.46mmol) stirring 2h in ethylene dichloride (4.2mL).Add then triacetyl oxygen base sodium borohydride (267mg, 1.26mmol), and restir reaction mixture 12h.With methylene dichloride (10mL) diluted reaction mixture, with saturated aqueous carbonic acid hydrogen sodium (10mL) washing, dry (sal epsom) under reduced pressure removes and desolvates.Obtain title compound (144mg, 0.20mmol, productive rate 48%) with hurried chromatography purification crude product mixture (the 5-10% methyl alcohol in methylene dichloride, 0.5% ammonium hydroxide).HPLC (10-70) R _t=3.48; C ₄₅H ₅₅N ₅O ₄MS m/z:[M+H ⁺] calculated value is 730.4; Measured value is 730.7.

Embodiment 1

1-xenyl-2-base-3-(1-{9-[2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } piperidin-4-yl) urea

Palladium (10wt.% (butt) is on gac) (63mg) is added preparation 7 product, and (144mg 0.20mmol) in the solution through stirring in methyl alcohol (2mL), and places this reaction mixture under nitrogen atmosphere.After stirring 12h, filter this reaction mixture, with methyl alcohol (2mL) washing, removal of solvent under reduced pressure then through Celite pad.Residue with preparation property HPLC purifying obtains obtains title compound (10mg).HPLC (10-70) R _t=2.8; C ₃₈H ₄₉N ₅O ₄MS m/z:[M+H ⁺] calculated value is 640.3; Measured value is 640.5.

Preparation 8

Xenyl-2-aminocarbamic acid piperidin-4-yl ester

To all be from Aldrich, Milwaukee, the xenyl that WI buys-2-isocyanate (97.5g, 521mmol) with 4-hydroxyl-1-benzyl piepridine (105g, 549mmol) together at 70 ℃ of heating 12h, by the formation of LCMS monitoring xenyl-2-aminocarbamic acid-1-benzyl piepridine-4-base ester in the meantime.Then reaction mixture is cooled to 50 ℃ and add ethanol (1L), slowly adds 6M hydrochloric acid (191mL) then.Then reaction mixture is cooled to room temperature, (98.5g 1.56mol), and acutely fed nitrogen 20 minutes in solution to add ammonium formiate.Add palladium (10wt.% (butt) is on gac) then (20g).At 40 ℃ of reacting by heating mixture 12h, filter through Celite pad then.Removal of solvent under reduced pressure and in rough residue, add 1M hydrochloric acid (40mL) then.Add sodium hydroxide (10N) then and regulate pH to 12.Extract water layer and dry (sal epsom) with ethyl acetate (2x150mL), removal of solvent under reduced pressure obtains title compound (155g, 100%) then.HPLC (10-70) R _t=2.52; C ₁₈H ₂₀N ₂O ₂MS m/z:[M+H ⁺] calculated value is 297.15; Measured value is 297.3.

Preparation 9

N, N-(two-tert-butoxycarbonyl)-9-bromine nonyl amine

(3.15g, 14.5mmol) at N, the solution in the dinethylformamide (0.28mL) is cooled to 0 ℃ of about 10min with two-tert-butoxycarbonyl amine.(0.58g is 14.5mmol) and at 0 ℃ of stirred reaction mixture 10min to add 60% sodium hydride in mineral oil.Take out reaction mixture and make it to be warmed to the about 30min of room temperature from ice bath.Reaction mixture is cooled back 0 ℃ then, add 1,9-two bromononanes (2.46mL, 12.1mmol) solution in dimethyl formamide (100mL).Spend the night at the stirring at room reaction mixture.Behind the 24h, MS analyzes the demonstration reaction and finishes.Reaction mixture is concentrated into dry doubling to be diluted with ethyl acetate (100mL).With saturated sodium bicarbonate (2x100mL), salt solution (100mL) washing organic layer, dry (sal epsom) and concentrating under reduced pressure obtain crude product, by utilizing the silica gel chromatography purifying crude product of 5% ethyl acetate in hexane, obtain title compound.C ₁₉H ₃₆N ₁O ₄The MS m/z:[M+H of Br ⁺] calculated value is 423.18; Measured value is 423.

Preparation 10

Xenyl-2-aminocarbamic acid 1-(9-two-tert-butoxycarbonyl amino) nonyl] the piperidin-4-yl ester

With acetonitrile and N, the mixture of N dimethyl formamide (50mL) add preparation 8 product (3.0g, 10.1mmol) and the product of preparation 9 (5.1g, 12.2mmol) and triethylamine (1.42mL, 10.1mmol) in.Monitor at stirring at room reaction mixture 24h and by lcms analysis.Concentrated reaction mixture is also with ethyl acetate (50mL) dilution then.With saturated sodium bicarbonate (2x50mL) and salt solution (50mL) washing organic layer.Then through dried over mgso organic phase and the concentrated 6.5g raw oil that obtains.By utilizing the chromatography purification oil of 1: 1 hexane/ethyl acetate on silica gel to obtain title compound (3g).C ₃₇H ₅₅N ₃O ₆MS m/z:[M+H ⁺] calculated value is 638.41; Measured value is 639.

Preparation 11

Xenyl-2-aminocarbamic acid 1-(the amino nonyl of 9-) piperidin-4-yl ester

Trifluoracetic acid (11mL) is added the product of preparation 10, and (7.2g is 11.3mmol) in the solution in methylene dichloride (56mL).Behind the 12h, lcms analysis shows to react to be finished.Concentrated reaction mixture to dry doubling dilutes with ethyl acetate (75mL) then.Add sodium hydroxide (1N) then and reach 14 up to the pH of mixture.Collect organic phase then, with saturated sodium bicarbonate (2x50mL) and salt solution (50mL) washing.Through dried over mgso organic phase and concentrated, obtain title compound (5.5g) then.C ₂₇H ₃₉N ₃O ₂MS m/z:[M+H ⁺] calculated value is 438.30; Measured value is 439.

Preparation 12

Xenyl-2-aminocarbamic acid 1-{9-[2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] nonyl } the piperidin-4-yl ester

With preparation 11 product (196mg, 0.43mmol) be dissolved in the ethylene dichloride (4mL) and add triacetyl oxygen base sodium borohydride (101mg, 0.48mmol).The about 10min of stirring at room reaction mixture add then 8-benzyloxy-5-(2,2-dihydroxyl ethanoyl)-1H-quinoline-2-one-(preparation 6) (141mg, 0.43mmol).After being reflected at 2h, the lcms analysis demonstration finishes.Methyl alcohol (1mL) is added reaction mixture, slowly add then sodium borohydride (18mg, 0.48mmol).After 1 hour, lcms analysis shows to react to be finished.Use aqueous ammonium chloride quencher reaction mixture then, and with this mixture of dichloromethane extraction.With saturated sodium bicarbonate (2x50mL) and salt solution (10mL) washing organic phase.Then through dried over mgso organic phase and the concentrated 315mg yellow solid that obtains.Obtain title compound (64mg) by the silica gel chromatography purifying solid that utilizes 10% methyl alcohol in methylene dichloride.C ₄₃H ₅₅N ₄O ₅MS m/z:[M+H ⁺] calculated value is 730.40; Measured value is 731.

Embodiment 2

Xenyl-2-aminocarbamic acid 1-{9-[2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } piperidin-4-yl ester two trifluoro-acetates

(64mg 0.09mmol) charges into nitrogen in the solution in methyl alcohol (450mL) at the product for preparing 12.Add then carbon carry palladium (10%, 10mg), under the hydrogenous balloon of bag, place reaction mixture and stir.After being reflected at 9h, the lcms analysis demonstration finishes.Filter reaction mixture then, concentrated filtrate obtain yellow easily crushed solid.Obtain title compound (19mg) by preparation property HPLC purifying solid (5-35 is through 60min).C ₃₈H ₄₈N ₄O ₅MS m/z:[M+H ⁺] calculated value is 641.36; Measured value is 641.

Preparation 13

The 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyl dimethyl-silicon alcoxyl base) ethyl]-the 1H-quinoline-2-one-

(a) 8-benzyloxy-5-(2-acetyl bromide)-1H-quinoline-2-one-

(20.0g 68.2mmol) is dissolved in the methylene dichloride (200mL) and is cooled to 0 ℃ with 5-ethanoyl-8-benzyloxy-1H-quinoline-2-one-(preparation 6).(10.4mL, 82.0mmol) also this mixture is warmed to room temperature obtains thick suspension to add boron trifluoride Anaesthetie Ether compound via syringe.Add bromine (11.5g, 72.0mmol) solution in methylene dichloride (100mL) at 45 ℃ of heating these suspensions (oil bath) and through 40 minutes.Keep this mixture at 45 ℃ of 15min again, be cooled to room temperature then.This mixture of concentrating under reduced pressure uses 10% aqueous carbonic acid sodium (200mL) to grind then 1 hour.On B, collect solid, wash (4x100mL) and drying under reduced pressure with water.Merge twice product and come purifying.50% methyl alcohol that is used in the chloroform (500mL) ground crude product (52g) 1 hour.On B, collect product, be used in 50% methyl alcohol and methyl alcohol (2x50mL) washing in the chloroform (2x50mL).The drying under reduced pressure solid obtains being the title compound (34.1g) of powder.

(b) 8-benzyloxy-5-((R)-2-bromo-1-hydroxyethyl)-1H-quinoline-2-one-

With (R)-(+)-α, α-phenylbenzene prolinol (30.0g, 117mmol) and the trimethylammonium boroxine (11.1mL, 78mmol) in toluene (300mL) the merging and at stirring at room 30min.This mixture is placed 150 ℃ of oil baths and distills out liquid.Add toluene and continue distillation 4h with the 20mL aliquot.Add 300mL toluene altogether.Then mixture is cooled to room temperature.500 μ L aliquot are evaporated to dry doubling and weigh (246mg) to determine that catalyst concentration is 1.8M.

With 8-benzyloxy 5-(2-acetyl bromide)-1H-quinoline-2-one-(90.0g 243mmol) is placed under the nitrogen, adds tetrahydrofuran (THF) (900mL), add subsequently above-mentioned catalyzer (1.8M in toluene, 15mL, 27mmol).In ice/isopropanol bath, this suspension is cooled to-10 ± 5 ℃.Through 4h add borane (1.0M in THF, 294mL, 294mmol).-10 ℃ of restir reactants 45 minutes, slowly add methyl alcohol (250mL) then then.This mixture of vacuum concentration also is dissolved in residue in the ebullient acetonitrile (1.3L), and filtered while hot is cooled to room temperature then.Filtering for crystallizing obtains title compound (productive rate 81%, 95% enantiomeric excess is by HPLC purity 95% for 72.5g, 196mmol) with acetonitrile washing and vacuum-drying.

(c) 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyl dimethyl-silicon alcoxyl base) ethyl]-the 1H-quinoline-2-one-

(70.2g adds N in 189mmol), and N dimethyl formamide (260mL) also cools off this mixture under nitrogen in ice bath to the product of step (b).Added 2 through 5 minutes, (40.3g, 376mmol), (99.8g, 378mmol), holding temperature is below 20 ℃ simultaneously slowly to add t-butyldimethylsilyl trifluoromethayl sulfonic acid ester then for the 6-lutidine.Make this mixture be warmed to room temperature 45 minutes.Through 10 minutes methyl alcohol (45mL) is added dropwise to this mixture, and ethyl acetate/hexanaphthene (1: 1,500mL) and water/salt solution (1: 1, distribute mixture between 500mL).Water/salt solution (1: 1, each 500mL) washing organism is twice again.The organism that reduction vaporization merges obtains light yellow oil.Two independent part hexanaphthene (400mL) is added in the oil, continue distillation up to the thick white slurries of formation.Hexanaphthene (300mL) is added slurries, filter the white crystal that obtains, with hexanaphthene (300mL) washing, drying under reduced pressure obtains title compound (75.4g, 151mmol, productive rate 80%, 98.6% enantiomeric excess).

Preparation 14

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] nonyl } the piperidin-4-yl ester

With preparation 13 product (3.9g, 8.17mmol) add preparation 11 product (5.0g, 11.4mmol) in the solution in THF (20mL), add then sodium bicarbonate (2.0g, 24.5mmol) and sodium iodide (1.8g, 12.2mmol).Reaction mixture is heated to 80 ℃ of 72h.Cool off this reaction mixture then, wash organic phase with methylene dichloride (20mL) dilution and with saturated sodium bicarbonate (2x50mL) and salt solution (50mL).Dry then (sal epsom) organic phase concentrates and obtains the 6.5g crude product.3% methanol-eluted fractions that is used in the methylene dichloride by the chromatography on silica gel obtains title compound (1.4g, productive rate 21%).

Preparation 15

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] nonyl } the piperidin-4-yl ester

(376pL, (1.3g is 1.5mmol) in the solution in THF (8mL), and at the stirring at room reaction mixture 2.3mmol) to add the product of preparation 14 with the triethylamine hydrofluoride.Behind the 5h, come finishing of assaying reaction with lcms analysis.With 1N NaOH quencher reaction mixture, be 14 up to pH, use ethyl acetate (20mL) dilution then, with 1N NaOH (20mL) and salt solution (20mL) washing.Separate organic phase then,, concentrate and obtain title compound (1.1g) through dried over mgso.

Embodiment 3

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydro-quinoline-5-yl) ethylamino] nonyl } piperidin-4-yl ester two triflutates

Preparation 15 product (1.1g, solution 1.5mmol) fill with nitrogen and add carbon carry palladium (10%, 110mg).Stirred reaction mixture under balloon pressure hydrogen.Lcms analysis demonstration 9h afterreaction is finished.Filter reaction mixture, and the concentrated yellow solid that obtains then.Obtain title compound (510mg) by this solid of preparation property HPLC (5-30 is through 60min) purifying.C ₃₈H ₄₈N ₄O ₅MS m/z:[M+H ⁺] calculated value is 641.36; Measured value is 641.HPLC method 10-70:3.207.[α] ²⁰ _D=-23.6 (c=1.0mg/mL, water).

Embodiment 3A

Perhaps, be prepared as follows title compound:

(a) 9-bromine aldehyde C-9

Under nitrogen, to be equipped with magnetic stirrer, dose add in the 100-mL round-bottomed flask of funnel and temperature regulator 9-bromine nonyl alcohol (8.92g, 40mmol) and methylene dichloride (30mL).With the mixture that obtains be cooled to 5 ℃ and be added in sodium bicarbonate in the water (10mL) (0.47g, 5.6mmol) and Potassium Bromide (0.48g, 4mmol) solution.Add 2,2,6,6-tetramethyl--1-piperidines oxygen base radical (TEMPO) (63mg, 0.4mmol), drip the sodium hypochlorite solution (27mL) of 10-13% by dosing funnel with certain speed then, so as with ice-cold bath with temperature maintenance at about 8 ℃ (+/-2 ℃) (through about 40min).After the sodium hypochlorite solution interpolation is finished, stirred this mixture 30 minutes.Holding temperature is at about 0 ℃ simultaneously.Add the solution of sodium bisulfite (1.54g) in water (10mL), the mixture that obtains in stirring at room 30 minutes.Separating mixture layer then, (1x20mL) extracts milky water layer with methylene dichloride.Water (1x30mL) washs the dichloromethane layer that merges then, dry (MgSO ₄), filtering, concentrating under reduced pressure obtains title intermediate (8.3g, 94% productive rate), and it is used and need not to be further purified in next step.

(b) the 9-bromo-1,1-dimethoxy nonane

In the 100mL round-bottomed flask, add 9-bromine aldehyde C-9 (7.2g, 32.5mmol), methyl alcohol (30mL) and the positive manthanoate of trimethylammonium (4mL, 36.5mmol).Add 4N hydrochloric acid at two  alkane (0.2mL, the 0.8mmol) solution in, the mixture 3h that refluxes and obtain.Then reaction mixture is cooled to room temperature and add solid sodium bicarbonate (100mg, 1.2mmol).The mixture that concentrating under reduced pressure obtains adds ethyl acetate (50mL) then to 1/4th of its initial volume.Water (2x40mL) washing organic layer, dry (MgSO ₄), filtering, concentrating under reduced pressure obtains being the title intermediate (8.44g, (productive rate 97%)) of liquid, and it is used to next step and need not to be further purified.

(c) xenyl-2-aminocarbamic acid 1-(9,9-dimethoxy nonyl) piperidin-4-yl ester

In 50mL three neck round-bottomed flasks, add xenyl-2-aminocarbamic acid piperidin-4-yl ester (1g, 3.38mmol) and acetonitrile (10mL) to form slurries.In these slurries, add 9-bromo-1,1-dimethoxy nonane (1.1g, 1.3mmol) and triethylamine (0.57g, 4.1mmol) and the mixture 6h that obtains 65 ℃ of heating (by the HPLC monitoring reaction up to raw material＜5%).Then reaction mixture is cooled to room temperature, at this moment this mixture forms the heavy-gravity slurries.Add entry (5mL), filtering mixt is collected solid on the rough porous glass filter.With the aqueous premix washing solid of acetonitrile (10mL) and water (5mL), use another aqueous premix washing solid of acetonitrile (10mL) and water (2mL) then.The solid that dry air obtains, provide the solid title intermediate that is white in color (1.37g, 84%, purity＞96% is by LC, 1HNMR).

(d) xenyl-2-aminocarbamic acid 1-(9-oxygen nonyl) piperidin-4-yl ester

(7.7g 15.9mmol), adds acetonitrile (70mL) and moisture 1M hydrochloric acid (70mL) then to add xenyl-2 aminocarbamic acid 1-(9,9-dimethoxy nonyl) piperidin-4-yl ester in the 500mL round-bottomed flask that has magnetic stirring apparatus.At the mixture 1h that stirring at room obtains, add methylene dichloride (200mL) then.Stir this mixture 15min, then separating layer.Dry (MgSO ₄) organic layer, filtration and concentrating under reduced pressure obtain title intermediate (6.8g), and it is used to next step and need not to be further purified.

(e) xenyl-2-aminocarbamic acid 1-(9-{ benzyl-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl] amino } nonyl)-piperidin-4-yl ester

In the 300mL round-bottomed flask, add 5-[(R)-2-benzylamino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-benzyloxy-1H-quinoline-2-one-(5g, 9.73mmol), methylene dichloride (100mL) and Glacial acetic acid (0.6mL, 10mmol).Utilize ice bath that this mixture is cooled to 0 ℃, with stir to add xenyl-2-aminocarbamic acid 1-(9-oxygen nonyl) piperidin-4-yl ester (4.6g, 9.73mmol).Stirred this mixture 30 minutes at 0 ℃, then through gradation in 15 minutes add triacetyl oxygen base sodium borohydride (6.15g, 29mmol).0 ℃ of-10 ℃ of stirred reaction mixture 2 hours, add saturated sodium bicarbonate aqueous solution (50mL) then and stirred this mixture 15 minutes.Separating layer is washed organic layer with 5% sodium chloride aqueous solution (50mL) then, dry (MgSO ₄), filtration and concentrating under reduced pressure obtain title intermediate (8.5g, 80% purity is passed through HPLC), and it is used and need not to be further purified.

(f) xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } the piperidin-4-yl ester

In the 200mL round-bottomed flask, add intermediate from step e (8.5g, 9mmol), (0.54mL 18mmol), stirs this mixture and dissolves up to solid for ethanol (100mL) and Glacial acetic acid.With hydrogen purification reaction mixture 5min, add 10% carbon then and carry palladium (1.7g).At this mixture of stirring at room, simultaneously feed hydrogen to reaction mixture lentamente, up to observing with HPLC＞95% conversion (about 8-9h).Filter this mixture, removal of solvent under reduced pressure through Celite pad then.By the 5%MeOH/0.5%NH of silica gel chromatography (15g silica gel/1g crude product) utilization in DCM ₄OH (10x150mL), the 8%MeOH/0.5%NH in DCM ₄OH (10x150mL) and the 10%MeOH/0.5%NH in DCM ₄OH (10x150mL) purifying residue.Merge suitable fraction, removal of solvent under reduced pressure, simultaneously holding temperature＜35 ℃ obtain title intermediate (4.05g, 97% purity).

(g) xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } the piperidin-4-yl ester

In the 200mL round-bottomed flask, add intermediate from step F (4.05g, 5.36mmol) and the mixture that obtains of methylene dichloride (80mL) and stirring dissolve up to solid.Add triethylamine three hydrofluorides (2.6mL, 16mmol) and under nitrogen, continue to stir 18-20h.Add methyl alcohol (20mL), the aqueous carbonic acid hydrogen sodium (50mL) that slow then adding is saturated also stirred the mixture 15 minutes.Separate each layer then, with saturated sodium chloride aqueous solution (20mL) washing, dry (MgSO ₄), filtration and concentrating under reduced pressure obtain being the title compound (3.5g, recording purity by HPLC is 98%) of yellow solid.

Embodiment 3B

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } piperidin-4-yl ester naphthalene-1, the 5-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate

With xenyl-2-aminocarbamic acid 1-{9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } piperidin-4-yl ester (1.0g, 1.56mmol, free alkali) is dissolved in methyl alcohol (10mL; Low water content) in.Add naphthalene-1, (0.45g is 1.56mmol) at methyl alcohol (5mL for the 5-disulfonic acid; Low water content) solution in is 30 ℃ of stirred reaction mixtures two hours, then at ambient temperature overnight (18h).The thick slurries that filtration obtains, with methyl alcohol (5mL) washing leaching cake, the dry then title compound (1.16g, 80% productive rate) that obtains being canescence crystalline solid.

Preparation 16

The N-{2-benzyloxy-5-[(R)-2-bromo-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl] phenyl }-methane amide

(9.9g 28mmol) is dissolved in the dimethyl formamide (36mL) with (R)-2-bromo-1-(3-formamido--4-benzyloxy phenyl) ethanol.Add imidazoles (2.3g, 34mmol) and the tert-butyldimethylsilyl chloride thing (4.7g, 31mmol).Under nitrogen atmosphere, stir this solution 72h.Add other imidazoles (0.39g, 5.7mmol) and the tert-butyldimethylsilyl chloride thing (0.64g, 4.3mmol) and this reactant of restir 20h.Use the mixture diluted reaction mixture of Iso Butyl Acetate (53mL) and hexane (27mL) then and be transferred to separating funnel.With the mixture washed twice of organic layer water (27mL) and saturated sodium chloride aqueous solution (27mL), use the final washing of saturated sodium chloride aqueous solution (27mL) subsequently.Through the dried over sodium sulfate organic layer.Add silica gel (23.6g) and hexane (27mL) and stirred this suspension 10 minutes.By solids removed by filtration and vacuum concentrated filtrate.Obtain 8.85g from hexane (45mL) crystalline residue and be solid title compound (19mmol, 68%).C ₂₂H ₃₀NO ₃The MS m/z:[M+H of SiBr ⁺] calculated value is 464.1; Measured value is 464.2.

Can be as at U.S. Patent No. 6,268,533B1; Or R.Hett etc., OrganicProcess Research and Development, 1998, the description among the 2:96-99; Or utilize and at Hong etc. Tetrahedron Lett., 1994, the similarity method of describing among the 35:6631; Or utilize with in U.S. Patent No. 5,495, the similarity method of description prepares raw material-(R)-2-bromo-1-(3-formamido--4-benzyloxy phenyl) ethanol in 054.

Preparation 17

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(4-benzyloxy-3-formyl radical aminophenyl)-2-(tert-butyl dimethyl-silicon alcoxyl base) ethylamino] nonyl } the piperidin-4-yl ester

Room temperature will prepare 16 product (500mg, 1.008mmol) and sodium iodide (243mg 1.62mmol) stirs 15min in tetrahydrofuran (THF) (0.5mL).Add then preparation 11 product (564mg, 1.29mmol) and sodium bicarbonate (272mg, 3.24mmol), and at 80 ℃ of reacting by heating mixture 24h.Make the reaction mixture cooling then.Add entry (2mL) then, and extract this mixture with methylene dichloride (2x2mL).With the organic extraction that 1M hydrochloric acid (2x1mL) washing merges, dry (sal epsom) and removal of solvent under reduced pressure.Obtain title compound (360mg, 0.44mmol, 41% productive rate) by the rough residue of hurried chromatography purification (5-10% ethanol/methylene).HPLC (10-70) R _t=4.96; C ₄₉H ₆₈N ₄O ₅MS m/z:[M+H ⁺] calculated value is 821.51; Measured value is 821.9.

Preparation 18

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(4-benzyloxy-3-formyl radical aminophenyl)-2-hydroxyethyl amino] nonyl } the piperidin-4-yl ester

Room temperature to preparation 17 product (360mg, 0.44mmol) add in the solution in tetrahydrofuran (THF) (2.2mL) through stirring triethylamine three hydrofluorides (108 μ L, 0.66mmol).Stir this reaction mixture 24h, use methylene dichloride (5mL) dilution then and wash with 1M hydrochloric acid (2mL) and saturated sodium bicarbonate aqueous solution (2mL).Dry organic phase (sal epsom) and removal of solvent under reduced pressure.Rough title compound is directly used in next step and need not to be further purified.HPLC (10-70) R _t=4.6; C ₄₃H ₅₄N ₄O ₅MS m/z:[M+H ⁺] calculated value is 707.43; Measured value is 707.8.

Embodiment 4

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] nonyl } piperidin-4-yl ester two triflutates

Palladium (10wt.% (butt) is on gac) (124mg) is added preparation 18 product, and (311mg is 0.44mmol) in the solution through stirring in ethanol (4mL) and place reaction mixture under nitrogen atmosphere.After stirring 12h, by the Celite pad filter reaction mixture, with methyl alcohol (2mL) washing and removal of solvent under reduced pressure.The residue that obtains by preparation property HPLC purifying obtains title compound (41mg).HPLC (10-70) R _t=3.0; C ₃₆H ₄₈N ₄O ₅MS m/z:[M+H ⁺] calculated value is 617.39; Measured value is 617.5.

Embodiment 5

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2,3,4-tetrahydroquinoline-5-yl) ethylamino] nonyl } piperidin-4-yl ester two triflutates

Palladium (10wt.% (butt) is on gac) (80mg) is added the product of embodiment 3, and (80mg is 0.11mmol) in the solution through stirring in ethanol (1.1mL) and place reaction mixture under nitrogen atmosphere.Reaction mixture is stirred 12h, filter by Celite pad then, with methyl alcohol (2mL) washing and removal of solvent under reduced pressure.Make crude material stand above-mentioned condition again to guarantee to finish reaction.The rough residue that obtains with preparation property HPLC purifying obtains title compound (6mg).HPLC (10-70) R _t=3.23; C ₃₈H ₅₀N ₄O ₅MS m/z:[M+H ⁺] calculated value is 643.39; Measured value is 643.7.

Preparation 19

3-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] the propionic acid methyl ester

50 ℃ with the 3-methyl bromide c (553 μ L, 5.07mmol) add preparation 8 product (1.00g, 3.38mmol) and DIPEA (1.76mL, 10.1mmol) in acetonitrile (34mL) in the solution of stirring, and 50 ℃ of reacting by heating mixture overnight.Under reduced pressure remove then and desolvate, and residue is dissolved in the methylene dichloride (30mL).With the solution that saturated sodium bicarbonate aqueous solution (10mL) washing obtains, dry (sal epsom) and removal of solvent under reduced pressure.Obtain title compound (905mg, 70%) by column chromatography (5-10%MeOH/DCM) purification of crude residue.

Preparation 20

3-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] propionic acid

Product (902mg with preparation 19,2.37mmol) and lithium hydroxide (171mg, 7.11mmol) stirred solution in 50%THF/ water (24mL) is 30 ℃ of heated overnight, obtains title compound (～100% productive rate also comprises LiCl salt) with concentrated hydrochloric acid acidifying and freeze-drying then.

Preparation 21

5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alkoxyl group) ethylamino] amyl group } the carboxylamine tertiary butyl ester

(600mg, 1.23mmol) and N-tert-butoxycarbonyl-1, (622mg 3.07mmol) is dissolved in the dimethyl sulfoxide (DMSO) (1.23mL) and is heated to 105 ℃ of 6h 5-diamino pentane with preparation 13 product.Reaction mixture then, and wash with ethyl acetate (10mL) dilution with saturated sodium bicarbonate aqueous solution (4mL).Dry organic phase (sal epsom) and removal of solvent under reduced pressure.Obtain title compound (～100% productive rate) by column chromatography (5-10% ethanol/methylene) purification of crude residue.

Preparation 22

5-[(R)-2-(the amino amyl group amino of 5-)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-benzyloxy-1H-quinoline-2-one-

(800mg, 1.31mmol) (25%, 12mL) solution in was stirring at room 1 hour at trifluoracetic acid/methylene dichloride with preparation 21 product.Removal of solvent under reduced pressure then, and rough residue is dissolved in the methylene dichloride (15mL), with 1N sodium hydroxide (8mL) washing.Separate organic phase, dry (sal epsom) and removal of solvent under reduced pressure obtain title compound (509mg is through 2 steps, productive rate 81%).

Preparation 23

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] the amyl group carbamyl } ethyl) the piperidin-4-yl ester

To preparation 20 product (417mg, 1.13mmol) and HATU (430mg, be added in 1.13mmol) preparation 22 among the DMF (1.8mL) product (458mg, 0.90mmol), add then DIPEA (204 μ L, 1.17mmol).50 ℃ of stirred reaction mixture 12h, removal of solvent under reduced pressure then.Rough residue is dissolved in the methylene dichloride (10mL).With the solution that saturated sodium bicarbonate aqueous solution (4mL) washing obtains, dry (sal epsom) and removal of solvent under reduced pressure.By column chromatography purification of crude residue (5-10% ethanol/methylene and 0.5%NH ₄OH) obtain title compound (240mg, 31% productive rate).

Preparation 24

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] the amyl group carbamyl } ethyl) the piperidin-4-yl ester

To preparation 23 product (240mg, 0.28mmol) add in the solution in methylene dichloride (2.8mL) through stirring triethylamine three hydrofluorides (91 μ L, 0.56mmol).Stirred reaction mixture 10h uses methylene dichloride (10mL) dilution then.The solution of using saturated sodium bicarbonate aqueous solution (5mL) washing to obtain then, dry then organic phase (sal epsom), removal of solvent under reduced pressure obtain title compound (209mg, productive rate 100%).

Embodiment 6

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the amyl group carbamyl } ethyl) the piperidin-4-yl ester, two triflutates

(209mg 0.28mmol) adds palladium (10wt.% (butt) is on gac) (81mg) in the solution through stirring in ethanol (2.8mL), is placed on reaction mixture under the nitrogen atmosphere and stirs and spend the night to preparation 24 product.Filter reaction mixture then, removal of solvent under reduced pressure.Obtain title compound (58mg) by preparation property HPLC purification of crude residue.HPLC (10-70) R _t=2.30; C ₃₇H ₄₅N ₅O ₆MS m/z:[M+H+] calculated value is 656.34; Measured value is 656.6; [α] ²⁰ _D=-6.5 (c=1.0mg/mL, water).

Embodiment 6A

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the amyl group carbamyl } ethyl) the piperidin-4-yl ester

Perhaps, title compound can be prepared as follows:

(a) 5-chlorine valeral

Under nitrogen to be equipped with magnetic stirring apparatus, add add in the 2L three neck round-bottomed flasks of funnel and temperature regulator 5-chlorine amylalcohol (53g, 0.433mol) and methylene dichloride (300mL).With this mixture be cooled to 5 ℃ and add sodium bicarbonate (5g, 0.059mol) and Potassium Bromide (5.1g, 0.043mol) solution in water (225mL).Add 2,2,6,6-tetramethyl--1-piperidines oxygen base radical (TEMPO) (63mg, 0.4mmol), drip 10-13% liquid lime chloride (275mL) with certain speed by adding funnel then, so as with ice-cold bath holding temperature at about 8 ℃ (+/-2 ℃) (through about 45min.).After the sodium hypochlorite solution interpolation is finished, stir this mixture 30min.By holding temperature at about 5 ℃.Add the solution of sodium bisulfite (4g) in water (30mL) and the mixture 30min that obtains in stirring at room.Each of separating mixture layer then, and with methylene dichloride (1x50mL) aqueous layer extracted.Water (1x50mL) washs the dichloromethane layer that merges then, dry (MgSO ₄), filtration and concentrating under reduced pressure obtain title compound (53g).Obtain being the title compound (31.16g) (GC purity is 70-80%) of orange oil at 65 ℃/8 these products of holder distillation.

Be further purified this product by the mixture that crude material (4g) is added ethanol (920mL), ethyl acetate (12mL) and water (4mL).Add sodium bisulfite (4g), heat this mixture, be cooled to room temperature then and form very thick slurries at stirring at room 14h to the 4h that refluxes.This solid is filtered on the raw glass filter, and with solvent mixture (5mL) washing, and dry this solid obtains the 8.4g bisulfite adduct on filter.Then this material is added MTBE (20mL), and add 1N aqueous sodium hydroxide solution (45mL) with vigorous stirring.The biphase mixture that vigorous stirring obtains all dissolves (about 15min) up to all solids, separates each layer then.Extract water layer and the dry MTBE layer (MgSO that merges with MTBE (20mL) ₄), filter and concentrate and obtain the title compound (GC purity＞90%) that 3.46g is colourless liquid.

(b) 5-[(R)-2-[benzyl-(5-chlorine amyl group) amino]-1-(tert-butyl dimethyl-silicon alcoxyl base) ethyl]-8-benzyloxy-1H-quinoline-2-one-

In 1L three neck round-bottomed flasks, add preparation 28 product (48.4g, 94mmol), methylene dichloride (400mL) and Glacial acetic acid (11.3mL).Stir this mixture at 0 ℃ (ice bath), add product (12.5g, 103.6mmol) also lasting the stirring 15 minutes from step (a).Then through gradation in 15 minutes add triacetyl oxygen base sodium borohydride (59.8g, 282mmol), at 0 ℃ of-10 ℃ of mixture 2h that stirring obtains.Add saturated sodium hydrogen carbonate solution (200mL) (gas is emitted) then lentamente and continue to stir 15min.It is about 9 regulating pH with solid sodium carbonate then, and separates each layer.With 5% sodium chloride aqueous solution (200mL) washing organic layer, dry (MgSO ₄), filtration and concentrating under reduced pressure obtain title compound (53g).

(c) 5-[(R)-and 2-[(5-N, the amino amyl group of N-diformyl) benzylamino]-1-(tertiary butyl dimethyl-silicon alkoxyl group) ethyl]-8-benzyloxy-1H-quinoline-2-one-

To the product of step (b) (26.5g, 42.8mmol) add in the solution in 1-Methyl-2-Pyrrolidone (175mL) through stirring diformyl acid amides sodium (6.1g, 64.2mmol) and sodium iodide (2.13g, 14.3mmol).Towards reaction flask, heat this mixture 8h at 65 ℃ with nitrogen then.Then this mixture is cooled to room temperature, adds entry (300mL) and ethyl acetate (100mL).Stirred this mixture 10 minutes.With ethyl acetate (150mL) aqueous layer extracted, the organic layer that water (300mL), 50% salt brine solution (300mL), water (300mL) washing merge, dry (MgSO ₄) filter and the concentrated title compound (23.3g) that obtains.

(d) 5-[(R)-and the amino amyl group of 2-[(5-) benzylamino]-1-(tert-butyl dimethyl-silicon alcoxyl base) ethyl]-8-benzyloxy-1H-quinoline-2-one-

Will be from product (10.5g, 16mmol) the adding right-toluenesulphonic acids (7.42g.39mmol) in the solution in methyl alcohol (75mL) of step (c) through stirring.At the mixture 15h that 40 ℃ of heating obtain, be evaporated to then its volume pact half.Add methyl alcohol (70mL), at 50 ℃ of this mixture of heating 2h, concentrating under reduced pressure then.Add entry (100mL), methyl alcohol (50mL) and MTBE (100mL), stirred this mixture 15 minutes, separate each layer then.In water layer, add 1N aqueous sodium hydroxide solution (45mL) and MTBE (100mL), stir this mixture 15min.Separate each layer then, with MTBE (100mL) aqueous layer extracted.Dry (MgSO ₄) the MTBE layer that merges, filter and concentrate the title compound (7.3g) that obtains being yellow oil.This material comprises taking off accordingly-the t-butyldimethylsilyl compound of about 13% (HPLC).

(e) 3-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] propionic acid

To preparation 8 product (50g, 67.6mmol) add in the solution in methylene dichloride (500mL) vinylformic acid (15.05mL, 100mmol).Mixture 18h in that 50 ℃ of reflux obtain removes then and desolvates.Add methyl alcohol (600mL), and, be cooled to room temperature then to form thick slurries at 75 ℃ of this mixture of heating 2h.By solid collected by filtration, with methyl alcohol (50mL) washing, dry air obtain the being white in color title compound (61g, purity＞96%) of powder.

(f) xenyl-2-aminocarbamic acid 1-[2-(5-{ benzyl-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl] amino }-amyl group carbamyl) ethyl] the piperidin-4-yl ester

(3.68g, 10mmol) and N, the mixture of N dimethyl formamide (50mL) thoroughly dissolves up to solid, is cooled to room temperature then at the product of 60 ℃ of heating stepses (e).(6g 10mmol) and diisopropylethylamine (3.5mL), cools off this reaction mixture to 0 ℃ to add the product of step (d).Add a PyBOP (6.25g, 12mmol) and at 0 ℃ to stirring at room reaction mixture 2 hours.Pour reaction mixture into cold water (500mL) and utilize moisture 1M hydrochloric acid to regulate the pH value about 2 of the mixture that obtains with stirring then.Stirred this mixture 15 minutes, and filtered then and collect solid, with its water (100mL) washing and the dry title compound (8.7g, HPLC purity＞95%) that obtains being pale solid.

(g) xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the amyl group carbamyl } ethyl) the piperidin-4-yl ester

Can utilize as product and obtain title compound in preparation 24 and those identical in essence step deprotection steps (f) of 6 kinds of descriptions of embodiment.

Preparation 25

2-(N-benzyloxycarbonyl-N-methylamino) acetaldehyde

(a) 2-(N-benzyloxycarbonyl-N-methylamino) ethanol

Will (19g, (10g be 133.3mmol) in the solution through stirring in THF (100mL) and aqueous sodium carbonate (100mL) 111.1mmol) to be added dropwise to 2-(methylamino) ethanol at the benzyl chloride manthanoate among the THF (20mL) at 0 ℃ through 15 minutes.Stir this reaction mixture 12h at 0 ℃, use EtOAc (2x200mL) extraction then.With aqueous sodium carbonate (200mL) washing organic layer, dry (salt of wormwood), removal of solvent under reduced pressure obtains title compound (22.5g, productive rate 97%).

(b) 2-(N-benzyloxycarbonyl-N-methylamino) acetaldehyde

(71mL, 1mol) (87.1mL, 0.5mol) (20.9g is 0.1mol) in the solution through stirring in methylene dichloride (200mL) for the product of adding step (a) with DI PEA with DMSO at-10 ℃.Stir this reaction mixture 15min at-10 ℃, (79.6g 0.5mol), and stirred the mixture that obtains 1 hour to add sulfur trioxide pyridine complex then.Drip 1M hydrochloric acid (200mL) quencher reaction mixture.Separate organic layer, and wash with saturated sodium bicarbonate aqueous solution (100mL), salt solution (100mL), dry (salt of wormwood) and removal of solvent under reduced pressure obtain title compound (20.7g, productive rate～100%).

Preparation 26

Xenyl-2-aminocarbamic acid 1-[2-(methylamino) ethyl] the piperidin-4-yl ester

To preparation 25 product (20.7g, 100mmol) and the product of preparation 8 (25g, 84.7mmol) add in the solution in MeOH (200mL) through stirring triacetyl oxygen base sodium borohydride (21.2g, 100mmol).At this reaction mixture of stirring at room 12h, use quencher of 2M hydrochloric acid and removal of solvent under reduced pressure then.Residue is dissolved in the ethyl acetate (200mL), with saturated sodium bicarbonate aqueous solution (100mL) and salt solution (50mL) washing, dry then (sal epsom) and removal of solvent under reduced pressure.Obtain being buttery xenyl-2-aminocarbamic acid 1-[2-(benzyloxycarbonyl-methylamino) ethyl by column chromatography purification of crude residue (50-90%EtOAc/ hexane)] the piperidin-4-yl ester.

This oil is dissolved in the methyl alcohol (100mL), adds palladium (10wt.% (butt) is on gac) (5g).Stirred reaction mixture 12h under hydrogen (30psi) then through diatomite filtration, uses methanol wash, and evaporating solvent obtains title compound (13.2g, 44% productive rate).

Preparation 27

Xenyl-2-aminocarbamic acid 1-{2-[(6-bromine caproyl) methylamino] ethyl } the piperidin-4-yl ester

(3.23mL, 21.1mmol) (6.2g, 17.6mmol) (6.13mL is 35.2mmol) in the solution through stirring in ethylene dichloride (170mL) with DI PEA for the product of adding preparation 26 with 6-bromine caproyl muriate.Stirred this reaction mixture 1 hour, and used EtOAc (250mL) dilution then and wash dry (sal epsom) then with saturated sodium bicarbonate aqueous solution (2x200mL) and salt solution (200mL).Removal of solvent under reduced pressure obtains title compound (6.6g, productive rate 73%).

Preparation 28

The 8-benzyloxy-5-[(R)-2-(N-benzylamino)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-the 1H-quinoline-2-one-

With preparation 13 product (1.00g, 2.05mmol) and benzyl amine (493 μ L, 4.51mmol) solution through stirring in DMSO (1.7mL) is at 105 ℃ of heating 4h.Make the reaction mixture cooling, use EtOAc (10mL) dilution then, with saturated aqueous ammonium chloride solution (5mL) and 1N sodium hydroxide (5mL) washing, dry (MgSO ₄) and removal of solvent under reduced pressure.Obtain title compound (700mg, 67%) by column chromatography purification of crude residue (50%EtOAc/ hexane).C ₃₁H ₃₈N ₂O ₃The MS m/z:[M+H+ of Si] calculated value is 515.27; Measured value is 515.5.

Preparation 29

Xenyl-2-aminocarbamic acid 1-{2-[(6-{ benzyl-[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl] amino } caproyl)-methylamino] ethyl } the piperidin-4-yl ester

To preparation 28 product (807mg, 1.57mmol) and DIPEA (819 μ L, 4.7mmol) add in the solution in acetonitrile (3.14mL) through stirring prepare 27 product (995mg, 1.88mmol).Reaction mixture is heated to 80 ℃ of 24h.Removal of solvent under reduced pressure is dissolved in residue among the EtOAc (10mL), uses saturated sodium bicarbonate aqueous solution (5mL) washing then, dry (sal epsom), removal of solvent under reduced pressure.Obtain title compound (452mg, productive rate 30%) by column chromatography purification of crude material (4-6%MeOH/DCM).

Preparation 30

Xenyl-2-aminocarbamic acid 1-{2-[(6-{ benzyl-[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl] amino } caproyl) methylamino] ethyl } the piperidin-4-yl ester

To preparation 29 product (452mg, 0.47mmol) add in the solution in methylene dichloride (4.7mL) through stirring triethylamine three hydrofluorides (116 μ L, 0.71mmol).Stir this reaction mixture 10h.Use methylene dichloride (10mL) dilution then and wash with saturated sodium bicarbonate aqueous solution (5mL).Dry then (MgSO ₄) organic phase and removal of solvent under reduced pressure obtain title compound (productive rate 100%).

Embodiment 7

Xenyl-2-aminocarbamic acid 1-[2-(6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] caproyl } methylamino) ethyl] piperidin-4-yl ester two triflutates

(400mg 0.47mmol) adds palladium (10wt.% (butt) is on gac) (160mg) in the solution through stirring in ethanol (4.7mL), and is placed on reaction mixture under the nitrogen atmosphere and stirs and spend the night to preparation 30 product.Filter reaction mixture then, removal of solvent under reduced pressure.Obtain title compound (73mg) by preparation property HPLC purification of crude residue.HPLC (10-70) R _t=2.33; C ₃₈H ₄₇N ₅O ₆MS m/z:[M+H+] calculated value is 670.36; Measured value is 670.[α] ²⁰ _D=-9.4 (c=1.0mg/mL, water).

Preparation 31

Xenyl-2-aminocarbamic acid 1-[2-(4-(amino methyl) phenylamino formyl radical)-ethyl] the piperidin-4-yl ester

To 4-(N-tert-butoxycarbonyl amino methyl) aniline (756mg, 3.4mmol), preparation 20 product (1.5g, 4.08mmol) and HATU (1.55g, 4.08mmol) add in the solution in DMF (6.8mL) through stirring DI PEA (770 μ L, 4.42mmol).Spend the night at 50 ℃ of stirred reaction mixtures, then removal of solvent under reduced pressure.The residue that obtains is dissolved in the methylene dichloride (20mL), washs with saturated sodium bicarbonate aqueous solution (10mL).Dry then (sal epsom) organic phase and removal of solvent under reduced pressure.Obtain solid by hurried chromatography purification crude product (5-10%MeOH/DCM), with its be dissolved in TFA/DCM (25%, 30mL) in and at stirring at room 2h.Removal of solvent under reduced pressure then, and rough residue is dissolved in the methylene dichloride (30mL) and with 1N sodium hydroxide (15mL) washs.Separate organic phase, dry (sal epsom) and removal of solvent under reduced pressure obtain title compound (1.5g is through 2 steps 94%).

Preparation 32

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] methyl } the phenylamino formyl radical) ethyl]-the piperidin-4-yl ester

With preparation 31 product (489mg, 1.04mmol), the product of preparation 13 (610mg, 1.25mmol), sodium bicarbonate (262mg, 3.12mmol) and sodium iodide (203mg, 1.35mmol) solution in THF (0.52mL) heats 12h at 80 ℃.With methylene dichloride (10mL) diluted reaction mixture, wash with saturated sodium bicarbonate aqueous solution (5mL).Dry (MgSO ₄) organic phase and removal of solvent under reduced pressure.Obtain being solid title compound (687mg, productive rate 77%) by the rough residue of hurried chromatography purification (10%MeOH/DCM).

Preparation 33

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester

To preparation 32 product (687mg, 0.8mmol) add in the solution in methylene dichloride (8mL) through stirring triethylamine three hydrofluorides (261 μ L, 1.6mmol).Stirred reaction mixture 10h uses methylene dichloride (20mL) dilution then and washs with saturated sodium bicarbonate aqueous solution (10mL).Dry then (sal epsom) organic phase and removal of solvent under reduced pressure obtain title compound (500mg, productive rate 81%).

Embodiment 8

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] piperidin-4-yl ester two triflutates

(500mg 0.65mmol) adds palladium (10wt.% (butt) is on gac) (200mg) in the solution through stirring in ethanol (6.5mL), and is placed on this reaction mixture under the nitrogen atmosphere and stirs and spend the night to preparation 33 product.Filter reaction mixture then, removal of solvent under reduced pressure.Obtain title compound (81mg, 2TFA salt) by preparation property HPLC purification of crude residue.HPLC (10-70) R _t=2.41; C ₃₉H ₄₁N ₅O ₆MS m/z:[M+H+] calculated value is 676.32; Measured value is 676.5.

Preparation 34

Xenyl-2-aminocarbamic acid 1-(uncle 2--butoxy carbonyl amino-ethyl) piperidin-4-yl ester

At 50 ℃ of product (2.00g to preparation 8,6.76mmol) and DI PEA (3.54mL, 20.3mmol) add in the stirred solution in acetonitrile (67.6mL) 2-tert-butoxycarbonyl amino-ethyl bromide (1.82g, 8.11mmol), and 50 ℃ of reacting by heating mixture overnight.Removal of solvent under reduced pressure then, and residue is dissolved in methylene dichloride (60mL) neutralization washs with saturated sodium bicarbonate aqueous solution (30mL).Dry (sal epsom) organic phase and removal of solvent under reduced pressure.Obtain being solid title compound (2.32g, productive rate 78%) by column chromatography purification of crude residue (5%MeOH/DCM).

Preparation 35

Xenyl-2-aminocarbamic acid 1-(2-amino-ethyl) piperidin-4-yl ester

With preparation 34 product be dissolved in TFA/DCM (25%, 52mL) in, and at stirring at room 2h.Removal of solvent under reduced pressure is dissolved in rough residue in the methylene dichloride (30mL) then, with 1N sodium hydroxide (15mL) washing.Separate organic phase, dry (sal epsom) and removal of solvent under reduced pressure obtain title compound (1.61g, productive rate 90%).

Preparation 36

Xenyl-2-aminocarbamic acid 1-[2-(4-amino methyl benzoyl-amido) ethyl] the piperidin-4-yl ester

To preparation 35 product (339mg, 1mmol), 4-(tert-butoxycarbonyl amino methyl) phenylformic acid (301mg, 1.2mmol) and HATU (456mg, 1.2mmol) adding DI PEA in the solution in DMF (2mL) through stirring (226 μ L, 1.3mmol).Spend the night at this reaction mixture of stirring at room, then removal of solvent under reduced pressure.The residue that obtains is dissolved in methylene dichloride (20mL) neutralization to be washed with saturated sodium bicarbonate aqueous solution (10mL).Dry (sal epsom) organic phase and removal of solvent under reduced pressure.With crude product be dissolved in TFA/DCM (25%, 10mL) in, at this mixture of stirring at room 2h.Removal of solvent under reduced pressure and rough residue is dissolved in methylene dichloride (15mL) neutralization with 1N sodium hydroxide (5mL) washing.Separate organic phase, dry (sal epsom) and removal of solvent under reduced pressure obtain title compound (472mg ,～100% through 2 steps).

Preparation 37

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tert-butyl dimethyl-silicon alcoxyl base) ethylamino] methyl } benzoyl-amido) ethyl]-the piperidin-4-yl ester

With preparation 36 product (520mg, 1.1mmol), the product of preparation 13 (634mg, 1.3mmol), sodium bicarbonate (277mg, 3.3mmol) and sodium iodide (215mg, 1.43mmol) solution in THF (0.55mL) heats 12h at 80 ℃.Use methylene dichloride (10mL) diluted reaction mixture then and wash with saturated sodium bicarbonate aqueous solution (5mL).Dry then (sal epsom) organic phase and removal of solvent under reduced pressure.Obtain being solid title compound (316mg, productive rate 33%) by the rough residue of hurried chromatography purification (5-10%MeOH/DCM).

Preparation 38

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] methyl } benzoyl-amido) ethyl] the piperidin-4-yl ester

To preparation 37 product (316mg, 0.36mmol) add in the solution in methylene dichloride (3.6mL) through stirring triethylamine three hydrofluorides (117 μ L, 0.72mmol).Stirred reaction mixture 10h uses methylene dichloride (10mL) dilution then and washs with saturated sodium bicarbonate aqueous solution (5mL).Dry (MgSO ₄) organic phase and removal of solvent under reduced pressure obtain title compound, it is directly used in next step (productive rate 100%).

Embodiment 9

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzoyl-amido) ethyl] piperidin-4-yl ester two triflutates

(275mg 0.36mmol) adds palladium (10wt.% (butt) is on the gac) (275mg) and be placed on reaction mixture under the nitrogen atmosphere and stir and spend the night in the solution through stirring in ethanol (3.6mL) to preparation 38 product.Filter reaction mixture and removal of solvent under reduced pressure then.Obtain title compound (6mg, 2TFA salt) by preparation property HPLC purification of crude residue.HPLC (10-70) R _t=2.26; C ₃₉H ₄₁N ₅O ₆MS m/z:[M+H ⁺] calculated value is 676.32; Measured value is 676.5.

Preparation 39

Xenyl-2-aminocarbamic acid 1-(2-amino-ethyl) piperidin-4-yl ester

With 2-tert-butoxycarbonyl amino-ethyl bromide (1.22g, 5.44mmol) add preparation 8 product (1.46g, 4.95mmol) and diisopropyl ethyl amine (1.03mL is 5.94mmol) in the solution in acetonitrile (24mL).65 ℃ of stirred reaction mixtures 12 hours, at this moment MS analyzed and shows that reaction finishes.Concentrated reaction mixture adds methylene dichloride (10mL) then to doing.Trifluoracetic acid added this mixture and in this mixture of stirring at room 4 hours, at this moment MS analyzes and shows that reaction finishes.Then this mixture is concentrated into half of its volume, in this solution, adds 1N sodium hydroxide up to pH regulator to 14.With salt water washing organic layer, then through dried over mgso and filtration.Concentrated filtrate obtains being solid 1.6g title compound.C ₂₀H ₂₅N ₃O ₂MS m/z:[M+H ⁺] calculated value is 340.2; Measured value is 340.

Preparation 40

With N-tert-butoxycarbonyl-1, (1.04g, 5.12mmol) (1.00g is 2.05mmol) in the solution in dimethyl sulfoxide (DMSO) (2mL) for the product of adding preparation 13 for 5-diamino pentane.Stirred this solution 12 hours at 75 ℃, the reaction of lcms analysis demonstration is at this moment finished.The vacuum concentration reaction mixture is to doing then.In residue, add methylene dichloride (2mL), add trifluoracetic acid (1mL) then.At this solution of stirring at room about 3 hours, at this moment MS analyzed and shows that reaction finishes.Then this mixture is concentrated into half of its volume, in this solution, adds 1N sodium hydroxide up to pH regulator to 14.Collected organic layer is used the salt water washing, then through dried over mgso, concentrates then and obtains 782mg and be the buttery title compound.C ₂₉H ₄₃N ₃O ₃The MS m/z:[M+H of Si ⁺] calculated value is 510.8; Measured value is 510.

Preparation 41

Xenyl-2-aminocarbamic acid 1-[2-(3-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] amyl group }-urea groups) ethyl] the piperidin-4-yl ester

With carbonyl dimidazoles (127mg, 0.78mmol) add preparation 39 product (266mg, 0.78mmol) in the solution in dimethyl formamide (4mL), the mixture that obtains in stirring at room 3 hours.After 3 hours, (399mg 0.78mmol) adds this reaction mixture, and in this mixture of stirring at room 12 hours, at this moment the lcms analysis assaying reaction was finished with preparation 40 product.Vacuum concentration reaction mixture and with ethyl acetate (5mL) dilution residue.With saturated sodium bicarbonate (5mL) washed twice, use salt solution (5mL) washing then.Through the dried over mgso organic layer, filter, concentrate then and obtain 597mg and be the solid title compound, it is used and need not to be further purified.C ₅₀H ₆₆N ₆O ₆The MS m/z:[M+H of Si ⁺] calculated value is 875.5; Measured value is 875.

Preparation 42

Xenyl-2-aminocarbamic acid 1-[2-(3-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] amyl group } urea groups) ethyl] the piperidin-4-yl ester

(0.16mL, (597mg 0.68mmol) in the solution in tetrahydrofuran (THF) (3.4mL), at this mixture of stirring at room about 12 hours, at this moment finishes by MS assay determination reaction 1.02mmol) to add the product of preparation 41 with triethylamine three hydrofluorides.With ethyl acetate (5mL) diluted reaction mixture with 1N sodium hydroxide (5mL), this mixture of salt water washing,, concentrate and to obtain 417mg and be the solid title compound through dried over mgso.C ₄₄H ₅₁N ₆O ₆MSm/z:[M+H ⁺] calculated value is 760.4; Measured value is 760.

Embodiment 10

Xenyl-2-aminocarbamic acid 1-[2-(3-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] amyl group } urea groups) ethyl] piperidin-4-yl ester two triflutates

(417mg, 0.55mmol) solution in ethanol (3mL) is about 10 minutes with the product of nitrogen purge preparation 42.Add palladium (10wt.% (butt) is on gac) (200mg), and again with nitrogen towards solution about 10 minutes.The vacuum purification flask is used the nitrogen filling three times then, and the balloon that will be full of hydrogen then is placed on the flask.Stirred reaction mixture is 12 hours under hydrogen, at this moment finishes by MS assay determination reaction.Filter reaction mixture concentrates organic filtrate then, obtains the title compound that 146mg is powder by HPLC purifying (10-35% was through 60 minutes).C ₃₇H ₄₆N ₆O ₆MS m/z:[M+H ⁺] calculated value is 671.4; Measured value is 670.HPLC (10-70) R _t=2.6 minutes.

Embodiment 11

Xenyl-2-aminocarbamic acid 1-[3-(3-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] amyl group } urea groups) propyl group] piperidin-4-yl ester two triflutates

Utilization in preparation 39-42 and embodiment 10 aforesaid method and substitute the 2-tert-butoxycarbonyl amino-ethyl bromide for preparing in 39 with 3-tert-butoxycarbonyl amino third-1-base bromide and prepare title compound.C ₃₈H ₄₈N ₆O ₆MS m/z:[M+H ⁺] calculated value is 685.4; Measured value is 684.HPLC (1070) R _t=2.6 minutes.

Preparation 43

6-(2-bromo-(R)-1-tert-butyl dimethylsilane oxygen base) ethyl-2,2-dimethyl-1,3-benzo two  alkane

(a) the 6-bromo-2,2-dimethyl-4H-benzo [1,3] two  alkane

To at 2.0L 2, add 700mL acetone in the 5-bromo-2-hydroxybenzyl alcohol (93g, 0.46mol is available from Sigma-Aldrich) in the 2-Propanal dimethyl acetal, add zinc chloride (170g) then.After stirring 18 hours, adding the 1.0M aqueous sodium hydroxide solution is alkalescence up to water.Anaesthetie Ether is added in the slurries, and the organic phase decantation is gone into separating funnel.With salt water washing organic phase, through Na ₂SO ₄Drying is filtered and concentrating under reduced pressure obtains being the buttery title compound.

(b) 6-ethanoyl-2,2-dimethyl-4H-benzo [1,3] two  alkane

-78 ℃ will the product of the step among the 1.0L THF (a) (110g, 0.46mol) by dropping funnel add the 2.14M of 236mL (0.51mol) in hexane just-butyllithium.After 30 minutes, add N-methyl-N-methoxyl group ethanamide (71g, 0.69mol derive from TCI).After two hours, water quencher reaction mixture dilutes and with Anaesthetie Ether extraction once with 2.0L1.0M water-bearing phosphate salt buffer (pH=7.0).With salt water washing Anaesthetie Ether once, through Na ₂SO ₄Drying is filtered and concentrating under reduced pressure obtains light orange oil.This oil is dissolved in the minimum volume ethyl acetate,, obtains being the title compound of crystalline solid with the hexane dilution.

(c) 6-acetyl bromide-2,2-dimethyl-4H-benzo [1,3] two  alkane

At-78 ℃ of products (23.4g, 0.113mol) the middle 1.0M hexamethyldisilazane sodium of 135mL in THF (Sigma-Aldrich) that adds to the step in 600mL THF (b).After 1 hour, and the adding trimethylsilyl chloride (15.8mL, 0.124mol).Again after 30 minutes, add bromine (5.82mL, 0.113mol).After 10 minutes, by with the Anaesthetie Ether diluted reaction mixture and be poured into and 500mL5%NaHCO ₃The premixed 500mL5%Na of the aqueous solution ₂SO ₃The aqueous solution comes the quencher reaction.Separate each phase, and with salt water washing organic phase, through Na ₂SO ₄Drying is filtered and concentrating under reduced pressure obtains being the buttery title compound, solidifies when it is stored in refrigerator.

(d) (R)-2-bromo-1-(2,2-dimethyl-4H-benzo [1,3] two  alkane-6-yl) ethanol

To the product of the step in 100mL THF (c) (10g adds the solid catalyst of preparation 13 in 35.1mmol), step (c) (1) (0.97g, 3.5mmol).This solution is cooled to-20 ℃ to-10 ℃, and drips the BH that dilutes with 50mL THF by addition funnel ₃-THF (35mL, 35mmol).After finishing interpolation, make reaction mixture be warmed to room temperature.After 30 minutes, come the quencher reaction mixture, be concentrated into viscous crude then by slow adding 50mL methyl alcohol.Come purifying oil by silica gel chromatography with 1: 2 ethyl acetate/hexane wash-out.Merge fraction and concentrate the title compound that obtains being pale solid.

(e) [(R)-2-bromo-1-(2,2-dimethyl-4H-benzo [1,3] two  alkane-6-yl) oxyethyl group]-the tert-butyl dimethylsilane

The product of the step in being dissolved in 100mL DMF (d) (10g, 34.8mmol) and imidazoles (4.7g, add in 69.7mmol) the tert-butyldimethylsilyl chloride thing (5.78g, 38.3mmol).Stirred reaction mixture 18 hours.Between saturated sodium-chlor of 200mL and 200mL Anaesthetie Ether, distribute reaction mixture then.With 200mL Anaesthetie Ether aqueous layer extracted.Merge organic layer then, with saturated sodium-chlor (3x100mL) washing, through MgSO ₄Dry and concentrated.By this product of silica gel chromatography purifying, use the hexane wash-out, be used in 5% eluent ethyl acetate in the hexane then.Merge the fraction that needs and concentrate and obtain being the buttery title compound.

Preparation 44

Xenyl-2-aminocarbamic acid 1-{9-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(2,2-dimethyl-4H-benzo [1,3] two  alkane-6-yl) ethylamino] nonyl } the piperidin-4-yl ester

Envrionment temperature will prepare 43 product (802mg, 2.00mmol) and sodium iodide (300mg 2.00mmol) stirs 15min in tetrahydrofuran (THF) (0.77mL).Add preparation 11 product (675mg, 1.54mmol) and sodium bicarbonate (388mg is 4.62mmol) and at 80 ℃ of reacting by heating mixture 24h.Reaction mixture and add entry (2mL) then.Use methylene dichloride (2x2mL) to extract this mixture then.Dry organic extract (sal epsom) and the removal of solvent under reduced pressure that merges.Obtain being solid title compound (798mg, 1.05mmol, productive rate 60%) .C by the rough residue of hurried chromatography purification (5-10% ethanol/methylene) ₄₅H ₆₇N ₃O ₅The MS m/z:[M+H of Si ⁺] calculated value is 758.5; Measured value is 758.6.

Preparation 45

Xenyl-2-aminocarbamic acid 1-{9-[2-(2,2-dimethyl-4H-benzo [1,3] two  alkane-6-yl)-2-hydroxyethyl amino] nonyl } the piperidin-4-yl ester

(342 μ L, (798mg is 1.05mmol) in the solution through stirring in methylene dichloride (10.5mL) 2.10mmol) to join preparation 44 product with triethylamine three hydrofluorides in room temperature.Stir this reaction mixture 24h, use methylene dichloride (20mL) dilution then and wash with saturated sodium bicarbonate aqueous solution (15mL).Dry (sal epsom) organic layer and removal of solvent under reduced pressure.Separation is the rough title compound of buttery, and (659mg, 1.02mmol), it is used to next step and need not to be further purified.C ₃₉H ₅₃N ₃O ₅MS m/z:[M+H ⁺] calculated value is 644.4; Measured value is 644.8.

Embodiment 12

Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(4-hydroxyl-3-hydroxymethyl phenyl) ethylamino] nonyl } piperidin-4-yl ester two triflutates

Trifluoracetic acid (2.80mL) is joined preparation 45 product, and (600mg is 0.93mmol) in the solution through stirring in the THF/ water (14mL, 1: 1), and at stirring at room reaction mixture 2h.This reaction mixture of concentrating under reduced pressure, and be dissolved in the 20%MeCN/ water, title compound (200mg, 2TFA salt) obtained by preparation property HPLC purifying then.HPLC (10-70) R _t=2.76; C ₃₆H ₄₉N ₃O ₅MS m/z:[M+H ⁺] calculated value is 604.4; Measured value is 604.8.

Preparation 46

1-[1-(9-benzylamino nonyl) piperidin-4-yl]-3-xenyl-2-base urea

(0.903ml, (2.40g is 5.52mmol) in the solution in methyl alcohol (25mL), and the mixture that obtains in stirring at room 8.30mmol) to add the product of preparation 4 with N-benzyl amine.After 10 minutes, (1.75g 8.30mmol) adds this reaction mixture with triacetyl oxygen base sodium borohydride.Analyze the tracking reaction process by HPLC.Behind envrionment temperature 2h, water (5mL) quencher reaction mixture, vacuum concentration is to half of its volume then.With methylene dichloride (15mL) diluted reaction mixture, and, use salt solution (5mL) washing then with 1N sodium hydroxide (2x10mL) washing.Through dried over mgso organic layer and the concentrated title compound that obtains.

Preparation 47

2-benzyloxy-5-(2-acetyl bromide) benzoic acid methyl ester

(a) 2-benzyloxy-5-acetylbenzoic acid methyl ester

In that (100g 0.515mol) is dissolved in the acetonitrile (1L) with methyl 5-acetylsalicylic acid ester in the 2L flask under reflux conditions and the nitrogen atmosphere.Added through 15 minutes in batches salt of wormwood (213.5g, 1.545mol).Utilized through 15 minutes addition funnel add the benzyl bromide (67.4mL, 0.566mol).Reaction is heated to 85 ℃ of 9h, filters and use acetonitrile (100mL) flushing then.This solution decompression is concentrated into about 300mL volume, and between water (1L) and ethyl acetate (1L), distributes.With saturated sodium-chlor (250mL) washing organic layer, utilize sal epsom (75g) drying, filter and use ethyl acetate (100mL) flushing then.Concentrated organic layer obtains being solid 2-benzyloxy-5-acetylbenzoic acid methyl ester (productive rate 100%).

(b) 2-benzyloxy-5-(2-acetyl bromide) methyl benzoate

Under nitrogen atmosphere, in the 500mL flask, (10.0g 35.2mmol) is dissolved in the chloroform (250mL) with the product of step (a).Utilized dropping funnel to add to be dissolved in through 30 minutes bromine in the chloroform (50mL) (1.63mL, 31.7mmol).Reaction mixture is stirred 2.5h, concentrate then and obtain solid.Low-grade fever is dissolved in this solid in the toluene (150mL), adds the title compound (productive rate 55%) that ether (150mL) obtains being crystalline solid then.

Preparation 48

5-[2-(benzyl-and 9-[4-(3-xenyl-2-base urea groups) piperidines-1-yl] nonyl } amino) ethanoyl]-2-benzyloxy methyl benzoate

With preparation 47 product (371mg, 1.00mmol) add preparation 46 (448mg, in the solution of product 0.85mmol) in dimethyl sulfoxide (DMSO) (4.5mL), add then salt of wormwood (234mg, 1.7mmol).Stir this reaction mixture 6h at 40 ℃, analyze the product of no longer observing preparation 46 this moment by HPLC.Reaction mixture is cooled to envrionment temperature and filtration, uses ethanol (4mL) dilution then.(63mg 1.7mmol) adds this reaction mixture, at this reactant of stirring at room 24h with sodium borohydride.With 0.5M ammonium chloride (5mL) quencher reaction mixture, with ethyl acetate (2x10mL) extraction.With saturated sodium bicarbonate (10mL), the organic layer of using salt solution (5mL) washing to merge then.Through the dried over mgso organic layer, and removal of solvent under reduced pressure.Go up the purification of crude residue by chromatography at silica gel (3% methyl alcohol is in chloroform) and obtain title compound.

Preparation 49

1-[1-(9-{ benzyl-[2-(4-benzyloxy-3-hydroxymethyl phenyl)-2-hydroxyethyl] amino } nonyl) piperidin-4-yl]-3-xenyl-2-base urea

(163mg, 0.20mmol) solution in tetrahydrofuran (THF) (1.00mL) is cooled to 0 ℃ with preparation 48 product.(1.0M is in THF to drip lithium aluminum hydride to this mixture; 0.50mL, 0.50mmol).Behind the 1h, water (1mL) quencher reaction mixture and dilute with ethyl acetate (2mL).With salt water washing organic layer, through dried over mgso, merge organic extract, concentrate and obtain title compound.

Embodiment 13

1-xenyl-2-base-3-(1-{9-[2-hydroxyl-2-(4-hydroxyl-3-hydroxymethyl phenyl) ethylamino] nonyl } piperidin-4-yl) the urea dihydrochloride

(130mg, 0.16mmol) solution in Virahol (0.80ml) is 10 minutes, adds palladium (10wt.% (butt) (60mg) on gac then to be equipped with 49 product with the nitrogen punching out.Use the nitrogen purge reaction flask, the balloon that will be full of hydrogen then is connected with flask, and under nitrogen atmosphere stirred reaction mixture.Behind the 72h, filter reaction mixture also concentrates and with preparation property HPLC purifying residue.Be dissolved in two trifluoroacetates of the title compound that obtains in the 1N hydrochloric acid (5mL) and freeze-drying obtains being the title compound of its dihydrochloride.

Preparation 50

5-[(R)-and 2-[(3-amino methyl cyclohexyl methyl) amino]-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-benzyloxy-1H-quinoline-2-one-

(1.46g, 3mmol) and 1, (426mg, 3mmol) solution through stirring in DMSO (3mL) is at 100 ℃ of heating 6h for 3-hexanaphthene two (methylamine) with preparation 13 product.Allow reaction mixture cooling, use methylene dichloride (20mL) dilution then and wash with saturated sodium bicarbonate aqueous solution (10mL).Dry (MgSO ₄) organic layer and removal of solvent under reduced pressure.By the rough residue of hurried chromatography purification (10%MeOH/DCM and 0.5%NH ₄OH) obtain being solid title compound (775mg, productive rate 50%).C ₃₂H ₄₇N ₃O ₃The MS m/z:[M+H of Si ⁺] calculated value is 550.3; Measured value is 550.6.

Preparation 51

Xenyl-2-aminocarbamic acid 1-{2-[(3-{[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydro-quinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] methyl }-cyclohexyl methyl) carbamyl] ethyl } the piperidin-4-yl ester

To preparation 50 product (552mg, 1.01mmol), the product of preparation 20 (309mg, 0.84mmol) and HATU (384mg, 1.01mmol) DMF (1.68mL) in the solution of stirring, add DIPEA (190 μ L, 1.09mmol).This reaction mixture is spent the night 50 ℃ of stirrings, then removal of solvent under reduced pressure.The residue that obtains is dissolved in the methylene dichloride (20mL), and washs with saturated sodium bicarbonate aqueous solution (10mL).Dry (sal epsom) organic phase and removal of solvent under reduced pressure.Obtain being solid title compound (267mg, 36% productive rate) by hurried chromatography purification crude product (5-10%MeOH/DCM).LCMS(10-70)R _t＝5.04。C ₅₃H ₆₉N ₅O ₆The MS m/z:[M+H of Si ⁺] calculated value is 900.5; Measured value is 900.6.

Preparation 52

Xenyl-2-aminocarbamic acid 1-{2-[(3-{[(R)-and 2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] methyl } cyclohexyl methyl) carbamyl] ethyl } the piperidin-4-yl ester

To preparation 51 product (267mg, 0.30mmol) add in the solution in methylene dichloride (3mL) through stirring triethylamine three hydrofluorides (98 μ L, 0.6mmol).Stir this reaction mixture 10h, use methylene dichloride (10mL) to dilute it then and wash with saturated sodium bicarbonate aqueous solution (5mL).Dry organic phase (sal epsom) and removal of solvent under reduced pressure obtain being solid title compound (236mg, productive rate 100%).C ₄₇H ₅₅N ₅O ₆MS m/z:[M+H ⁺] calculated value is 786.4; Measured value is 786.5.

Embodiment 14

Xenyl-2-aminocarbamic acid 1-{2-[(3-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-cyclohexyl methyl) carbamyl] ethyl }-the piperidin-4-yl ester

Palladium (10wt.% (butt) is on gac) (120mg) is added preparation 52 product, and (236mg is 0.30mmol) in the solution through stirring in ethanol (3mL).Placement reaction mixture and stirring are spent the night under nitrogen atmosphere.Filter reaction mixture and removal of solvent under reduced pressure then.Obtain title compound (27mg, 2TFA salt) by preparation property HPLC purification of crude residue.HPLC(10-70)R _t＝2.76。C ₄₀H ₄₉N ₅O ₆MS m/z:[M+H ⁺] calculated value is 696.4; Measured value is 696.6.

Preparation 53

Xenyl-2-aminocarbamic acid 1-{2-[((1R, 3S)-3-amino cyclopentyl alkyl carbonyl) amino]-ethyl } the piperidin-4-yl ester

Product (318mg to preparation 39,0.94mmol), (1R, 3S)-3-tert-butoxycarbonyl Aminocyclopentane carboxylic acid (258mg, 1.1mmol) and HATU (428mg, 1.1mmol) add in the solution in DMF (5mL) through stirring DI PEA (245 μ L, 1.09mmol).Spend the night at the stirring at room reaction mixture, then removal of solvent under reduced pressure.The residue that obtains is dissolved in methylene dichloride (20mL) neutralization to be washed with saturated sodium bicarbonate aqueous solution (10mL).Dry (sal epsom) organic layer and removal of solvent under reduced pressure.By hurried chromatography purification crude product (5-10%MeOH/DCM) be dissolved in then in trifluoracetic acid/DCM mixture (1mL/5mL) and at stirring at room 1h.Removal of solvent under reduced pressure.Residue is dissolved in methylene dichloride (20mL) neutralization washs with 1M sodium hydroxide (10mL), dry (sal epsom) and minimizing solvent obtain title compound (167mg, 39% productive rate).

Preparation 54

Xenyl-2-aminocarbamic acid 1-[2-((1R, 3S)-3-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino]-the pentamethylene carbonyl } amino) ethyl] the piperidin-4-yl ester

With preparation 53 product (167mg, 0.38mmol) and the product of preparation 13 (92mg, 0.19mmol) solution through stirring in DMSO (0.38mL) is at 90 ℃ of heating 5h.Cool off this solution, and, use saturated sodium bicarbonate aqueous solution (5mL) washing then with ethyl acetate (10mL) dilution.Dry (sal epsom) organic phase and removal of solvent under reduced pressure.Obtain title compound (343mg, 100% productive rate) by hurried chromatography purification crude product (5-10%MeOH/DCM).LCMS(10-70)R _t＝4.97。C ₅₀H ₆₃N ₅O ₆The MS m/z:[M+H of Si ⁺] calculated value is 858.5; Measured value is 858.8.

Preparation 55

Xenyl-2-aminocarbamic acid 1-[2-((I R, 3S)-3-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] the pentamethylene carbonyl } amino) ethyl]-the piperidin-4-yl ester

To preparation 54 product (343mg, 0.4mmol) add in the solution in THF (2mL) through stirring triethylamine three hydrofluorides (130 μ L, 0.8mmol).This reaction mixture is stirred 10h, use EtOAc (10mL) dilution then.(5mL) washs this reaction mixture with saturated sodium bicarbonate aqueous solution, and dry then (sal epsom) organic phase and removal of solvent under reduced pressure obtain being solid title compound (298mg, productive rate 100%).HPLC(10-70)R _t＝2.8。C ₄₄H ₄₉N ₅O ₆MS m/z:[M+H ⁺] calculated value is 744.4; Measured value is 744.4.

Embodiment 15

Xenyl-2-aminocarbamic acid 1-[2-((1R, 3S)-3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2,3,4-tetrahydroquinoline-5-yl) ethylamino]-the pentamethylene carbonyl } amino) ethyl]-piperidin-4-yl ester two triflutates

(236mg 0.40mmol) adds palladium (10wt.% (butt) (120mg) on gac in the solution through stirring in ethanol (3mL) to the product for preparing 55.Placement reaction mixture and stirring are spent the night under nitrogen atmosphere.Filter this reaction mixture and removal of solvent under reduced pressure.Obtain title compound (3mg, 2TFA salt) by preparation property HPLC purification of crude residue.HPLC (5-75) R _t=2.18.C ₃₇H ₄₅N ₅O ₆MS m/z:[M+H ⁺] calculated value is 656.3; Measured value is 656.2.

Preparation 56

4-(tert-butoxycarbonyl amino methyl)-2-chloro-phenyl-amine

(940mg, 6mmol) (1.44g, 6.6mmol) solution through stirring in methylene dichloride (30mL) is finished by the LCMS assaying reaction at stirring at room 4h at this moment with two-tertiary butyl, two carbonic ethers with 4-amino methyl-2-chloro-phenyl-amine.Use saturated sodium bicarbonate aqueous solution (15mL) washing reaction mixture then and through dried over sodium sulfate organic layer and removal of solvent under reduced pressure.The orange solids that obtains from the re-crystallizing in ethyl acetate solid title intermediate (productive rate～100%) that obtains being white in color.

Preparation 57

N-[4-(tert-butoxycarbonyl amino methyl)-2-chloro-phenyl-] acrylamide

To preparation 56 product (1.54g, 6.0mmol) dropping acryloyl chlorination thing in the solution in the mixture of Anaesthetie Ether (35mL) and 1M sodium hydroxide (35mL) through stirring (687 μ L, 8.45mmol).Behind the 1h, separate organic layer, dry (Na ₂SO ₄) and the removal of solvent under reduced pressure solid title intermediate (1.8g, productive rate 96%) that obtains being white in color.

Preparation 58

Xenyl-2-aminocarbamic acid 1-[2-(4-(tert-butoxycarbonyl amino methyl)-2-chloro-phenyl-carbamyl) ethyl] the piperidin-4-yl ester

With preparation 8 product (1.04g, 3.5mmol) and the product of preparation 57 (1.19g, 3.85mmol) solution in the mixture of methylene dichloride and methyl alcohol (12mL, 1: 1) is at 60 ℃ of heating 12h.Allow reaction mixture cool off and removal of solvent under reduced pressure.By column chromatography purification of crude material (5-10%MeOH/DCM) the solid title intermediate (2.00g, productive rate 94%) that obtains being white in color.

Preparation 59

Xenyl-2-aminocarbamic acid 1-[2-(4-amino methyl-2-chloro-phenyl-carbamyl) ethyl]-the piperidin-4-yl ester

(2.00g, solution 3.3mmol) stir 1h, removal of solvent under reduced pressure then in methylene dichloride (24mL) and TFA (8mL) with preparation 58 product.Crude reaction mixture is dissolved in the methylene dichloride (30mL) also with 1M sodium hydroxide (2x30mL) washing.Dry (Na ₂SO ₄) organic layer and removal of solvent under reduced pressure obtain being the title intermediate (1.46g, productive rate 88%) of oily white solid.

Preparation 60

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-tert-butyl dimethyl-silicon alcoxyl base) ethylamino] methyl }-2-chloro-phenyl-carbamyl)-ethyl] the piperidin-4-yl ester

With preparation 59 product (1.41g, 2.79mmol) and the product of preparation 13 (680mg, 1.39mmol) solution through stirring in DMSO (1.39mL) is cooled to room temperature then at 90 ℃ of heating 8h.Wash organic layer with ethyl acetate/chloroform (20mL, 1/1) diluted reaction mixture with saturated sodium bicarbonate aqueous solution (10mL), dry (Na ₂SO ₄) and removal of solvent under reduced pressure.The rough residue (5-10%MeOH/DCM) that obtains by the column chromatography purifying solid title intermediate (1.12g, productive rate 88%) that obtains being white in color.MS m/z M+H ⁺＝914.9。

Preparation 61

Xenyl-2-base-carboxylamine 1-[2-(4-{[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] methyl }-2-chloro-phenylamino formyl radical) ethyl] the piperidin-4-yl ester

(1.12g 1.23mmol) adds Et in the solution through stirring in methylene dichloride (12mL) to the product for preparing 60 ₃N.3HF (401 μ L, 0.6mmol).This reaction mixture is stirred 10h, use methylene dichloride (10mL) dilution then.Wash this mixture and drying (Na with saturated sodium bicarbonate aqueous solution (5mL) ₂SO ₄) organic layer and removal of solvent under reduced pressure solid title intermediate (959mg, productive rate 100%) the .MS m/z M+H that obtains being white in color ⁺=800.5.

Embodiment 16

Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] piperidin-4-yl ester two triflutates

(959mg 1.2mmol) adds Pd/C (290mg) in the solution through stirring in ethanol (12mL), and is placed on this reaction mixture under the nitrogen atmosphere and stirs and spend the night to preparation 61 product.Filter this reaction mixture and removal of solvent under reduced pressure then.Obtain title compound (67mg, 2TFA salt) by preparation property HPLC purification of crude residue.HPLC(10-70)R _t＝2.76；MS m/z M+H ⁺＝710.6。

Preparation 62

2-monochloroethane sulfonic acid (the amino amyl group of 5-tert-butoxycarbonyl) acid amides

0 ℃ to 5-(tert-butoxycarbonyl amino) amylamine (1.00g, 4.94mmo l) and triethylamine (689 μ L g, 4.94mmol) add in the solution in methylene dichloride (22mL) through stirring 2-chloro-1-ethyl sulfonyl chloride (470 μ L, 4.50mmol).At this reaction mixture of stirring at room 2h, use saturated sodium bicarbonate aqueous solution (15mL) washing then.Dry (Na ₂SO ₄) organic layer and removal of solvent under reduced pressure obtain title compound (productive rate 100%), it is used to next step and need not to be further purified.

Preparation 63

Xenyl-2-aminocarbamic acid 1-[2-(the amino amyl group sulfamyl of uncle 5--butoxy carbonyl)-ethyl] the piperidin-4-yl ester

With preparation 8 product (1.33g, 3.5mmol) and the product of preparation 62 (1.62g, 4.94mmol) solution in methylene dichloride and methyl alcohol (22mL, 1: 1) is at 60 ℃ of heating 5h.Allow reaction mixture be cooled to room temperature and removal of solvent under reduced pressure.Rough residue is dissolved in the methylene dichloride (20mL) and washs with saturated sodium bicarbonate aqueous solution (10mL).Dry then (Na ₂SO ₄) organic layer and removal of solvent under reduced pressure.By column chromatography purification of crude residue (5-10%MeOH/DCM) the solid title intermediate (1.6g, 55%) that obtains being white in color.MSm/z M+H ⁺＝589.6。

Preparation 64

Xenyl-2-aminocarbamic acid 1-[2-(the amino amyl group sulfamyl of 5-) ethyl] the piperidin-4-yl ester

(1.6g, solution 2.72mmol) stir 1h, removal of solvent under reduced pressure then in methylene dichloride (21mL) and TFA (7mL) with preparation 63 product.Crude reaction mixture is dissolved in the methylene dichloride (30mL) also with 1M sodium hydroxide (2x30mL) washing.Dry (Na ₂SO ₄) organic layer, removal of solvent under reduced pressure obtains being the title intermediate (1.19g, productive rate 90%) of oily white solid then.

Preparation 65

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-(tert-butyl dimethyl-silicon alcoxyl base) ethylamino] the amyl group sulfamyl } ethyl) the piperidin-4-yl ester

With preparation 64 product (917mg, 1.88mmol) and the product of preparation 13 (460mg, 0.94mmol) solution through stirring in DMSO (0.92mL) is cooled to room temperature then at 90 ℃ of heating 8h.With ethyl acetate/chloroform (20mL, 1/1) diluted reaction mixture, dry (Na ₂SO ₄) and removal of solvent under reduced pressure.The rough residue (3-6%MeOH/DCM) that obtains by the column chromatography purifying solid title intermediate (500mg, productive rate 60%) that obtains being white in color.MS m/z M+H ⁺＝896.9。

Preparation 66

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino] the amyl group sulfamyl } ethyl) the piperidin-4-yl ester

To preparation 65 product (500mg, 0.56mmol) add in the solution in methylene dichloride (5.6mL) through stirring triethylamine three hydrofluorides (183 μ L, 1.12mmol).Stir this reaction mixture 10h and add methylene dichloride (10mL).Wash the mixture that obtains with saturated sodium bicarbonate aqueous solution (5mL).Dry (Na ₂SO ₄) organic layer and removal of solvent under reduced pressure obtain being title intermediate (437mg, the productive rate 100% of yellow solid.MS m/z M+H ⁺＝782.8。

Embodiment 17

Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the amyl group sulfamyl } ethyl) piperidin-4-yl ester two triflutates

(437mg 0.56mmol) adds Pd/C (131mg) in the solution through stirring in ethanol/methyl alcohol (5.6mL, 1/1), and is placed on reaction mixture under the nitrogen atmosphere and stirring is spent the night to preparation 66 product.Filter reaction mixture and removal of solvent under reduced pressure then.Obtain being the title compound (71mg) of two trifluoracetic acid salt forms by preparation property HPLC purification of crude residue.HPLC(10-70)R _t＝2.59；MS m/z M+H ⁺＝692.6。

Preparation 67

Xenyl-2-aminocarbamic acid 1-{2-[(4-formyl radical benzenesulfonyl) methylamino]-ethyl } the piperidin-4-yl ester

To preparation 26 product (350mg, 1mmol) and triethylamine (167 μ L, 1.2mmol) adding 4-formyl radical benzenesulfonyl muriate in the solution in methylene dichloride (5mL) through stirring (225mg, 1.1mmol).Behind room temperature 1h, finish by the MS monitoring reaction, use saturated sodium bicarbonate aqueous solution (5mL) washing reaction mixture then.Dry then (Na ₂SO ₄) organic layer and removal of solvent under reduced pressure obtain title intermediate (323mg, productive rate 62%).MS m/z M+H ⁺＝522.4。

Preparation 68

Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-and 2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzenesulfonyl)-methylamino] ethyl } the piperidin-4-yl ester

With 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-(293mg, 0.74mmol) and preparation 67 product at methylene dichloride and methyl alcohol (6.2mL, 1/1) solution in is at stirring at room 1h, add then triacetyl oxygen base sodium borohydride (394mg, 1.86mmol).Stir this reaction mixture 4h, finish by the MS assaying reaction.Obtain title compound with this reaction mixture of concentrated hydrochloric acid acidifying and removal of solvent under reduced pressure then, it is used to next step and need not to be further purified.MS m/z M+H ⁺＝840.8。

Embodiment 18

Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzenesulfonyl) methylamino] ethyl }-piperidin-4-yl ester two triflutates

With preparation 68 product in that (520mg, 0.62mmol) solution through stirring in 1M hydrochloric acid (5mL) and acetonitrile (5mL) heats 8h at 60 ℃.This reaction mixture is cooled to room temperature and removal of solvent under reduced pressure.Obtain being the title compound (220mg) of two trifluoracetic acid salt forms by preparation property HPLC purification of crude residue.HPLC(10-70)R _t＝2.77；MS m/z M+H ⁺＝726.7。

Preparation 69

(3-aminomethyl phenyl) methylate hydrochlorate

(a) (3-tert-butoxycarbonyl aminomethyl phenyl) methyl alcohol

(2.05mL, (1.81g is 7.20mmol) in the solution in tetrahydrofuran (THF) (24mL), and the mixture that obtains in stirring at room 3 hours 21.6mmol) to add 3-(tert-butoxycarbonyl amino methyl) phenylformic acid with the borine dimethylsulphide.Mixture and the separating layer of using ethyl acetate (20mL) dilution to obtain then.Wash organic layer with saturated sodium bicarbonate, saturated sodium-chlor,, concentrate the title compound (1.71g) that obtains being yellow oil through dried over mgso.

(b) (3-aminomethyl phenyl) methylate hydrochlorate

To the product of step (a) (1.71g, add in 7.2mmol) solution of 4M hydrochloric acid in two  alkane (9mL, 36mmol), and the mixture 1h that obtains in stirring at room.Concentrated reaction mixture then, and dilute this residue and the filtration solid title compound (1.09g) that obtains being white in color with Anaesthetie Ether (50mL).

Preparation 70

Xenyl-2-aminocarbamic acid 1-{2-[3-(3-hydroxymethylbenzyl) urea groups] ethyl } the piperidin-4-yl ester

Product (760mg with preparation 35,2.24mmol) at N, 0.2M drips of solution in the dinethylformamide adds 1,1 '-carbonyl dimidazoles (364mg, 2.24mmol) and diisopropyl ethyl amine (0.31mL, 2.24mmol) at N, in the solution in the dinethylformamide (11mL), and the mixture 2h that obtains in stirring at room.(0.31mL, 2.24mmol) (578mg 3.4mmol) and at 50 ℃ stirred these mixtures 12 hours with the product for preparing 69 to add diisopropyl ethyl amine.Concentrate this reaction mixture then to doing, and dilute this residue and with saturated sodium bicarbonate (2x), saturated sodium-chlor washs this solution, through dried over mgso and the concentrated title compound (1.12g) that obtains with methylene dichloride (20mL).LCMS(2-90)R _t＝4.01min.；MS m/z M+H＝503.5。

Preparation 71

Xenyl-2-aminocarbamic acid 1-{2-[3-(3-formyl radical benzyl) urea groups] ethyl } the piperidin-4-yl ester

With preparation 70 product (1.12g, 2.23mmol) solution in methylene dichloride (11.1mL) be cooled to 0 ℃ and add diisopropyl ethyl amine (1.17mL, 6.70mmol) and dimethyl sulfoxide (DMSO) (0.949mL, 13.4mmol).After about 10 minutes, add pyridine sulphur trioxide complex compound (1.06g, 6.70mmol), and the mixture 2h that obtains 0 ℃ of stirring.Water (15mL) quencher is reacted and with cold water (3x) washing organic layer, is obtained being the yellow title compound (609mg) that easily minces through dried over mgso with concentrating then.LCMS(2-90)R _t＝4.13min；MS m/z M+H＝501.3。

Preparation 72

Xenyl-2-aminocarbamic acid 1-{2-[3-(3-{[(R)-2-(tert-butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzyl) urea groups] ethyl }-the piperidin-4-yl ester

With 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-(575mg, 1.40mmol) add the product (609mg of preparation 71,1.2mmol) and diisopropylamine (0.25mL, 1.40mmol) in the solution in methylene dichloride (6mL), the mixture 45min that obtains in stirring at room.Add then triacetyl oxygen base sodium borohydride (385mg, 1.80mmol), at this mixture of stirring at room 12h.Use 10% aqueous hydrochloric acid (5mL) quencher reaction then, separate each layer.Wash organic layer with saturated sodium bicarbonate, saturated sodium-chlor, through dried over mgso and the concentrated title compound (1.1g) that obtains.HPLC(10-70)R _t＝3.55min；MS m/z M+H＝819.7。

Embodiment 19

Xenyl-2-aminocarbamic acid 1-{2-[3-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzyl) urea groups] ethyl } piperidin-4-yl ester two triflutates

(2.4mL, (1.1g is 1.36mmol) in the solution in methylene dichloride (2mL), and the mixture 15h that obtains in stirring at room 13.6mmol) to add the product of preparation 72 with triethylamine three hydrofluorides.The vacuum concentration reaction mixture is to doing then, and this residue is dissolved in 1: 1 mixture of the water of 0.1%TFA and acetonitrile, obtain being the title compound (296mg, purity 99%) of two trifluoracetic acid salt forms by this mixture of HPLC (5-35 is through 60min) purifying.MS m/z M+H＝705.6。

Preparation 73

Xenyl-2-aminocarbamic acid 1-[(E)-and 3-(4-nitrophenyl) allyl group] the piperidin-4-yl ester

With preparation 8 product (2.96g, 0.01mol) and right-nitro cinnamaldehyde (1.77g 0.01mol) stirs 2h in the 50mL methylene dichloride.Add triacetyl oxygen base sodium borohydride (6.33g, 0.03mol) and stir the mixture 2h that obtains.Dilute this mixture with 10mL water quencher reaction and with methylene dichloride (100mL) then.With saturated sodium bicarbonate (2x), salt water washing organic layer, through Na ₂SO ₄Drying is filtered and is concentrated and obtains being yellow foamy title compound (3.8g, productive rate 80%).

Preparation 74

Xenyl-2-aminocarbamic acid 1-[3-(4-aminophenyl) propyl group] the piperidin-4-yl ester

(2.5g 5.4mmol) is dissolved in the 100mL ethanol, the solution that obtains with nitrogen purge 30 minutes with preparation 73 product.Then, add carbon and carry palladium (2.5g; 50%w/w water; 10%Pd; 1.1mmol Pd), outgas with nitrogen simultaneously.Then this mixture is placed on (50psi) under the hydrogen, up to no longer consuming hydrogen (～30 minutes).Use the nitrogen purge mixture then, through diatomite filtration and concentrated.This residue is dissolved in the ethyl acetate and with saturated sodium bicarbonate (2x), this mixture of salt water washing, dry (Na ₂SO ₄), filter and the concentrated title compound (2.08g, productive rate 90%) that obtains.MS m/z M+H＝430.5。

Preparation 75

Xenyl-2-aminocarbamic acid 1-{3-[4-(4-{2-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydro-quinoline-5-yl)-2-(tertiary butyl dimethyl-silicon alcoxyl base) ethylamino] ethyl } phenyl amino)-phenyl] propyl group } the piperidin-4-yl ester

The product of adding preparation 74 in the 25mL round-bottomed flask (400mg, 0.8mmol); The 8-benzyloxy-5-[(R)-2-[2-(4-bromophenyl) ethylamino]-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-the 1H-quinoline-2-one-(769mg, 1.2mmol); Three (dibenzalacetones), two palladiums (O) (73mg, 0.08mmol, 20%Pd); And 2-(dicyclohexylphosphontetrafluoroborate) xenyl (84mg, 0.24mmol).With this mixture of nitrogen purge, dry then, add the degassing toluene (8mL, 0.1M) and the mixture 30min that obtains 70 ℃ of heating.(382mg 4.0mmol), is increased to 95 ℃ of 4h with temperature, and this moment, LCMS showed that the product of preparation 74 exhausts and big product peak (M+H=956.7) fully to add sodium tert-butoxide then.Then reaction mixture is cooled to chamber Gentle ethyl acetate dilution.With saturated sodium bicarbonate (2x), this mixture of salt water washing, dry (Na ₂SO ₄), filtering and concentrate and obtain title compound (1.5g), it is used and need not to be further purified.

Preparation 76

Xenyl-2-aminocarbamic acid 1-{3-[4-(4-{2-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydro-quinoline-5-yl)-2-hydroxyethyl amino] ethyl } phenyl amino) phenyl] propyl group } the piperidin-4-yl ester

Be dissolved in the methylene dichloride (10mL) product of preparation 75 and adding triethylamine three hydrofluorides (10 equivalent).Stirred reaction mixture spends the night, then with methylene dichloride dilution with saturated sodium bicarbonate (2x), salt water washing organic layer, drying (Na ₂SO ₄), filter and the concentrated 1.3g crude product that obtains.Obtain title compound (300mg, purity about 75%) by this material of silica gel chromatography purifying (DCM increases to 50% methyl alcohol), it is used and need not to be further purified.

Embodiment 20

Xenyl-2-aminocarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) phenyl] propyl group } piperidin-4-yl ester two triflutates

Preparation 76 product (300mg) is dissolved in the 10mL ethanol and with this mixture of nitrogen purge 15 minutes.Add carbon simultaneously in the degassing and carry palladium (10%Pd, 50%w/w water, 0.2 equivalent Pd).Then the mixture that obtains is placed on 2h under 1 atmospheric pressure hydrogen, at this moment finishes by the LCMS assaying reaction.Then with this solution of nitrogen purge 15min, then through diatomite filtration and concentrated.Obtain being the title compound (59mg, purity＞95%) of two trifluoracetic acid salt forms by preparation property HPLC purifying.MS m/z M+H＝752.8。

Preparation 77

Xenyl-2-aminocarbamic acid 1-[2-fluoro-3-(4-hydroxymethyl piperidines-1-ylmethyl)-benzyl] the piperidin-4-yl ester

Product (500mg with preparation 8,1.69mmol), 2,6-two (brooethyl)-1-fluorobenzene (476mg, 1.69mmol, piperidin-4-yl methyl alcohol (195mg, 1.69mmol) and salt of wormwood (466mg 3.37mmol) is suspended in the acetonitrile (5mL) and at stirring at room 18h.Concentrate this reaction mixture then, and this residue is dissolved in methylene dichloride/water.Separate each layer, water (2x), salt water washing organic layer, dry (MgSO ₄) and concentrate.By silica gel column chromatography with 3% methyl alcohol/chloroform wash-out purification of crude material foamy title compound (282mg) that obtains being white in color.MS m/z M+H＝532.3。

Preparation 78

Xenyl-2-aminocarbamic acid 1-[2-fluoro-3-(4-formyl piperidine-1-ylmethyl) benzyl]-the piperidin-4-yl ester

With preparation 77 product (282mg 0.53mmol) is dissolved in the methylene dichloride, and in this mixture, add diisopropyl ethyl amine (280 μ L, 1.6mmol) and dimethyl sulfoxide (DMSO) (115 μ L, 1.6mmol).Under nitrogen, this reaction mixture is cooled off at-15 ℃, and (255mg 1.6mmol), and stirs the mixture 40min that obtains to add pyridine sulphur trioxide complex compound.Water quencher reaction then, and separate each layer.Use moisture NaH ₂PO ₄(1Mx3), salt water washing organic layer, dry (MgSO ₄) and concentrate and to obtain being foamy title compound (253mg).MS m/z M+H＝530.4。

Embodiment 21

Xenyl-2-aminocarbamic acid 1-[2-fluoro-3-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } piperidines-1-ylmethyl) benzyl] piperidin-4-yl ester two triflutates

Product (253mg with preparation 78,0.48mmol) be dissolved in 1: 1 mixture (6mL) of methylene dichloride and methyl alcohol, and in this mixture, add 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-acetic ester (228mg, 0.58mmol) and triacetyl oxygen base sodium borohydride (317mg, 1.5mmol).Under nitrogen,, concentrate then at this reaction mixture of stirring at room 18h.This residue is dissolved in 2: 3 mixtures of acetonitrile and moisture 6N hydrochloric acid, this mixture was heated 4 hours at 55 ℃.Concentrate this reaction mixture then, and this residue is dissolved in water/acetonitrile/trifluoracetic acid (1: 1: 0.005) neutralization by the reversed-phase column chromatography method purifying solid title compound (175mg) that obtains being white in color.MS m/z M+H＝734.5。

Preparation 79

2-[4-(3-bromine propoxy-) phenyl] ethanol

To the 4-hydroxylphenylethyl alcohol (4.37g, 31.0mmol) and salt of wormwood (6.55g, 47.0mmol) add in the solution in acetonitrile (62.0mL) 1,3 dibromopropane (31.0mL, 316mmol).With this reaction mixture be heated to 70 ℃ 12 hours, be cooled to room temperature then, filter and vacuum concentration.The oil that the silica gel chromatography purifying of the mixture by utilizing 4: 1 hexanes and ethyl acetate the obtains solid title compound (6.21g) that obtains being white in color.

Preparation 80

Xenyl-2-aminocarbamic acid 1-{3-[4-(2-hydroxyethyl) phenoxy group] propyl group } the piperidin-4-yl ester

To preparation 79 product (1.11g, 4.30mmol) and diisopropyl ethyl amine (0.90mL, 5.10mmol) add in the solution in acetonitrile (21.5mL) prepare 8 product (1.27g, 4.30mmol) and the mixture 12h that obtains 60 ℃ of stirrings.Then this reaction mixture is washed with methylene dichloride (20mL) dilution with saturated sodium bicarbonate (25mL), saturated sodium-chlor (25mL), through dried over mgso and the concentrated title compound (1.98g, purity 85%) that obtains.MS m/z M+H＝475.5。

Preparation 81

Xenyl-2-aminocarbamic acid 1-{3-[4-(2-oxygen ethyl) phenoxy group] propyl group } the piperidin-4-yl ester

With preparation 80 product (723mg, 1.53mmol) and the solution of methylene dichloride (75mL) be cooled to about 5 ℃, and the adding diisopropyl ethyl amine (798mL, 4.58mmol) and dimethyl sulfoxide (DMSO) (649mL, 9.15mmol).Add then the pyridine sulphur trioxide (728mg, 4.58mmol), and the mixture 45min that obtains 5 ℃ of stirrings.Use methylene dichloride (20mL) to dilute this reaction mixture then and with saturated sodium bicarbonate (25mL), the washing of saturated sodium-chlor (25mL), through dried over mgso with concentrate and obtain title compound (604mg).MS m/zM+H＝473.4.

Preparation 82

Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(R)-2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl }-phenoxy group) propyl group] the piperidin-4-yl ester

Product (604mg with preparation 81,1.28mmol) be dissolved in the methyl alcohol (6.4mL) and adding 5-[(R)-2-amino-1-(tert-butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-(605mg, 1.53mmol) and diisopropyl ethyl amine (0.27mL, 1.53mmol).Add then triacetyl oxygen base sodium borohydride (405mg, 1.91mmol), and at stirring at room reaction mixture 3h.Concentrated reaction mixture is to doing and washing this solution with ethyl acetate (20mL) dilution residue with saturated sodium bicarbonate (25mL), saturated sodium-chlor (25mL), through dried over mgso and the concentrated title compound (704mg) that obtains then.MSm/z M+H＝791.8。

Embodiment 22

Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenoxy group) propyl group] piperidin-4-yl ester two triflutates

(1.5mL 8.87mmol) adds product (702mg, 0.89mmol) the mixture 24h that obtains in the solution in methylene dichloride (4.5mL) and in stirring at room of preparation 82 with triethylamine three hydrofluorides.This mixture of vacuum concentration and by HPLC purifying (2-35 is through 90min) obtain the being white in color title compound (92mg) of powder then.MS m/z M+H＝677.4。

Preparation 83

Methyl 4-iodophenyl acetic ester

(5.0g 19.1mmol) is added in 4N hydrochloric acid in the two  alkane (10mL) in the solution through stirring in MeOH (200mL) to 4-iodophenyl acetic acid.At this reaction mixture of stirring at room 24h, removal of solvent under reduced pressure obtains title compound (5.17g, productive rate 98%) then, and it is used and need not to be further purified.

Preparation 84

Methyl [4-(4-hydroxyl fourth-1-alkynyl) phenyl] acetic ester

To preparation 83 product (4.5g, 16.3mmol) add in the solution in diethylamide (100mL) through stirring fourth-3-alkynes-1-alcohol (1.9mL, 32.6mmol), Pd (PPh ₃) ₂Cl ₂(500mg, 1.63mmol) and CuI (154mg, 0.815mmol) and the mixture 17h that obtains in stirring at room.Remove removal of solvent under reduced pressure then and this residue be dissolved in this solution of Anaesthetie Ether (200mL) neutralization filtration to come except that desalting.Removal of solvent under reduced pressure and obtain title intermediate (3.03g, productive rate 91%) then by silica gel chromatography purifying crude product (60%EtOAc/ hexane).

Preparation 85

Methyl [4-(4-hydroxybutyl) phenyl] acetic ester

With the nitrogen punching out be equipped with 84 product (2.8g, 12.8mmol) the solution in methyl alcohol (50mL) through stirring, add then 10% carbon carry palladium (400mg, 20%wt/wt).Alternately reaction flask is placed on then under the vacuum and dashes and reach several cycles, under hydrogen, stir 14h then with nitrogen.Towards reaction mixture, filtration and removal of solvent under reduced pressure obtain title compound (2.75g, productive rate 97%) then with nitrogen, and it is used and need not to be further purified.

Preparation 86

Methyl (4-{4-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] butyl } phenyl) acetic ester

(a) methyl { 4-[4-(toluene-4-sulfonyloxy) butyl] phenyl } acetic ester

To preparation 85 product (2.6g, 12.5mmol) add in the solution in THF (100mL) through stirring DABCO (2.6g, 25.0mmol), add then p-toluenesulfonyl chloride (2.44g, 13.75mmol).At this reaction mixture of stirring at room 23h, removal of solvent under reduced pressure then, and residue is dissolved in the methylene dichloride (200mL).Wash (2X100mL), 1N hydrochloric acid (100mL) and saturated sodium chloride aqueous solution (100mL) washing organic layer then with water, dry (MgSO ₄), filtration and removal of solvent under reduced pressure obtain title compound, and it is used and need not to be further purified.

(b) methyl (4-{4-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] butyl } phenyl) acetic ester

To add from the crude product of step (a) DMF (50mL), diisopropyl ethyl amine (3.0mL, 17.3mmol) and the product of preparation 8 (2.4g, 8.1mmol).At stirring at room reaction mixture 18h, removal of solvent under reduced pressure obtains title compound (3.5g, 86.3% productive rate) then.MS m/z 501.6 (MH ⁺), R _f(4.89min 10-70%ACN: water, reversed-phase HPLC).

Preparation 87

Xenyl-2-aminocarbamic acid 1-{4-[4-(2-hydroxyethyl) phenyl] butyl } the piperidin-4-yl ester

(2.0g 4.0mmol) drips DIBAL (1.0M is in THF for 24mL, 24mmol) in the solution through stirring in THF (100mL) to the product for preparing 86.After interpolation was finished, stirred reaction mixture 3h came quencher reaction mixture (stopping up to venting) by slow adding methyl alcohol then.Stir this mixture 30min then, add ethyl acetate (200mL) and 1N aqueous sodium hydroxide solution (200mL) then.Separate organic layer and wash dry (MgSO with saturated sodium chloride aqueous solution (100mL) ₄), filtration and removal of solvent under reduced pressure obtain title compound (1.3g, 69% productive rate), and it is used and need not be further purified.MS m/z473.4 (MH+), R _f4.53min (10-70%ACN:H ₂O, reversed-phase HPLC).

Embodiment 23

Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl) ethyl] the piperidin-4-yl ester

To preparation 87 product (500mg, 1.06mmol) add in the solution in methylene dichloride (25mL) through stirring dimethyl sulfoxide (DMSO) (0.60mL, 10.6mmol) and diisopropyl ethyl amine (0.921mL, 5.3mmol).Then reaction mixture is cooled to-10 ℃ and add the pyridine sulphur trioxide (842mg, 5.3mmol).Stirred reaction mixture 1h comes the quencher reaction by adding entry (100mL) then.Stirred this mixture 10 minutes, and removed organic layer then and wash dry (Mg SO with saturated sodium chloride aqueous solution (100mL) ₄), filter then.

In this filtrate, add methyl alcohol (25mL), 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-acetic ester (419mg, 1.06mmol) and triacetyl oxygen base sodium borohydride (468mg, 2.12mmol).Stir this mixture 16h, concentrate then, and in the mixture that obtains, add 1: 1 mixture (20mL) of acetonitrile and moisture 4N hydrochloric acid.This mixture is heated 17h, removal of solvent under reduced pressure then at 50 ℃.In this residue, add 1: 1 mixture (8.0mL) of acetic acid and water and this mixture is obtained title compound (67mg, productive rate 7% is through 3 steps) at the enterprising circumstances in which people get things ready for a trip spectrometry of reverse phase silica gel (gradient elution, 10-50%ACN/ water).MS m/z (MH+) 675.5; R _f(3.07 10-70%ACN: water, reversed-phase HPLC).

Preparation 88

Ethyl 3-[5-(2-ethoxy carbonyl vinyl) benzene sulphur-2-yl] acrylate

(10mL 50mmol), observes hydrogen and emits, and stirring reaction is up to stopping venting (about 30min) to add triethyl phosphine acyl acetic acid ester in the solution through stirring of sodium hydride (60% in mineral oil for 2.1g, 53mmol) in THF (200mL).Add 2 in this reaction mixture, (3g is 21mmol) with stirred reaction mixture 1h for 5-thiophene dicarboxyl aldehyde.Removal of solvent under reduced pressure and in methylene dichloride (200mL) dissolving this residue.Water (100mL), moisture 1N hydrochloric acid (100mL), saturated sodium chloride aqueous solution (100mL) wash organic layer, dry (MgSO ₄), filtration and removal of solvent under reduced pressure obtain title compound (5.8g, productive rate 98%), and it is used and need not to be further purified.

Preparation 89

3-[5-(2-ethoxy carbonyl ethyl) benzene sulphur-2-yl] ethyl propionate

With the nitrogen punching out be equipped with 88 product (5.8g, 21mmol) the solution in methyl alcohol (200mL) through stirring, and add 10% carbon carry palladium (576mg, 10%wt/wt).Alternately be placed on reaction flask under the vacuum and pour 3 circulations of hydrogen, stirred reaction mixture 1h under hydrogen then.Then mixture is dashed with nitrogen, filtration and removal of solvent under reduced pressure obtain title compound (5.8g, productive rate 99%), and it is used and need not to be further purified.

Preparation 90

3-[5-(3-hydroxypropyl) benzene sulphur-2-yl] third-1-alcohol

-78 ℃ of products that in the solution through stir of DIBAL (1.0M is in hexanaphthene for 88mL, 88mmol) in THF (300mL), drip preparation 89 (5.0g, 17.6mmol).After interpolation is finished, through 30min reaction mixture is warmed to room temperature, come the quencher reaction mixture by the moisture 1N hydrochloric acid of slow adding (200mL).Add methylene dichloride (400mL) and separate each layer.Wash the organic layer that merges with methylene dichloride (4x100mL) washing water layer with saturated sodium chloride aqueous solution (100mL), dry (MgSO ₄), filtration and removal of solvent under reduced pressure obtain title compound (3.0g, productive rate 85%), and it is used and need not to be further purified.

Preparation 91

Xenyl-2-aminocarbamic acid 1-{3-[5-(3-hydroxypropyl) benzene sulphur-2-yl] propyl group } the piperidin-4-yl ester

(a) toluene-4-sulfonic acid 3-[5-(3-hydroxypropyl) benzene sulphur-2-yl] propyl diester

To preparation 90 product (423mg, 2.1mmol) add in the solution in THF (20mL) through stirring DABCO (420mg, 4.2mmol), add then p-toluenesulfonyl chloride (442mg, 2.3mmol).At this reaction mixture of stirring at room 2h, removal of solvent under reduced pressure and residue is dissolved in the methylene dichloride (200mL) then.Water (2x100mL), saturated sodium chloride aqueous solution (100mL) wash organic layer, dry MgSO ₄), filtration and removal of solvent under reduced pressure obtain title compound, and it is used and need not to be further purified.

(b) xenyl-2-aminocarbamic acid 1-{3-[5-(3-hydroxypropyl) benzene sulphur-2-yl] propyl group } the piperidin-4-yl ester

In product, add from step (a) acetonitrile (20mL), diisopropyl ethyl amine (0.5mL, 2.8mmol) and the product of preparation 8 (626mg, 2.11mmol).Heat this reaction mixture to 50 ℃ 20h, be cooled to room temperature and removal of solvent under reduced pressure then.(contain 0.6%NH by silica gel chromatography purifying residue ₃The 5%MeOH/DCM of (moisture)) obtains title compound (450mg, productive rate 44%).MS m/z (MH ⁺) 479.6; R _f(4.15min 10-70%ACN: water, reversed-phase HPLC).

Preparation 92

Xenyl-2-aminocarbamic acid 1-[3-(5-{3-[(R)-2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } benzene sulphur-2-yl) propyl group-piperidin-4-yl ester

To preparation 91 product (450mg, 0.94mmol) add in the solution in methylene dichloride (20mL) through stirring dimethyl sulfoxide (DMSO) (0.21mL, 3.7mmol) and diisopropyl ethyl amine (0.65mL, 3.7mmol).With this mixture be cooled to-10 ℃ and add the pyridine sulphur trioxide (444mg, 2.8mmol).Stir this reaction mixture 3h, come the quencher reaction by adding entry (100mL) then.Stirred this mixture 10 minutes, and removed organic layer then and wash dry (MgSO with saturated sodium chloride aqueous solution (100mL) ₄) and filter.

In filtrate, add methyl alcohol (20mL), 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-acetic ester (368mg, 0.93mmol), add then triacetyl oxygen base sodium borohydride (412mg, 1.86mmol).Stir this mixture 19h, concentrate this mixture then and obtain title compound, it is used and need not to be further purified.MS m/z (MH ⁺) 795.8; R _f(4.93min 10-70%ACN: water, reversed-phase HPLC).

Embodiment 24

Xenyl-2-aminocarbamic acid 1-[3-(5-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } benzene sulphur-2-yl) propyl group] the piperidin-4-yl ester

Always from preparing 1: 1 mixture (25mL) that adds acetonitrile and moisture 4N hydrochloric acid in 92 the crude product.50 ℃ of this mixture of heating 17h, removal of solvent under reduced pressure then.In this residue, add 1: 1 mixture (8.0mL) of acetic acid and water and mixture is obtained title compound (135mg, 3 step productive rates 16%) at the enterprising circumstances in which people get things ready for a trip spectrometry of reverse phase silica gel (gradient, 10-50%ACN/ water).MS m/z (MH ⁺) 681.5; R _f(3.03 10-70%ACN: water, reversed-phase HPLC).

Preparation 93

Methyl 4-amino-5-chloro-O-Anisic Acid ester

0 ℃ to 4-amino-5-chloro-O-Anisic Acid (1.008g, 5.0mmol) drip in the solution in toluene (9mL) and methyl alcohol (1mL) mixture (trimethyl silyl) diazomethane (2.0M in hexane, 3.0mL, 6.0mmol).Then this reaction mixture is warmed to room temperature and stirs 16h.By adding excessive (trimethyl silyl) diazomethane of acetic acid quencher, up to bright yellow disappearance of reaction mixture.This mixture of vacuum concentration obtains being the title compound that pale solid arrives then, and it is used and need not to be further purified.

Preparation 94

4-acrylamido-5-chloro-O-Anisic Acid methyl esters

In preparation 93 crude product, add methylene dichloride (10mL, 0.5M) and triethylamine (2.1mL, 15mmol).This mixture is cooled to 0 ℃, and with the agitation and dropping acrylate chloride (812 μ L, 10mmol).Behind the 2h, react the mixture 15m i n that obtains in stirring at room, vacuum concentration then by adding methyl alcohol (about 2mL) quencher at 0 ℃.Methylene dichloride (30mL) and water (30mL) are added this residue and thoroughly mix this mixture.Separate each layer, and with methylene dichloride (20mL) aqueous layer extracted.Merge organic layer, dry (Na ₂SO ₄), filtration and solvent removed in vacuo obtain being brown spumescence solid title compound, and it is used and need not to be further purified.

Preparation 95

4-{3-[4-(xenyl-2-base carbamoyloxy group) piperidines-1-yl] propionyl amino }-5-chloro-O-Anisic Acid methyl esters

Always from prepare the product that adds preparation 8 in 94 the crude product (1.33g, 4.5mmol) and the mixture of THF (22.5mL) and methyl alcohol (2.5mL).With being stirred in 50 ℃ of these mixtures of heating 16 hours, solvent removed in vacuo then.Residue is carried out chromatography (silica gel; EtOAc) obtain being canescence spumescence solid title compound (0.82g; R _f=0.4, productive rate 29% is through 3 steps).MS m/z 566.4 (M+H, C ₃₀H ₃₂ClN ₃O ₆Desired value be 565.20).

Preparation 96

Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-hydroxymethyl-5-methoxyl group-phenylamino formyl radical) ethyl] the piperidin-4-yl ester

0 ℃ to preparation 95 product (0.82mg, 1.45mmol) add in the solution in the mixture of THF (4.5mL) and methyl alcohol (0.5mL) lithium borohydride (32mg, 1.45mmol).Make this reaction mixture be warmed to room temperature and stir 41h.Come the quencher reaction at 0 ℃ by adding the 1N aqueous hydrochloric acid then, up to no longer observing bubble, and stir this mixture 10min.Solvent removed in vacuo, and residue is dissolved in the acetonitrile (about 2mL).By preparation-RP-HPLC (gradient: this solution of the purifying 2-50% acetonitrile in water that 0.05%TFA is arranged).Collect suitable part, merging and freeze-drying obtain being the title compound of trifluoracetic acid salt form.Handle this salt and collected organic layer with sec.-propyl acetic ester (10mL) and 1N aqueous NaOH (10mL), dry (Na ₂SO ₄), filter and the solvent removed in vacuo spumescence solid title compound (161mg, 21% productive rate) that obtains being white in color.MS m/z 538.4 (M+H, C ₂₉H ₃₂ClN ₃O ₅Desired value be 537.20).

Preparation 97

Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-formyl radical-5-p-methoxy-phenyl carbamyl)-ethyl] the piperidin-4-yl ester

To preparation 96 product (161mg, 0.3mmol) add in the solution in methylene dichloride (3mL) dimethyl sulfoxide (DMSO) (213 μ L, 3.0mmol) and diisopropyl ethyl amine (261 μ L, 1.5mmol).With this mixture be cooled to-20 ℃ and slowly add sulfur trioxide pyridine complex (238mg, 1.5mmol).After 30 minutes, come the quencher reaction mixture by adding entry (about 3mL).Separate each layer and dry organic layer (Na ₂SO ₄), filtration and solvent removed in vacuo obtain being the title compound of faint yellow solid.MS m/z 536.3 (M+H, C ₂₉H ₃₀ClN ₃O ₅Desired value be 535.19).

Preparation 98

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2-chloro-5-methoxyl group-phenylamino formyl radical) ethyl] the piperidin-4-yl ester

In the product of the preparation 97 in methylene dichloride (0.5mL) and methyl alcohol (0.5mL) mixture, add 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-8-hydroxyl-1H-quinoline-2-one-acetic ester (124.1mg, 3.1mmol), and the mixture 1.5h that obtains in stirring at room.Adding triacetyl oxygen base sodium borohydride (190.7mg, 0.9mmol), and at stirring at room reaction mixture 15h.Come quencher reaction and this mixture of vacuum concentration to obtain title compound by adding entry (about 0.2mL), it is used and need not to be further purified.MS m/z 854.5 (M+H, C ₄₆H ₅₆ClN ₅O ₇The desired value of Si is 853.36).

Embodiment 25

Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-5-p-methoxy-phenyl carbamyl) ethyl] piperidin-4-yl ester two triflutates

To preparation 98 product methylene dichloride (1.0mL, 0.3M) add in the suspension in triethylamine three hydrofluorides (245 μ L, 1.5mmol).At this mixture of stirring at room 45h, this mixture of vacuum concentration then.Residue was dissolved in DMF (0.5mL), acetonitrile/water (1: 1, has 0.1%TFA, 0.6mL), in TFA (0.3mL) and acetonitrile (about 1mL) mixture, by this mixture of preparation-RP-HPLC purifying (gradient: the 2-50% acetonitrile of 0.05%TFA in water arranged).Collect suitable part, merging and freeze-drying obtain being the title compound (purity 98.7% is passed through HPLC for 100mg, productive rate 34%) of pale solid.MS m/z 740.5 (M+H, C ₄₀H ₄₂ClN ₅O ₇Desired value be 739.28).

Utilize aforesaid method and proper raw material, prepared following compound.

Embodiment	Compound	MS
Embodiment	Compound	MS	26	Xenyl-2-aminocarbamic acid 1-{7-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] heptyl } the piperidin-4-yl ester	613.5
27	Xenyl-2-aminocarbamic acid 1-{8-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] octyl group } the piperidin-4-yl ester	627.5	26		613.5
27		627.5	28	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl) urea groups] ethyl } the piperidin-4-yl ester	705.3
29	Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } piperidines-1-yl)-3-oxygen propyl group] the piperidin-4-yl ester	682.4	28		705.3
29		682.4	30	Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the hexanaphthene carbonyl) amino] ethyl } the piperidin-4-yl ester	682.7
31	Xenyl-2-aminocarbamic acid 1-[2-((1R, 3S)-3-[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino]-the pentamethylene carbonyl } amino) ethyl] the piperidin-4-yl ester	630.2	30		682.7
31		630.2	32	Xenyl-2-aminocarbamic acid 1-[2-(3-{5-[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] amyl group } urea groups) ethyl] the piperidin-4-yl ester	647.5
33	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) ethyl] the piperidin-4-yl ester.	662.5	32		647.5
33		662.5	34	Xenyl-2-aminocarbamic acid 1-[3-(3-{5-[2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] amyl group } urea groups) propyl group] the piperidin-4-yl ester	661.3
35	Xenyl-2-aminocarbamic acid 1-{2-[(4-{2-[(R)-2-hydroxyl-2-	697.5	34		661.3

	(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } piperidines-1-carbonyl) amino] ethyl } the piperidin-4-yl ester
			36	Xenyl-2-aminocarbamic acid 1-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl }-phenyl amino) benzyl] the piperidin-4-yl ester	724.5
37	Xenyl-2-aminocarbamic acid 1-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the benzyl carbamyl) ethyl] the piperidin-4-yl ester	690.3	36		724.5
37		690.3	38	3-[4-(3-xenyl-2-base-urea groups) piperidines-1-yl]-N-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenyl) propionic acid amide	675.5
39	Xenyl-2-aminocarbamic acid 1-{2-[(6-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } pyridine-2-ylmethyl) carbamyl] ethyl } the piperidin-4-yl ester	691.5	38		675.5
39		691.5	40	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the cyclohexyl carbamyl) ethyl] the piperidin-4-yl ester	682.7
41	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the cyclohexyl carbamyl) ethyl] the piperidin-4-yl ester	682.7	40		682.7
41		682.7	42	Xenyl-2-aminocarbamic acid 1-[2-(1R, 3S)-3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino]-the pentamethylene carbonyl } amino) ethyl] the piperidin-4-yl ester	654.8
43	Xenyl-2-aminocarbamic acid 1-{2-[(3-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl) methylamino] ethyl } the piperidin-4-yl ester	690.4	42		654.8
43		690.4	44	Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-2-hydroxyl-2-(8-	696.5

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the hexanaphthene carbonyl) methylamino]-ethyl } the piperidin-4-yl ester
			45	Xenyl-2-aminocarbamic acid 1-[2-(4-{[2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	NA
46	Xenyl-2-aminocarbamic acid 1-[2-(4-{ (S)-1-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	690.7	45		NA
46		690.7	47	Xenyl-2-aminocarbamic acid 1-[2-(4-{ (R)-1-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	690.7
48	Xenyl-2-aminocarbamic acid 1-((S)-1-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] pentanoyl } tetramethyleneimine-2-ylmethyl) the piperidin-4-yl ester	682.7	47		690.7
48		682.7	49	Xenyl-2-aminocarbamic acid 1-[(S)-and 1-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl) tetramethyleneimine-2-ylmethyl] the piperidin-4-yl ester	716.8
50	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy-phenyl)-2-hydroxyl-ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	652.6	49		716.8
50		652.6	51	Xenyl-2-aminocarbamic acid 1-[2-(4-{ (R)-1-[(R)-2-(3-formyl radical amino-4-hydroxy-phenyl)-2-hydroxyl-ethylamino] ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	666.5
52	Xenyl-2-aminocarbamic acid 1-[2-(4-chloro-3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	710.5	51		666.5
52		710.5	53	N-{2-[4-(3-xenyl-2-base-urea groups)-piperidines-1-yl] ethyl }-4-	675.5

	[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzamide
			54	1-xenyl-2-base-3-{1-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } piperidines-1-yl)-3-oxygen-propyl group] piperidin-4-yl } urea	681.7
55	3-[4-(3-xenyl-2-base-urea groups) piperidines-1-yl]-N-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzyl) propionic acid amide	689.5	54		681.7
55		689.5	56	Xenyl-2-aminocarbamic acid 1-(2-fluoro-3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzyl) the piperidin-4-yl ester	637.5
57	Xenyl-2-aminocarbamic acid 1-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-4-methyl-phenylamino formyl radical) ethyl] the piperidin-4-yl ester	690.4	56		637.5
57		690.4	58	Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	710.6
59	Xenyl-2-aminocarbamic acid 1-[2-(2,6-two chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	745.2	58		710.6
59		745.2	60	Xenyl-2-aminocarbamic acid 1-[1-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzoyl)-the piperidin-4-yl methyl] the piperidin-4-yl ester	730.8
61	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy-phenyl)-2-hydroxyethyl amino] methyl }-benzoyl-amido) ethyl] the piperidin-4-yl ester	652.5	60		730.8
61		652.5	62	Xenyl-2-aminocarbamic acid 1-{2-[ethyl-(4-{[(R)-the 2-hydroxyl	704.5

	-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenyl) carbamyl] ethyl } the piperidin-4-yl ester
			63	Xenyl-2-aminocarbamic acid 1-(3-{4-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] piperidines-1-yl }-3-oxygen-propyl group) the piperidin-4-yl ester	NA
64	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	690.3	63		NA
64		690.3	65	Xenyl-2-aminocarbamic acid 1-{2-[(5-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-thiophene-2-carbonyl) amino] ethyl } the piperidin-4-yl ester	682.5
66	Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-3-nitro-benzoyl) methylamino] ethyl } the piperidin-4-yl ester	735.7	65		682.5
66		735.7	67	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] methyl }-the cyclohexyl carbamyl) ethyl] the piperidin-4-yl ester	658.8
68	Xenyl-2-aminocarbamic acid 1-[2-(4-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the hexanaphthene carbonyl }-methylamino) ethyl] the piperidin-4-yl ester	682.7	67		658.8
68		682.7	69	Xenyl-2-aminocarbamic acid 1-(2-fluoro-3-{4-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] piperidines-1-ylmethyl } benzyl) the piperidin-4-yl ester	720.5
70	Xenyl-2-aminocarbamic acid 1-{2-[(6-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } pyridine-3-carbonyl) amino] ethyl } the piperidin-4-yl ester	677.5	69		720.5
70		677.5	71	Xenyl-2-aminocarbamic acid 1-[3-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl	654.5

	Base-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } piperidines-1-yl)-propyl group] the piperidin-4-yl ester
			72	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-(3-formamido group-4-hydroxy phenyl)-2-hydroxyl-ethylamino] ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	666.5
73	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) benzyl] the piperidin-4-yl ester	690.3	72		666.5
73		690.3	74	Xenyl-2-aminocarbamic acid 1-[2-fluoro-3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } piperidines-1-ylmethyl) benzyl] the piperidin-4-yl ester	748.5
75	Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) propyl group] the piperidin-4-yl ester	676.4	74		748.5
75		676.4	76	Xenyl-2-aminocarbamic acid 1-[2-(3-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	710.2
77	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2-trifluoromethoxy-phenylamino formyl radical) ethyl] the piperidin-4-yl ester	769.2	76		710.2
77		769.2	78	Xenyl-2-aminocarbamic acid 1-{3-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) phenyl] propyl group } the piperidin-4-yl ester	752.6
79	Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(S)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) benzyl] the piperidin-4-yl ester	NA	78		752.6
79		NA	80	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl	802.1

	-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2-iodo-phenylamino formyl radical) ethyl] the piperidin-4-yl ester
			81	Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-6-aminomethyl phenyl carbamyl) ethyl] the piperidin-4-yl ester	724.2
82	Xenyl-2-aminocarbamic acid 1-(2-{5-[2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the amyl group carbamyl } ethyl)-the piperidin-4-yl ester	656.5	81		724.2
82		656.5	83	Xenyl-2-aminocarbamic acid 1-[2-(2-bromo-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	756.2
84	Xenyl-2-aminocarbamic acid 1-{3-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino)-phenyl] propyl group } the piperidin-4-yl ester	752.8	83		756.2
84		752.8	85	Xenyl-2-aminocarbamic acid 1-[2-fluoro-3-(4-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } piperidines-1-ylmethyl) benzyl] the piperidin-4-yl ester	762.8
86	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2-methoxyl group-phenylamino formyl radical) ethyl] the piperidin-4-yl ester	706.3	85		762.8
86		706.3	87	Xenyl-2-aminocarbamic acid 1-[5-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) amyl group] the piperidin-4-yl ester	704.3
88	Xenyl-2-aminocarbamic acid 1-{2-[1-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl)-piperidin-4-yl] ethyl } the piperidin-4-yl ester	730.8	87		704.3
88		730.8	89	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-	704.4

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino]-1-methyl-ethyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester
			90	Xenyl-2-aminocarbamic acid 1-{2-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) cyclohexyl] ethyl } the piperidin-4-yl ester	744.4
91	Xenyl-2-aminocarbamic acid 1-[2-(2-fluoro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	694.3	90		744.4
91		694.3	92	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) phenyl] ethyl } the piperidin-4-yl ester	738.8
93	Xenyl-2-aminocarbamic acid 1-[2-(2,5-two fluoro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl] the piperidin-4-yl ester	712.3	92		738.8
93		712.3	94	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl }-benzoyl-amido) ethyl] the piperidin-4-yl ester	690.3
95	Xenyl-2-aminocarbamic acid 1-[6-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } piperidines-1-ylmethyl) pyridine-2-ylmethyl] the piperidin-4-yl ester	717.5	94		690.3
95		717.5	96	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl }-naphthalene-1-base carbamyl) ethyl] the piperidin-4-yl ester	740.6
97	Xenyl-2-aminocarbamic acid 1-{2-[1-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl) piperidin-4-yl] ethyl } the piperidin-4-yl ester	744.4	96		740.6
97		744.4	98	Xenyl-2-aminocarbamic acid 1-[3-(4-{3-[(R)-2-hydroxyl-2-(8-	704.2

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propionyl amino } phenyl) propyl group] the piperidin-4-yl ester
			99	Xenyl-2-aminocarbamic acid 1-[3-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) propyl group] the piperidin-4-yl ester	663.7
100	Xenyl-2-aminocarbamic acid 1-[2-(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-ethyl of 1H-benzimidazolyl-2 radicals-yl)] the piperidin-4-yl ester	673.7	99		663.7
100		673.7	101	Xenyl-2-aminocarbamic acid 1-[2-(4-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propionyl amino } cyclohexyl) ethyl] the piperidin-4-yl ester	696.4
102	Xenyl-2-aminocarbamic acid 1-[2-(4-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] pentanoyl amino } cyclohexyl) ethyl] the piperidin-4-yl ester	724.4	101		696.4
102		724.4	103	Xenyl-2-aminocarbamic acid 1-[2-(4-{6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino]-caproyl amino } cyclohexyl) ethyl] the piperidin-4-yl ester	738.4
104	Xenyl-2-aminocarbamic acid 1-[2-(1-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propionyl } piperidin-4-yl) ethyl] the piperidin-4-yl ester	682.4	103		738.4
104		682.4	105	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenyl) urea groups] ethyl } the piperidin-4-yl ester	691.7
106	Xenyl-2-aminocarbamic acid 1-{2-[(2-{4-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] cyclohexyl } ethyl) methylamino] ethyl } the piperidin-4-yl ester	682.7	105		691.7
106		682.7	107	Xenyl-2-aminocarbamic acid 1-[2-(2,3,5,6-tetrafluoro-4-	748.2

	[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical)-ethyl] the piperidin-4-yl ester
			108	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2,6-two iodo-phenylamino formyl radicals) ethyl] the piperidin-4-yl ester	928.0
109	Xenyl-2-aminocarbamic acid 1-[2-(1-{4-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino]-butyryl radicals } piperidin-4-yl) ethyl] the piperidin-4-yl ester	696.4	108		928.0
109		696.4	110	Xenyl-2-aminocarbamic acid 1-[2-(1-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] pentanoyl } piperidin-4-yl) ethyl] the piperidin-4-yl ester	710.4
111	Xenyl-2-aminocarbamic acid 1-[2-(1-{6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino]-caproyl } piperidin-4-yl) ethyl] the piperidin-4-yl ester	724.4	110		710.4
111		724.4	112	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the benzyl carbamyl) ethyl] the piperidin-4-yl ester	690.5
113	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy-phenyl)-2-hydroxyethyl amino] methyl }-the benzyl carbamyl) ethyl] the piperidin-4-yl ester	666.5	112		690.5
113		666.5	114	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzyl) urea groups] ethyl } the piperidin-4-yl ester	705.6
115	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] methyl } benzyl)-urea groups] ethyl } the piperidin-4-yl ester	681.7	114		705.6
115		681.7	116	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-	690.4

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-2-methyl-phenylamino formyl radical) ethyl] the piperidin-4-yl ester
			117	Xenyl-2-aminocarbamic acid 1-(3-{4-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } piperidines-1-yl) ethyl] phenoxy group } propyl group)-the piperidin-4-yl ester	774.4
118	Xenyl-2-aminocarbamic acid 1-[2-(3-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl }-the benzyl carbamyl) ethyl] the piperidin-4-yl ester	690.4	117		774.4
118		690.4	119	Xenyl-2-aminocarbamic acid 1-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethyl] the piperidin-4-yl ester	649.5
120	Xenyl-2-aminocarbamic acid 1-(2-{[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethanoyl] methylamino } ethyl) the piperidin-4-yl ester	720.4	119		649.5
120		720.4	121	Xenyl-2-aminocarbamic acid 1-(2-{[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethanoyl] methylamino } ethyl)-the piperidin-4-yl ester	720.4
122	Xenyl-2-aminocarbamic acid 1-{2-[(5-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } furans-2-carbonyl) methylamino] ethyl } the piperidin-4-yl ester	680.3	121		720.4
122		680.3	123	Xenyl-2-aminocarbamic acid 1-{2-[(5-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-thiophene-2-carbonyl) methylamino] ethyl }-the piperidin-4-yl ester	696.2
124	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] oxyethyl group } phenoxy group) ethyl] the piperidin-4-yl ester	679.3	123		696.2
124		679.3	125	Xenyl-2-aminocarbamic acid 1-{2-[4-(4-{[(R)-2-hydroxyl-2-	758.4

	(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl-amido) cyclohexyl] ethyl } the piperidin-4-yl ester
			126	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(2-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] cyclohexyl } ethyl)-the piperidin-4-yl ester	788.4
127	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] cyclohexyl } ethyl)-the piperidin-4-yl ester	788.4	126		788.4
127		788.4	128	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] cyclohexyl } ethyl)-the piperidin-4-yl ester	788.4
129	Xenyl-2-aminocarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } furans-2-carbonyl) amino] cyclohexyl }-ethyl) the piperidin-4-yl ester	748.4	128		788.4
129		748.4	130	Xenyl-2-aminocarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-thiophene-2-carbonyl) amino] cyclohexyl }-ethyl) the piperidin-4-yl ester	764.4
131	Xenyl-2-aminocarbamic acid 1-(2-{1-[2-(2-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethanoyl] piperidin-4-yl } ethyl)-the piperidin-4-yl ester	774.4	130		764.4
131		774.4	132	Xenyl-2-aminocarbamic acid 1-(2-{1-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethanoyl] piperidin-4-yl } ethyl)-the piperidin-4-yl ester	774.4
133	Xenyl-2-aminocarbamic acid 1-(2-{1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) ethanoyl] piperidin-4-yl } ethyl)-the piperidin-4-yl ester	774.4	132		774.4
133		774.4	134	Xenyl-2-aminocarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxyl-2-	734.4

	(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } furans-2-carbonyl) piperidin-4-yl] ethyl } the piperidin-4-yl ester
			135	Xenyl-2-aminocarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-thiophene-2-carbonyl) piperidin-4-yl] ethyl } the piperidin-4-yl ester	750.2
136	Xenyl-2-aminocarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl-amido) phenyl] ethyl } the piperidin-4-yl ester	752.4	135		750.2
136		752.4	137	Xenyl-2-aminocarbamic acid 1-{2-[4-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl-amido) phenyl] ethyl } the piperidin-4-yl ester	752.4
138	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(2-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] phenyl } ethyl)-the piperidin-4-yl ester	782.4	137		752.4
138		782.4	139	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] phenyl } ethyl)-the piperidin-4-yl ester	782.4
140	Xenyl-2-aminocarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) acetylamino] phenyl } ethyl)-the piperidin-4-yl ester	782.4	139		782.4
140		782.4	141	Xenyl-2-aminocarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } furans-2-carbonyl) amino] phenyl } ethyl) the piperidin-4-yl ester	742.4
142	Xenyl-2-aminocarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-thiophene-2-carbonyl) amino] phenyl }-ethyl) the piperidin-4-yl ester	758.2	141		742.4
142		758.2	143	Xenyl-2-aminocarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxyl-2-(8-	758.4

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-benzoyl-amido) cyclohexyl] ethyl } the piperidin-4-yl ester
			144	Xenyl-2-aminocarbamic acid 1-[3-(3-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group)-propyl group] the piperidin-4-yl ester	663.4
145	Xenyl-2-aminocarbamic acid 1-[2-hydroxyl-3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) propyl group] the piperidin-4-yl ester	692.3	144		663.4
145		692.3	146	Xenyl-2-aminocarbamic acid 1-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) butyl] the piperidin-4-yl ester	690.4
147	Xenyl-2-aminocarbamic acid 1-{2-[4-(2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] acetylamino }-methyl) the phenylamino formyl radical] ethyl } the piperidin-4-yl ester	733.3	146		690.4
147		733.3	148	Xenyl-2-aminocarbamic acid 1-{2-[4-(2-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] acetylamino } ethyl) the phenylamino formyl radical] ethyl } the piperidin-4-yl ester	747.4
149	Xenyl-2-aminocarbamic acid 1-{2-[(4-{[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-cyclohexyl methyl) carbamyl] ethyl } the piperidin-4-yl ester	696.6	148		747.4
149		696.6	150	Xenyl-2-aminocarbamic acid 1-(2-{6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] caproyl amino }-ethyl) the piperidin-4-yl ester	656.6
151	Xenyl-2-aminocarbamic acid 1-[2-(3-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] oxyethyl group } phenoxy group) ethyl] the piperidin-4-yl ester	679.3	150		656.6
151		679.3	152	Xenyl-2-aminocarbamic acid 1-[2-(2-{2-[(S)-2-hydroxyl-2-(8-	679.3

	Hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] oxyethyl group } phenoxy group) ethyl] the piperidin-4-yl ester
			153	Xenyl-2-aminocarbamic acid 1-[2-(2-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } phenoxy group) benzyl] the piperidin-4-yl ester	711.3
154	Xenyl-2-aminocarbamic acid 1-(2-{6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the hexyl carbamyl } ethyl) the piperidin-4-yl ester	670.4	153		711.3
154		670.4	155	Xenyl-2-aminocarbamic acid 1-[2-((1R, 3S)-3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the pentamethylene carbonyl } amino) ethyl] the piperidin-4-yl ester	654.8
156	Xenyl-2-aminocarbamic acid 1-[3-(4-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } phenyl) propyl group] the piperidin-4-yl ester	675.5	155		654.8
156		675.5	157	Xenyl-2-aminocarbamic acid 1-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl) propyl group] the piperidin-4-yl ester	661.3
158	Xenyl-2-aminocarbamic acid 1-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl) butyl] the piperidin-4-yl ester	675.5	157		661.3
158		675.5	159	Xenyl-2-aminocarbamic acid 1-[3-(5-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } furans-2-yl) propyl group] the piperidin-4-yl ester	665.6
160	Xenyl-2-aminocarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl)-1-methyl urea groups] ethyl } the piperidin-4-yl ester	719.2	159		665.6
160		719.2	161	Xenyl-2-aminocarbamic acid 1-{2-[1-(4-{2-[(R)-2-hydroxyl	773.3

	-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } the phenylamino formyl radical) piperidin-4-yl] ethyl } the piperidin-4-yl ester
			162	Xenyl-2-aminocarbamic acid 1-[3-(3-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] propyl group } phenyl) propyl group] the piperidin-4-yl ester	675.5
163	Xenyl-2-aminocarbamic acid 1-[3-(5-{3-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1 ', 2-dihydroquinoline-5-yl) ethylamino] propyl group } tetrahydrofuran (THF)-2-yl) propyl group] the piperidin-4-yl ester	669.6	162		675.5
163		669.6	164	Xenyl-2-aminocarbamic acid 1-[2-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] the ethyl carbamyl } phenoxy group) ethyl] the piperidin-4-yl ester	706.5
165	(5-bromo biphenyl base-2-yl) carboxylamine 1-{9-[2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl }-the piperidin-4-yl ester	NA	164		706.5
165		NA	166	(2 '-fluorine xenyl-2-yl) carboxylamine 1-{9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl }-the piperidin-4-yl ester	659.5
167	(3 '-chloro-3,5-difluoro biphenyl-2-yl) carboxylamine 1-{9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl)-ethylamino] nonyl } the piperidin-4-yl ester	711.8	166		659.5
167		711.8	168	(3 ', 5 '-two chloro-3,5-difluoro biphenyl-2-yl) carboxylamine 1-9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl)-ethylamino] nonyl } the piperidin-4-yl ester	745.5
169	(3,5-difluoro biphenyl-2-yl) carboxylamine 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl } the piperidin-4-yl ester	677.5	168		745.5

Preparation 99

Xenyl-2-aminocarbamic acid 1-[2-(4-[1,3] dioxolane-2-base phenylamino formyl radical)-ethyl]-4 methyl piperidines-4-base ester

50 ℃ under nitrogen with xenyl-2-aminocarbamic acid 4-methyl piperidine-4-base ester (2.73g, 8.79mmol) and N (4-[1,3] dioxolane-2-base-phenyl) (2.05g, mixture 8.80mmol) in ethanol/methylene heats 1h at 100mL to acrylamide at 1: 1.Dilute this solution and water, salt water washing organic layer with ethyl acetate then, dry (MgSO ₄) and concentrating under reduced pressure obtain title compound.C ₃₁H ₃₅N ₃O ₅MS m/z (M+H) ⁺Calculated value is 530.6; Measured value is 530.4.

Preparation 100

Xenyl-2-aminocarbamic acid 1-[2-(4-formyl radical phenylamino formyl radical) ethyl]-4 methyl piperidines-4-base ester

Be dissolved in preparation 99 product in the 40mL methyl alcohol again and add the moisture 1N hydrochloric acid of 25mL.Remove organic solvent in mixture overnight and decompression that stirring at room obtains.Residue is dissolved in the ethyl acetate water, salt water washing organic layer, dry (MgSO ₄) and removal of solvent under reduced pressure.With methylene dichloride grinding product obtain the being white in color title compound (2.47g) of powder.LCMS (2-90) R _t=4.27min; C ₂₉H ₃₁N ₃O ₄(M+H) ⁺MS m/z calculated value be 486.6, measured value is 486.5.

Preparation 101

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl]-4-methyl-piperidin-4-yl ester

To prepare 100 product (1.70g in room temperature, 3.51mmol) and 5-[(R)-2-amino-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-(1.65g, mixture 4.19mmol) stir in 1: 1 methyl alcohol of 40mL and methylene dichloride and spend the night 8-hydroxyl-1H-quinoline-2-one-acetic ester.Add then a triacetyl oxygen base sodium borohydride (2.23g, 10.5mmol), and stirring at room reaction mixture 6 hours.The water quencher is reacted and is diluted with ethyl acetate then.Separate each layer, and with saturated sodium bicarbonate, salt water washing organic layer, dry (MgSO ₄) and removal of solvent under reduced pressure obtain title compound (2.9g).C ₄₆H ₅₇N ₅O ₆Si (M+H) ⁺MS m/z calculated value be 805.0, measured value is 804.6.

Embodiment 170

Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-the phenylamino formyl radical) ethyl]-4-methyl piperidine-4-base ester

With preparation 101 product (2.9g, 3.6mmol) be dissolved in the 75mL methylene dichloride and add triethylamine three hydrofluorides (0.85mL, 5.2mmol).In the mixture overnight that stirring at room obtains, removal of solvent under reduced pressure obtains being the buttery crude product then.Then this product is dissolved in acetic acid/water (1: 1) and obtains being the title compound of pale solid by preparation property HPLC purifying.LCMS (2-90) R _t=3.67min.; C ₄₀H ₄₃N ₅O ₆(M+H) ⁺MS m/z calculated value be 690.8, measured value is 690.3.

Utilize aforesaid method and proper raw material, can prepare following compound.

Embodiment	Compound	MS
Embodiment	Compound	MS	171	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] methyl } the phenylamino formyl radical)-ethyl]-4-methyl piperidine-4-base ester	NA
172	Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl }-4-methyl piperidine-4-base ester	NA	171		NA
172		NA	173	Xenyl-2-aminocarbamic acid 1-{9-[(R)-and 2-(3-formyl radical amino-4-hydroxy-phenyl)-2-hydroxyethyl amino] nonyl }-4-methyl piperidine-4-base ester	NA
174	Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,	NA	173		NA

	2-dihydroquinoline-5-yl) ethylamino] the amyl group carbamyl }-ethyl)-4-methyl piperidine-4-base ester
			175	Xenyl-2-aminocarbamic acid 1-(2-{5-[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] the amyl group carbamyl } ethyl)-4-methyl piperidine-4-base ester	NA
176	Xenyl-2-aminocarbamic acid 1-(2-{6-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] caproyl amino } ethyl)-4-methyl piperidine-4-base ester	NA	175		NA
176		NA	177	Xenyl-2-aminocarbamic acid 1-(2-{6-[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] caproyl amino } ethyl)-4-methyl piperidine-4-base ester	NA
178	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } benzoyl-amido) ethyl]-4-methyl piperidine-4-base ester	NA	177		NA
178		NA	179	Xenyl-2-aminocarbamic acid 1-[2-(4-{[(R)-2-(3-formyl radical amino-4-hydroxy phenyl)-2-hydroxyethyl amino] methyl } benzoyl-amido) ethyl]-4-methyl piperidine-4-base ester	NA
180	Xenyl-2-aminocarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] ethyl } phenyl amino) phenyl] propyl group }-4-methyl piperidine-4-base ester	776.5	179		NA
180		776.5	181	Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl } the phenylamino formyl radical) ethyl]-4-methyl piperidine-4-base ester	724.5
182	Xenyl-2-aminocarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] methyl }-5-p-methoxy-phenyl carbamyl) ethyl]-4-methyl piperidine-4-base ester	754.5	181		724.5

Preparation 102

Xenyl-2-aminocarbamic acid (R)-(1-azabicyclic [3.2.1] suffering-4-yl) ester

With 2-xenyl isocyanate (1.00g, 5.12mmol) and (R)-(-)-3-hydroxyl quinine pyridine (quinuclidinol) hydrochloride (921mg, 5.63mmol) together at N, in the N dimethyl formamide (2.06mL) at 110 ℃ of heating 12h.Cool off this reaction mixture and, use saturated sodium bicarbonate aqueous solution (2x10mL) washing then with ethyl acetate (15mL) dilution.With 1M hydrochloric acid (3x20mL) extraction organic layer, with salt of wormwood make the aqueous extract of merging be alkalescence to pH be 8-9.With the organic layer that ethyl acetate (3x20mL) aqueous layer extracted and drying (sal epsom) merge, removal of solvent under reduced pressure obtains being the title compound (1.64g, 99% productive rate) of yellow oil.

Preparation 103

(R)-4-(xenyl-2-base carbamoyloxy group)-assorted dicyclo [3.2.1] octane bromide of 1-(9-bromine nonyl)-1-nitrogen 

To preparation 102 product (1.21g, 3.76mmol) and triethylamine (1.05mL, (994 μ L 4.89mmol) and at 50 ℃ heat this reaction mixture 4h 7.52mmol) to add 1,9 two bromononane in the solution through stirring in acetonitrile (18.8mL).Cool off this reaction mixture and removal of solvent under reduced pressure then.Residue is dissolved in methylene dichloride (20mL) neutralization washs organic layer, dry (sal epsom) and removal of solvent under reduced pressure with saturated sodium bicarbonate aqueous solution (10mL).Obtain title compound (1.04g, 1.97mmol, productive rate 52%) by hurried chromatography purification crude product (10% ethanol/methylene, 0.5% ammonium hydroxide).

Preparation 104

(R)-1-(9-N, the amino nonyl of N-two (uncle-butoxy carbonyl))-4-(xenyl-2-base carbamoyloxy group)-assorted dicyclo [3.2.1] octane bromide of 1-nitrogen 

At 0 ℃ under nitrogen atmosphere, to sodium hydride (60% in mineral oil dispersion) (126mg, 3.15mmol) at N, be added in N in the solution in the dinethylformamide (10mL) through stirring, two-tertbutylimido dicarboxylic ester in the dinethylformamide (5mL) (513mg, 2.36mmol).This reaction mixture of stirring at room 15 minutes, then it is cooled to 0 ℃ and be added in N, the product of the preparation 103 in the N dimethyl formamide (5mL) (1.04g, 1.97mmol).Through 12 hours reaction mixture is warmed to room temperature, removal of solvent under reduced pressure obtains title compound then, and it is employed and need not to be further purified.

Preparation 105

(R)-1-(the amino nonyl of 9-)-4-(xenyl-2-base carbamoyloxy group)-assorted dicyclo [3.2.1] octane bromide of 1-nitrogen 

(1.31g 1.97mmol) is dissolved in methylene dichloride (15mL) neutralization and slowly adds trifluoracetic acid (5mL) with preparation 104 product.In stirring at room reaction mixture 1h, removal of solvent under reduced pressure then.Residue is dissolved in the methylene dichloride (20mL) also with 1M aqueous sodium hydroxide solution (20mL) washing.With 1M hydrochloric acid (3x20mL) extraction organic layer, make the aqueous extract of merging be alkalescence also with methylene dichloride (3x20mL) extraction with salt of wormwood.Organic layer and removal of solvent under reduced pressure that dry (sal epsom) merges obtain title compound (210mg, productive rate 23% is through 2 steps).

Preparation 106

(R)-1-{9-[(R)-2-(8-benzyloxy-2-oxygen-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl amino]-nonyl }-4-(xenyl-2-base carbamoyloxy group)-assorted dicyclo [3.2.1] octane bromide of 1-nitrogen 

With preparation 105 product (210mg, 0.45mmol) and triacetyl oxygen base sodium borohydride (286mg, 1.35mmol) in ethylene dichloride (4.5mL) at stirring at room 2h, add then preparation 6 product (163mg, 0.50mmol).Stir this reaction mixture 12h, use methylene dichloride (10mL) dilution then and wash dry (sal epsom) and removal of solvent under reduced pressure with saturated sodium bicarbonate aqueous solution (10mL).Obtain title compound (131mg, productive rate 38%) by hurried chromatography purification crude reaction product (10-50% ethanol/methylene, 0.5% ammonium hydroxide).

Embodiment 183

4-(xenyl-2-base carbamoyloxy group)-1-{9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl)-ethylamino] nonyl }-assorted dicyclo [2.2.2] octane bromide two triflutates of 1-nitrogen 

To preparation 105 product (131mg, (the 10wt.% butt is on gac 0.17mmol) to add palladium in the solution through stirring in methyl alcohol (1.8mL); 39mg) and with reaction mixture be placed under the nitrogen atmosphere.After stirring 12h, through the Celite pad filter reaction mixture, with methyl alcohol (2mL) washing and removal of solvent under reduced pressure.The resistates that obtains by preparation property HPLC purifying obtains being title compound (8mg) the .MS m/z 667.5 of its two trifluoroacetates.

Utilize method described herein and proper raw material, can be prepared as follows compound.

Embodiment	Compound	MS
Embodiment	Compound	MS	184	Xenyl-2-aminocarbamic acid 8-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl }-8-azabicyclo [3.2.1] oct-3-yl ester	667.3
185	7-(xenyl-2-base carbamoyloxy group)-9-{9-[(R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl)-ethylamino] nonyl }-assorted three ring [3.3.1,02,4] the nonane bromides of 9-methyl-3-oxa--9-nitrogen 	695.5	184		667.3
185		695.5	186	Xenyl-2-aminocarbamic acid 9-{9-[(R)-and 2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-yl) ethylamino] nonyl }-3-oxa--9-azepine-three ring [3.3.1.02,4] ninth of the ten Heavenly Stems-7-base ester	681.5

Preparation A

Cell cultures and from expressing human β ₁, β ₂Or β ₃The membrane prepare of the cell of adrenergic receptor

In the presence of 500 μ g/mL Geneticins, make stably express clone's people β respectively ₁, β ₂Or β ₃The Chinese hamster ovary of adrenergic receptor (CHO) clone grows in the Hams F-12 substratum of 10%FBS is arranged near converging.The 2mM EDTA that is used among the PBS floats cell monolayer.By coming sedimentation cell in that 1000rpm is centrifugal, with cell precipitation-80 ℃ of refrigerated storage or prepare film immediately and use.For β ₁And β ₂The preparation of expression of receptor film is suspended in cell precipitation in dissolving damping fluid (pH7.4 is at 4 ℃ for 10mM HEPES/HCl, 10mM EDTA) again and utilizes the Dounce glass homogenizer that closely is fit at homogenize on ice (30 stroke).For more protease-sensitive β ₃The expression of receptor film, make the cell precipitation thing be supplemented with dissolving damping fluid (the Roche Catalog No.1697498 of a slice " the adequate proteins enzyme inhibitors cocktail sheet that 2mM DETA is arranged " at every 50mL damping fluid, Roche Molecular Biochemicals, Indianapolis, IN) middle homogenize.20,000xg is centrifugal with this homogenate, and with the dissolving damping fluid by suspendible and the centrifugal precipitation that once obtains of washing again as mentioned above.Then final precipitation is suspended in again ice-cold combination test damping fluid (75mM Tris/HCl pH7.4,12.5mM MgCl ₂, 1mM EDTA) in.By in Lowry etc., 1951, Journalof Biological Chemisty, 193,265; And Bradford, AnalyticalBiochemistry, 1976,72, the method for describing among the 248-54 is measured the protein concn of film suspension.With all films with aliquot-80 ℃ of refrigerated storage or use immediately.

Preparation B

Cell cultures and from expressing human M ₁, M ₂, M ₃And M ₄The membrane prepare of the cell of M-ChR

Make stably express clone's people hM respectively ₁, hM ₂, hM ₃And hM ₄The Chinese hamster ovary celI of M-ChR hypotype ties up to and grows in the HAM ' s F-12 substratum that is supplemented with 10%FBS and 250 μ g/mL Geneticins near converging.Make cell at 5%CO ₂, growth and the 2mM EDTA that is used among the dPBS float it in 37 ℃ of incubators.By at 650xg5 minute centrifugal collecting cell, with cell precipitation-80 ℃ of refrigerated storage or prepare film immediately and use.As for membrane prepare, cell precipitation is suspended in the dissolving damping fluid more also with Polytron PT-2100 tissue disruption machine (Kinematica AG; Break for 20 seconds x2 time) homogenate.4 ℃ 40, the centrifugal rough film of 000xg 15 minutes.Then the film precipitation is used suspendible damping fluid suspendible more again, and use the homogenate of Polytron tissue disruption machine once more.By at Lowry etc., 1951, Journal ofBiochemistry, the method for describing in 193,265 is measured the protein concn of film suspension.All films are kept in cold storage or use immediately at-80 ℃ with aliquot.The hM of the preparation of aliquot ₅Receptor membrane is directly available from Perkin Elmer and be stored in-80 ℃ up to use.

Method for testing and detecting A

People β ₁, β ₂And β ₃The radioligand of adrenergic receptor is in conjunction with test

Overall test volume with 100 μ l in 96 hole microtiter plates carries out the combination test, and the test damping fluid (75mM tris/HCl pH7.4, at 25 ℃, 12.5mM MgCl ₂, 1mMEDTA has 10-15 μ g to comprise the membrane protein of people β 1, β 2 or beta 3 adrenoreceptor in 0.2%BSA).Measuring the saturated of radioligand Kd value is to utilize for β in conjunction with research ₁And β ₂Acceptor [ ³H]-the dihydro alprenolol (NET-720,100Ci/mmol, PerkinElmerLife Sciences Inc., Boston, MA) and [ ¹²⁵I]-(-)-iodine cyanoindole Luo Er (NEX-189,220Ci/mmol, PerkinElmer Life Sciences Inc., Boston MA), carries out with 10 or 11 different concns of 0.01nM-20nM scope.The displacement test of determination test compound K i value is to use 1nM[ ³H]-dihydro alprenolol and 0.5nM[ ¹²⁵I]-(-)-iodine cyanoindole Luo Er, be used for that test compound at 10 or 11 different concns of 10pM-10 μ M scope carries out.In the presence of 10 μ M propranolols, measure non-specific binding.Trier was cultivated 1 hour at 37 ℃, then by in being immersed in 0.3% polymine in advance for β ₁And β ₂The GF/B of acceptor or for β ₃(CT) filtration stops association reaction to the GF/C glass fibre filter plate of acceptor fast for PackardBioScience Co., Meriden.(75mM tris/HCl pH7.4 is at 4 ℃, 12.5mM MgCl with filtering damping fluid ₂, 1mM EDTA) washing filter plate remove not binding radioactivity three times.Dry then this plate, add 50 μ lMicroscint-20 liquid scintillation solutions (Packard BioScience Co., Meriden is CT) and at Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden, CT) middle this plate of counting.The 3-parametric model that utilizes a site to compete is used the GraphPadPrism software package, and (San Diego CA) analyzes binding data by nonlinear regression analysis for GraphPad Software, Inc..When in the presence of 10 μ M propranolols, measuring, curve minimum is fixed on the value of non-specific binding.Utilize the Cheng-Prusoff equation from observed IC ₅₀The K of value and radioligand _dValue is calculated the K of test compound _iValue (Cheng Y and Prusoff WH., Biochemical Pharmacology, 1973,22,23,3099-108).

In this test, lower Ki value shows that test compound has higher binding affinity to the acceptor that is tried.The illustration compound of the present invention that is tried in this test is found usually to β ₂Adrenergic receptor has the K less than about 300nM _iValue.For example, embodiment 3 and 6 compound are found the K that has less than 10nM _iValue.

If desired, the receptor subtype selectivity of test-compound can be calculated as K _i(β ₁)/K _i(β ₂) ratio or K _i(β ₃)/K _i(β ₂) the ratio.Usually, The compounds of this invention is proved to be and β ₁Or β ₃Adrenergic receptor is compared at β ₂Bigger combination is arranged, i.e. K on the adrenergic receptor _i(β ₁) or K _i(β ₃) usually greater than K _i(β ₂).Usually, with respect to β ₁Or β ₃Adrenergic receptor is to β ₂Adrenergic receptor has optionally, and compound is preferred; Particularly have greater than about 5; And especially greater than about 8 optionally compound.By way of example, embodiment 3 and 6 compound have the K greater than 8 _i(β ₁)/K _i(β ₂) ratio.

Method for testing and detecting B

About the radioligand of M-ChR in conjunction with test

The radioligand of people's M-ChR of cloning with the overall test volume of 100 μ l in 96 hole microtiter plates is in conjunction with test.With stably express hM ₁, hM ₂, hM ₃, hM ₄Or hM ₅The Chinese hamster ovary celI film of muscarine hypotype is diluted in the test damping fluid to following specific target protein concentration (μ g/ hole): for hM ₁10 μ g are for hM ₂10 μ g-15 μ g are for hM ₃10 μ g-20 μ g are for hM ₄L0 μ g-20 μ g and for hM ₅10 μ g-12 μ g obtain similar signal (cpm).Before adding, test board utilizes Polytron tissue disruption machine this film of homogenize (10 seconds) momently.Measure radioligand K _DValue saturated in conjunction with research be utilize the L-[N-of 0.001nM-20nM concentration methyl- ³H] the chloromethane Scopolamine ([ ³H]-NMS) (TRK666,84.0Ci/mmol, Amersham Pharmacia Biotech, Buckinghamshire England) carries out.The determination test compound K _iThe displacement test of value is to use 1nM[ ³H]-NMS and 11 different tests compound concentrations carry out.At first test compound is dissolved in the dilution buffer liquid to concentration be 400 μ M, then with dilution buffer liquid dilute 5 continuously * to ultimate density be 10pM to 100 μ M.The order and the volume that are added into test board are as follows: 25 μ L radioligands, the test compound and the 50 μ L films of 25 μ L dilution.37 ℃ of culture experiment plates 60 minutes.By (MA) filtration stops association reaction fast for PerkinElmer Inc., Wellesley through pretreated GF/B glass fibre filter plate in 1%BSA.Remove not binding radioactivity three times with lavation buffer solution (10mM HEPES) flushing filter plate.This plate of dry air then, and to each hole add 50 μ L Microscint-20 liquid scintillation solutions (Perkin Elmer Inc., Wellesley, MA).Then at PerkinElmer Topcount liquid scintillation counter (PerkinElmer Inc., Wellesley, MA) middle this plate of counting.(San Diego CA) analyzes binding data by nonlinear regression analysis for GraphPad Software, Inc. with Gra phPad Prism software package to utilize a site competitive model.Utilize the Cheng-Prusoff equation from observed IC ₅₀The K of value and radioligand _DValue is calculated the K of test compound _iValue (Cheng Y; Prusoff WH. (1973) BiochemicalPharmacology, 22 (23): 3099-108).With K _iValue changes into pK _iValue is determined geometric mean and 95% fiducial interval.Then these generalized statistical figure are transformed back K again _iValue is used for data report.

In this test, lower K _iValue shows that test compound has higher binding affinity to the acceptor that is tried.The compound for example of the present invention that is tried in this test is found usually for M ₃M-ChR has the K less than about 300nM _iValue.For example, embodiment 3 and 6 compound are found the K that has less than 10nM _iValue.

Method for testing and detecting C

At heterology expressing human β ₁, β ₂Or β ₃Full cell cAMP Flash board test in the Chinese hamster ovary celI system of adrenergic receptor

Explanation utilization according to the manufacturer have [ ¹²⁵I]-the Flash board adenylate cyclase activating pilot system of cAMP with the radioimmunoassay form carry out the cAMP test (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA).For beta receptor agonist usefulness (EC ₅₀) mensuration, make stably express clone's people β ₁, β ₂Or β ₃The CHO-K1 clone of adrenergic receptor grows in HAM ' the s F-12 substratum that is supplemented with 10%FBS and Geneticin (250 μ g/ml) near converging.Wash cell with PBS, and at the dPBS (Dulbecco ' s phosphate buffered saline (PBS), the no CaCl that comprise 2mM BDTA or trypsinase-EDTA solution (0.05% trypsinase/0.53mM EDTA) ₂And MgCl ₂) middle isolated cell.In the Coulter cell counter behind the counting cells, by 1000rpm centrifugal come sedimentation cell and be suspended in again in the stimulation damping fluid that comprises I BMX (PerkinElmer test kit) that is warmed to room temperature in advance to concentration be every milliliter of 1.6x10 ⁶To 2.8x10 ⁶Cell.In this test, use every hole about 60000-80000 cell.(10mM is in DMSO) is diluted among the PBS that comprises 0.1%BSA in Beckman Biomek-2000 with test-compound, and tests under 11 different concns of 100 μ M-1pM.Reactant was cultivated 10 minutes at 37 ℃, and by adding comprise [ ¹²⁵I]-(Boston MA) comes stopped reaction for NEN SMP004, PerkinElmer Life Sciences for the ice-cold detection damping fluid of 100 μ L of cAMP.Calculate the amount (pmol/ hole) of the cAMP of generation based on the counting of observed sample and the cAMP standard in manufacturer's user manual, described.(San Diego CA) comes analytical data by nonlinear regression analysis for GraphPad Software, Inc. with GraphPad Prism software package with contrary flexure (sigmoidal) equation.Use Cheng-Prusoff equation (Cheng Y, and PrusoffWH., Biochemical Pharmacology, 1973,22,23,3099-108) calculate the EC50 value.

In this test, lower EC ₅₀Value shows that test-compound has higher functionally active at the acceptor that is tried.The compound for example of the present invention that is tried in this test is found usually for β ₂Adrenergic receptor has the EC less than about 300nM ₅₀Value.For example, embodiment 3 and 6 compound are found the EC that has less than 10nM ₅₀Value.

If desired, the receptor subtype selectivity of test-compound can be calculated as EC ₅₀(β ₁)/EC ₅₀(β ₂) ratio or EC ₅₀(β ₃)/EC ₅₀(β ₂) the ratio.Usually, The compounds of this invention proof and β ₁Or β ₃Adrenergic receptor is compared at β ₂Bigger functionally active is arranged, i.e. EC on the adrenergic receptor ₅₀(β ₁) or EC ₅₀(β ₃) usually greater than EC ₅₀(β ₂).Usually, with respect to β ₁Or β ₃Adrenergic receptor is to β ₂Adrenergic receptor has optionally, and compound is preferred; Particularly have greater than about 5; And especially greater than about 8 optionally compound.By way of example, embodiment 3 and 6 compound have the EC greater than 10 ₅₀(β ₁)/EC ₅₀(β ₂) ratio.

Method for testing and detecting D

Function test to the antagonistic action of M-ChR hypotype

The retardance of the inhibition of A.cAMP cumulative agonist mediation

In this test, be arrested in expression hM by the experiment with measuring compound ₂The ability that the cAMP cumulative oxotremorine of forskolin-mediation in the CHO-K1 cell of acceptor suppresses is measured the function of test-compound and is renderd a service.According to manufacturer's explanation, utilization has ¹²⁵The Flash board adenylate cyclase activating pilot system of I-cAMP with the radioimmunoassay form carry out cAMP test (NEN SMP004B, PerkinElmer Life Sciences Inc., Boston, MA).With dPBS flushing cell once, and with trypsinase-EDTA solution (0.05% trypsinase/0.53mM EDTA) float cell as description in cell cultures and the membrane prepare partly in the above.By in 50mL dPBS, washing isolated cells twice in centrifugal five minutes at 650xg.Then cell precipitation is suspended among the 10mL dPBS again, and (Beckman Coulter, Fullerton CA) come counting cells with Coulter Z1 binary alpha counter.In this cell of 650xg recentrifuge five minutes, and be suspended in again stimulate in the damping fluid to analytical concentration be every milliliter of 1.6x10 ⁶-2.8x10 ⁶Individual cell.

Earlier test-compound is dissolved in the dilution buffer liquid (being supplemented with the dPBS of 1mg/mL BSA (0.1%)) to concentration be 400 μ M, being diluted to final volumetric molar concentration with dilution buffer liquid continuously then is 100 μ M to 0.1nM.Dilute oxotremorine in a similar manner.

Suppress for measuring the active oxotremorine of adenylate cyclase (AC), with the oxotremorine and the 50 μ L cells adding agonist test holes of 25 μ L forskolins (being diluted in 25 μ M ultimate densities among the dPBS), 25 μ L dilution.Be to measure the active ability of AC that test-compound retardance oxotremorine suppresses, the test-compound and the 50 μ L cells of 25 μ L forskolins and oxotremorine (being respectively the 25 μ M and the 5 μ M ultimate densities that are diluted among the dPBS), 25 μ L dilution are added remaining test holes.

Reactant is come stopped reaction 37 ℃ of cultivations 10 minutes and by adding the ice-cold detection damping fluid of 100 μ L.Sealing plate spends the night and (PerkinElmer Inc., Wellesley MA) go up counting at the PerkinElmerTopCount liquid scintillation counter in morning next day in incubated at room temperature.Calculate the amount (pmol/ hole) of the cAMP of generation based on the counting of observed sample and the cAMP standard in manufacturer's user manual, described.(San Diego CA) comes analytical data by nonlinear regression analysis for GraphPad Software, Inc. with GraphPad Prism software package to utilize non-linear regression, a site competition equation formula.Use the Cheng-Prusoff equation to come calculating K _i, utilize the EC of oxotremorine concentration-response curve respectively ₅₀With the oxotremorine experimental concentration as K _D[L].

In this test, lower K _iValue shows that test-compound has higher binding affinity at the acceptor that is tried.The compound for example of the present invention that is tried in this test is found usually for being arrested in expresses hM ₂The cAMP cumulative oxotremorine of forskolin one mediation suppresses to have the K less than about 300nM in the CHO-K1 cell of acceptor _iValue.For example, the compound of embodiment 3 is found the K that has less than 10nM _iValue.

B. agonist mediation [ ³⁵S] retardance of GTP γ S bonded

In second function test, expressing hM by measuring compound ₂The retardance oxotremorine stimulates in the CHO-K1 cell of acceptor [ ³⁵S] the bonded ability of the GTP γ S function of measuring test-compound renders a service.

In use, the refrigerated film that thaws, being diluted in every hole then has in the test damping fluid of the proteinic final target tissue concentration of 5-10 μ g.Utilize Polytron PT-2100 to organize fracture machine homogenize film momently, add test board then.

In each test, the stimulation of mensuration agonist oxotremorine [ ³⁵S] GTP γ S bonded EC ₉₀Value (for the effective concentration of 90% peak response).

For determination test compound inhibited oxidation tremorine-stimulation [ ³⁵S] GTP γ S bonded ability, following substances is added in each hole of 96 orifice plates: 25 μ L have [ ³⁵S] the test damping fluid of GTP γ S (0.4nM), 25 μ L oxotremorine (EC ₉₀) and GDP (3uM), the test-compound and the 25 μ L of 25 μ L dilution express hM ₂The Chinese hamster ovary celI film of acceptor.Then 37 ℃ of culture experiment plates 60 minutes.Utilize PerkinElmer 96-hole results instrument through the pretreated GF/B filter of 1%BSA filtration test plate.With ice-cold dcq buffer liquid flushing plate 3x3 second, air or vacuum-drying then.(50 μ L) adds in each hole with the Microscint-20 scintillation solution, seals each plate, and goes up the counting radioactivity at Topcounter (PerkinElmer).(San Diego CA) comes analytical data by nonlinear regression analysis for GraphPadSoftware, Inc. with GraphPad Prism software package to utilize non-linear regression, a site competition equation formula.Use the Cheng-Prusoff equation to come calculating K _i, utilize the IC of the concentration-response curve of test compound respectively ₅₀Oxotremorine concentration in value and the test is as K _D[L], ligand concentration.

In this test, lower K _iValue shows that test-compound has higher functionally active on the acceptor that is tried.The compound for example of the present invention that is tried in this test is found usually for expressing hM ₂In the CHO-K1 cell of acceptor oxotremorine-stimulation [ ³⁵S] GTP γ S bonded retardance has the K less than about 300nM _iValue.For example, the compound of embodiment 3 is found the K that has less than 10nM _iValue.

C. via the retardance of the calcium release of the agonist-mediation of FLIPR test

With G _qMuscarinic receptor hypotype (the M of albumen coupling ₁, M ₃And M ₅Acceptor), when the agonist bind receptor, activate Phospholipase C (PLC) path.As a result, activatory PLC hydrolytic phosphatide acyl inositol diphosphate (PIP ₂) one-tenth DG (DAG) and phosphatidyl-1,4,5-triphosphoric acid (IP ₃), its again in the cell depository be that endoplasmic reticulum and sarcoplasmic reticulum produce calcium and discharge.FLIPR (Molecular Devices, Sunnyvale, CA) test by utilize when free ca in conjunction with the time fluorescigenic calcium sensitivity dyestuff (Eugene OR) utilizes this increase of intracellular Ca2+ for Fluo-4AM, Molecular Probes.With this fluorescent event of FLIPR The real time measure, it detects personnel selection M ₁And M ₃And chimpanzee M ₅The change in fluorescence of the monolayer cell of receptor cloning.Suppress the ability of the intracellular Ca2+ increase of agonist mediation by antagonist and can measure antagonist usefulness.

For FLIPR calcium irritant test, the evening before testing is with stably express hM ₁, hM ₃And cM ₅The Chinese hamster ovary celI of acceptor is inoculated into 96-hole FLIPR plate.By Cellwash (MTXLabsystems, Inc.) with FLIPR damping fluid (10mM HEPES, pH7.4,2mM calcium chloride, 2.5mM third semi-annular jade pendant in the Hank ' of no calcium and magnesium s buffer salt solution (HBSS) relaxes) cell of washing inoculation removes the FLIPR damping fluid in growth medium and residual 50 μ L/ holes for twice.The 4 μ M FLUO-4AM (making 2X solution) that use 50 μ L/ holes then are at 37 ℃, and culturing cell is 40 minutes under 5% carbonic acid gas.Behind the dyestuff incubation period,, stay the cumulative volume in 50 μ L/ holes with FLIPR damping fluid washed cell twice.

Render a service for measuring antagonist, at first measure the interior Ca of cell of oxotremorine ²⁺The dose-dependently that discharges stimulates, so that can measure at EC subsequently ₉₀The antagonist that the anti-oxidant tremorine of concentration stimulates is renderd a service.At first use diluted chemical compound damping fluid culturing cell 20 minutes, add agonist subsequently, this is undertaken by FLI PR.According to the detailed method in FLIPR measures and below data conclude part, in conjunction with formula EC _F=((F/100-F) ^1/H) * EC ₅₀Produce the EC of oxotremorine ₉₀Value.In stimulating plate, prepare 3xEC _FOxotremorine concentration, with EC ₉₀The oxotremorine of concentration adds in each hole of antagonist inhibition test plate.

The parameter that is used for FLIPR is: exposure time is 0.4 second, and laser intensity is 0.5 watt, and excitation wavelength is that 488nm and emission wavelength are 550nm.By before adding agonist, measuring change in fluorescence definite baseline in 10 seconds.After agonist stimulated, the every 0.5-1 of FLIPR measured change in fluorescence second continuously and caught maximum fluorescence in 1.5 minutes and change.

Change in fluorescence is represented as the big fluorescence of every Kongzui and deducts baseline fluorescence.Utilization is used GraphPad Prism to the incorporation model of contrary flexure dose response, and (SanDiego is CA) by the logit analysis raw data of non-linear regression to drug level for GraphPad Software, Inc..According to Cheng-Prusoff equation (Cheng ﹠amp; Prusoff, 1973), utilize oxotremorine EC ₅₀Value is as K _DOxotremorine EC with ligand concentration ₉₀Determine antagonist K by Prism _iValue.

In this test, lower Ki value shows that test-compound has higher functionally active on the acceptor that is tried.The illustration compound of the present invention that is tried in this test is found usually for being arrested in stably expresses hM ₁, hM ₃And cM ₅The calcium of agonist mediation discharges the K that has less than about 300nM in the Chinese hamster ovary celI of acceptor _iValue.For example, the compound of embodiment 3 is found hM ₁, hM ₃And cM ₅Acceptor has the K less than 10nM _iValue.

Method for testing and detecting E

With endogenous expression people β ₂The full cell cAMP fluorescent plate test of the pulmonary epithelial cells system of adrenergic receptor

Express β in order to be determined at ₂Agonist is renderd a service and effect (intrinsic activity) in the clone of adrenergic receptor endogenous level, adopt (the BEAS-2B) (ATCCCRL-9609 of people's pulmonary epithelial cells system, American type culture collection, Manassas, VA) (January B waits British Journal of Pharmacology, 1998,123,4,701-11).Make cell the substratum of complete, serum-free (the LHC-9 substratum that comprises suprarenin and tretinoin, cat#181-500, Biosource Internation8l, Camarillo grows to 75%-90% in CA) and converges.The test the day before yesterday, with substratum convert to LHC-8 (no suprarenin or tretinoin cat#141-500, Biosource International, Camarillo, CA).Explanation utilization according to the manufacturer have [ ¹²⁵I]-the Flash board adenylate cyclase activating pilot system of cAMP with the radioimmunoassay form carry out the cAMP test (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA).On test same day, wash cell with PBS, scrape and float cell and counting by being used in 5mM EDTA among the PBS.By coming sedimentation cell in that 1000rpm is centrifugal, and be suspended in the stimulation damping fluid that is warmed to 37 ℃ in advance, ultimate density is 600,000 cells/mL again.Ultimate density in the 100000-120000 cells/well in this test is used cell.In Beckman Biomek-2000, the test-compound serial dilution is gone into to test damping fluid, and (75mM Tris/HCl pH7.4 is at 25 ℃, 12.5mM MgCl ₂, 1mM EDTA, 0.2%BSA).Under 11 different concns of 10 μ M-10pM, test test-compound in test.Cultivated reactant 10 minutes at 37 ℃, and come stopped reaction by adding the ice-cold detection damping fluid of 100 μ L.Sealing plate, 4 ℃ of overnight incubation and morning next day the Topcount scintillometer (Packard BioScience Co., Meriden, CT) in the counting.Calculate every milliliter of amount of reacting the cAMP that produces based on the counting of observed sample and the cAMP standard of in manufacturer's user manual, describing.(San Diego CA) comes analytical data by nonlinear regression analysis for GraphPad Software, Inc. to use GraphPad Prism software package with the 4-parametric model of contrary flexure dose response.

In this test, lower EC ₅₀Value shows that test-compound has higher functionally active on the acceptor that is tried.The illustration compound of the present invention that is tried in this test is found usually for β ₂Adrenergic receptor has the EC less than about 300nM ₅₀Value.For example, embodiment 3 and 6 compound are found the EC that has less than 10nM ₅₀Value.

If desired, calculate test-compound effect (% effect) from observed Emax (vertex of matched curve) with to the peak response that the Racemic isoproterenol dose response curve obtains, and be expressed as % effect with respect to Racemic isoproterenol.The compound for example of the present invention that is tried in this test is proved to be the % effect greater than about 40 usually.

Method for testing and detecting F

The time length of guinea pig model mesobronchus protection acetylcholine-induced or histamine inductive bronchoconstriction

Adopt these in vivo test to estimate and show muscarinic receptor antagonist and β ₂The segmental bronchus provide protection of two kinds of active test-compounds of 3 adrenergic receptor agonists.For the muscarine antagonist activity in the separating acetyl choline inductive bronchoconstriction model, before the administration vagusstoff, give animal Propranololum-active compound of a kind of blocking-up beta receptor.Time length in the protection of histamine inductive bronchoconstriction model mesobronchus has been reflected β ₂The activity of 3 adrenergic receptor agonists.

The group of 6 male guinea pigs by the heavy 250-350g of the single evaluation of cage card (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, WI).In whole research, allow random contacting foodstuff of animal and water.

Be exposed to coyote hole (R ﹠amp at the whole body body; S Molds, San Carlos gave test compound through 10 minutes by suction in CA).Arrange to give coyote hole, so that can give 6 independent chamber aerosols simultaneously from central house steward.Cavy is exposed in the aerosol of test-compound or carrier (WFI).This aerosol produces from the aqueous solution, example with LC Star atomizer arrangement (Model22F51, the PARI respiration apparatus, Inc.Midlothian, VA) at the pressure of 22psi by gaseous mixture (CO ₂=5%, O ₂=21% and N ₂=74%) advances.At the gas flow of this working pressure by spraying gun is about 3L/ minute.By malleation the aerosol that produces is driven and to be entered the room.In the solution process of administration atomizing, do not use diluent air.Between 10 minute atomization period, approximately the solution of 1.8mL is atomized.By before the spraying gun atomizing of relatively filling and the weight after the atomizing come gravimetric analysis ground to calculate this value.

After administration 1.5,24,48 and 72 hours, utilize the segmental bronchus provide protection of the test-compound that the evaluation of whole body volume scan art gives via suction.

Began preceding 45 minutes in the lung evaluation, with ketamine (43.75mg/kg), every cavy is anaesthetized in xylazine (3.50mg/kg) and vetrnquil (1.05mg/kg) intramuscularly.At the surgery location preserved skin with after, do the 2-3cm median incision of the neck outside of belly with 70% ethanol cleaning.Separate jugular vein then and insert and be full of the brinish polyethylene catheter (Sparks is MD) so that vagusstoff (Ach) or the histamine of infusion in salt solution for PE-50, BectonDickinson.Dissect then make out tracheae free and insert the 14G teflon tube (#NE-014, Sma11Parts, Miami Lakes, FL).If desired, keep anesthesia by the aforementioned anesthesia mixture of further intramuscularly.If if animal to the pawl response of pinching it or respiration rate greater than 100 breaths/min, monitoring and regulate depth of anesthesia.

In case intubate is finished, just animal is placed the volume scan device (#PLY 3114, BuxcoElectronics, Inc., Sharon, CT) neutralization is inserted the esophageal pressure conduit (Sparks MD) is measured lung and drives and press (pressure) for PE-160, Becton Dickinson.The teflon tracheal catheter is connected to the opening of volume scan device so that cavy can be from outdoor breathe air.Sealing chamber then.Use heating lamp to keep body temperature, and (Kansas City MO) make the atelectasis 3 times of cavy to guarantee that not avalanche of downtake and this animal can hyperventilations with the 4mL air for #5520Series, Hans Rudolph to utilize 10mL calibration syringe.

In case measure the conformability baseline value in 0.3-0.9mL/cm water scope, and the resistance baseline value just begins the lung evaluation in 0.1-0.199cm water/mL/ scope second.Buxco lung metering computer program makes it possible to collect and derive the value of lung.

Begin this program and come starting characteristics test scheme and data gathering.Measure the volume that in the volume scan device, takes place with each breathing over time by the Buxco pressure transmitter.By integrating this signal in time, calculate each flow measurements of breathing.The lung driving pressure that connects this signal and utilize Sensym pressure transmitter (#TRD4100) to collect by Buxco (MAX 2270) prime amplifier is changed to data gathering interface (# ' s SFT3400 and SFT3813).Derive all other lung parameters from these two inputs.

Collect baseline value 5 minutes, and attacked cavy with Ach or histamine afterwards.Do the time spent when estimating muscarine antagonist, attack with Ach gave in preceding 15 minutes Propranololum (5mg/Kg, iv) (Sigma-Aldrich, St.Louis, MO).From on-test with following dosage and given time from syringe pump (sp210iw, World Precision Instruments, Inc., Sarasota, FL) intravenous infusion Ach (Sigma-Aldrich, St.Louis, MO) (0.1mg/mL) 1 minute: at the 5th minute 1.9 μ g/ minute, at the 10th minute 3.8 μ g/ minute, at the 15th minute 7.5 μ g/ minute, at the 20th minute 15.0 μ g/ minute, at the 25th minute 30 μ g/ minute with at the 30th minute 60 μ g/ minute.Perhaps, in pretreated vagusstoff attack model, estimate the segmental bronchus provide protection of test-compound without the β blocking compound.

At the β that estimates test-compound ₂3 adrenergic receptor agonists is done the time spent, from on-test with following dosage and given time from syringe pump intravenous infusion histamine (25 μ g/mL) (Sigma-Aldrich, St.Louis, MO) 1 minute: at the 5th minute 0.5 μ g/ minute, at the 10th minute 0.9 μ g/ minute, at the 15th minute 1.9 μ g/ minute, at the 20th minute 3.8 μ g/ minute, at the 25th minute 7.5 μ g/ minute with at the 30th minute 15 μ g/ minute.If 3 minutes resistances or conformability are not returned baseline value behind each Ach or histamine dosage, then from 10mL calibration injection device with the lung of 4mL air expansion cavy 3 times.The lung parameter of record comprises respiratory rate (breaths/min), conformability (mL/cm water) and lung resistance (cm water/mL/ second).In case finish lung function tests the 35th minute of this scheme, just remove cavy and suffocate and put to death cavy by carbonic acid gas from the volume scan device.

Come evaluating data in one of two ways:

(a) from " pressure change " ratio calculation lung resistance (R with " fluctuations in discharge " _L, cm water/mL/ second).Calculation medium and test-compound group are to Ach (60 μ g/min, R 1H) _LResponse.Calculating is the average A Ch of time response before each is handled in the media processes animal, and the time that is used for before corresponding the processing is calculated the inhibition percentage that ACh responds under each test-compound dosage.Utilize GraphPad Prism, (GraphPadSoftware, San Diego California) makes ' R to be used for 3.00 editions of Wi ndows _L' inhibition dose response curve and four parameter logical equatiion matches estimate segmental bronchus protection ID ₅₀(suppress ACh (60 μ g/min) bronchoconstriction and respond 50% required dosage).The equation that uses is as follows:

Y=Min+ (Max-Min)/(1+10 ^{((log ID50-X) * Xi Er slope)})

Wherein X is the logarithm of dosage, and Y is response (ACh inductive R _LThe inhibition percentage that increases).Y is initial and progressive near Max with the contrary flexure shape at Min.

(b) amount PD ₂, it is defined as causing that the baseline lung resistance doubles the amount that needs, and utilizes following equation (derived from being used to calculate PC in clinical ₂₀The equation of value (seeing Am.ThoracicSoc, 2000) calculates from flow and pressure deutero-lung resistance value during utilizing a series of Ach or histamine to attack:

{PD}_{2} = anti \log [\log C_{1} + \frac{({\log C}_{2} - {\log C}_{1}) ({2 R}_{0} - R_{1})}{R_{2} - R_{1}}]

Wherein:

C ₁=C ₂The preceding Ach or the concentration of histamine

C ₂=cause lung resistance (R _L) Ach of at least 2 times of increases or the concentration of histamine.

R ₀=baseline R _LValue

R ₁=C ₁After R _LValue

R ₂=C ₂After R _LValue

Utilize two tails-student t-check to carry out the statistical analysis of these data.It is remarkable that P value＜0.05 is considered to.

The illustration compound of testing in this test of the present invention produces the dosage-dependency segmental bronchus provide protection of anti-MCh inductive bronchoconstriction and His inductive bronchoconstriction usually.Usually, in this test, ACh inductive bronchoconstriction had be lower than about 300 μ g/mL and His inductive bronchoconstriction had the effectiveness (ID of 1.5h after administration that is lower than about 300 μ g/mL ₅₀) test-compound normally preferred.For example, embodiment 3 and 6 compound are found in after the administration 1.5 hours has the ID that is lower than about 100 μ g/mL for ACh inductive bronchoconstriction ₅₀For His inductive bronchoconstriction the ID that is lower than about 100g/mL is arranged ₅₀

In addition, in this test, have at least about 24 hours segmental bronchus and protect (PD T of active time length _1/2) test-compound normally preferred.By way of example, embodiment 3 and 6 compound are found the PD T that has after the administration at least about 24 hours _1/2

Method for testing and detecting G

Measure the Einthoven model that the cavy ventilation changes

Estimate the bronchodilator activity of test-compound in the guinea pig model (Einthoven model) of anesthesia, it uses venting pressure to measure as the surrogate of Raw air way resistance.For example see Einthoven (1892) Pfugers Arch.51:367-445; With (2000) Pulm Pharmacol Ther.13 (6): 287-92 such as Mohammed.In this model, estimate muscarine antagonist and β by the provide protection of measuring anti-methacholine (MCh) and histamine (His) inductive bronchoconstriction ₂Agonist activity.

(Harlan, Indianapolis IN) carry out this test to utilize the Duncan-Hartley cavy that weighs 300-400g.

(R+S Molds, San Carlos give test-compound or medium (being sterilized water) through 10 fens clock times by sucking (IH) in CA) to utilize 5mL to be exposed to coyote hole at the whole body body for drug solns.Animal is exposed to aerosol, its produce from LC Star Nebulizer Set (model 22F51, the PARI respiration apparatus, Inc.Midlothian, VA), under the pressure of 22psi by Bioblend-gaseous mixture (5%CO ₂21%O ₂And 74%N ₂) advance.Different time points is estimated pulmonary function behind inhalation.

Began preceding 45 minutes in pulmonary function evaluation, inject anaesthetized guinea pig with the mixture intramuscular (IM) of ketamine (13.7mg/kg)/xylazine (3.5mg/kg)/vetrnquil (1.05mg/kg).Administration when needed replenishes this mixture (predose 50%) of dosage.Separate jugular vein and carotid artery, and insert be full of the brinish polyethylene catheter (be respectively micro-renathane and PE-50, Becton Dickinson, Sparks, MD).Carotid artery is connected the IV that makes energy measurement blood pressure, jugular vein intubate be used to MCh or His to be injected with pressure transmitter.Dissect free tracheae then and insert the 14G pin (#NE-014, SmallParts, Miami Lakes, FL).In case intubate is finished, just utilize that but to be arranged on every 100g body weight 1mL kinetoplast long-pending be no more than the respirator of 2.5mL volume (Inc. MA), ventilates to cavy with the speed that per minute 100 is fought for model 683, HarvardApparatus.Utilize the Biopac transmitter that is connected with Biopac (TSD 137C) prime amplifier in trachea cannula, to measure venting pressure (VP).Utilize heating cushion that body temperature is maintained 37 ℃.Before the beginning data gathering, intraperitoneal (IP) administration Sodital (25mg/kg) suppresses spontaneous breathing and obtains stable baseline.With the VP change records on Biopac Windows data gathering interface.Collected baseline value at least 5 minutes, the non-IV cumulatively of bronchoconstriction agent (MCh or His) with 2 multiplication dosages attacks cavy afterwards.When MCh was used as the bronchoconstriction agent, (5mg/kg, IV) the pre-treatment animal was to isolate the Antimuscarinic effect of test-compound with Propranololum.(Santa Barbara, CA) record VP changes to utilize Acknowledge Data Collection Software.After research is finished, put to death animal.

Cm with water measures the VP variation.VP changes (cm water)=peak pressure (back is attacked in the bronchoconstriction agent)-peak base and presses.Utilize GraphPad Prism, and Windows 3.00 versions (GraphPad Software, San Diego, California), with MCh or His dose response curve fit line four parameter logical equatiions.The equation that uses is as follows:

Y=Min+ (Max-Min)/(1+10 ^{(log ID50-x) * Xi Er slope)})

Wherein X is the logarithm of dosage, and Y is response.Y at Min initial and with the contrary flexure shape gradually near Max.

Utilize following equation at the inhibition percentage that calculates under each dosage of test-compound the bronchoconstriction agent response of MCh or His maximal dose: ((peak pressure is (after bronchoconstriction agent attack for the inhibition percentage=100-of response, handle)-peak base pressure (administration group) * 100%/(peak pressure (after the bronchodilator attack, water)-peak base is pressed (water)).Utilize four parameter logical equation matches of GraphPad software to suppress curve.When needs, also estimate ID ₅₀(produce bronchoconstriction agent response 50% and suppress required dosage) and Emax (the maximum inhibition).

The segmental bronchus protection value of different time points is estimated drug effect transformation period (PD T behind the utilization suction test-compound _1/2).Utilize single-phase exponential decay equation (GraphPad Prism, 4.00 editions): Y=span * index (K*X)+plateau value utilizes nonlinear regression and fitting to determine PD T _1/2Begin and decay to plateau value in span+plateau value with velocity constant K.PD T _1/2＝0.69/K。Force plateau value to return 0.

The illustration compound of the present invention of test produces the dose-dependently segmental bronchus provide protection of anti-MCh inductive bronchoconstriction and His-inductive bronchoconstriction usually in this test.Usually, in this test, after administration, had ID for MCh inductive bronchoconstriction in 1.5 hours less than about 300 μ g/mL ₅₀With the ID that has for His inductive bronchoconstriction less than about 300 μ g/mL ₅₀Test-compound be preferred.In addition, in this test, have at least about 24 hours segmental bronchus and protect (PD T of active time length _1/2) test-compound normally preferred.

Method for testing and detecting H

Suck the test of cavy hydrostomia

(Charles River, Wilmington MA) adapted within doors the cavy residence at least 3 days after arrival to make the cavy of heavy 200-350g.Pie-shaped give coyote hole (R+S Molds, San Carlos, CA) in through 10 minute time period by sucking (IH) medicine-feeding test compound or medium.Be dissolved in testing liquid in the sterilized water and utilize and be full of the spraying gun administration that 5.0mL gives drug solns.Cavy is limited in the suction chamber 30 minutes.At this time durations, cavy is limited in about 110 square centimeters zone.This space freely turns to for animal, and it is enough oneself resetting and allowing grooming.After adapting to 20 minutes, animal is exposed under 22psi pressure by the propulsive LS of the resulting from Star of room air Nebulizer Set (model 22F51, PARI respiration apparatus, Inc.Midlothian, aerosol VA).When atomizing is finished, 1.5,6,12,24,48 or 72 hours evaluation cavys after processing.

Come anaesthetized guinea pig at last hour mixture of test with 0.88mL/kg volume intramuscular (I M) injection ketamine 43.75mg/kg, xylazine 3.5mg/kg and vetrnquil 1.05mg/kg.The belly of animal is placed on the blanket of heating (37 ℃) up, and their head has the inclination of 20 degree on downward slope.(Arlington TX) fills in the cavy mouth for the general cotton balls of the husky cloth of Nu-, Johnson and Johnson with 4-layer 2x2 inch Sticky pad.After five minutes, (3.0mg/kg s.c.) also loses Sticky pad and replaces the new Sticky pad of weighing in advance administration muscarinic agonist pilocarpine immediately.Collected saliva 10 minutes, at weigh Sticky pad and determine the amount (mg) of cumulative saliva with the weight difference that writes down of this point.The mean vol of the saliva that calculating is collected the animal of accepting medium and each dosage test-compound.It is hydrostomia that media pack mean value is considered to 100%.The result utilizes (n=3 or more) of mean value calculation as a result.Utilize dual factors ANOVA to each Rapid Dose Calculation fiducial interval (95%) of each time point.This model is at Rechter, " Estimation of anticholinergic drug effects inmice by antagonism against pilocarpine-induced salivation " AtaPharmacol Toxicol, 1996, the modified version of the model of describing among the 24:243-254.

Calculating is the time before each treatment, the weight in average of saliva in the animal of media processes, and be used for inhibition percentage at each dosage Time Calculation hydrostomia before corresponding treatment.Utilize GraphPad Prism, (GraphPad Software, San Diego California) fit to the amount of suppression response data four parameter logical equations and estimate anti-sialagogue ID Windows 3.00 editions ₅₀(the required dosage of hydrostomia that the pilocarpine of inhibition 50% brings out).The equation that adopts is as follows:

Y=Min+ (Max-Min)/(1+10 ^{(logID50-x* Xi Er slope)})

Wherein X is the logarithm of dosage, and Y is response (the inhibition percentage of hydrostomia).Y Min begin and with the contrary flexure shape gradually near Max.

Anti--sialagogue ID ₅₀With segmental bronchus protection ID ₅₀Ratio be used to calculate the apparent lung selectivity index of test-compound.Usually, the compound that has greater than about 5 apparent lung selectivity index is preferred.In this test, the compound of embodiment 3 has the apparent lung selectivity index greater than 5.

Though the present invention is described with concrete aspect or its embodiment, it should be understood by one skilled in the art that not departing from the present invention and really can make various changes under the situation of spirit and scope and maybe can do and be equal to replacement.In addition, in the scope that the patent statute and the rule of application allows, the patent that this paper quotes all is introduced into identical scope as a reference fully with patent application, seems every piece of article all to be introduced separately into as a reference by this paper.

Claims

1. the compound of formula I, or its pharmacy acceptable salt or steric isomer,

Wherein:

R ⁴Be selected from:

Wherein, m is 2 to 10 integer; And n is 2 to 10 integer; Condition is that m+n is 4 to 12 integer;

Wherein, o is 2 to 7 integer; And p is 1 to 6 integer; Condition is that o+p is 3 to 8 integer; And benzene wherein-1, the 4-subunit optional by 1 to 4 be independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group ,-S-(1-4C) alkyl ,-S (O)-(1-4C) alkyl ,-S (O) ₂-(1-4C) alkyl ,-substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replaces;

Wherein, q is 2 to 6 integer; R is 1 to 5 integer; And s is 1 to 5 integer; Condition is that q+r+s is 4 to 8 integer; And benzene wherein-1, the 4-subunit optional by 1 to 4 be independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group ,-S-(1-4C) alkyl ,-S (O)-(1-4C) alkyl ,-S (O) ₂-(1-4C) alkyl ,-substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replaces;

Wherein, t is 2 to 10 integer; And u is 2 to 10 integer; Condition is that t+u is 4 to 12 integer;

Wherein, v is 2 to 7 integer; And w is 1 to 6 integer; Condition is that v+w is 3 to 8 integer; And benzene wherein-1, the 4-subunit optional by 1 to 4 be independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group ,-S-(1-4C) alkyl ,-S (O)-(1-4C) alkyl ,-S (O) ₂-(1-4C) alkyl ,-substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replaces; And

Wherein, x is 2 to 6 integer; Y is 1 to 5 integer; And z is 1 to 5 integer; Condition is that x+y+z is 4 to 8 integer; And benzene wherein-1, the 4-subunit optional by 1 to 4 be independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxyl group ,-S-(1-4C) alkyl ,-S (O)-(1-4C) alkyl ,-S (O) ₂-(1-4C) alkyl ,-substituting group of C (O) O (1-4C) alkyl, carboxyl, cyano group, hydroxyl, nitro, trifluoromethyl and trifluoromethoxy replaces;

R ⁶Be-NHCHO or-CH ₂OH and R ⁷Be hydrogen; Or R ⁶And R ⁷Formation-NHC (O)-CH=CH-together.

2. the compound of claim 1, or its pharmacy acceptable salt, wherein this compound has formula II:

Wherein, R ⁴Has defined identical meanings in the claim 1.

3. the compound of claim 1, or its pharmacy acceptable salt, wherein this compound has formula III:

Wherein, R ⁴Has defined identical meanings in the claim 1.

4. the compound of claim 1, or its pharmacy acceptable salt, wherein this compound has formula IV:

Wherein, R ⁴Has defined identical meanings in the claim 1.

5. the compound of claim 1, or its pharmacy acceptable salt, wherein this compound has following formula:

6. the compound of claim 1, or its pharmacy acceptable salt, wherein this compound has following formula:

7. each compound of claim 2 to 4, wherein R ⁴Be selected from:

-(CH ₂) ₂C(O)NH(CH ₂) ₅-；

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(benzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (4-methylbenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (6-chlorobenzene-1,3-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chlorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2,6-dichlorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (3-chlorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-(CF ₃O-) benzene-1, the 4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-iodobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chloro-5-anisole-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-chloro-6-methylbenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-bromobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-anisole-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-fluorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2,5-two fluorobenzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂NHC (O) (benzene-1,4-subunit) (CH ₂) ₂-;

-(CH ₂) ₂C (O) NH (2,3,5,6-tetra fluoro benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2,6-diiodo-benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NHCH ₂(benzene-1,4-subunit) CH ₂-;

-(CH ₂) ₂C (O) NH (2-methylbenzene-1,4-subunit) CH ₂-;

-(CH ₂) xC (O) NHCH ₂(benzene-1,3-subunit) (CH ₂) ₂-;

-(CH ₂) ₂NHC (O) (CH ₂) ₅-; And

-(CH ₂) ₂C(O)NH(CH ₂) ₆-。

8. pharmaceutical composition, it comprises each the compound of claim 1 to 7 of pharmaceutically acceptable carrier and treatment significant quantity.

9. each compound of claim 1 to 7 is used for the treatment of purposes in the medicine of tuberculosis in preparation.

10. the purposes of claim 9, wherein said tuberculosis is chronic obstructive pulmonary disease or asthma.