CN101622242A

CN101622242A - Bicyclic derivatives as CETP inhibitors

Info

Publication number: CN101622242A
Application number: CN200780020590A
Authority: CN
Inventors: 岸田雅司; 松浦尚子; 今濑英智; 岩城雪; 梅村一郎; 大森修; 川原荣治
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-05-10
Filing date: 2007-05-08
Publication date: 2010-01-06
Anticipated expiration: 2027-05-08
Also published as: BRPI0711384A2; GB0609268D0; JP2009536172A; RU2008148290A; CN101622242B; RU2430917C2; JP4926241B2; PE20080066A1

Abstract

The present invention relates to novel compounds of formula (I): or a pharmaceutical composition thereof, with all the variables being defined in the text. The present invention further relates to the use of the compounds herein for treatment of or delay progression to overt to diseases in which CETP is involved.

Description

Bicyclic derivatives as the CETP inhibitor

The present invention relates to formula (I) compound of new free form or salt form:

Wherein

Unsubstituted with ring B condensed ring A representative or replace carbocyclic aromatic group; Or heterocyclic group unsubstituted or that replace;

Wherein Ar represents carbocyclic aromatic group unsubstituted or that replace;

R ₁For group C (=O)-R ₃,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2, perhaps R ₁Be Z;

R ₂Be selected from following groups :-CN ,-OR ₃,-COR ₃,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-N (R ₄) (R ₅) ,-S (O) _mR ₃,-S (O) _m-N (R ₄) (R ₅) and-NR ₃-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2, perhaps R ₂Be Z;

Wherein, under any circumstance independent each other,

Z is selected from following groups: (i) unsubstituted or the monocyclic cycloalkyl or the monocycle cycloalkenyl group unsubstituted or that replace that replace, (ii) unsubstituted or the carbocyclic aromatic group or the heterocyclic group unsubstituted or that replace that replace;

R ₃Independent represent hydrogen, alkyl, haloalkyl, the unsubstituted or cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces, wherein cycloalkyl moiety be unsubstituted or cycloalkyl-alkyl of replacing, wherein cycloalkenyl group partly for unsubstituted or cycloalkenyl group-alkyl of replacing, the unsubstituted or carbocyclic aromatic group that replaces, the unsubstituted or heterocyclic group that replaces or wherein aryl moiety be aralkyl unsubstituted or replacement;

R ₄And R ₅Independently each other represent hydrogen, alkyl, be selected from the alkyl of substituting group replacement of following groups by one or more: halogen, hydroxyl ,-N (R ₄) (R ₅) ,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅), the unsubstituted or cycloalkyl that replaces, unsubstituted or the cycloalkenyl group and the heterocyclic group unsubstituted or that replace that replace; Perhaps R ₄And R ₅Unsubstituted or the cycloalkyl that replaces of independent each other representative, the unsubstituted or cycloalkenyl group that replaces or the unsubstituted or carbocyclic aromatic group that replaces, the unsubstituted or heterocyclic group that replaces;

R ₄And R ₅Together for the unsubstituted or alkylidene group that replaces or contain O, NR ₃' or S unsubstituted or the alkylidene group that replaces; R ₃' be R ₃Or-C (=O)-OR ₃And

Wherein be R ₁In radicals R ₄And R ₅Situation under, R then ₄And R ₅Represent hydrogen;

M is an integer 0,1 or 2;

X is CR ₆Or N, Y is N; Perhaps X is N, and Y is CR ₆

R ₆Be hydrogen, halogen, NO ₂, CN, OH, alkyl, alkoxyl group-alkyl, hydroxyl-alkyl, halo-alkyl, alkoxyl group, alkoxyl group-alkoxyl group, halogenated alkoxy ,-C (=O)-R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅) ,-NR ₃-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2; Alkyloyl, the unsubstituted or cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces, wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or that replace; And

Wherein the cycloalkenyl group of cycloalkyl of Qu Daiing or replacement each all replaced by the substituting group that one or more is selected from following groups: alkyl, alkoxyl group ,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-N (R ₄) (R ₅), cycloalkyl-alkyl, the unsubstituted or carbocyclic aromatic group that replaces, the unsubstituted or heterocyclic group that replaces, wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or that replace; And

Wherein heterocyclic radical be unsubstituted partly for heterocyclic radical-alkyl, aryl moiety unsubstituted or that replace or the aralkyl that replaces, heterocyclic radical partly for unsubstituted or heterocyclic radical-alkyl of replacing in, carbocyclic aromatic group or heterocyclic aromatic group or heterocyclic group or ring A or Ar are each other independently for unsubstituted or replaced by one or more substituting group that is selected from following groups: halogen, NO ₂, CN, OH, alkyl, alkoxyl group-alkyl, hydroxyl-alkyl, halo-alkyl, alkoxyl group, alkoxyl group-alkoxyl group, halogenated alkoxy ,-C (=O)-R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅) ,-NR ₃-S (O) _m-N (R ₄) (R ₅) and alkyloyl, m under any circumstance is integer 0,1 or 2; Unsubstituted or the cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces, wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or that replace;

Relate to the method for preparing these compounds, relate to the purposes of these compounds and contain free form or the pharmaceutical preparation of the compound (I) of salt form (particularly pharmacy acceptable salt).

In one embodiment, the present invention relates to new formula (I) compound that exists with free form or salt form or its salt:

Wherein unsubstituted or replace carbocyclic aromatic group or heterocyclic aromatic group unsubstituted or that replace with ring B condensed ring A representative;

Wherein Ar represents carbocyclic aromatic group unsubstituted or that replace;

R ₁For group-C (=O)-R ₃,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2, or R ₁Be Z,

R ₂Be selected from following groups :-C (=O) R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-S (O) _m-N (R ₄) (R ₅) and-NR ₃-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2;

R ₃Independent represent hydrogen, alkyl, haloalkyl, the unsubstituted or cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces, wherein cycloalkyl moiety is unsubstituted or cycloalkyl-alkyl of replacing, wherein cycloalkenyl group partly is unsubstituted or cycloalkenyl group-alkyl of replacing, the unsubstituted or carbocyclic aromatic group that replaces, the unsubstituted or heterocyclic group that replaces or wherein aryl moiety be aralkyl unsubstituted or replacement;

R ₄And R ₅Independent each other hydrogen, alkyl represent, this alkyl is replaced by the substituting group that one or more is selected from following groups: the unsubstituted or cycloalkyl that replaces, unsubstituted or the cycloalkenyl group and the heterocyclic group unsubstituted or replacement that replace;

R ₇And R ₈Unsubstituted or the cycloalkyl that replaces of independent each other representative, the unsubstituted or cycloalkenyl group that replaces or the unsubstituted or carbocyclic aromatic group that replaces, the unsubstituted or heterocyclic group that replaces; Perhaps

M is an integer 0,1 or 2;

X is CR ₆Or N, Y is N; Or X is N, and Y is CR ₆

R ₆Be hydrogen, halogen, NO ₂, CN, OH, alkyl, alkoxyl group-alkyl, hydroxyl-alkyl, halo-alkyl, alkoxyl group, alkoxyl group-alkoxyl group, halogenated alkoxy ,-C (=O)-R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅) ,-NR ₃-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2; Alkyloyl, the unsubstituted or cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces; Wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or replacement; And

Wherein the alkylidene group of the cycloalkenyl group of cycloalkyl of Qu Daiing or replacement or replacement each all replaced by the substituting group that one or more is selected from following groups: alkyl, alkoxyl group ,-C (=O)-O-R ₃,-C (=O)-N (alkyl) (alkyl) ,-N (alkyl) (alkyl), H ₂N-C (=O)-, H ₂N-C (=O)-alkyl-, formyl radical, formyl radical-alkyl-, cycloalkyl-alkyl, carbocyclic aromatic group, heterocyclic group, aralkyl and heterocyclic radical-alkyl; And

Wherein aryl moiety be unsubstituted or the aralkyl that replaces, heterocyclic radical partly for unsubstituted or heterocyclic radical-alkyl of replacing in, carbocyclic aromatic group or heterocyclic aromatic group or heterocyclic group or ring A or Ar are each other independently for unsubstituted or replaced by one or more substituting group that is selected from following groups: halogen, NO ₂, CN, OH, alkyl, alkoxyl group-alkyl, hydroxyl-alkyl, halo-alkyl, alkoxyl group, alkoxyl group-alkoxyl group, halogenated alkoxy ,-C (=O)-R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅) ,-NR ₃-S (O) _m-N (R ₄) (R ₅) and alkyloyl, m under any circumstance is integer 0,1 or 2; Unsubstituted or the cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces, wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or that replace.

Compound (I) can exist with the form of salt, particularly pharmacy acceptable salt.If when compound (I) for example contained at least one basic center, then they can form acid salt.The compound (I) that contains at least one acidic-group can form salt with alkali.Also comprise being not suitable as medicinal but operable salt, be used for the separation and the purifying of free cpds (I) for example or its pharmacy acceptable salt.Consider the free form of new compound and being closely connected of its salt form, in context, free cpds or its salt can be correspondingly or also can be interpreted as easily and be meant its corresponding salt or free cpds.

Salt is in particular the pharmacy acceptable salt of formula (I) compound or the salt of described intermediate herein, wherein also comprises the salt of understandable chemical principle of those technician thereby use.When salt formation group when for example alkalescence or acidic-group exist, they can form, described group is to exist, perhaps can separate, particularly with solid (especially crystallization) isolated in form with (being that part the is dissociated at least) form of dissociating in the aqueous solution of 4-10 in for example pH scope.

This type of salt can be for example base addition salt, preferably adopts organic or inorganic alkali and formula (I) compound that contains acid carboxyl or described any intermediate to form herein, particularly forms pharmacy acceptable salt.The proper metal ion of mineral alkali is for example basic metal or alkaline-earth metal, for example sodium, potassium, magnesium or calcium salt.Suitable organic bases is for example ammonium salt or suitable organic amine, and for example uncle's monoamine as triethylamine or three (2-hydroxyethyl) amine, perhaps is the heterocycle bases, for example N-ethyl-piperidines or N, N '-lupetazin.

In the presence of positive electric charge group is for example amino, also can form salt with acid.This type of salt can for example form acid salt, preferably forms with organic or inorganic acid.Suitable mineral acid is for example haloid acid (for example hydrochloric acid), sulfuric acid or phosphoric acid.Suitable organic acid is for example carboxylic acid, phosphoric acid, sulfonic acid or thionamic acid, for example acetate, propionic acid, lactic acid, fumaric acid, succsinic acid, citric acid, amino acid (for example L-glutamic acid or aspartic acid), toxilic acid, hydroxymaleic acid, methyl-maleic acid, phenylformic acid, methylsulfonic acid or ethyl sulfonic acid, second-1,2-disulfonic acid, Phenylsulfonic acid, 2-naphthene sulfonic acid, 1,5-naphthalene-disulfonic acid, N-cyclohexyl thionamic acid, N-methyl-, N-ethyl-or N-propyl group-thionamic acid or other organic protonic acid, for example xitix.

In the time of in basic group and acidic-group are present in a part, formula (I) compound or described herein any intermediate also can form inner salt.

For formula (I) compound or usually for the isolated or purified of described any intermediate herein, also can adopt pharmaceutically unacceptable salt, for example picrate or perchlorate.When being used for the treatment of, can only adopt pharmacy acceptable salt or free formula (I) compound (being suitable in the pharmaceutical preparation), so they are preferred at least under the situation of formula (I) compound.

Consider the compound of free form and salt form and being closely connected of intermediate, comprise that those can be as the salt of intermediate, for example at the purifying of compound or its salt or the salt that uses in identifying, when in context, mentioning " compound ", when " raw material " and " intermediate ", when particularly mentioning formula (I) compound, if suitably and easily talk about, if and when in addition not specifying, can be understood as and also be meant its one or more salt or corresponding free cpds, the mixture of intermediate or raw material and one or more salt thereof, they each all should comprise any solvate of formula (I) compound or any one or more these salt, metabolic precursor thereof is ester or acid amides for example.Also can obtain different crystallized forms, so in they are also included within.

In order to explain this specification sheets, adopt following definition, and under any circumstance, the term of singulative also comprises plural form, vice versa.

Unless otherwise defined, the generic definition in the context has following meanings:

If not in addition explanation is in particular C as group or as the alkyl of a group part ₁-C ₇-alkyl, preferred C ₁-C ₄-alkyl.Alkyl can be for having at the most the straight or branched of 20 carbon atoms (side chain, perhaps, if desired and if possible, a plurality of side chains) alkyl, preferred C ₁-C ₇-alkyl.Term " rudimentary " or " C ₁-C ₇-" representative has at the most and comprises the group of maximum 7 (particularly at the most and comprise maximum 4) carbon atoms, described group be side chain (one or more side chain) or straight chain and connect by terminal or non-end carbon.Rudimentary or C ₁-C ₇-alkyl for example for just-amyl group, just-hexyl or just-heptyl, or be preferably C ₁-C ₄-alkyl, particularly methyl, ethyl, just-propyl group, the second month in a season-propyl group, just-butyl, isobutyl-, the second month in a season-butyl, tert-butyl.

That aryl (carbocyclic aromatic group) unsubstituted or that replace is preferably is single-or many cyclic groups, the monocycle, dicyclo or the three cyclophane base groups that particularly have 6-22 carbon atom, especially phenyl or naphthyl, described aryl is by unsubstituted or preferably independently be selected from following group by one or more (particularly 1-3) and replaced: C ₁-C ₇-alkyl, particularly methyl; C ₁-C ₇-alkenyl; C ₁-C ₇-alkynyl; Halo-C ₁-C ₇-alkyl, for example trifluoromethyl; Halogen, particularly fluorine, chlorine, bromine or iodine; Hydroxyl; C ₁-C ₇-alkoxyl group, particularly methoxyl group; Phenoxy group; Naphthyloxy; Phenyl-or naphthyl-C ₁-C ₇-alkoxyl group; C ₁-C ₇-alkyloyl oxygen base; Phenyl-or naphthyl-C ₁-C ₇-alkyloyl oxygen base; Amino; The N-list-or N, N-two-(C ₁-C ₇-alkyl, phenyl, naphthyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkyloyl and/or phenyl-or naphthyl-C ₁-C ₇-alkyloyl)-amino; Carboxyl; C ₁-C ₇-alkoxy carbonyl; Phenyloxycarbonyl; The naphthyloxy carbonyl; Phenyl-C ₁-C ₇-alkyl oxy carbonyl; Naphthyl-C ₁-C ₇-alkoxy carbonyl; Formamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl, phenyl, naphthyl, phenyl-C ₁-C ₇-alkyl and/or naphthyl-C ₁-C ₇-alkyl)-aminocarboxyl; Cyano group; Sulfo group; Sulfamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl, phenyl, naphthyl, phenyl-C ₁-C ₇-alkyl and/or naphthyl-C ₁-C ₇-alkyl)-amino-sulfonyl; Nitro and heterocyclic radical, particularly morpholinyl (morphilinyl).Preferred aryl substituent is selected from following groups: C ₁-C ₇-alkyl, particularly methyl; Halogen, particularly fluorine, chlorine, bromine or iodine; C ₁-C ₇-alkoxyl group, particularly methoxyl group; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-amino; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-aminocarboxyl; Carboxyl; Cyano group and heterocyclic radical, particularly morpholinyl.The carbocyclic aromatic group is in particular phenyl, xenyl or naphthyl.Xenyl is for example 4-xenyl, also can be 2-or 3-xenyl.Naphthyl is 1-or 2-naphthyl.

The heterocyclic aromatic group is in particular heteroaryl, and it is 5-14 unit monocycle-or dicyclo-or condense polynary ring system, has 1-8 heteroatoms that is selected from N, O or S.Preferred heteroaryl is a 5-10 unit ring system.Heterocyclic group can for single-, two-, three-or polynary ring, preferred single-, two-or three rings, more preferably single-or dicyclo.Heterocyclic group also can be part or all of saturated heteroaryl.

Heterocyclic group is in particular 5-6 unit heterocyclic ring unsubstituted or that replace, has 1,2,3 or 4 heteroatoms that is selected from N, S and O.

Heterocyclic group be in particular unsubstituted or replace with phenyl ring condensed heterocycle ring, have 1 or 2 heteroatoms that is selected from N, S and O, heterocyclic ring can be for saturated or have 1 or 2 two key.

Typical heteroaryl comprises 2-or 3-thienyl, 2-or 3-furyl, 2-or 3-pyrryl, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 3-or 5-1,2,4-triazolyl, 4-or 5-1,2,3-triazolyl, tetrazyl, 2-, 3-or 4-pyridyl, 3-or 4-pyridazinyl, 3-, 4-or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-or 5-pyrimidyl.

Heterocycle also can be wherein heteroaromatic rings and one or more aryl, aliphatics ring or heterocyclic ring condensed group, and these groups or tie point are on heteroaromatic rings.Non-limiting example includes but not limited to 1-, 2-, 3-, 5-, 6-, 7-or 8-indolizine base; 1-, 3-, 4-, 5-, 6-or 7-pseudoindoyl; 2-, 3-, 4-, 5-, 6-or 7-indyl; 2-, 3-, 4-, 5-, 6-or 7-indazolyl; 2-, 4-, 5-, 6-, 7-or 8-purine radicals; 1-, 2-, 3-, 4-, 6-, 7-, 8-or 9-quinolizinyl; 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl; 1-, 4-, 5-, 6-, 7-or 8-2, the 3-phthalazinyl; 2-, 3-, 4-, 5-or 6-1, the 5-phthalazinyl; 2-, 3-, 5-, 6-, 7-or 8-quinazolyl; 3-, 4-, 5-, 6-, 7-or 8-cinnolines base; 2-, 4-, 6-or 7-pteridyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-4aH-carbazyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-carbazyl; 1-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenanthridinyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridyl; 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-perimidinyl; 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-or 9-phenazinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or lysivane base; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenoxazinyl; 2-, 3-, 4-, 5-, 6-or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-benzoquinoline base, 2-, 3-, 4-or thieno-[2,3-b] furyl; 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-7H-pyrazine be [2,3-c] carbazyl also; 2-, 3-, 5-, 6-or 7-2H-furo [3,2-b]-pyranyl; 2-, 3-, 4-, 5-, 7-or 8-5H-pyrido [2,3-d]-o-oxazinyl; 1-, 3-or 5-1H-pyrazolo [4,3-d]-oxazolyls; 2-, 4-or 5-4H-imidazo [4,5-d] thiazolyl; 3-, 5-or 8-pyrazine be [2,3-d] pyridazinyl also; 2-, 3-, 5-or 6-imidazo [2,1-b] thiazolyl; 1-, 3-, 6-, 7-, 8-or 9-furo [3,4-c] cinnolines base; 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido [2,3-c] carbazyl; 2-, 3-, 6-or 7-imidazo [1,2-b] [1,2,4] triazinyl; 7-benzo [b] thienyl; 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl-; 2-, 4-, 4-, 5-, 6-or 7-benzothiazolyl; 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-benzoxapinyl; 2-, 4-, 5-, 6-, 7-or 8-benzoxazinyl; 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-1H-pyrrolo-[1,2-b] [2] benzazapinyl.Typical condensed heteroaryl group includes but not limited to 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl; 2-, 3-, 4-, 5-, 6-or 7-indyl; 2-, 3-, 4-, 5-, 6-or 7-benzo [b] thienyl; 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl-; 2-, 4-, 5-, 6-or 7-benzothiazolyl.

Suitable 5-or 6-unit monocycle are for having 4 identical or different heteroatomic monocyclic groups at the most, and described heteroatoms is for example nitrogen, oxygen or sulphur atom, preferred 1,2,3 or 4 nitrogen-atoms, an oxygen or a sulphur atom.Suitable 5-unit heteroaryl for for example single azepine-, diaza-, three azepines-, four azepines-, single oxa--or single thia-cyclophane base, for example pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, furyl and thienyl, and suitable suitable 6-unit group is in particular pyridyl and pyrimidyl.Suitable aromatic group is single the replacement or polysubstituted group, for example two-or trisubstituted, for example can be replaced by identical or different group.

Pyrryl is for example 2-or 3-pyrryl.Pyrazolyl is 3-or 4-pyrazolyl.Imidazolyl is 2-or 4-imidazolyl.Triazolyl is for example 1,3,5-1H-triazole-2-base or 1,3,4-triazole-2-base.Tetrazyl is for example pyrrotriazole-5-base.Furyl is 2-or 3-furyl, and thienyl is 2-or 3-thienyl, and suitable pyridyl is 2-, 3-or 4-pyridyl.

Preferred pyrrotriazole-5-base or 1,3,4-triazole-2-base.

Have 1 or 2 and be selected from the heteroatomic of N, S and O and phenyl ring condensed heterocycle ring and heterocyclic ring saturated or that have 1 or 2 two key is for example indoles, quinoline, indoline or tetrahydroisoquinoline.

Have 1,2 or 3 first heterocyclic ring of heteroatomic 5-6 that is selected from N, S and O and be in particular the tetrazolium of replacement, the triazole of replacement (for example methyl-triazole), the pyrimidine that replaces or the pyrazoles (for example methylpyrazole) of replacement.The pyridine, the triazine of replacement, imidazoles, oxazole, the thiazole that also comprise replacement in addition.Preferred substituted is alkyl, for example methyl.

Have 1-8 be selected from the heteroatomic 5-14 unit monocycle of N, S and O-or dicyclo-or the polynary ring system of condensed also can be partially or completely saturated.

Preferably have 1,2,3 or 4 are selected from N, the heteroatomic partially or completely saturated heteroaryl 5-6 unit heterocyclic ring of S and O is for example pyrroline group, pyrrolidino group, dihydro-or tetrahydrochysene-thienyl, dihydro-or tetrahydrochysene-furan group, dihydro-or tetrahydrochysene-pyridine group, tetrahydroglyoxaline or imidazolidine group, pyrazoline or pyrazolidine group, thiazoline or thiazolidine group; oxazoline or oxazolidine group, dihydro-or tetrahydrochysene-pyridine or piperidines group or dihydro-or tetrahydrochysene-pyrans group.The preferred 5-6 N-of unit heterocyclic group is for for example passing through N-atom bonded, particularly tetramethyleneimine-1-base.

Heterocyclic group is unsubstituted or is replaced by one or more (for example 2 or 3) substituting group.The group of preferred corresponding C-replacement.

Cycloalkyl is for example C ₃-C ₇-cycloalkyl for example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.Preferred cyclopentyl and cyclohexyl.

Cycloalkenyl group is for example C ₃-C ₇-cycloalkenyl group for example is cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl and cycloheptenyl.Cyclopentene base and cyclohexenyl.

Halo or halogen are preferably fluorine, chlorine, bromine or iodine.Most preferably fluorine, chlorine or bromine.

Halo-alkyl is for example halo-C ₁-C ₇Alkyl is in particular halo-C ₁-C ₄Alkyl, as trifluoromethyl, 1,1,2-three fluoro-2-chloro ethyl or chloro methyl.Preferred halo-C ₁-C ₇Alkyl is a trifluoromethyl.

Aralkyl is for example isocyclic aryl (carboxylic aryl)-alkyl, preferred phenyl-C ₁-C ₄-alkyl, for example benzyl or 2-styroyl.

Alkoxyl group is for example C ₁-C ₇-alkoxyl group, for example be methoxyl group, oxyethyl group, just-propoxy-, isopropoxy, just-butoxy, isobutoxy, the second month in a season-butoxy, uncle-butoxy, also comprise corresponding pentyloxy, hexyloxy and heptan the oxygen base.Preferred C ₁-C ₄Alkoxyl group.

Alkyloyl is for example C ₂-C ₇-alkyloyl, for example ethanoyl, propionyl, butyryl radicals, isobutyryl or pentanoyl.Preferred C ₂-C ₅-alkyloyl, particularly ethanoyl.

The C of the alkylidene group that replaces for replacing ₂-C ₇The C of-alkylidene group or replacement ₂-C ₇-alkylidene group wherein can contain O, N or S.Described alkylidene group can be substituted, and for example, is replaced by following groups: C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, carboxyl, C ₁-C ₇-alkoxyl group-carbonyl, C ₃-C ₇-cycloalkyl or condensed or be connected to C on the described alkylidene group by form with spiral shell ₃-C ₇-cycloalkyl substituted.

Alkoxyalkyl can be a straight or branched.Described alkoxyl group preferably contains 1-4 and particularly 1 or 2 carbon atom, and described alkyl preferably contains 1-4 carbon atom.Example is methoxymethyl, 2-methoxy ethyl, 3-methoxy-propyl, 4-methoxyl group butyl, 5-methoxyl group amyl group, 6-methoxyl group hexyl, ethoxyl methyl, 2-ethoxyethyl group, 3-ethoxycarbonyl propyl, 4-oxyethyl group butyl, 5-oxyethyl group amyl group, 6-oxyethyl group hexyl, propoxy-methyl, butyl oxygen ylmethyl, 2-propoxy-ethyl and 2-butyl oxygen base ethyl.

The preferred embodiment of the invention

The embodiment preferred of respectively organizing of the present invention described below is not exclusive, be on the contrary, for example in order to replace universal expression or symbol with more specific definition, these parts of respectively organizing in the compound adopt top given definition to exchange or exchange, if it is perhaps suitable, can omit, and each more specific definition independent of each other can independently be introduced or introduces other more general expression or symbol with one or more other more specific definition.

Preferred ring A is the benzo ring, and it can be unsubstituted or be replaced by one or more (for example 2 or 3) substituting group.Preferred substituted is selected from following groups on the A ring: C ₁-C ₇-alkyl (particularly methyl), halogen (particularly fluorine, chlorine, bromine or iodine), C ₁-C ₇-alkoxyl group (particularly methoxyl group), N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino, N-single-or N, N-two-(C ₁-C ₇-alkyl)-aminocarboxyl, carboxyl, cyano group and heterocyclic radical (particularly morpholinyl).Most preferred substituting group is selected from F, Cl, Br, OMe, Me, CN, CO on the A ring ₂H, NMe ₂, C (=O) NMe ₂And morpholine.

Another preferably encircles A is the quinoline ring, and it can be unsubstituted or is selected from following group by 1-3 and replace: C ₁-C ₇-alkyl (particularly methyl), halogen (particularly fluorine, chlorine, bromine or iodine), C ₁-C ₇-alkoxyl group (particularly methoxyl group), N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino, N-single-or N, N-two-(C ₁-C ₇-alkyl)-aminocarboxyl, carboxyl, cyano group and heterocyclic radical (particularly morpholinyl).Most preferred substituting group is selected from F, Cl, Br, OMe, Me, CN, CO on the A ring ₂H, NMe ₂, C (=O) NMe ₂With morpholine etc.

Another preferably encircles A is pyrrole ring, and it can be unsubstituted or be replaced by one or more (for example 2 or 3) substituting group.Preferred substituted is C on the A ring ₁-C ₇-alkyl, for example methyl.

Preferred Ar is by the phenyl of 1 or 2 substituting group replacement.Preferred substituted is halogen and haloalkyl, for example Cl and CF ₃

R ₁Particularly preferred example is:

More preferably R ₁Be 2-C ₁-C ₇-alkyl-2H-tetrazolium-5-base.

R ₂Particularly preferred example is:

Preferred X is N.

Preferred Y is CH.

In this article, unless otherwise indicated or in contrast expression is arranged in context clearly, (particularly in the context of claim) employed term " ", " a kind of " and similar term should comprise odd number and plural number in the context of the present invention.Only to should be understood to be a kind of method of breviary to the scope of numerical value herein, and it is meant each the single numerical value that is positioned at described scope.Unless explanation in addition herein, each single numerical value all can specifically appear in the specification sheets, as institute herein indivedual as described in.Unless otherwise indicated or in contrast expression is arranged in context clearly, described herein all methods all can be carried out with any suitable order.The purposes of any He all examples that provided herein or typical term (for example " for example ") are only used for illustrating better the present invention, and scope of the present invention is limited.It is necessary non-claimed key element that term in this specification sheets should not be interpreted as implementing the present invention.

Deep pharmaceutical research shows, cholestery ester transfer protein inhibitors, particularly Compound I and pharmacy acceptable salt thereof for example, have significant selectivity to CETP (cholesteryl ester transfer protein) when suppressing.CETP has participated in the metabolism of all lipoprotein in the organism, has vital role in anti-phase cholesterol transfer system.That is to say that CETP gathers with prevention of arterial hardened mechanism as the prevention cholesterol and caused attention in peripheral cell.In fact, consider the vital role of HDL in anti-phase cholesterol transfer system, many epidemic research persons have been found that it is one of risk factors of coronary artery disease that the CE (cholesteryl ester) of HDL in the blood reduces.It will be clear that, the CETP activity changes according to the kind of animal, wherein in the low animal of activity, be difficult to induce and produce owing to the cholesterol load increases the arteriosclerosis that causes, on the contrary, in the high animal of activity, be easy to induce this kind of generation arteriosclerosis, be that height-HDL-mass formed by blood stasis and low-LDL (low-density lipoprotein)-mass formed by blood stasis are to induce generation under the situation that CETP lacks, therefore can make arteriosclerotic hard going, thereby make people recognize the importance of blood HDL, recognize that also the CE that can mediate HDL is converted into the importance of the CETP of blood LDL.Carried out a large amount of research in recent years, wished that exploitation can suppress this type of active medicine of CETP, does not have gratifying active medicine yet up to the present develop as yet.

Adopt experimental model known to the skilled in the association area, can prove the CETP restraining effect of The compounds of this invention, for example, adopt following experimental model:

(1) preparation of human apolipoprotein (pro-apolipoprotein) AI (pro-apoAI)

From human liver Quick-Clone ^TMCDNA (Clontech, CA) clone humans cDNA (the NCBI preserving number: NM_000039), be inserted into the pET28a carrier (Novagen, Germany) that is used for bacterial expression of pro-apoAI.As (Strategene, the terminal bonded Expression of Fusion Protein of N-CA) albumen can adopt HiTrap Chelating, and (GEHealthcare CT) carries out purifying at BL-21 Gold (DE3) with 6xHis-tag.

(2) preparation of donor micro emulsion

(J.Biol.Chem., 280:14918-22), preparation contains the micro emulsion of Pro-apoAI as donor particle according to previous reported method.With triolein (62.5ng, Sigma, MO), the 3-sn-phosphatidylcholine (583ng, Wako Pure Chemical Industries, Japan) and cholesterol

FL C ₁₂(250ng, Invitrogen CA) are dissolved in the 1mL chloroform.With solution evaporation, vacuum is removed residual solvent above 1h then.The exsiccant lipid mixtures is dissolved in 500 μ L analysis buffer (the 50mM Tris-HCl (pH7.4) that contains 150mM NaCl and 2mM EDTA), adopts microtip (MICROSON ^TMULTRASONIC CELL DISRUPTOR, Misonix, Farmingdale, NY) ultrasonic 2 minutes in 50 ℃ with output rating 006.After ultrasonic, solution is cooled to 40 ℃, adds the human pro-apoAI of 100 μ g, ultrasonic 5 minutes with output rating 004 in 40 ℃.Behind 0.45 μ m PVDF membrane filtration, with solution (as the BODIPY-CE micro emulsion of donor molecule) in 4 ℃ of storages.

(3) the external CETP activation analysis of human plasma

The human edta plasma sample of healthy male is available from New Drug Development ResearchCenter, Inc.By adopting analysis buffer dilution donor micro emulsion, preparation donor solution.Human plasma (50 μ L), analysis buffer (35 μ L) and the test compound that is dissolved in dimethyl sulfoxide (DMSO) (1 μ L) are added to 96 holes, and half is in each hole of flat-floored of black.Begin reaction by in each hole, adding donor solution (14 μ L).Adopt excitation wavelength 485nm and emission wavelength 535nm to measure first order fluorescence intensity in per 30 minutes in 37 ℃.CETP activity (FI/min) is defined as the change of fluorescence intensity in 30-90 minute.Adopt Origin software 7.5 SR3 versions, calculate IC by retardance equation (logistic equation) ₅₀Value ((bottom)+(high (top)-end)/(1+ (x/IC at the bottom of the Y= ₅₀) ^ slope (Hill slope)).The scope of the active IC50 value of the inhibition of formula I compound is about 0.001 to 100 μ M, particularly between 0.01 to 10 μ M.

(4) to the influence of hamster blood plasma HDL level

Revise by reported method (Eur, J.Phamacol, 466 (2003) 147-154) being carried out part, studied the effect of compound hamster HDL-cholesterol levels.In brief, feeding for female Syrian hamster (SLC, Shizuoka, Japan) raises 2 weeks of high-cholesterol diet.Then, give the compound in the cmc soln of being suspended in of animal single dose.After containing the lipoprotein of apolipoprotein B (apoB) with 13% polyethylene glycol 6000 precipitation, adopt to derive from commercial test kit (Wako Pure Chemical, Japan) and measure the HDL-cholesterol levels.Compared with the control, compound has improved the HDL cholesterol levels more than 5%.

The compounds of this invention or its pharmacy acceptable salt have outstanding CETP and suppress active in Mammals, for example in the mankind, monkey, ox, horse, dog, cat, rabbit etc., can be used as the CETP activity inhibitor.In addition, utilize the outstanding CETP of The compounds of this invention or its pharmacy acceptable salt to suppress promoting agent, The compounds of this invention can be used as effective pharmaceutical cpd, be used to prevent or disease that treatment is obviously relevant with CETP or delay its development, described disease for example, hyperlipidaemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc., can be used as the prevention or the medicine of hyperlipidaemia or arteriosclerotic disease especially, also be used for the treatment of schistosomicide (or ovum embryo).

Another aspect of the invention is the purposes as the CETP inhibitor, be used for preventing or treating following disease or delay its development: coronary heart disease, coronary artery disease, coronary vessels diseases, myocardial infarction, apoplexy, peripheral vascular disease, diabetes are type ii diabetes, congestive heart failure and reperfusion injury for example.

The present invention preferably relates to formula (IA) or (IB) compound or its salt:

Wherein X is N, and Y is CH or N;

R ₁For being selected from following heterocycle:

They under any circumstance are unsubstituted or are selected from the substituting group N or C-replacement: the C of following groups ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, hydroxyl-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl-, (R ₄) (R ₅) N-C ₁-C ₇-alkyl-,-N (R ₄) (R ₅) and phenyl-C ₁-C ₇-alkyl-;

R ₂Be selected from following groups :-C (=O) R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-S (O) _m-N (R ₄) (R ₅) and-NR ₃-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2; Or R ₂Be Z;

Z is selected from following groups: (i) the unsubstituted or C that replaces ₃-C ₇-cycloalkyl or C unsubstituted or that replace ₃-C ₇-cycloalkenyl group and carbocyclic ring phenyl (ii) unsubstituted or that replace, naphthyl or xenyl or pyrryl unsubstituted or that replace, pyrazolyl, imidazolyl, triazolyl, tetrazyl, furyl, thienyl, pyridyl, pyrimidyl, pyrrolinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, homopiperidinyl, high piperazinyl, dihydro-or tetrahydrochysene-thienyl, dihydro-or tetrahydrochysene-furyl, dihydro-or tetrahydrochysene-pyridyl, imidazolinyl or imidazolidyl, pyrazolinyl or pyrazolidyl, thiazolinyl or thiazolidyl oxazolinyl Huo oxazolidinyl, dihydro-or tetrahydrochysene-pyridyl or piperidyl or dihydro-or tetrahydrochysene-pyranyl;

R ₃Independent hydrogen, the C of representing ₁-C ₇-alkyl, halo-C ₁-C ₇-alkyl, the unsubstituted or C that replaces ₃-C ₇-cycloalkyl, the unsubstituted or C that replaces ₃-C ₇-cycloalkenyl group, wherein cycloalkyl moiety is unsubstituted or the C that replaces ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl, wherein cycloalkyl moiety is unsubstituted or the C that replaces ₃-C ₇-cycloalkyl-C ₂-C ₇-alkenyl, the unsubstituted or phenyl or naphthyl that replaces, the unsubstituted or heterocyclic aromatic group that replaces or wherein aryl moiety be phenyl-C unsubstituted or that replace ₁-C ₇-alkyl;

R ₄And R ₅The independent each other C that represents ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl, described C ₁-C ₇-alkyl is replaced by one or two substituting group that is selected from following groups: the unsubstituted or cycloalkyl that replaces, unsubstituted or the cycloalkenyl group and the heterocyclic group unsubstituted or that replace that replace;

Wherein the alkylidene group of the cycloalkenyl group of cycloalkyl of Qu Daiing or replacement or replacement each all replaced by one or two substituting group that is selected from following groups: alkyl, alkoxyl group ,-C (=O)-O-R ₃,-C (=O)-N (alkyl) (alkyl) ,-N (alkyl) (alkyl), H ₂N-C (=O)-, H ₂N-C (=O)-alkyl-, formyl radical, formyl radical-alkyl-, cycloalkyl-alkyl, carbocyclic aromatic group, heterocyclic group, aralkyl and heterocyclic radical-alkyl; Perhaps

R ₉And R ₁₀Independent each other is hydrogen, halogen, NO ₂, CN, OH, C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, pyridyl-C ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkoxyl group, naphthyl-C ₁-C ₇-alkoxyl group, pyridyl-C ₁-C ₇-alkoxyl group, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkoxyl group, halo-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, carboxyl, C ₁-C ₇-alkoxyl group-carbonyl, C ₁-C ₇-alkyl-S (O) _m-, phenyl-C ₁-C ₇-alkyl-S (O) _m, naphthyl-C ₁-C ₇-alkyl-S (O) _m, pyridyl-C ₁-C ₇-alkyl-S (O) _m, halo-C ₁-C ₇-alkoxyl group and C ₂-C ₇-alkyloyl (oxygen base); M under any circumstance is integer 0,1 or 2; C ₃-C ₇-cycloalkyl, C ₃-C ₇-cycloalkenyl group, wherein phenyl moiety is unsubstituted or phenyl-C of replacing ₁-C ₇-alkyl and wherein pyridyl partly be unsubstituted or pyridyl-C of replacing ₁-C ₇-alkyl; And

Wherein corresponding cycloalkyl, cycloalkenyl group, carbocyclic aromatic group, heterocyclic group or heterocyclic aromatic group are optional to be replaced by one or more substituting group that is selected from following groups: halogen, hydroxyl, cyano group, alkyl or alkoxyl group;

Wherein p is 0 or 1 or 2 or 3;

Wherein n is 0 or 1 or 2 or 3;

R ₁₁Be C ₁-C ₇-alkyl;

The substituting group that connects among the Z independently is selected from the substituting group of following groups for hydrogen or one or more each other: halogen, OH, NH ₂, carbonyl (=O), C ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl-, C ₃-C ₇-cycloalkyl oxy-C ₁-C ₇-alkyl-, phenyl-C ₁-C ₇-alkoxyl group-, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkoxyl group-, halo-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxyl group-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group-, carboxyl-, C ₁-C ₇-alkoxyl group-carbonyl-, C ₁-C ₇-alkyl-S (O) _m-, phenyl-C ₁-C ₇-alkyl-S (O) _m-, halo-C ₁-C ₇-alkoxyl group-and C ₂-C ₇-alkyloyl-, C ₁-C ₇-alkoxy-C ₃-C ₇-cycloalkyl-, phenyl-C ₁-C ₇-alkoxy-C ₃-C ₇-cycloalkyl-, hydroxyl-C ₃-C ₇-cycloalkyl-, hydroxyl-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, formyl radical-C ₃-C ₇-cycloalkyl-, formyl radical-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, carboxyl-C ₃-C ₇-cycloalkyl-, carboxyl-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, H ₂NC (=O)-C ₃-C ₇-cycloalkyl-, H ₂NC (=O)-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-.

The present invention more preferably relates to formula (IC) compound or its salt:

Wherein X is N, and Y is CH or N;

R ₁Be 2-C ₁-C ₇-alkyl-2H-tetrazolium-5-base;

Group-N (R ₄) (R ₅) be tetramethyleneimine-1-base, it is replaced by one or two substituting group that is selected from following groups: C ₁-C ₇-alkyl-, C ₃-C ₇-cycloalkyl-, C ₃-C ₇-cycloalkyl-methyl-, C ₁-C ₇-alkoxyl group-methyl-, hydroxyl-C ₁-C ₂-alkyl-C ₃-C ₇-cycloalkyl-, formyl radical-C ₃-C ₇-cycloalkyl-, formyl radical-C ₁-C ₂-alkyl-C ₃-C ₇-cycloalkyl-, HO ₂C-C ₃-C ₇-cycloalkyl-, HO ₂C-C ₁-C ₂-alkyl-C ₃-C ₇-cycloalkyl-, H ₂NC (=O)-C ₃-C ₇-cycloalkyl-or H ₂NC (=O)-C ₁-C ₂-alkyl-C ₃-C ₇-cycloalkyl-;

R ₉Replaced by one or two substituting group that is selected from following groups: hydrogen ,-CN, C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxyl group, (C ₁-C ₇-alkyl) (C ₁-C ₇-alkyl-) amine-, halo-C ₁-C ₇-alkyl or halogen;

R ₁₂And R ₁₃Independent each other is halo-C ₁-C ₇-alkyl or be halogen; Wherein p is 0 or 1 or 2; Perhaps

R ₄Be (C ₁-C ₄) alkyl-or (C ₃-C ₅) cycloalkyl-; And

R ₅Be (C ₃-C ₇) cycloalkyl-(C ₁-C ₂) alkyl-, it is optional by one or two substituting group replacement that is selected from following groups: hydroxyl, alkoxyl group, HO ₂C-, HO ₂C-(C ₁-C ₃) alkyl-, hydroxyl-(C ₁-C ₃) alkyl-, (C ₁-C ₆) alkoxyl group-carbonyl-or (C ₁-C ₆) alkoxyl group-carbonyl-(C ₁-C ₃) alkyl-.

In one embodiment, the present invention relates to formula (II) compound or its salt:

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (III):

R wherein ₆Be (C ₁-C ₄) alkyl-or (C ₃-C ₅) cycloalkyl-; Rb is-(CH ₂) _n-Rc; N is 0 or 1 or 2 or 3; Rc is carboxyl, hydroxyl, (C ₁-C ₄)-alkoxyl group or (C ₁-C ₄)-alkoxy carbonyl.Preferably, n is 0, and Rc is hydroxyl or (C ₁-C ₄)-alkoxyl group.Also preferred n is 1 or 2 or 3, and Rc is carboxyl, hydroxyl, (C ₁-C ₄)-alkoxyl group or (C ₁-C ₄)-alkoxy carbonyl.

In another embodiment, the present invention relates to formula (II) compound or its salt:

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (IIIA):

R wherein ₆Be (C ₁-C ₄) alkyl-or (C ₃-C ₅) cycloalkyl-; Rb is-(CH ₂) _n-Rc; N is 0 or 1 or 2 or 3; Rc is carboxyl, hydroxyl, (C ₁-C ₄)-alkoxyl group or (C ₁-C ₄)-alkoxy carbonyl.Preferred n is 0, and Rc is hydroxyl or (C ₁-C ₄)-alkoxyl group.Also preferred n is 1 or 2 or 3, and Rc is carboxyl, hydroxyl, (C ₁-C ₄)-alkoxyl group or (C ₁-C ₄)-alkoxy carbonyl.

Wherein p is 0 or 1 or 2 or 3;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (IV):

Wherein Rb is-(CH ₂) _n-Rc; N is 0 or 1 or 2 or 3; Rc is carboxyl, hydroxyl, formyl radical, (C ₁-C ₄)-alkoxyl group, H ₂NC (=O)-, (C ₁-C ₄)-alkoxy carbonyl or halo-(C ₁-C ₄)-alkoxy carbonyl.

In another embodiment, the present invention relates to formula (II) compound or its salt, wherein R ₂Be formula (IVA):

In another embodiment, the present invention relates to formula (II) compound or its salt, wherein R ₂Be formula (IVA); P is 1 or 2; Ra is a halogen; R ₁₂And R ₁₃Be halo-(C ₁-C ₄) alkyl; Rb is-(CH ₂) _n-Rc, wherein n is 0 or 1; Rc is carboxyl or (C ₁-C ₄)-alkoxy carbonyl or halo-(C ₁-C ₄)-alkoxy carbonyl.

In another embodiment, the present invention relates to formula (II) compound:

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₇And R ₈Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be selected from formula (III) or (IV):

Wherein Rb is-(CH ₂) _n-C (O)-O-Rc; N is 1 or 2 or 3; Rc is hydrogen, H ₂N-, (C ₁-C ₄)-alkyl or halo-(C ₁-C ₄) alkyl.

In another embodiment, the present invention relates to formula (II) compound:

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₇And R ₈Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be selected from formula (III) or (IV):

Wherein Rb is-(CH ₂) _n-C (O)-O-Rc; N is 0 or 1 or 2 or 3; Rc is hydrogen, H ₂N-, (C ₁-C ₄)-alkyl or halo-(C ₁-C ₄) alkyl.

In another embodiment, the present invention also is particularly related to the new compound shown in the embodiment, also relates to described preparation method herein.

Abbreviation:

Ac: ethanoyl; AcOEt: ethyl acetate; AIBN:2,2 '-Diisopropyl azodicarboxylate; BOP: benzotriazole-1-base oxygen base three (dimethylamino) phosphofluoric acid phosphine; BPO: benzoyl peroxide; N-BuLi: n-Butyl Lithium; DCC:N, N '-dicyclohexylcarbodiimide; DHP:3,4-dihydro-2H-pyrans; DIPEA:N, the N-diisopropylethylamine; DMAP:4-N, the N-dimethyl aminopyridine; MCPBA: m-chloro benzoic acid; EtOH: ethanol; EDC:N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; The HATU:N-[(dimethylamino)-and 1H-1,2,3-triazolo [4,5-b] pyridine-1-methylene]-N-methyl first ammonium hexafluorophosphate N-oxide compound; Hex: just-hexane; KOt-Bu: potassium tert.-butoxide; LiAlH ₄: lithium aluminum hydride; MeOH: methyl alcohol; Ms: methylsulfonyl; NaBH ₄: four sodium borohydrides; The NBS:N-bromo-succinimide; POCl ₃: phosphorus oxychloride (III); Sat.: saturated; TEA: triethylamine; THF: tetrahydrofuran (THF); Ms: methylsulfonyl; DMF:N, dinethylformamide; TFA: trifluoroacetic acid; UPLC: Ultra Performance Liquid Chromatography.

The present invention relates to prepare the method for The compounds of this invention.The preparation of formula (I) compound or its salt comprises for example following flow process:

Flow process 1.

Employed intermediate 1-1,1-2 and 1-3 can buy among the present invention, perhaps according to flow process 1 preparation.Suitably the arylamines 1-1 that replaces (wherein encircle A such as herein or in the claim definition) can adopt diacetyl oxide (Ac ₂O) or the 4-N of Acetyl Chloride 98Min. (AcCl) and catalytic amount, N-dimethyl aminopyridine (DMAP) is at CH ₂Cl ₂The middle processing obtains corresponding intermediates 1-2.By adopting phosphoryl chloride (POCl ₃) in DMF, handle the Vilsmeier cyclization carry out intermediate 1-2, can obtain corresponding intermediates 1-3[referring to for example: Meth-Cohn etc., J.Chem.Soc., Perkin Trans.1 1520 (1981)].

Flow process 2.

Intermediate 2-1 used in the present invention, 2-2,2-3 and 2-4 can buy, perhaps according to flow process 2 preparations.Suitably the aromatic bromide 2-1 that replaces (wherein encircle A such as herein or in the claim definition) can adopt oxidising agent for example m-chloro benzoic acid (m-CPBA) etc. at appropriate solvent (CH for example ₂Cl ₂Deng) handle, obtain corresponding intermediates 2-2.By adopting phosphoryl chloride (POCl ₃) handle, carry out the chlorination reaction of intermediate 2-2, obtain corresponding intermediates 2-3[referring to for example: Grig-Alexa etc., Synlett 11,2000 (2004)].Adopt n-BuLi and DMF to carry out the formylation of intermediate 2-3, can obtain corresponding intermediates 2-4.Perhaps, adopt carbon monoxide and sodium formiate or hydrogen in the presence of palladium catalyst, also can carry out formylation reaction [referring to for example: Okano etc., Bull.Chem.Soc.Jap.67,2329 (1 994)].

Flow process 3.

Intermediate 3-1 of the present invention (wherein encircle A such as herein or in the claim definition) can buy, perhaps prepare according to method shown in flow process 1 and 2.At suitable alkali (for example triethylamine (TEA), salt of wormwood (K ₂CO ₃) etc.) exist down, in appropriate solvent (for example tetrahydrofuran (THF) (THF), toluene, toluene), at the amine [(R of the aryl chloride 3-1 of suitable replacement and suitable replacement ₄) (R ₅) NH] or H-Z (wherein encircle A, R ₄, R ₅And Z such as herein or in the claim definition) between carry out coupled reaction, can obtain corresponding intermediates 3-2 and (wherein encircle A, R ₂, Z, R ₄And R ₅Such as herein or in the claim definition).Perhaps, adopt suitable amine [R ₄-NH ₂Or R ₅-NH ₂] handle 3-1, adopt suitable reagent [R subsequently ₅-L or R ₄-L (L is a leavings group, for example halogen ,-OMs etc.)] carry out alkylated reaction, can prepare intermediate 3-2.Original reagent (for example sodium borohydride etc.) reduction aldehyde 3-2 in methyl alcohol or ethanol etc. is gone back in employing, can obtain corresponding alcohols 3-4.Perhaps, adopt and to go back original reagent (for example sodium borohydride etc.) and can adopt the amine [(R4) (R5) NH] of suitable replacement or H-Z to carry out amination reaction subsequently muriate 3-1 reduction, obtain corresponding pure 3-4.

Flow process 4.

Employed intermediate 4-1,4-2 and 4-3 among the present invention (wherein encircle A such as herein or in the claim definition) can buy, perhaps according to flow process 4 preparations [referring to for example: Katou etc., Heterocycles, 52,911 (2000)].

Flow process 5.

Intermediate 5-1 of the present invention (wherein encircle A and Y such as herein or in the claim definition) can buy, perhaps according to flow process 4 described methods preparations.At suitable alkali (for example triethylamine (TEA), salt of wormwood (K ₂CO ₃) etc.) exist down, in appropriate solvent (for example tetrahydrofuran (THF) (THF), toluene, toluene), at the amine [(R of the aryl chloride 5-1 of suitable replacement and suitable replacement ₄) (R ₅) NH] or H-Z (wherein encircle A, R ₄, R ₅And Z such as herein or in the claim definition) between carry out coupled reaction, can obtain corresponding intermediates 5-2 and (wherein encircle A, R ₂With Y such as herein or in the claim definition).Perhaps, adopt suitable amine [R ₄-NH ₂Or R ₅-NH ₂] handle 5-1, adopt suitable reagent [R subsequently ₅-L or R ₄-L (L is a leavings group, for example halogen ,-OMs etc.)] carry out alkylated reaction, can prepare intermediate 5-2.At 2 of catalytic amount, 2 '-Diisopropyl azodicarboxylate (AIBN) exists and to adopt halide reagent (for example N-bromosuccinimide etc.) down, perhaps at CCl ₄In adopt benzoyl peroxide (BPO), carry out the halogenating reaction of intermediate 5-2, can obtain corresponding benzyl halogenide 5-3.

Flow process 6.

The compounds of this invention 6-3 (wherein encircles A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition) can prepare according to method described in the flow process 6.Intermediate 6-1 of the present invention and 6-2 (L is a leavings group, for example halogen ,-OMs etc.) (wherein encircle A, R ₂, X and Y such as herein or in the claim definition) can be respectively according to method preparation as described in flow process 3 and the flow process 5.Having or alkali-free (for example triethylamine and N, N-diisopropylethylamine etc.) exists down, in solvent (for example THF or toluene), the pure 6-1 of suitable replacement can adopt processing such as thionyl chloride or methylsulfonyl chloride, obtains corresponding intermediates 6-2.Perhaps, in appropriate solvent (for example methylene dichloride etc.), handle 6-1, can prepare intermediate 6-2 by adopting carbon tetrabromide and triphenyl phosphine etc.Preferred leavings group is bromide anion or chlorion, but also can be iodide ion, methanesulfonate, tosylate etc.Intermediate 6-2 can adopt suitable amine [(Ar-CH ₂-) (R ₁) NH] (wherein Ar and R ₁Such as herein or in the claim definition) and alkali (for example potassium tert.-butoxide etc.) in solvent (for example DMF or THF etc.), handle, obtain corresponding coupling product 6-3.

Flow process 7.

The compounds of this invention 7-3 (wherein encircles A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition) can be according to method preparation as described in the flow process 7.Intermediate 7-1 of the present invention (wherein encircles A, R ₂, X and Y such as herein or in the claim definition) can prepare according to method described in the flow process 3.Going back in the presence of original reagent (for example sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride etc.) and the acid (for example acetate, trifluoroacetic acid), at methyl alcohol, ethanol, CH ₂Cl ₂, 1, in the 2-ethylene dichloride etc., the aryl that adopt to replace-methylamine is handled the aldehyde 7-1 of suitable replacement, obtains corresponding intermediates 7-2.Perhaps, intermediate 7-2 can adopt the acid of benzyl amine and catalytic amount for example right-toluenesulphonic acids etc. handles in toluene, obtains corresponding imines, adopt subsequently go back original reagent for example sodium borohydride with the imines reduction that obtains.In appropriate solvent (for example toluene, THF, DMF etc.), in the presence of suitable alkali (for example salt of wormwood, triethylamine, sodium hydride, two (trimethyl silyl) ammonification potassium etc.), adopt suitable R1-L (for example chloro-pyridine of acyl chlorides, (alkoxymethyl)-2 acyl chlorides, replacement, the Chloropyrimide of replacement) to handle, compound 7-2 can be converted into compound 7-3.

Flow process 8.

Compound 8-2 of the present invention (wherein encircles A, Ar, R ₁, X and Y such as herein or in the claim definition, wherein-(linking group)-CO ₂H such as R ₂Described in [ex.-N (C ₁-C ₄-alkyl) (C ₁-C ₄-alkyl-C ₃-C ₇-cycloalkyl-C ₁-C ₃-alkyl-CO ₂H)]) can prepare according to method described in the flow process 8.

Compound 8-1 of the present invention (wherein encircles A, Ar, R ₁, X and Y such as herein or in the claim definition, and W wherein ₂Be C ₁-C ₆Alkyl) can prepare according to method described in flow process 6 or 7.Intermediate 8-1 can adopt alkali (for example lithium hydroxide, sodium hydroxide, potassium hydroxide etc.) to handle in appropriate solvent (for example methyl alcohol, ethanol, THF etc.), obtains corresponding carboxylic acid 8-2.

Flow process 9.

Compound 9-2 of the present invention, 9-3 and 9-4 (wherein encircle A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition) can prepare according to method described in the flow process 9.Compound 9-1 of the present invention (wherein encircles A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition, wherein halogen is preferably iodine or bromine) can be according to flow process 6 or 7 described methods preparations.Compound 9-1 can adopt CuCN to handle in DMF at elevated temperatures, obtains corresponding compounds 9-2.Perhaps, in the presence of CuI and palladium (II) salt or in the presence of some copper or nickel composite, the coupled reaction by compound 9-1 and KCN can prepare nitrile 9-2.In appropriate solvent (for example methyl alcohol, ethanol, THF etc.), adopt lithium hydroxide, sodium hydroxide etc. to handle 9-2, can prepare carboxylic acid 9-3.At appropriate solvent (CH for example ₂Cl ₂) in adopt the DMF of oxalyl chloride and catalytic amount or adopt thionyl chloride in appropriate solvent (for example toluene), can carry out the chlorination of carboxylic acid 9-3.In the THF equal solvent, adopt amine (for example dimethylamine) to carry out amination reaction subsequently, obtain acid amides 9-4.Perhaps, in the presence of coupling reagent (for example DCC, EDC, BOP, HATU etc.), at appropriate solvent (CH for example ₂Cl ₂, THF etc.) in, acid amides 9-4 can prepare by adopting amine carry out amination reaction.

Flow process 10.

Compound 10-2 of the present invention or 10-4 (wherein encircle A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition, wherein R is alkyl, alkoxyl group, dialkylamine or cyclammonium) can prepare according to method described in the flow process 10.Compound 10-1 of the present invention or 10-3 (wherein encircle A, Ar, R ₁, R ₂, X and Y such as herein or in the claim definition, wherein halogen is preferably iodine or bromine) can prepare according to method described in flow process 6 or 7.In the presence of alkali (for example NaOt-Bu, KOt-Bu etc.), palladium or nickel catalyzator and part (for example 2-(two-tert-butyl phosphino-) biphenyl etc.), in appropriate solvent (for example toluene, THF, dioxane etc.), under the temperature that raises, can between compound 10-1 or 10-3 and suitable alcohol, amine or alkyl Grignard reagent, carry out coupled reaction, obtain corresponding coupling product 10-2 or 10-4.

Flow process 11.

Compound 11-2 of the present invention, 11-3,11-4 and 11-5 (wherein Ar, R ₁, R ₄, R ₅, X and Y such as herein or in the claim definition, p is as defined integer herein or in the claim) can prepare according to method described in the flow process 11.Compound 11-1 of the present invention (wherein Ar, R ₁, R ₄, R ₅, X and Y such as herein or in the claim definition, p is as defined integer herein or in the claim) can prepare according to method described in flow process 6 or 7.According to Peter G; M Wuts and Theodora W.Greene " blocking group in the organic synthesis (Protective Groups in Organic Synthesis) ". the 4th edition; method described in Wiley and the wherein said reference; go protection can obtain pure 11-2 compound 11-1 (Pro is the suitable blocking group of alcohol, for example benzyl, THP trtrahydropyranyl etc.).In appropriate solvent, by adopting oxidising agent (for example PCC, PDC, KMnO ₄) oxidizing reaction, perhaps, compound 11-2 can be converted into aldehyde 11-3 or carboxylic acid 11-4 by Swern oxidizing reaction, Dess-Martin oxidizing reaction, TEMPO oxidizing reaction etc.In appropriate solvent, by adopting oxidising agent (KMnO for example ₄) oxidizing reaction, perhaps by Textone oxidizing reaction (ex.NaClO ₂/ NaH ₂PO ₄/ 2-methyl-2-butene), TEMPO oxidizing reaction etc., also aldehyde 11-3 can be converted into carboxylic acid 11-4.In the presence of coupling reagent (for example DCC, EDC, BOP, HATU etc.) and alkali (for example triethylamine etc.), at appropriate solvent (CH for example ₂Cl ₂, THF etc.) in, adopt NH ₄Cl handles carboxylic acid 11-4, can obtain acid amides 11-5.Perhaps, at appropriate solvent (for example toluene, CH ₂Cl ₂Deng) in, by with the reaction of thionyl chloride, oxalyl chloride etc., carboxylic acid 11-4 can be converted into acyl chlorides, subsequently with ammonia at appropriate solvent (for example THF, CH ₂Cl ₂Deng) middle reaction, obtain acid amides 11-5.

Consider the free form of new compound and the close relation between its salt form, in context, free cpds or its salt also can be correspondingly and are interpreted as the compound that is meant corresponding salt or free form easily.

According to selected raw material and method, new compound can exist with the form of one of possible isomer or its mixture, for example pure optical isomer, as enantiomorph, perhaps isomer mixture for example, as racemic modification, non-enantiomer mixture or racemic mixture, this depends on the number of unsymmetrical carbon.

The present invention also relates to the embodiment of described method, according to these embodiments, obtainable compound as intermediate can and carry out the elliptical step as raw material in any step of described method, perhaps adopt the raw material of derivative or salt and/or its racemic modification or enantiomeric form, perhaps the compound that particularly under reaction conditions, forms.

In the method for the invention, preferably those can be formed in the just raw material of the special compound that uses of initial period.The invention still further relates to new raw material, they are to develop especially to be used to prepare The compounds of this invention, the invention still further relates to the purposes and their method of preparation of these raw materials.

The invention still further relates to formula (I), (IA), (IB), (IC) or (II) compound or its pharmacy acceptable salt respectively with the combined utilization of other activeconstituents.

Described combined utilization can adopt and for example be selected from following activeconstituents:

(i) HMG-Co-A reductase inhibitor or its pharmacy acceptable salt,

(ii) angiotensin II receptor antagonists or its pharmacy acceptable salt,

(iii) Zinc metallopeptidase Zace1 (ACE) inhibitor or its pharmacy acceptable salt,

(iv) calcium channel blocker or its pharmacy acceptable salt,

(v) aldosterone synthetase inhibitors or its pharmacy acceptable salt,

(vi) aldosterone antagonists or its pharmacy acceptable salt,

(vii) two-way Zinc metallopeptidase Zace1/neutral endopeptidase (ACE/NEP) inhibitor or its pharmacy acceptable salt,

(viii) endothelin antagonist or its pharmacy acceptable salt,

(ix) renin inhibitor or its pharmacy acceptable salt,

(x) diuretic(s) or its pharmacy acceptable salt,

(xi) the ApoA-I stand-in and

(Xii) DGAT inhibitor.

Angiotensin II receptor antagonists or its pharmacy acceptable salt can be understood as be can with the AT of angiotensin-ii receptor ₁-receptor subtype in conjunction with but can not cause the activeconstituents of receptor activation.Because can suppress AT ₁Acceptor so these antagonists can for example be used as antihypertensive drug, perhaps is used for the treatment of congestive heart failure.

AT ₁The kind of receptor antagonist comprises the compound with different structure feature, main preferred those non-peptide compounds.For example, described compound can be selected from: valsartan, losartan, Candesartan, Eprosartan, irbesartan, Saprisartan, Tasosartan, telmisartan, name are called the following formula: compound of E-1477

Name is called the following formula: compound of SC-52458

And name is called the following formula: compound of ZD-8731

Perhaps, under any circumstance, its pharmacy acceptable salt.

Preferred AT ₁-receptor antagonist is those medicines that gone on the market, most preferably valsartan or its pharmacy acceptable salt.

HMG-Co-A reductase inhibitor (being also referred to as beta-hydroxy-Beta-methyl glutaryl--coenzyme-A reductase inhibitor) is meant that those can reduce the activeconstituents of (comprising cholesterol levels) of lipid level in the blood.

The kind of HMG-Co-A reductase inhibitor comprises the compound with different structure feature, for example described compound is selected from: atorvastatin, Cerivastatin, mevastatin, Dalvastatin, dihydro mevastatin (dihydrocompactin), fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, Pravastatin, rivastatin, Simvastatin and velostatin, perhaps, under any circumstance, its pharmacy acceptable salt.

Preferred HMG-Co-A reductase inhibitor is those medicines that gone on the market, most preferably fluvastatin and pitavastatin, perhaps, and under any circumstance, its pharmacy acceptable salt.

Adopting ACE-inhibitor (being also referred to as angiotensin converting enzyme inhibitor) blocking-up angiotensin I is the alternative of the success of blood pressure regulation to the degraded of the enzyme of Angiotensin II conversion, therefore also can be used as the methods of treatment of treatment congestive heart failure.

The kind of ACE inhibitor comprises the compound with different structure feature, for example described compound is selected from: alacepril, benazepril, benazepril, captopril, SQ-29852, Yipingshu, delapril, enalapril, enalapril, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, Ramipril, spirapril, temocapril and Trolapril, perhaps, under any circumstance, its pharmacy acceptable salt.

Preferred ACE inhibitor is those medicines that gone on the market, most preferably benazepril and enalapril.

The kind of CCBs mainly comprises dihydropyridines (DHPs) and non--DHP class, for example Odizem class and verapamil class CCBs.

The preferred DHP of CCB that is used for described combined utilization, representative medicine is selected from: amlodipine, felodipine, ryosidine, Isrodipine, Lacidipine (62, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nilvadipine, the representative medicine of preferably non--DHP is selected from: flunarizine, prenylamine, Odizem, Fendiline, methoxyverapamil, rice shellfish ground that, anipamil, tiapamil and verapamil, and its pharmacy acceptable salt under any circumstance.These all CCBs all can use in treatment, for example as antihypertensive drug, antianginal drug or antiarrhythmic drug.

Preferred CCBs comprises amlodipine, Odizem, Isrodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil, perhaps depends on specific CCB and pharmacy acceptable salt thereof.Particularly preferred DHP is amlodipine or its pharmacy acceptable salt, particularly its benzene sulfonate.Particularly preferred representative non--DHPs is verapamil or its pharmacy acceptable salt, particularly its hydrochloride.

The aldosterone synthetase inhibitors be for can being converted into Kendall compound the enzyme of aldosterone, described conversion by the Kendall compound hydroxylation is formed the 18-OH-Kendall compound, the 18-OH-Kendall compound forms aldosterone and carries out then.The known kind that is used for the treatment of the aldosterone synthetase inhibitors of hypertension and primary aldosteronism comprises steroidal and nonsteroidal aldosterone synthetase inhibitors, the most preferably latter.

Preferably derive from commercial aldosterone synthetase inhibitors or those aldosterone synthetase inhibitors through the health agency approval.

The kind of aldosterone synthetase inhibitors comprises the compound with different structure feature.For example, described compound is selected from: non-steroidal aromatase inhibitor Anastrozole, fadrozole (comprising its (+)-enantiomorph), and steroidal aromatase inhibitor exemestane, perhaps, and under any circumstance, its pharmacy acceptable salt.

(+)-enantiomorph (United States Patent (USP) 4617307 and 4889861) that most preferred non-steroidal aldosterone synthetase inhibitors is the CGS-16949A of following formula:

Preferred steroidal aldosterone antagonists is the eplerenone of following formula:

Spironolactone.

Preferred two-way Zinc metallopeptidase Zace1/neutral endopeptidase (ACE/NEP) inhibitor is for example Ao Palate (omapatrilate) (cf.EP 629627), Fasidotril or fasidotrilate, perhaps, if the available word, its pharmacy acceptable salt.

Preferred endothelin antagonist also comprises tezosentan (tezosentan) (cf.WO 96/19459) for for example bosentan (bosentan) (cf.EP 526708 A), perhaps, under any circumstance, its pharmacy acceptable salt.

Renin inhibitor is for example non-peptide class renin inhibitor, for example following formula: compound:

Chemical name is 2 (S), 4 (S), 5 (S), 7 (S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-two (1-methylethyl)-4-hydroxyl-5-amino-8-[4-methoxyl group-3-(3-methoxyl group-propoxy-) phenyl]-decoylamide.This typical medicaments is disclosed in EP 678503 A especially.Preferred especially its hemifumarate.

Diuretic(s) is for example thiazides derivative, is selected from: chlorothiazide, hydrochlorothiazide, Methyclothiazide and chlorthalidone.Most preferably be hydrochlorothiazide.

The ApoA-I stand-in are for example D4F peptide, particularly formula D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F.

The DGAT inhibitor is for for example one or more is disclosed in the compound in WO2005072740 and the U.S. Provisional Application number 60/787859.

Preferably, the co-therapy significant quantity of the activeconstituents of combined utilization of the present invention can be simultaneously or according to any order administration, can be in different products or administration in the fixed combined prod.

Can derive from " The Merck Index (the Merck index) " standard directories of current edition according to the structure of popular name or the determined activeconstituents of trade(brand)name, or derive from database, IMSLifeCycle (for example IMS World Publications (IMS is international open)) for example.Its content corresponding is hereby incorporated by.According to these references, those skilled in the art can determine activeconstituents fully, equally can be outside standard body and body in preparation and test the indication and the performance of described medicine in the experimental model.

The present invention be more particularly directed to be used for the formula (I), (IA), (IB), (IC) of the mankind or animal body treatment or (II) compound or its pharmacy acceptable salt.

The invention still further relates to formula I compound or have the purposes of pharmacy acceptable salt of this compounds of salify performance, particularly as the active substance of pharmacology (mainly being the CETP inhibitor).For this reason, they can preferably use with the form of pharmaceutically acceptable preparation, are used to prevent and/or treat animal or human's class, particularly use as the CETP inhibitor.

The present invention be more particularly directed to formula (I), (IA), (IB), (IC) or (II) compound or its pharmacy acceptable salt and the optional at least a purposes that is used for the treatment of the composition of disease listed in cardiovascular disorder and relative disease and the context of combination with it, be used to produce prevention or the treatment disease relevant or delay the medicine of its development with CETP, described disease comprises for example hyperlipidaemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc. are especially for the medicine of prevention or treatment hyperlipidaemia or arteriosclerotic disease.

The invention still further relates to prevention or the treatment disease relevant or delay the method for its development with CETP, described disease comprises for example hyperlipidaemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc., especially for the medicine of prevention or treatment hyperlipidaemia or arteriosclerotic disease, described method comprises that the animal that needs this type of treatment respectively comprises human formula (I), (IA), (IB), (IC) or (II) compound or its pharmacy acceptable salt and the optional at least a composition that is used for the treatment of disease listed in cardiovascular disorder and relative disease and the context of combination with it.

The invention still further relates to and contain formula (I) respectively, (IA), (IB), (IC) or (II) compound or its pharmacy acceptable salt and the optional at least a medicinal compositions that is used for the treatment of the composition of disease listed in cardiovascular disorder and relative disease and the context of combination with it, be used to prevent or disease that treatment is relevant with CETP or delay the method for its development, described disease comprises for example hyperlipidaemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc. are especially for the medicine of prevention or treatment hyperlipidaemia or arteriosclerotic disease.

The pharmaceutical preparation of the present invention that contains The compounds of this invention or its pharmacy acceptable salt is that those can be through gi tract (for example per os and per rectum) and parenteral admin in the preparation of warm-blooded animal, described pharmacologically active principles can be individually dosed, perhaps with pharmaceutically acceptable carrier administration.The per daily dose of activeconstituents depends on age and individual instances, also depends on the pattern of administration.

The dosage of activeconstituents depends on kind, age and the individual instances of warm-blooded animal, also depends on the pattern of administration.

The following example has been illustrated the invention described above, yet they are not to limit its scope in any form.Temperature is all with a degree centigrade expression.

Embodiment:

Embodiment 1:N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

With methylsulfonyl chloride (MsCl, 15mg, 0.13mmol) drop to 2-[N-(cyclopentyl-methyl)-N-ethylamino] quinoline-3-yl methyl alcohol (25mg, 0.088mmol) and N, N-diisopropylethylamine (23mg, 0.18mmol) toluene (1mL) solution in, reaction mixture was stirred under room temperature 2 hours.In mixture, add 1N HCl aq and ethyl acetate.Organic layer, filters and vacuum concentration through dried over mgso with saturated sodium bicarbonate aqueous solution, salt water washing.In residue, add N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine (29mg, 0.089mmol) and DMF (1mL), mixture is stirred, add then potassium tert.-butoxide (11mg, 0.098mmol), with mixture restir 1 hour.After adding 1N HCl aq, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The mixture that obtains obtains N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino through silica gel chromatography } methyl) quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.10(m，2H)，1.08(t，3H)，1.37-1.60(m，6H)，2.03-2.20(m，1H)，3.18(q，2H)，3.23(d，2H)，4.22(s，3H)，4.67(s，2H)，4.83(s，2H)，7.32(m，1H)，7.56(d，1H)，7.57(m，1H)，7.66(s，2H)，7.72(s，1H)，7.78(s，1H)，7.85(d.1H)。

ESI-MS?m/z：592[M+1] ⁺

Embodiment 2: according to the method for embodiment 1, the employing replacement 2-[N-(methyl cycloalkyl)-N-ethylamino] and quinoline-3-yl } methyl alcohol and N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine, the preparation following compounds.

Embodiment 3: according to the method for embodiment 1, adopt quinoline-3-base-methyl alcohol and the N-[3 that replaces, 5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine, the preparation following compounds.

Embodiment 4: trans-[4-({ N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoline-2-yl]-N-ethylamino } methyl) cyclohexyl] acetate synthetic

To trans-[4-({ N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoline-2-yl]-the N-ethylamino } methyl) cyclohexyl] ethyl acetate (39mg, 0.056mmol) THF-methyl alcohol (2: 1,0.9mL) add 2N LiOH (0.1mL) in the mixture, mixture was stirred 3 hours in 40 ℃.Mixture is diluted with 1N HCl and ethyl acetate, with salt water washing organic layer, through dried over mgso, filter and concentrate and obtain trans-[4-({ N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoline-2-yl]-N-ethylamino methyl) cyclohexyl] acetate.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.80-0.93(m，4H)，1.05-1.80(m，9H)，2.16(2H，d)，3.00-3.55(br，4H)，4.21(s，3H)，4.72(brs，2H)，4.79(brs，2H)，7.57(d，1H)，7.65(s，2H)，7.73(s，1H)，7.73-8.10(br，4H)。

ESI-MS?m/z：664[M+1] ⁺

Embodiment 5: according to the method for embodiment 4, adopt trans-[4-({ N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoline-2-yl of replacing]-the N-ethylamino } methyl) cyclohexyl] ethyl acetate, the preparation following compounds.

Embodiment 6:3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formonitrile HCN synthetic

With N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-7-bromo quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine (140mg, 0.21mmol) and CuCN (110mg, DMF suspension 1.23mmol) stirred 16 hours in 165 ℃.Reaction mixture is cooled to room temperature, then with ammoniacal liquor and ethyl acetate dilution.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains 3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formonitrile HCN.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.12(m，2H)，1.10(t，3H)，1.41-1.60(m，6H)，2.11-2.20(m，1H)，3.23(q，2H)，3.26(d，2H)，4.23(s，3H)，4.67(s，2H)，4.80(s，2H)，7.44(dd，1H)，7.60(d，1H)，7.63(s，2H)，7.71(s，1H)，7.78(s，1H)，8.18(s，1H)。

ESI-MS?m/z：617[M+1] ⁺

Embodiment 7:3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formic acid synthetic

With 3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formonitrile HCN (40mg, 0.06mmol) and the suspension of the EtOH (2mL) of the 2NLiOH aqueous solution (2.0mL) stirred 2 hours down in refluxing.Reaction mixture is cooled to room temperature, then with 1N HCl and ethyl acetate dilution.Organic layer salt water washing, through dried over mgso, filter and concentrate obtain 3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formic acid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.15(m，2H)，1.12(t，3H)，1.41-1.60(m，6H)，2.12-2.22(m，1H)，3.22-3.30(m，4H)，4.23(s，3H)，4.70(s，2H)，4.83(s，2H)，7.62(d，1H)，7.70(s，2H)，7.73(s，1H)，7.83(s，1H)，7.95(dd，1H)，8.66(s，1H)。

ESI-MS?m/z：636[M+1] ⁺

Embodiment 8:3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formic acid dimethylformamide synthetic

With 3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] and quinoline-7-formic acid (30mg, 0-047mmol), the CH of the DMF of oxalyl chloride (10ul) and catalytic amount ₂Cl ₂(2mL) mixture stirred under room temperature 3 hours and vacuum concentration.Residue is dissolved in THF,, the THF mixture that obtains was stirred under room temperature 3 hours with the THF processing of 2M dimethyl amine.Mixture with 1N HCl cancellation, is extracted with EtOAc.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains 3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-2-[N '-(cyclopentyl-methyl)-N '-ethylamino] quinoline-7-formic acid dimethylformamide.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.02-1.11(m，2H)，1.09(t，3H)，1.65-1.38(m，6H)，2.08-2.18(m，1H)，3.05(s，3H)，3.16(s，3H)，3.00-3.26(m，4H)，4.23(s，3H)，4.68(s，2H)，4.81(s，2H)，7.36(d，1H)，7.59(d，1H)，7.64(s，2H)，7.72(s，1H)，7.79(s，1H)，7.89(s，1H)。

ESI-MS?m/z：663.7[M+1] ⁺

Embodiment 9:N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-7-N ", N "-dimethylamino quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

With N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-7-bromo quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine (110mg, 0.16mmol), dimethylamine (the THF solution of 2M, 0.18mL, 0.36mmol), NaOt-Bu (25mg, 0.26mmol), Pd ₂(dba) ₃(8mg, 0.0087mmol) and 2-(two-tert-butyl phosphino-) biphenyl (5mg, 0.017mmol) suspension in toluene (1mL) stirred 4 hours in 100 ℃.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-7-N ", N "-dimethylamino quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.02-1.11(m，2H)，1.04(t，3H)，1.37-1.63(m，6H)，2.11-2.20(m，1H)，3.07(s，6H)，3.15(d，2H)，3.86(d，2H)，4.21(s，3H)，4.63(s，2H)，4.80(s，2H)，6.95-6.98(m，2H)，7.40-7.43(m，1H)，7.63(s，1H)，7.66(s，2H)，7.72(s，1H)。

ESI-MS?m/z：635.7[M+1] ⁺

Embodiment 10: according to the method for embodiment 9, adopt N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-7-bromo quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine, the preparation following compounds.

Embodiment 11:N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(5-brominated pyrimidine-2-yl) amino } methyl)-7-fluorine quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

With N-(3-{N '-[3,5-two (trifluoromethyl) benzylamino] methyl-7-fluorine quinoline-2-yl)-N-(cyclopentyl-methyl) ethamine (610mg, 1.2mmol), 5-bromo-2-Chloropyrimide (449mg, 2.3mmol) and K ₂CO ₃(321mg, 2.3mmol) suspension in toluene stirred 5 days under refluxing.Reaction mixture is cooled to room temperature, then water and CH ₂Cl ₂Dilution.Organic layer filters and concentrates through phase separator.The crude product product is through silica gel chromatography, obtains N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(5-brominated pyrimidine-2-yl) amino } methyl)-7-fluorine quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

Rf value=0.69 (hexane/AcOAt=9/1)

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.04-1.12(m，2H)，1.10(t，3H)，1.41-1.61(m，6H)，2.13-2.20(m，1H)，3.21(dd，2H)，3.25(d，2H)，4.80(s，2H)，4.95(s，2H)，7.08(ddd，1H)，7.48(ddd，1H)，7.52(s，1H)，7.65(s，2H)，7.72(s，1H)，8.42(s.2H)。

Embodiment 12:N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(5-morpholine-4-base-pyrimidine-2-base) amino } methyl)-7-fluorine quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

With N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(5-brominated pyrimidine-2-yl) amino } methyl)-7-fluorine quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine (420mg, 0.61mmol), morpholine (80 μ L, 0.93mmol), NaOt-Bu (94mg, 0.98mmol), Pd ₂(dba) ₃(28mg, 0.031mmol) and 2-(two-tert-butyl phosphino-) biphenyl (18mg, 0.060mmol) suspension in toluene (4mL) stirred 2.5 hours in 100 ℃.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution then.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-(5-morpholine-4-base-pyrimidine-2-base) amino } methyl)-7-fluorine quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.87-1.11(m，2H)，1.09(t，3H)，1.38-1.62(m，6H)，2.13-2.20(m，1H)，3.07-3.09(m，4H)，3.18-3.27(m，4H)，3.87-3.90(m，4H)，4.81(s?2H)，4.93(s，2H)，7.55-7.60(m，1H)，7.60(s，1H)，7.66(s，2H)，7.70(s，1H)，8.18(s.2H)。

ESI-MS?m/z：691[M+1] ⁺

Embodiment 13: according to the method for embodiment 11 and 12, adopt N-(3-{N '-[3,5-two (trifluoromethyl) benzylamino] methyl-quinoline-2-yl of replacing)-N-(cyclopentyl-methyl) ethamine, the preparation following compounds.

Embodiment 14:N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-hydroxyethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

Step 1:

Method according to embodiment 1 and A, N-{3-[(N '-[3,5-two (trifluoromethyl) benzyl]-N '-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-2H-tetrazolium-5-yl } amino) methyl]-5,7-difluoro-quinoline-2-yl }-N-(cyclopentyl-methyl) ethamine can adopt 2-chloro-5,7-difluoro-quinoline-3-formaldehyde, N-(cyclopentyl-methyl)-N-ethamine and N-[3,5-two (trifluoromethyl) benzyl]-N-{2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-2H-tetrazolium-5-yl } the amine preparation.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.12(m，2H)，1.11(t，3H)，1.41-1.79(m，12H)，2.12-2.22(m，1H)，3.20-3.26(m，4H)，3.43-3.49(m，1H)，3.67-3.73(m，1H)，3.97(ddd，1H)，4.20(ddd，1H)，4.58-4.61(m，1H)，4.63-4.69(m，4H)，4.80(s，2H)，6.75-6.80(m，1H)，7.25-7.28(m，1H)，7.64(s，2H)，7.71(s，1H)，7.93(d，1H)。

ESI-MS?m/z：742[M+1] ⁺

Step 2:

5N HCl (0.2mL) aqueous solution is dropped to N-{3-[(N '-[3,5-two (trifluoromethyl) benzyl]-N '-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-2H-tetrazolium-5-yl } amino) methyl]-5,7-difluoro-quinoline-2-yl }-N-(cyclopentyl-methyl) ethamine (0.25g, 0.34mmol) MeOH/THF (1/4,2.5mL) in, mixture was stirred under room temperature 12 hours.Reaction mixture is by adding NaHCO ₃Ethyl acetate extraction is used in aqueous solution cancellation.Organic layer salt water washing, through dried over mgso, filter and concentrate and obtain N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-hydroxyethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.12(m，2H)，1.10(t，3H)，1.41-1.62(m，6H)，2.12-2.22(m，1H)，2.29(t，1H)，3.21-3.26(m，4H)，4.14-4.16(m，2H)，4.62-4.65(m，2H)，4.67(s，2H)，4.81(s，2H)，6.76-6.81(m，1H)，7.26-7.28(m，1H)，7.64(s，2H)，7.72(s，1H)，7.95(d，1H)。

ESI-MS?m/z：658[M+1] ⁺

Embodiment 15:N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-methoxy ethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

With NaH (60% oil solution, 5mg, 0.13mmol) add to N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-hydroxyethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine (70mg, 0.11mmol) DMF (0.5mL) solution in, stirred 30 minutes in 0 ℃.(10 μ L 0.16mmol), stirred the mixture that obtains 2 hours under room temperature to add MeI in mixture.Reaction mixture is used CH by adding saturated aqueous ammonium chloride solution cancellation ₂Cl ₂Extraction.Organic layer filters and concentrates through phase separator.The crude product product is through silica gel chromatography, obtains N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-methoxy ethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine.

Rf value=0.63 (hexane/AcOEt=4/1)

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.04-1.11(m，2H)，1.09(t，3H)，1.40-1.63(m，6H)，2.12-2.20(m，1H)，3.24(t，3H)，3.35(s，3H)，3.90(t，2H)，4.63-4.66(m，4H)，4.80(s，2H)，6.75-6.80(m，1H)，7.64(s，2H)，7.70(s，1H)，7.95(s.1H)。

Embodiment 16:N-{3-[(N '-[3,5-two (trifluoromethyl) benzyl]-N '-2-[2-(N ", N "-dimethylamino) ethyl]-2H-tetrazolium-5-yl } amino) methyl]-5,7-difluoro-quinoline-2-yl }-N-(cyclopentyl-methyl) ethamine synthetic

With MsCl (20mg, 0.17mmol) employing N-[3-({ N '-[3,5-two (trifluoromethyl) benzyl]-N '-[2-(2-hydroxyethyl)-2H-tetrazolium-5-yl] amino } methyl)-5,7-difluoro-quinoline-2-yl]-N-(cyclopentyl-methyl) ethamine (70mg, 0.11mmol) and N, (25mg, toluene 0.19mmol) (2mL) mixture process stirred 14 hours under room temperature the N-diisopropylethylamine.Mixture is adopted the cancellation of the 1N HCl aqueous solution, use ethyl acetate extraction.Organic layer is with saturated sodium bicarbonate aqueous solution and salt water washing.Through dried over mgso, filter and the concentrated crude product mesylate that obtains.The mesylate that obtains is dissolved in THF (1.0mL) solution of 2M dimethyl amine, and mixture was stirred 2 days in 70 ℃.Reaction mixture is cooled to room temperature, water and CH ₂Cl ₂Dilution.Organic layer filters and concentrates through phase separator.The crude product product is through silica gel chromatography, obtain N-{3-[(N '-[3,5-two (trifluoromethyl) benzyl]-N '-2-[2-(N ", N "-dimethylamino) ethyl]-2H-tetrazolium-5-yl } amino) methyl]-5,7-difluoro-quinoline-2-yl }-N-(cyclopentyl-methyl) ethamine.

Rf value=0.22 (hexane/AcOEt=3/1)

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.02-1.13(m，2H)，1.10(t，3H)，1.39-1.65(m，6H)，2.12-2.20(m，1H)，2.29(s，6H)，2.88-2.98(m，2H)，3.21-3.26(m，4H)，4.57-4.60(m，2H)，4.65(s，2H)，4.80(s，2H)，6.75-7.00(m，1H)，7.24-7.29(m，1H)，7.64(s，2H)，7.71(s，1H)，7.95(s.1H)。

Embodiment 17: trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) methyl alcohol synthetic

In 0 ℃, to trans-N-(2-{ (R)-2-[4-(2-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl-6,7-difluoro-quinoline-3-ylmethyl)-N-[3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amine (7.47g, CH 9.7mmol) ₂Cl ₂(80mL) drip BBr in the stirred solution ₃(1.0MCH ₂Cl ₂Solution, 11.6mL 11.6mmol), stirred 1 hour under room temperature.Reaction mixture passes through to add saturated sodium bicarbonate aqueous solution cancellation in 0 ℃, uses ethyl acetate extraction, with salt water washing organic layer, through dried over mgso, filters also concentrated.The crude product product is through silica gel chromatography, obtains trans-2-(4-{ (R)-1-[3-({ [N-3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) methyl alcohol.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.73-0.95(m，2H)，1.00-1.13(m，2H)，1.21(t，1H)，1.34-1.44(m，1H)，1.57-1.61(m，1H)，1.64-1.79(m，6H)，1.83-1.92(m，1H)，1.98-2.02(m，1H)，3.18-3.24(m，1H)，3.39(t，2H)，3.48-3.57(m，1H)，4.21(s，3H)，4.56(d，1H)，4.57(d，1H)，4.62-4.70(m，1H)，4.78(d，1H)，4.99(d，1H)，7.22(dd，1H)，7.48(dd，1H)，7.56(s，1H)，7.63(s，2H)，7.73(s.1H)。

ESI-MS?m/z：684[M+1] ⁺

Embodiment 18: according to the method for embodiment 17, adopt trans-N-(2-{ (R)-2-[4-(2-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-quinoline-3-ylmethyl of replacing)-benzyl that N-[replaces] (2-methyl-2H-tetrazolium-5-yl) amine, the preparation following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	18-1	7-F	CF ₃	666 [M+1] ⁺	0.74-0.96 (m, 2H), 1.01-1.14 (m, 2H), 1.21 (t, 1H), and 1.34-1.44 (m, 1H), 1.54-1.61 (m, 1H), 1.66-1.79 (m, 6H), 1.83-1.93 (m, 1H), 1.98-2.05 (m, 1H), and 3.22-3.28 (m, 1H), 3.39 (t, 2H), and 3.51-3.59 (m, 1H), 4.20 (s, 3H), 4.58 (d, 1H), 4.59 (d, 1H), and 4.67-4.73 (m, 1H), 4.77 (d, 1H), 4.98 (d, 1H), 7.00 (1H, ddd), 7.37 (dd, 1H), 7.46 (dd, 1H), and 7.62-7.65 (m, 3H), 7.72 (s.1H).

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	18-2	7-F	Cl	632 [M+1] ⁺	0.75-0.96 (m, 2H), 1.01-1.13 (m, 2H), 1.21 (t, 1H), and 1.34-1.45 (m, 1H), 1.51-1.61 (m, 1H), 1.66-1.80 (m, 6H), 1.85-1.92 (m, 1H), 1.97-2.05 (m, 1H), 3.22-3.27 (m, 1H), 3.40 (t, 2H), 3.51-3.59 (m, 1H), 4.21 (s, 3H), 4.46 (d, 1H), 4.55 (d, 1H), 4.66-4.73 (m, 1H), 4.73 (d, 1H), 4.95 (d, 1H), 7.00 (1H, ddd), 7.31 (1H, s), 7.33 (1H, s), 7.37 (dd, 1H), 7.44 (1H, s), 7.47 (dd, 1H), 7.62 (s.1H).
??18-3	??6，7-F ₂	??Cl	??651??[M+1] ⁺	??0.77-0.98(m，2H)，1.11-1.14(m，2H)，1.19(dd，1H)，??1.29-1.44(m，1H)，1.55-1.63(m，1H)，1.66-1.80(m，6H)，??1.84-1.93(m，1H)，1.97-2.07(m，1H)，3.21(dd，1H)，??3.40(dd，2H)，3.49-3.57(m，1H)，4.21(s，3H)，4.47(d，??1H)，4.52(d，1H)，4.66(dd，1H)，4.74(d，1H)，4.96(d，??1H)，7.23(dd，1H)，7.32(d，2H)，7.45(s，1H)，7.48(dd，??1H)，7.56(s，1H)。	18-2	7-F	Cl	632 [M+1] ⁺

Embodiment 19: trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } hexanaphthene formaldehyde synthetic

In 0 ℃ with Dai Si-Martin's reagent (4.07g, 9.6mmol) add to trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) methyl alcohol (6.25g, CH 9.1mmol) ₂Cl ₂(75mL) in the suspension, the mixture that obtains is stirred 20min under room temperature.Reaction mixture adopts dichloromethane extraction by adding saturated sodium bicarbonate aqueous solution cancellation.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } hexanaphthene formaldehyde.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.04-1.28(m，4H)，1.65-2.15(m，10H)，3.19-3.25(m，1H)，3.50-3.57(m，1H)，4.20(s，3H)，4.56(d，1H)，4.60(d，1H)，4.66-4.73(m，1H)，4.81(d，1H)，4.97(d，1H)，7.23(dd，1H)，7.48(dd，1H)，7.57(s，1H)，7.65(s，2H)，7.74(s，1H)，9.55(d.1H)。

ESI-MS?m/z：682[M+1] ⁺

Embodiment 20: according to the method for embodiment 19, adopt trans-(quinoline-2-yl of 4-{ (R)-1-[3-({ benzyl that N-[replaces]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-replace] tetramethyleneimine-2-yl } cyclohexyl) methyl alcohol to prepare following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	20-1	7-F	CF ₃	664 [M+1] ⁺	1.04-1.25 (m, 4H), 1.65-2.16 (m, 10H), 3.22-3.29 (m, 1H), 3.51-3.58 (m, 1H), 4.20 (s, 3H), 4.59 (d, 1H), 4.60 (d, 1H), 4.71-4.77 (m, 1H), 4.79 (d, 1H), 4.96 (d, 1H), 7.02 (ddd, 1H), 7.37 (dd, 1H), 7.47 (dd, 1H), 7.63 (s, 1H), 7.64 (s, 2H), 7.73 (s, 1H), 9.55 (d.1H).
??20-2	??7-F	??Cl	??630??[M+1] ⁺	??1.04-1.25(m，4H)，1.65-2.16(m，10H)，3.22-3.28(m，??1H)，3.51-3.58(m，1H)，4.20(s，3H)，4.48(d，1H)，??4.56(d，1H)，4.71-4.77(m，1H)，4.75(d，1H)，4.94(d，??1H)，7.02(ddd，1H)，7.32(s，1H)，7.34(s，1H)，7.35(dd，??1H)，7.38(s，1H)，7.48(dd，1H)，7.63(s，1H)，9.56(d.??1H)。	20-1	7-F	CF ₃	664 [M+1] ⁺

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	20-3	6,7-F2	Cl	649 [M+1] ⁺	1.04-1.29 (m, 4H), 1.67-2.17 (m, 10H), 3.20-3.27 (m, 1H), 3.50-3.57 (m, 1H), 4.20 (s, 3H), 4.49 (d, 1H), 4.53 (d, 1H), 4.69 (dd, 1H), 4.76 (d, 1H), 4.95 (d, 1H), 7.22-7.28 (m, 1H), 7.33 (d, 2H), 7.46 (s, 1H), 7.48 (dd, 1H), 7.57 (s, 1H), 9.56 (d, 1H).

Embodiment 21: trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } naphthenic acid synthetic

In 0 ℃ with NaClO ₂(2.20g, 24mmol) and NaH ₂PO ₄Water (40mL) mixture of (2.19g 18mmol) drops to trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } hexanaphthene formaldehyde (4.15g, 6.1mmol) 2-methyl-2-butene (6.4mL)/t-BuOH (40mL) solution in, the mixture that obtains was stirred under room temperature 1.5 hours.Reaction mixture passes through to add saturated aqueous ammonium chloride solution cancellation in 0 ℃, uses ethyl acetate extraction.Organic layer salt water washing, through dried over mgso, filtering and concentrating.The crude product product is through silica gel chromatography, obtains trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } naphthenic acid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.01-1.14(m，2H)，1.22-1.43(m，2H)，1.55-1.80(m，5H)，1.85-2.05(m，4H)，2.21(tt，1H)，3.17-3.24(m，1H)，3.49-3.56(m，1H)，4.19(s，3H)，4.57(d，1H)，4.60(d，1H)，4.64-4.70(m，1H)，4.79(d，1H)，4.95(d，1H)，7.23(dd，1H)，7.47(dd，1H)，7.57(s，1H)，7.64(s，2H)，7.74(s.1H)。

ESI-MS?m/z：698[M+1] ⁺

Embodiment 22: according to the method for embodiment 21, adopt trans-(quinoline-2-yl of 4-{ (R)-1-[3-({ benzyl that N-replaces]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-replace] tetramethyleneimine-2-yl } cyclohexyl) methyl alcohol to prepare following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	22-1	7-F	CF ₃	680 [M+1] ⁺	1.04-1.15 (m, 2H), 1.20-1.45 (m, 2H), 1.55-1.80 (m, 5H), 1.85-2.05 (m, 4H), 2.21 (tt, 1H), 3.22-3.28 (m, 1H), 3.51-3.58 (m, 1H), 4.19 (s, 3H), 4.60 (d, 2H), 4.68-4.76 (m, 1H), 4.78 (d, 1H), 4.94 (d, 1H), 7.02 (ddd, 1H), 7.36 (dd, 1H), 7.47 (dd, 1H), 7.63 (s, 1H), 7.64 (s, 2H), 7.73 (s.1H).
??22-2	??7-F	??Cl	??646??[M+1] ⁺	??1.02-1.14(m，2H)，1.23-1.45(m，2H)，1.55-1.80(m，5H)，??1.85-2.05(m，4H)，2.22(tt，1H)，3.21-3.28(m，1H)，??3.51-3.58(m，1H)，4.19(s，3H)，4.49(d，1H)，4.57(d，??1H)，4.69-4.75(m，1H)，4.74(d，1H)，4.92(d，1H)，??7.01(ddd，1H)，7.33(s，2H)，7.37(dd，1H)，7.45(s，1H)，??7.48(dd，1H)，7.62(s，1H)	22-1	7-F	CF ₃	680 [M+1] ⁺
??22-2	??7-F	??Cl	??646??[M+1] ⁺		??22-3	??6，7-F ₂	??Cl	??665??[M+1] ⁺	??1.03-1.15(m，2H)，1.25-1.44(m，2H)，1.60-1.82(m，5H)，??1.84-1.94(m，1H)，1.96-2.07(m，3H)，2.17-2.27(m，1H)，??3.19-3.27(m，1H)，3.48-3.60(m，1H)，4.20(s，3H)，??4.51(dd，1H)，4.54(d，1H)，4.64-4.75(m，1H)，4.75(d，??1H)，4.92(d，1H)，7.21-7.28(m，1H)，7.33(s，2H)，7.46(s，??2H)，7.57(s，1H)。

Embodiment 23: trans-4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexane carboxamide synthetic

With trans-(quinoline-2-yl of 4-{ (R)-1-[3-({ benzyl that N-[replaces]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-replace] tetramethyleneimine-2-yl } cyclohexyl) acetate (135mg, 0.19mmol), NH ₄Cl (21mg, 0.38mmol), N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl, 56mg, 0.29mmol), 1-hydroxyl-7-azepine benzotriazole (HOAt, 26mg, 0.19mmol) and triethylamine (0.054mL, 0.38mmol) mixture in DMF (1mL) stirs 3h under room temperature.After adding entry, reaction mixture extracts with EtOAc.Organic layer salt water washing is through dried over sodium sulfate and vacuum concentration.Residue obtains trans-4-{ (R)-1-[3-({ N-[3 through silica gel chromatography, 5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } the naphthenic acid acid amides, be colourless soup compound.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.16(m，2H)，1.24-1.35(m，2H)，1.35-1.45(m，2H)，1.63-1.81(m，5H)，1.87-1.97(m，3H)，1.99-2.11(m，2H)，3.20-3.26(m，1H)，3.50-3.58(m，1H)，4.19(s，3H)，4.58(d，1H)，4.60(d，1H)，4.66(dd，1H)，4.79(d，1H)，4.95(d，1H)，5.14(s，1H)，5.34(s，1H)，7.23(dd，1H)，7.47(dd，1H)，7.57(s，1H)，7.65(s，2H)，7.74(s，1H)。

ESI-MS?m/z：697[M+1] ⁺

Embodiment 24: trans-2-(4-{ (R)-1-[3-({ [3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) alcoholic acid is synthetic

In 0 ℃ to trans-N-[2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-ylmethyl]-N-[3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amine (11.0g, CH 14.0mmol) ₂Cl ₂(120mL) drip BBr in the stirred solution ₃(1.0MCH ₂Cl ₂Solution, 18.0mL 18.0mmol), stirs 10min under room temperature.Reaction mixture is used ethyl acetate extraction by adding saturated sodium bicarbonate aqueous solution cancellation, with salt water washing organic layer, through dried over mgso, filters and concentrates.The crude product product is through silica gel chromatography, obtains trans-2-(4-{ (R)-1-[3-({ [3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) ethanol.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.72-0.93(m，2H)，1.01-1.18(m，3H)，1.26-1.36(m，1H)，1.39-1.44(m，2H)，1.47-1.55(m，1H)，1.63-1.77(m，6H)，1.83-1.90(m，1H)，1.97-2.05(m，1H)，3.18-3.24(m，1H)，3.48-3.55(m，1H)，3.62-3.67(m，2H)，4.21(s，3H)，4.24(d，1H)，4.56(d，1H)，4.61-4.67(m，1H)，4.79(d，1H)，4.99(d，1H)，7.22(dd，1H)，7.47(dd，1H)，7.56(s，1H)，7.63(s，2H)，7.73(s.1H)。

ESI-MS?m/z：698[M+1] ⁺

Embodiment 25: according to the method for embodiment 24, adopt trans-N-(2-{ (R)-2-[4-(2-benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine-1-yl }-quinoline-3-ylmethyl of replacing)-benzyl that N-[replaces] (2-methyl-2H-tetrazolium-5-yl) amine prepares following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	25-1	7-F	CF ₃	680 [M+1] ⁺	0.72-0.93 (m, 2H), 1.00-1.13 (m, 3H), 1.25-1.35 (m, 1H), and 1.39-1.44 (m, 2H), 1.50-1.54 (m, 1H), 1.64-1.76 (m, 6H), 1.84-1.90 (m, 1H), 1.97-2.04 (m, 1H), and 3.21-3.27 (m, 1H), 3.48-3.56 (m, 1H), and 3.62-3.67 (m, 2H), 4.21 (s, 3H), 4.56 (d, 1H), 4.57 (d, 1H), and 4.66-4.71 (m, 1H), 4.77 (d, 1H), 4.98 (d, 1H), 7.00 (ddd, 1H), 7.36 (dd, 1H), 7.46 (dd, 1H), and 7.52-7.64 (m, 3H), 7.72 (s.1H).
??25-2	??7-F	??Cl	??646??[M+1] ⁺	??0.73-0.95(m，2H)，1.00-1.14(m，3H)，1.25-1.35(m，??1H)，1.39-1.45(m，2H)，1.50-1.54(m，1H)，??1.64-1.76(m，6H)，1.84-1.90(m，1H)，1.97-2.04(m，??1H)，3.21-3.27(m，1H)，3.49-3.57(m，1H)，??3.63-3.68(dt，2H)，4.21(s，3H)，4.45(d，1H)，4.54(d，??1H)，4.65-4.73(m，1H)，4.74(d，1H)，4.95(d，1H)，??7.00(ddd，1H)，7.31(s，1H)，7.33(s，1H)，7.37(dd，??1H)，7.44(s，1H)，7.48(dd，1H)，7.62(s.1H)。	25-1	7-F	CF ₃	680 [M+1] ⁺
??25-2	??7-F	??Cl	??646??[M+1] ⁺		??25-3	??6，7-F ₂	??Cl	??663??[M+1] ⁺	??0.77-0.88(m，2H)，1.01-1.10(m，2H)，1.11-1.14(m，??1H)，1.25-1.36(m，1H)，1.39-1.44(m，2H)，??1.65-1.78(m，6H)，1.83-1.87(m，1H)，1.97-2.03(m，??1H)，3.18-3.24(m，1H)，3.46-3.55(m，1H)，??3.62-3.67(m，2H)，4.21(s，3H)，4.45(d，1H)，4.51(d，??1H)，4.59-4.63(m，1H)，4.76(d，1H)，4.93(d，1H)，??7.20-7.23(m，1H)，7.30(s，1H)，7.32(s，1H)，??7.45-7.49(m，3H)，7.56(s，1H)。

Embodiment 26: trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) acetaldehyde (acetoardehyde) synthetic

In 0 ℃ with Dai Si-Martin's reagent (6.40g, 15mmol) add to trans-2-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) ethanol (8.80g, CH 12.6mmol) ₂Cl ₂(160mL) in the suspension, the mixture that obtains is stirred 40min under room temperature.Reaction mixture is used CH by adding saturated sodium bicarbonate aqueous solution cancellation ₂Cl ₂Extract 2 times.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) acetaldehyde.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.80-1.01(m，2H)，1.04-1.16(m，2H)，1.55-1.83(m，8H)，1.85-1.93(m，1H)，1.98-2.04(m，1H)，2.24(dd，2H)，3.18-3.24(m，1H)，3.48-3.56(m，1H)，4.21(s，3H)，4.54(d，1H)，4.57(d，1H)，4.63-4.69(m，1H)，4.79(d，1H)，4.98(d，1H)，7.22(dd，1H)，7.47(dd，1H)，7.56(s，1H)，7.63(s，2H)，7.73(s，1H)，9.72(t，1H)。

ESI-MS?m/z：696[M+1] ⁺

Embodiment 27: according to the method for embodiment 26, adopt trans-(quinoline-2-yl of 4-{ (R)-1-[3-({ benzyl that N-[replaces]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-replace] tetramethyleneimine-2-yl } cyclohexyl) ethanol preparation following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	27-1	7-F	CF ₃	678 [M+1] ⁺	0.80-1.01 (m, 2H), 1.04-1.16 (m, 2H), 1.55-1.83 (m, 8H), 1.85-1.93 (m, 1H), 1.98-2.04 (m, 1H), 2.24 (dd, 2H), 3.21-3.27 (m, 1H), 3.50-3.57 (m, 1H), 4.20 (s, 3H), 4.54-4.60 (m, 2H), 4.66-4.73 (m, 1H), 4.77 (d, 1H), 4.97 (d, 1H), 7.01 (ddd, 1H), 7.36 (dd, 1H), 7.46 (dd, 1H), 7.60-7.64 (m, 3H), 7.72 (s, 1H), 9.72 (t, 1H).
??27-2	??7-F	??Cl	??644??[M+1] ⁺	??0.81-1.04(m，2H)，1.05-1.16(m，2H)，1.55-1.82(m，??8H)，1.84-1.93(m，1H)，1.96-2.04(m，1H)，2.25(dd，??2H)，3.21-3.27(m，1H)，3.50-3.57(m，1H)，4.20(s，3H)，??4.45(d，1H)，4.54(d，1H)，4.67-4.72(m，1H)，4.74(d，??1H)，4.95(d，1H)，7.01(ddd，1H)，7.30(s，1H)，7.32(s，??1H)，7.36(dd，1H)，7.44(s，1H)，7.47(dd，1H)，7.62(s，??1H)，9.73(t，1H)。	27-1	7-F	CF ₃	678 [M+1] ⁺
??27-2	??7-F	??Cl	??644??[M+1] ⁺		??27-3	??6，7-F ₂	??Cl	??661??[M+1] ⁺	??0.85-0.92(m，2H)，1.03-1.12(m，2H)，1.66-1.79(m，??8H)，1.85-1.90(m，1H)，1.97-2.02(m，1H)，2.22-2.25(m，??2H)，3.17-3.21(m，1H)，3.47-3.55(m，1H)，4.20(s，3H)，??4.45(d，1H)，4.52(d，1H)，4.61-4.65(m，1H)，4.74(d，??1H)，4.95(d，1H)，7.20-7.23(m，1H)，7.30(s，1H)，??7.32(s，1H)，7.44(s，1H)，7.46(dd，1H)，7.56(s，1H)。

Embodiment 28: trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) acetate synthetic

Under room temperature, with NaClO ₂(4.60g, 51mmol) and NaH ₂PO ₄(4.30g, water 36mmol) (20mL) mixed solution drops to trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) acetaldehyde (7.10g, 10.2mmol) 2-methyl-2-butene (15mL)/t-BuOH (115mL) solution in, the mixture that obtains was stirred under room temperature 1 hour.Reaction mixture passes through to add saturated aqueous ammonium chloride solution cancellation in 0 ℃, uses ethyl acetate extraction.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) acetate.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.78-1.00(m，2H)，1.03-1.17(m，2H)，1.60-1.80(m，8H)，1.83-1.93(m，1H)，1.96-2.06(m，1H)，2.17(d，2H)，3.15-3.24(m，1H)，3.46-3.54(m，1H)，4.20(s，3H)，4.54(d，1H)，4.57(d，1H)，4.60-4.68(m，1H)，4.79(d，1H)，4.98(d，1H)，7.22(dd，1H)，7.47(dd，1H)，7.56(s，1H)，7.63(s，2H)，7.72(s.1H)。

ESI-MS?m/z：712[M+1] ⁺

Embodiment 29: according to the method for embodiment 28, adopt trans-(quinoline-2-yl of 4-{ (R)-1-[3-({ benzyl that N-[replaces]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-replace] tetramethyleneimine-2-yl } cyclohexyl) acetaldehyde to prepare following compounds.

Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)
Numbering	Rn	R ₇	MS	¹H-NMR (400MHz, CDCl ₃), δ (ppm)	29-1	7-F	CF ₃	694 [M+1] ⁺	0.80-1.02 (m, 2H), 1.04-1.17 (m, 2H), 1.50-1.82 (m, 8H), and 1.83-1.93 (m, 1H), 1.95-2.05 (m, 1H), 2.17 (d, 2H), 3.21-3.28 (m, 1H), and 3.49-3.57 (m, 1H), 4.20 (s, 3H), 4.45 (d, 1H), 4.54 (d, 1H), and 4.65-4.72 (m, 1H), 4.73 (d, 1H), 4.95 (d, 1H), 7.00 (ddd, 1H), 7.31 (s, 1H), 7.32 (s, 1H), 7.36 (dd, 1H), 7.43 (s, 1H), 7.47 (dd, 1H), 7.63 (s.1H).
??29-2	??7-F	??Cl	??660??[M+1] ⁺	??0.80-1.00(m，2H)，1.04-1.15(m，2H)，1.50-1.80(m，??8H)，1.83-1.92(m，1H)，1.95-2.04(m，1H)，2.17(d，??2H)，3.21-3.27(m，1H)，3.49-3.57(m，1H)，4.20(s，??3H)，4.57(d，2H)，4.65-4.72(m，1H)，4.77(d，1H)，??4.97(d，1H)，7.00(ddd，1H)，7.36(dd，1H)，7.47(dd，??1H)，7.62(s.3H)，7.71(s，1H)。	29-1	7-F	CF ₃	694 [M+1] ⁺
??29-2	??7-F	??Cl	??660??[M+1] ⁺		??29-3	??6，7-F ₂	??Cl	??679??[M+1] ⁺	??0.83-0.96(m，2H)，1.04-1.10(m，2H)，1.52-1.78(m，??8H)，1.85-1.88(m，1H)，1.97-2.03(m，1H)，2.17(d，??2H)，3.18-3.22(m，1H)，3.47-3.55(m，1H)，4.20(s，??3H)，4.45(d，1H)，4.48(d，1H)，4.65-4.70(m，1H)，??4.74(d，1H)，4.95(d，1H)，7.22(dd，1H)，7.30(s，1H)，??7.32(s，1H)，7.44(s，1H)，7.47(dd，1H)，7.56(s，1H)。

Embodiment 30: trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) ethanamide synthetic

To trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) (85mg adds NH in DMF 0.12mmol) (3mL) mixture to acetate ₄Cl (10mg, 0.18mmol), N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl 41mg, 0.18mmol), 1-hydroxyl-7-azepine benzotriazole (HOAt, 24mg, 0.18mmol) and triethylamine in a small amount.After stirring 2 hours under the room temperature, reaction mixture dilutes with ethyl acetate, and water and salt solution wash in proper order, through dried over mgso.Evaporating solvent, through the silicagel column purifying, adopt ethyl acetate-hexane wash-out, obtain trans-(4-{ (R)-1-[3-({ N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amino } methyl)-6,7-difluoro-quinoline-2-yl] tetramethyleneimine-2-yl } cyclohexyl) ethanamide.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.79-0.98(m，2H)，1.05-1.14(m，2H)，1..47-1.81(m，8H)，1.87-1.93(m，1H)，2.02-2.07(m，3H)，3.19-3.27(m，1H)，3.50-3.59(m，1H)，4.20(s，3H)，4.55(d，2H)，4.57-4.68(m，1H)，4.78(d，1H)，4.97(d，1H)，5.30(bs，2H)，7.20-7.24(m，2H)，7.35-7.40(m，1H)，7.63(s，2H)，7.73(s，1H)。

ESI-MS?m/z：710[M+1] ⁺

Embodiment 31:N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl) quinoxaline-2-yl]-N-(cyclopentyl-methyl) ethamine synthetic

In 5 ℃ with potassium tert.-butoxide (11mg 0.098mmol) adds to N-[3,5-two (trifluoromethyl) benzyl]-(46mg in DMF 0.14mmol) (1mL) solution, stirs 20min with mixture to N-(2-methyl-2H-tetrazolium-5-yl) amine under same temperature.In mixture, drip N-[3-(brooethyl) quinoxaline-2-yl in 3 minutes]-(38mg, DMF 0.11mmol) (1mL) solution is with mixture restir 30min for N-(cyclopentyl-methyl) ethamine.After adding 1N HCl aq, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The mixture that obtains obtains N-[(3-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino through silica gel chromatography } methyl) quinoxaline-2-yl]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.03-1.10(m，2H)，1.14(t，3H)，1.37-1.68(m，6H)，2.11-2.21(m，1H)，3.31(q，2H)，3.31(d，2H)，4.13(s，3H)，4.93(s，4H)，7.45(ddd，1H)，7.57(ddd，1H)，7.71(s，1H)，7.77(s，2H)，7.75-7.80(m，2H)。

ESI-MS?m/z：593[M+1] ⁺

Embodiment 32:N-(6-{N '-[3,5-two (trifluoromethyl) benzyl-N '-(2-methyl-2H-tetrazolium-5-yl) amino] methyl }-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-5-yl)-N-(cyclopentyl-methyl) ethamine

Under room temperature, to 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-yl } methyl alcohol (85mg, 0.30mmol) toluene (1.5mL) solution in add diisopropylethylamine (0.062mL, 0.35mmol) and methylsulfonyl chloride (0.027mL, 0.35mmol).Stir after 1 hour, add H ₂O.Mixture is extracted with EtOAc, use the salt water washing, through dried over sodium sulfate and vacuum concentration.In 0 ℃ to N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine (106mg, add in DMF 0.33mmol) (1.5mL) solution potassium tert.-butoxide (54mg, 0.44mmol).After stirring 30min, slowly add DMF (1mL) solution of residue, reaction mixture was stirred 1 hour.The cancellation of reaction mixture water extracts mixture with EtOAc.Organic layer salt water washing, through dried over sodium sulfate, concentrate and through silica gel chromatography, obtain N-(6-{N '-[3,5-two (trifluoromethyl) benzyl-N '-(2-methyl-2H-tetrazolium-5-yl) amino] methyl }-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-5-yl)-N-(cyclopentyl-methyl) ethamine, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.96-1.12(m，5H)，1.34-1.58(m，6H)，1.94-2.13(m，1H)，2.95-3.15(m，2H)，3.65-3.80(m，4H)，4.13-4.23(m，4H)，4.71(s，2H)，4.85-5.00(m，2H)，6.60(s，1H)，7.20(s，1H)，7.41(s，1H)，7.68(s，2H)，7.75(s，1H)。

ESI-MS?m/z：595[M+1] ⁺

Embodiment 33: according to the method for embodiment 32, N-(6-{N '-[3,5-two (trifluoromethyl) benzyl]-N '-(2-methyl-2H-tetrazolium-5-yl) amino } methyl isophthalic acid, 3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-5-yl)-employing of N-(cyclopentyl-methyl) ethamine 5-[N-(cyclopentyl-methyl) ethylamino]-1,3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-6-yl } methyl alcohol and N-[3,5-two (trifluoromethyl) benzyl]-preparation of N-(2-methyl-2H-tetrazolium-5-yl) amine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.99(t，3H)，1.03-1.12(m，2H)，1.34-1.56(m，6H)，1.94-2.08(m，1H)，2.32(s，3H)，3.00-3.09(m，4H)，3.59(s，3H)，4.20(s，3H)，4.66(s，2H)，4.94(s，2H)，6.93(d，1H)，7.33(s，1H)，7.67(s，2H)，7.72(s，1H)。

ESI-MS?m/z：609[M+1] ⁺

Embodiment 34: the inhibition activity of compound

Embodiment	?IC ₅₀μ M (damping fluid)	??IC ₅₀μ M (human plasma)
Embodiment	?IC ₅₀μ M (damping fluid)	??IC ₅₀μ M (human plasma)	??1	??0.16	??0.26
??2-6	??0.028	??0.092	??1	??0.16	??0.26
??2-6	??0.028	??0.092	??2-7	??0.044	??0.075
??2-8	??0.04	??0.024	??2-7	??0.044	??0.075
??2-8	??0.04	??0.024	??2-10	??0.036	??0.037
??2-12	??0.12	??0.094	??2-10	??0.036	??0.037
??2-12	??0.12	??0.094	??2-13	??0.032	??0.082
??2-15	??0.043	??0.062	??2-13	??0.032	??0.082
??2-15	??0.043	??0.062	??2-17	??0.25	??0.22
??2-22	??0.16	??0.03	??2-17	??0.25	??0.22
??2-22	??0.16	??0.03	??3-2	??0.039	??0.043
??3-4	??0.06	??0.062	??3-2	??0.039	??0.043
??3-4	??0.06	??0.062	??3-5	??0.12	??0.11
??6	??0.054	??0.039	??3-5	??0.12	??0.11
??6	??0.054	??0.039	??13-4	??0.0058	??0.033
??21	??0.021	??0.045	??13-4	??0.0058	??0.033
??21	??0.021	??0.045	??28	??0.025	??0.039

Raw material can for example be prepared as follows:

Embodiment A: the preparation of { 2-[N-(cyclopentyl-methyl)-N-ethylamino] quinoline-3-yl } methyl alcohol

Step 1:

With 2-chloro quinoline-3-formaldehyde (50mg, 0.26mmol), N-(cyclopentyl-methyl)-N-ethamine (50mg, 0.39mmol) and salt of wormwood (54mg, toluene suspension 0.39mmol) is shone 30min in microwave reactor.Reaction mixture obtains 2-[N-(cyclopentyl-methyl)-N-ethylamino through silica gel chromatography] quinoline-3-formaldehyde.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.11-1.23(m，2H)，1.21(t，3H)，1.45-1.60(m，4H)，1.65-1.74(m，2H)，2.34(m，1H)，3.48(d，2H)，3.53(q，2H)，7.32(ddd，1H)，7.66(ddd，1H)，7.76(dd，1H)，7.79(dd，1H)，8.45(s，1H)，10.15(s，1H)。

Step 2:

To 2-[N-(cyclopentyl-methyl)-N-ethylamino] (25mg, (5mg 0.13mmol), stirs mixture 1 hour quinoline-3-formaldehyde to add sodium borohydride in ethanol 0.088mmol) (1mL) solution.After adding saturated ammonium chloride and water, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges, through dried over mgso, filtration and concentrated obtaining 2-[N-(cyclopentyl-methyl)-N-ethylamino] and quinoline-3-yl } methyl alcohol, it can need not to be further purified direct use.

Embodiment B: the preparation of { 2-[N-(cyclohexyl methyl)-N-ethylamino]-7-fluorine quinoline-3-yl } methyl alcohol

Step 1:

Will in 0-10 ℃ of Vilsmeier reagent from the preparation of DMF (23mL) and phosphoryl chloride (78.4mL) slowly drop to the 3-fluoroacetanilide (18.5g, 0.12mol) in, the mixture that obtains was stirred 14 hours in 100 ℃.Mixture poured in the frozen water and with dichloromethane extraction 2 times.With the organic layer drying that merges, filter and concentrate.Collect crystallization, adopt washed with dichloromethane, obtain 2-chloro-7-fluorine quinoline-3-formaldehyde, be brown powder.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：7.45(ddd，1H)，7.72(dd，1H)，8.01(dd，1H)，8.76(s，1H)，10.55(s，1H)。

Step 2:

With 2-chloro-7-fluorine quinoline-3-formaldehyde (200mg, 0.95mmol), N-(cyclohexyl methyl)-N-ethamine (140mg, 0.99mmol) and salt of wormwood (140mg, toluene 1.0mmol) (3mL) suspension stirred 14 hours down in refluxing.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution then.Organic layer, filters and concentrates through dried over mgso with 1N HCl, salt water washing.The crude product product obtains 2-[N-(cyclohexyl methyl)-N-ethylamino through silica gel chromatography]-7-fluorine quinoline-3-formaldehyde.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.83-0.93(m，2H)，1.08-1.20(m，4H)，1.22(t，3H)，1.62-1.81(m，5H)，3.40(d，2H)，3.52(q，2H)，7.08(ddd，1H)，7.38(dd，1H)，7.73(dd，1H)，8.40(s，1H)，10.09(s，1H)。

Step 3:

To 2-[N-(cyclohexyl methyl)-N-ethylamino]-(230mg, (30mg 0.79mmol), stirs mixture 2 hours 7-fluorine quinoline-3-formaldehyde to add sodium borohydride in ethanol 0.73mmol) (2mL) mixture.After adding saturated ammonium chloride and water, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and concentrated [N-(the cyclopentyl-methyl)-N-ethylamino] quinoline-3-yl that obtains } methyl alcohol, it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.85-0.95(m，2H)，1.10-1.20(m，3H)，1.15(t，3H)，1.56-1.71(m，4H)，1.73-1.79(m，4H)，3.21(d，2H)，3.28(q，2H)，3.48(brs，1H)，4.82(s，2H)，7.14(ddd，1H)，7.48(dd，1H)，7.67(dd，1H)，7.98(s，1H)。

Embodiment C: the preparation of { 2-[N-(cyclopentyl-methyl)-N-ethylamino]-6,7-difluoro-quinoline-3-yl } methyl alcohol

Step 1:

Phosphoryl chloride (147.1mL) in 0-15 ℃ of phosphoryl chloride solution that adds to preparation vilsmeier reagent among the DMF (32.5mL) carefully, is warmed to 30 ℃ with mixture and obtains clarifying light yellow mixture.Add 3 in mixture, (30g 0.12mol), stirs 30min with the mixture that obtains in 80 ℃ to 4-two fluoroacetanilides, and 90 ℃ are stirred 30min, and 100 ℃ were stirred 18 hours, stirred 2 hours in 120 ℃ at last.Mixture is cooled to room temperature, pours in ice-water (1500mL), use CH ₂Cl ₂Extract 7 times (total amount 3000mL).The organic layer that merges filters and concentrates through dried over mgso.Collect the brown crystallization, use washed with dichloromethane, obtain 2-chloro-6,7-difluoro-quinoline-3-formaldehyde is buff powder.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：7.73(dd，1H)，7.84(dd，1H)，8.69(s，1H)，10.55(s，1H)。

Step 2:

With 2-chloro-6,7-difluoro-quinoline-3-formaldehyde (0.13g, 0.56mmol), N-(cyclopentyl-methyl)-N-ethamine (0.15g, 1.2mmol) and salt of wormwood (0.15g, toluene 1.1mmol) (2.0mL) suspension stirred 15 hours down in refluxing.Reaction mixture obtains 2-[N-(cyclopentyl-methyl)-N-ethylamino through silica gel chromatography]-6,7-difluoro-quinoline-3-formaldehyde.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.11-1.23(m，2H)，1.23(t，3H)，1.47-1.63(m，4H)，1.67-1.76(m，2H)，2.33(sep，1H)，3.47(d，2H)，3.54(q，2H)，7.49(dd，1H)，7.63(dd，1H)，8.36(s，1H)，10.12(s，1H)。

Step 3:

To 2-[N-(cyclopentyl-methyl)-N-ethylamino]-6, (0.10g, (14mg 0.37mmol), stirs mixture 2 hours 7-difluoro-quinoline-3-formaldehyde to add sodium borohydride in ethanol 0.31mmol) (2.0mL) mixture.After adding saturated ammonium chloride and water, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated, obtain 2-[N-(cyclopentyl-methyl)-N-ethylamino]-6,7-difluoro-quinoline-3-yl } methyl alcohol, it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.11-1.20(m，2H)，1.17(t，3H)，1.48-1.63(m，4H)，1.67-1.76(m，2H)，2.13(sep，1H)，3.23-3.28(m，4H)，3.85(brs，1H)，4.83(brs，2H)，7.43(dd，1H)，7.62(dd，1H)，7.91(s，1H)。

Embodiment D: trans-[4-({ N-ethyl-N-[3-(hydroxymethyl) quinoline-2-yl] amino } methyl) cyclohexyl] preparation of ethyl acetate

With 2-chloro quinoline-3-formaldehyde (93mg, 0.49mmol), trans-{ 4-[(N-ethylamino) methyl] cyclohexyl } ethyl acetate (165mg, 0.73mmol) and salt of wormwood (134mg, toluene 0.97mmol) (2mL) suspension stirred 3 days down in refluxing.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product residue is dissolved in ethanol (1.5mL), and (18mg 0.48mmol) handles to adopt sodium borohydride.Mixture was stirred under room temperature 2 hours.After adding saturated ammonium chloride and water, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains trans-[4-({ N-ethyl-N-[3-(hydroxymethyl) quinoline-2-yl] amino } methyl) cyclohexyl] ethyl acetate.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.86-1.02(m，4H)，1.14(t，3H)，1.22(t，3H)，1.48-1.53(m，1H)，1.65-1.87(m，5H)，2.13(d，2H)，3.21(d，2H)，3.25(q，2H)，3.87(brs，1H)，4.85(s，2H)，7.39(ddd，1H)，7.60(ddd，1H)，7.71(dd，1H)，7.87(d，1H)，7.99(s，1H)。

Embodiment E: (R)-preparation of 2-cyclohexyl tetramethyleneimine

According to the identical method of (S)-2-cyclopentyl tetramethyleneimine preparation (R)-2-cyclohexyl tetramethyleneimine, but adopt ((S)-(+)-phenyl glycinol replaces (R)-(-)-phenyl glycinol, referring to the J.Org.Chem. shown in following, and 1992,57,1656-1662).

Embodiment F: the preparation of ethyl [(tetrahydropyran-4-base) methyl)] amine

Step 1:

Under room temperature, (Argonaut Technologies, 1.35g 4.5mmol) add to C-(tetrahydropyran-4-base) methylamine (345mg, CH 3.0mmol) with PS-DIEA ₂Cl ₂(20ml) in the mixture.In mixture, add diacetyl oxide (367mg, 3.6mmol).After stirring 18 hours under the room temperature, add the methyl isocyanate polystyrene (Novabiochem, 1.84g, 3.0mmol) and N-(2-amino-ethyl) aminomethylpolystyre.e (Novabiochem, 1.07g, 3.0mmol).Under room temperature, stir 4h, remove by filter resin, with the resin washed with dichloromethane.Filtrate and washings merge, and vacuum-evaporation removes and desolvates, and obtains N-(tetrahydropyran-4-base methyl) ethanamide.

ESI-MS?m/z：158[M+1] ⁺

UPLC retention time: 0.94min.

Step 2:

In nitrogen environment, under room temperature, (10.2ml, 10.2mmol) solution adds to N-(tetrahydropyran-4-base methyl) ethanamide (235mg is among THF 1.50mmol) (15ml) with the THF of 1M borine THF mixture.Stir after 2 days, in room temperature downhill reaction mixture, add methyl alcohol (5ml).Stir after 1 hour, add 1N HCl (50ml) in mixture, part THF is removed in vacuum-evaporation.Mixture is washed with ether, in mixture, add 5N NaOH.Product adopts dichloromethane extraction, and organic phase salt water washing is through dried over mgso and the concentrated N-ethyl-N-[(tetrahydropyran-4-base that obtains) methyl)] amine.

ESI-MS?m/z：144[M+1] ⁺

HPLC retention time: 0.58min.

Embodiment G:N-[3,5-two (trifluoromethyl) benzyl]-preparation of N-(2-methyl-2H-tetrazolium-5-yl) amine

＜method 1 〉

Step 1:

With methyl-iodide (45mL,, 1.2eq., 0.72mol) add to the 5-amino tetrazole (51.1g, 0.60mol) and Cs ₂CO ₃(235.0g, 1.2eq. in acetonitrile 0.72mol) (500mL) mixture, stir the mixture that obtains 18 hours in 50 ℃.Mixture (in 50 ℃) is filtered, and residue washs (50 ℃) with hot acetonitrile.Filtrate concentrating obtains the 5-amino-2-methyl tetrazolium of needs and the mixture of 5-amino-1-methyl tetrazolium.

Step 2:

The crude mixture of 5-amino-2-methyl tetrazolium and 5-amino-1-methyl tetrazolium is adopted 3, and (toluene 0.29mol) (780mL) solution-treated stirs mixture and refluxed 5 hours 5-two (trifluoromethyl) phenyl aldehyde for 48mL, 71g.The mixture that obtains is removed by filter insoluble solid (5-amino-1-methyl tetrazolium), residue is washed with hot toluene.Filtrate concentrating obtained crude product 2-methyl-N-[3,5-two (trifluoromethyl) phenylmethylene]-2H-tetrazolium-5-amine (70.1g).

Step 3:

In 0 ℃ with NaBH ₄(8.2g, 0.22mol) gradation slowly adds to crude product 2-methyl-N-[3,5-two (trifluoromethyl) phenylmethylene]-EtOH (700mL) solution of 2H-tetrazolium-5-amine in, mixture was stirred under room temperature 1 hour.In 0 ℃ add saturated aqueous ammonium chloride solution and water after, mixture is concentrated to remove 300mL EtOH, use CH ₂Cl ₂Extraction (300mL * 4 time).The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.Residue through silica gel chromatography, is obtained N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine, be white crystalline solid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.61(s，3H)，4.66(d，2H)，5.03(t，1H)，7.79(s，1H)，7.83(s，1H)。

＜method 2 〉

Step 1:

(5.00g, 50mmol) with 3, (19.5g, toluene 81mmol) (100mL) mixture stirs also and refluxed 3 hours 5-two (trifluoromethyl) phenyl aldehyde with 5-amino-2-methyl tetrazolium.With the concentrated crude product 2-methyl-N-[3,5-two (trifluoromethyl) phenylmethylene of obtaining of the mixture that obtains]-2H-tetrazolium-5-amine.

Step 2:

In 0 ℃ with NaBH ₄(1.2g, 64mmol) gradation slowly adds to 2-methyl-N-[3,5-two (trifluoromethyl) phenylmethylene]-EtOH (100mL) solution of 2H-tetrazolium-5-amine in, mixture was stirred under room temperature 1 hour.In 0 ℃ add saturated aqueous ammonium chloride solution and water after, mixture is extracted with EtOAc.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.Residue through silica gel chromatography, is obtained N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine, be white crystalline solid.

Embodiment H:N-[3,5-two (trifluoromethyl) benzyl]-N-{2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-2H-tetrazolium-5-yl } preparation of amine

Step 1:

With the 5-amino tetrazole (10.0g, 0.12mol), bromoethyl acetate (20.0g, 0.12mol) and Cs ₂CO ₃(40.0g, acetonitrile 0.13mol) (220mL) mixed solution stirs and refluxed 5 hours.Mixture is also filtered for being cooled to 50 ℃.The filtrate that obtains concentrating obtains the crude product coupling product.With crude product product and 3, (25.0g, toluene 0.10mol) (220mL) mixture stirs and refluxed 5 hours 5-two (trifluoromethyl) phenyl aldehyde.After being cooled to room temperature, the mixture that obtains is concentrated.(4.4g, 0.12mol) gradation slowly adds in EtOH (220mL) solution of the residue that obtains, and mixture was stirred under room temperature 2 days with NaBH4.After adding saturated aqueous ammonium chloride solution and water, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The crude product product is through silica gel chromatography, obtains 2-(5-{N-[3,5-two (trifluoromethyl) benzyl] amino } tetrazolium-2-yl) ethanol.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：2.43-2.55(m，1H)，4.08-4.12(m，2H)，4.55-4.58(m，2H)，4.67(d，2H)，5.07-5.12(m，1H)，7.80(s，1H)，7.84(s，2H)。

Step 2:

With 2-(5-{N-[3,5-two (trifluoromethyl) benzyl] amino } tetrazolium-2-yl) ethanol (0.68g, 1.9mmol), 3,4-dihydro-2H-pyrans (DHP, 0.35g, 4.2mmol) and the right-toluenesulphonic acids pyridinium salt (PPTS of catalytic amount, 0.050g, CH 0.20mmol) ₂Cl ₂(10mL) mixture stirred under room temperature 10 hours.The mixture that obtains is passed through to add saturated sodium bicarbonate aqueous solution cancellation, extract with EtOAc.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product obtains N-[3 through silica gel chromatography, 5-two (trifluoromethyl) benzyl]-N-{2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-2H-tetrazolium-5-yl } amine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.42-1.76(m，6H)，3.43-3.48(m，1H)，3.68(ddd，1H)，3.89-3.95(m，1H)，4.12-4.18(m，1H)，4.57-4.58(m，1H)，4.61(t，2H)，4.67(d，2H)，4.89-4.97(m，1H)，7.79(s，1H)，7.84(s，2H)。

Example I: trans-(R)-2-[(4-benzyl oxygen ylmethyl) cyclohexyl] preparation of tetramethyleneimine

Step 1:

Adopt Dean-Rodney Stark (Dean-Stark) equipment, with 4-ethoxy carbonyl pimelinketone (175g, 1.03mol), ethylene glycol (ethylenegrycol) (70mL) and toluene (700mL) mixture of right-toluenesulphonic acids (2.1g) stir and refluxed 6 hours, constantly remove simultaneously and anhydrate.After being cooled to room temperature, in reaction mixture, add saturated NaHCO ₃The aqueous solution (1500mL) and EtOAc (800mL).Organic layer salt water washing through dried over mgso and concentrating under reduced pressure, obtains crude product 1, is yellow oil 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-formic acid ethyl ester (220g), and it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.24(t，3H)，1.50-1.60(m，2H)，1.75-1.86(m，4H)，1.90-1.98(m，2H)，2.29-2.35(m，1H)，3.94(s，4H)，4.12(q，2H)。

Step 2:

In ar gas environment, in 0 ℃, (50.5g adds crude product 1 in THF 1.06mol) (800mL) mixture carefully, THF (700mL) solution of 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-formic acid ethyl ester (220g) to lithium aluminum hydride in 2.5 hours.After stirring 1 hour under the room temperature, add Na in 0 ℃ ₂SO ₄-10H ₂O (175g) is with mixture restir 10min.Filtering insolubles, filtrate vacuum concentration obtain crude product (1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl) methyl alcohol, are colorless oil, and it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.22-1.33(m，2H)，1.45-1.60(m，3H)，1.75-1.83(m，4H)，3.49(d，2H)，3.91-3.98(m，4H)。

Step 3:

Under 10 ℃, ar gas environment, (60% oily dispersion liquid, 60.9g add crude product (1 in DMF 1.52mol) (1500mL) mixture carefully to NaH, 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl) DMF (50mL) solution of methyl alcohol (150g) stirs mixture 1 hour under room temperature.Add bromotoluene (181mL) in 10 ℃ in mixture, restir is 3 hours under room temperature.Add H in 10 minutes ₂Behind the O (70mL), pour mixture into H ₂In the mixture of O (4500mL) and EtOAc (2000mL).The water layer ethyl acetate extraction, the salt water washing of the organic layer of merging through dried over mgso and concentrating under reduced pressure, obtains crude product 8-benzyl oxygen ylmethyl-1, and 4-two oxa-s-spiral shell [4.5] decane is yellow oil.The crude product product need not to be further purified and can directly use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.22-1.33(m，2H)，1.50-1.59(m，2H)，1.62-1.74(m，1H)，1.73-1.86(m，4H)，3.31(d，2H)，3.90-3.97(m，4H)，4.50(s，2H)，7.26-7.35(m，5H)。

Step 4:

Under room temperature, to crude product 8-benzyl oxygen ylmethyl-1, add 3N HCl (900mL) in THF (600mL) solution of 4-two oxa-s-spiral shell [4.5] decane (297g), mixture is stirred spend the night.Add saturated NaHCO ₃Behind the aqueous solution, mixture is extracted with EtOAc.Water layer extracts with EtOAc, and the salt water washing of the organic layer of merging is through dried over mgso and concentrating under reduced pressure.Crude mixture obtains 4-benzyl oxygen ylmethyl pimelinketone through silica gel chromatography.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.41-1.53(m，2H)，2.03-2.18(m，3H)，2.28-2.43(m，4H)，3.39(d，2H)，4.53(s，2H)，7.26-7.38(m，5H)。

Step 5:

(168g 0.77mol) is dissolved in ethanol (2000mL), adds orthoformic acid triethyl ester (350mL) and right-toluenesulphonic acids (13.3g) then with 4-benzyl oxygen ylmethyl pimelinketone.The mixture that obtains was stirred 6 hours down in refluxing.After adding triethylamine (10.5mL) under the room temperature, mixture is concentrated (500mL).Add saturated NaHCO ₃Behind the aqueous solution, the mixture that obtains is extracted with EtOAc.Water layer extracts with EtOAc, and the salt water washing of the organic layer of merging is through dried over mgso and concentrating under reduced pressure.Crude mixture obtains (4,4-diethoxy cyclohexyl methoxymethyl) benzene through short silica gel chromatography.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.12-1.19(m，2H)，1.16(t，3H)，1.17(t，3H)，1.31-1.42(m，2H)，1.62-1.75(m，3H)，1.97-2.04(m，2H)，3.31(d，2H)，3.41(q，2H)，4.50(q，2H)，4.50(s，2H)，7.25-7.37(m，5H)。

Step 6:

In-56 to-47 ℃, in 40min to tin tetrachloride (199g, CH 0.77mol) ₂Cl ₂(1800mL) add (4,4-diethoxy cyclohexyl methoxymethyl) benzene (225g) and 1,2-two (trimethyl silicane alcoxyl base) cyclobutene (176g, CH 0.77mol) in the mixture ₂Cl ₂(900mL) solution.Mixture is stirred 15min in-50 ℃.The refrigerative reaction mixture is poured in the water (5000mL) into the water layer dichloromethane extraction.The saturated NaHCO of organic layer that merges ₃The aqueous solution and salt water washing are through dried over mgso and concentrating under reduced pressure.Crude mixture obtains 4-[4-(benzyl oxygen ylmethyl) cyclohexyl through short silica gel chromatography]-4-ketobutyric acid ethyl ester (cis/trans=1/1), be yellow oil.

¹H-NMR (400MHz, CDCl ₃, cis: trans 1: 1 mixture), δ (ppm): 0.97-1.08 (m, 1H), 1.24 (t, 3H), 1.33-1.44 (m, 2H), 1.55-1.67 (m, 3H), 1.77-1.98 (m, 3H), 2.34 (tt, 0.5H), 2.51-2.58 (m, 0.5H), 2.57 (t, 2H), 2.74 (t, 1H), 2.75 (t, 1H), 3.29 (d, 1H), 3.32 (d, 1H), 4.12 (q, 2H), 4.48 (s, 1H), 4.49 (s, 1H), 7.25-7.37 (m, 5H).

Step 7:

With potassium hydroxide (17.0g 0.30mol) adds 4-[4-(benzyl oxygen ylmethyl) cyclohexyl]-(cis/trans=1/1,33.0g 0.10mol) in the solution of EtOH (300mL), stir mixture 2 hours in 85 ℃ 4-ketobutyric acid ethyl ester.After being cooled to 0 ℃, 5N HCl is added to mixture (making pH reach 2-3), mixture is concentrated to remove ethanol.Crude mixture extracts with EtOAc.The water layer ethyl acetate extraction, the organic layer water of merging and salt water washing through dried over mgso and concentrating under reduced pressure, obtain crude product 4-[4-(benzyl oxygen ylmethyl) cyclohexyl]-4-ketobutyric acid (cis/trans=about 1/6).With ether-hexanes mixtures (about 1: 4,120mL) add in the solid that obtains and supersound process.Filter and collect crystallization,, obtain trans-4-[4-(benzyl oxygen ylmethyl) cyclohexyl with a spot of ether-hexane (1: 4) washing and dry]-the 4-ketobutyric acid, be light yellow solid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.97-1.09(m，2H)，1.31-1.43(m，2H)，1.56-1.68(m，1H)，1.89-1.98(m，4H)，2.34(tt，1H)，2.62(t，2H)，2.76(t，2H)，3.29(d，2H)，4.49(s，2H)，7.26-7.38(m.5H)。

Step 8:

To (S)-(+)-phenyl glycinol (6.85g, add trans-4-[4-(benzyl oxygen ylmethyl) cyclohexyl in toluene 50mmol) (150mL) stirred solution]-4-ketobutyric acid (15.2g, 50mmol), adopt Dean-Rodney Stark equipment in the heating down 4 hours that refluxes in the mixture that obtains, constantly remove simultaneously and anhydrate.The mixture that obtains is concentrated, and the residue that obtains is through silica gel chromatography, obtain trans-(3S, 7aS)-7a-[4-(benzyl oxygen ylmethyl) cyclohexyl]-3-phenyl Pyrrolidine also [2,1-b] oxazole-5-ketone.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.73-0.89(m，2H)，1.08-1.21(m，2H)，1.51(tt，1H)，1.53-1.63(m，1H)，1.83-2.97(m，4H)，1.98(tt，1H)，2.43(ddd，1H)，2.58(ddd，1H)，2.75(dt，1H)，3.23(d，2H)，4.07(dd，1H)，4.46(s，2H)，4.64(t，1H)，5.19(t，1H)，7.19-7.22(m，2H)，7.24-7.38(m.8H)。

Step 9:

To the anhydrous AlCl of refrigerative (0 ℃) ₃(4.70g, (4.34g 115mmol), stirs 30min with the mixture that obtains down in uniform temp slowly to add lithium aluminum hydride in THF 35mmol) (120mL) mixture.In 30 minutes, in stirring that obtains and refrigerative (78 ℃) THF mixture, add trans-(3S, 7aS)-7a-[4-(benzyl oxygen ylmethyl) cyclohexyl]-3-phenyl Pyrrolidine also [2,1-b] oxazole-5-ketone (15.5g, THF 38mmol) (80mL) solution.The mixture that obtains was stirred 1.5 hours down in uniform temp, be warmed to room temperature and restir 15min then.The mixture that obtains is cooled to 0 ℃, adds Na carefully ₂SO ₄-10H ₂O (5.0g) cancellation is stirred 30min again under room temperature.Insolubles is filtered, the filtrate vacuum concentration, obtain crude product trans-(S)-2-{ (R)-2-[4-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl-the 2-phenylethyl alcohol, it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.95-1.16(m，4H)，1.40-1.66(m，6H)，1.67-1.76(m，1H)，1.77-1.85(m，1H)，1.86-1.94(m，2H)，2.20-2.28(m，1H)，2.58-2.66(m，1H)，2.87-2.93(m，1H)，3.31(dd，2H)，3.59-3.65(m，1H)，3.96-4.04(m，2H)，4.51(s，2H)，7.15-7.17(m，2H)，7.25-7.49(m.8H)。

Step 10:

To anhydrous formic acid ammonium (6.87g, 0.11mol) and trans-(S)-and 2-{ (R)-2-[4-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-2-phenylethyl alcohol (10.7g, 0.027mol) MeOH (135mL) add 10% palladium carbon (0.54g) in stirring the mixture, the mixture that obtains was stirred 2 hours under room temperature, in the nitrogen environment.Add anhydrous formic acid ammonium (3.45g) and 10% palladium carbon (0.54g), restir is 3 hours under room temperature, in the nitrogen environment.Filter reaction mixture, filtrate concentrates.Crude product product (18.26g) is dissolved in 1N HCl, with extracted with diethyl ether to remove phenylethyl alcohol.Water layer adopts dichloromethane extraction by adding 2N NaOH neutralization.The dichloromethane layer salt water washing that merges, through dried over mgso, filter and concentrated obtain crude product trans-(R)-2-[4-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine (6.54g).To crude product trans-(R)-2-[4-benzyl oxygen ylmethyl) cyclohexyl] add in EtOH (20mL) mixture of tetramethyleneimine L-tartrate (3.59g, 0.024mol).Mixture is warmed to 60 ℃ up to the mixture clarification that becomes, then mixture is slowly cooled to room temperature.The throw out that obtains filtered and add washing with alcohol, obtain pure trans-(R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl] the tetramethyleneimine tartrate, be the canescence crystallization.Tartrate is dissolved in the 1N NaOH aqueous solution, adopts dichloromethane extraction.Organic layer is through dried over mgso, filter and evaporation obtain pure trans-(R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.89-1.06(m，4H)，1.11-1.20(m，1H)，1.24-1.34(m，1H)，1.46-1.78(m，4H)，1.80-1.89(m，3H)，1.95-2.00(m，1H)，2.62(dt，1H)，2.81(ddd，1H)，2.99(ddd，1H)，3.27(d，2H)，4.49(s，2H)，7.22-7.36(m.5H)。

Embodiment J: trans-N-(2-{ (R)-2-[4-(2-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-6,7-difluoro-quinoline-3-ylmethyl)-N-[3,5-two (trifluoromethyl) benzyl] preparation of (2-methyl-2H-tetrazolium-5-yl) amine

Step 1:

With 2-chloro-6,7-difluoro-quinoline-3-formaldehyde (4.97g, 18mmol), trans-(R)-2-[(4-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine (5.39g, 20mmol) and salt of wormwood (2.97g, toluene 21mol) (100mL) and water (10mL) mixture stirred 3 hours down in refluxing.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution then.Organic layer water, aqueous citric acid solution, salt water washing through dried over mgso, are filtered and are concentrated.The crude product product obtains 2-{ (R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl through silica gel chromatography] tetramethyleneimine-1-yl }-6,7-difluoro-quinoline-3-formaldehyde is yellow soup compound.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.81-1.04(m，2H)，1.08-1.21(m，2H)，1.55-1.74(m，3H)，1.76-1.90(m，4H)，1.91-2.07(m，3H)，3.18-3.24(m，1H)，3.25(d，2H)，3.69(dt，1H)，4.47(s，2H)，4.66-4.74(m，1H)，7.26-7.34(m，5H)，7.40-7.47(m，2H)，8.31(s，1H)，10.13(s，1H)。

Step 2:

With 2-{ (R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-6, (7.25g 16mmol) is dissolved in ethanol (80mL) to 7-difluoro-quinoline-3-formaldehyde, adopts sodium borohydride (0.30g, 7.9mmol) in 0 ℃ of processing, the mixture that obtains is stirred 30min under room temperature.After adding entry and ethyl acetate, with the mixture partial concentration to remove ethanol.Mixture is extracted with EtOAc, with salt solution, saturated NH ₄The Cl solution washing through dried over mgso, filters and concentrates.The crude product product obtains (2-{R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl through silica gel chromatography] tetramethyleneimine-1-yl }-6,7-difluoro-quinoline-3-yl) methyl alcohol, be yellow soup compound.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.74-0.97(m，2H)，1.00-1.14(m，2H)，1.49-1.63(m，2H)，1.69-1.84(m，6H)，1.88-2.05(m，2H)，2.44(dd，1H)，3.21(d，2H)，3.27-3.33(m，1H)，3.60(dt，1H)，4.45(s，2H)，4.62-4.66(m，1H)，4.73(dd，1H)，4.87(dd，1H)，7.22-7.34(m，5H)，7.37(dd，1H)，7.48(dd，1H)，7.93(s，1H)。

Step 3:

In 0 ℃, with methylsulfonyl chloride (1.52mL, 20mmol) drop to (2-{ (R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-6,7-difluoro-quinoline-3-yl) methyl alcohol (7.03g, 15mmol) and N, (DIPEA, 3.41mL is in toluene 15mmol) (75mL) mixture for the N-diisopropylethylamine.Reaction mixture was stirred under room temperature 1 hour.Add entry and ethyl acetate in mixture, organic layer, filters and vacuum concentration through dried over mgso with saturated sodium bicarbonate aqueous solution, salt water washing.Residue is dissolved in toluene and vacuum concentration, obtains crude product 2-{ (R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl }-3-(chloro methyl)-6, the 7-difluoro-quinoline.In 0 ℃, to N-[3,5-two (trifluoromethyl) benzyl]-(5.88g adds potassium tert.-butoxide (2.03g in the mixture of DMF 18mmol) (60mL) to N-(2-methyl-2H-tetrazolium-5-yl) amine, 18mmol), the mixture that obtains is stirred 30min down in uniform temp.To be dissolved in crude product 2-{ (R)-2-[4-(benzyl oxygen ylmethyl) cyclohexyl of DMF (30mL)] tetramethyleneimine-1-yl }-3-(chloro methyl)-6, the 7-difluoro-quinoline drops in the mixture in 0 ℃, and the mixture that obtains was stirred 1 hour down in uniform temp.In reaction mixture, add potassium tert.-butoxide (1.70g, 14mmol), with mixture restir 1 hour under room temperature.After adding entry, with the mixture ethyl acetate extraction.The organic layer salt water washing that merges through dried over mgso, is filtered and is concentrated.The mixture that obtains is through silica gel chromatography, obtain trans-N-(2-{ (R)-2-[4-(2-benzyl oxygen ylmethyl) cyclohexyl] tetramethyleneimine-1-yl-6,7-difluoro-quinoline-3-ylmethyl)-N-[3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amine, be yellow amorphous solid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.74-0.95(m，2H)，0.99-1.12(m，2H)，1.48-1.59(m，2H)，1.64-1.83(m，6H)，1.84-1.90(m，1H)，1.96-2.04(m，1H)，3.16-3.22(m，1H)，3.22(d，2H)，3.49-3.55(m，1H)，4.20(s，3H)，4.46(s，2H)，4.55(d，1H)，4.57(d，1H)，4.60-4.65(m，1H)，4.78(d，1H)，4.98(d，1H)，7.21(dd，1H)，7.25-7.33(m，5H)，7.47(dd，1H)，7.55(s，1H)，7.63(s，2H)，7.72(s.1H)。

Embodiment K: trans-(R)-2-[4-(2-benzyl oxygen base ethyl) cyclohexyl] preparation of tetramethyleneimine

Step 1:

In 0-5 ℃, (146mL, (60% oily dispersion liquid, 29.5g in the mixture of THF 0.74mol) (2500mL), stir 30min with mixture down in uniform temp 0.74mol) to add to NaH with the phosphoryl triethyl acetate.In 0-5 ℃, in mixture, drip 1, (100g, THF 0.64mol) (700mL) solution continue under the uniform temp and stirred 1 hour 4-cyclohexanedione monoethylene glycol acetal.Add H ₂Behind the O (1500mL), mixture is extracted (3000mL) with EtOAc.Water layer extracts (1500mL * 2) with EtOAc, and the salt water washing of the organic layer of merging through dried over mgso and concentrating under reduced pressure, obtains 8-ethoxy carbonyl methylene radical-1, and 4-dioxo spiro [4.5] decane (172.9g) is colorless oil.The crude product product need not to be further purified and can directly use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.28(t，3H)，1.74-1.80(m，4H)，2.38(ddd，2H)，3.00(ddd，2H)，3.98(s，4H)，4.15(q，2H)，5.67(s，1H)。

Step 2:

With 8-ethoxy carbonyl methylene radical-1, and 4-dioxo spiro [4.5] decane (crude product, 172.9g), (53.2% is wet, and EtOAc/MeOH 6.5g) (1250mL and 400mL) mixture stirred 4 hours in hydrogen environment, under room temperature for 10%Pd-C.Filter reaction mixture, filtrate vacuum concentration obtain crude product 8-ethoxy carbonyl methyl isophthalic acid, 4-dioxo spiro [4.5] decane.The crude product product need not to be further purified and can directly use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.25(t，3H)，1.27-1.37(m，2H)，1.57(ddd，2H)，1.70-1.78(m，4H)，1.80-1.90(m，1H)，2.22(d，2H)，3.91-3.95(m，4H)，4.13(q，2H)。

Step 3:

In 0 ℃, ar gas environment, (42.5g adds crude product 8-ethoxy carbonyl methyl isophthalic acid carefully in THF 1.12mol) (1200mL) mixture, the THF solution (640mL) of 4-dioxo spiro [4.5] decane (174.7g) to lithium aluminum hydride.After stirring 10min under the room temperature, add Na in 0 ℃ ₂SO ₄-10H ₂O (360.9g) was with mixture restir 3 hours.Filter insolubles, adopt the ethyl acetate washing, the filtrate vacuum concentration obtains crude product 2-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-yl) ethanol (139.5g).The crude product product need not to be further purified and can directly use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.22-1.36(m，4H)，1.44-1.58(m，4H)，1.70-1.78(m，4H)，3.69(dt，2H)，3.94(s，4H)。

Step 4:

In 0-5 ℃, (60% oily dispersion liquid, 43.6g add 2-(1 in DMF 1.09mol) (900mL) mixture carefully to NaH, 4-dioxo spiro [4.5] last of the ten Heavenly stems-8-yl) DMF (300mL) solution of ethanol (139.5g) stirs 30min with mixture down in uniform temp.(129.6mL, 1.09mol), restir is 1 hour under uniform temp to drip bromotoluene in 0-5 ℃ in mixture.Add H ₂Behind the O (1000mL), with mixture with the EtOAc-hexane (3: 1,1200mL) extraction.Water layer extracts with EtOAc-hexane (3: 1,1200mL * 2), and the salt water washing of the organic layer of merging through dried over mgso and concentrating under reduced pressure, obtains crude product 8-[2-(benzyl oxygen base) ethyl]-1,4-dioxo spiro [4.5] decane.The crude product product need not to be further purified and can directly use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.25(m，2H)，1.52(m，5H)，1.74(m，4H)，3.50(t，2H)，3.93(s，4H)，4.49(s，2H)，7.34(m，5H)。

Step 5:

Under room temperature, to crude product 8-[2-(benzyl oxygen base) ethyl]-1, add 5N HCl (600mL) in THF (500mL) mixture of 4-dioxo spiro [4.5] decane (227.8g), mixture was stirred 10 hours down in uniform temp.Add NaHCO ₃Behind the aqueous solution (300g is dissolved in the 500mL water), mixture is extracted with EtOAc (1500mL).Water layer extracts (1000mL * 2) with EtOAc, and the salt water washing of the organic layer of merging is through dried over mgso and concentrating under reduced pressure.Crude mixture obtains 4-(2-benzyl oxygen base ethyl) pimelinketone through silica gel chromatography.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.35-1.46(m，2H)，1.63(dt，2H)，1.87-2.00(m，1H)，2.01-2.09(m，2H)，2.28-2.42(m，4H)，3.54(t，2H)，4.52(s，2H)，7.27-7.36(m，5H)。

Step 6:

With 4-(2-benzyl oxygen base ethyl) pimelinketone (133.0g 0.57mol) is dissolved in ethanol (1200mL), add then orthoformic acid triethyl ester (296mL) and right-toluenesulphonic acids monohydrate (10.9g, 0.057mol).The mixture that obtains was stirred 2 hours down in refluxing.Under room temperature, add triethylamine (8.8mL, 0.063mol) after, mixture is concentrated.Add saturated NaHCO ₃Behind the aqueous solution (500mL), the mixture that obtains is extracted with EtOAc (1000mL).Water layer extracts with EtOAc (1000mL * 2), and the salt water washing of the organic layer of merging is through dried over mgso and concentrating under reduced pressure.Crude mixture obtains [2-(4,4-diethoxy cyclohexyl) ethoxyl methyl] benzene through short silica gel chromatography, is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.12-1.17(m，2H)，1.16(t，3H)，1.17(t，3H)，1.36(ddd，2H)，1.42-1.48(m，1H)，1.52-1.64(m，4H)，1.93-2.01(m，2H)，3.40(q，2H)，3.49(q，2H)，3.50(t，2H)，4.50(s，2H)，7.25-7.38(m，5H)。

Step 7:

In-70 ℃, to tin tetrachloride (131mL, CH 1.23mol) ₂Cl ₂(2600mL) add in the mixture [2-(4,4-diethoxy cyclohexyl) ethoxyl methyl] benzene (344g, 1.12mol) and 1,2-two (trimethyl silicane alcoxyl base) cyclobutene (317mL, CH 1.23mol) ₂Cl ₂(1500mL) solution.Mixture was stirred 2 hours in-40 ℃.The refrigerative reaction mixture is poured in the water (1000mL), used CH ₂Cl ₂(1000mL) extraction.The saturated NaHCO of organic layer that merges ₃The aqueous solution and salt water washing are through dried over mgso and concentrating under reduced pressure.Crude mixture obtains 4-{[4-(2-benzyl oxygen base) ethyl through silica gel chromatography] cyclohexyl }-4-ketobutyric acid ethyl ester (cis/trans=1/1), be light yellow oil.

¹H-NMR (400MHz, CDCl ₃, cis: trans=1/1), δ (ppm): 0.90-1.02 (m, 1H), 1.25 (t, 3H), 1.33-1.44 (m, 2H), 1.50-1.67 (m, 5H), 1.79-1.94 (m, 3H), 2.33 (tt, 0.5H), 2.47-2.53 (m, 0.5H), 2.56 (t, 1H), 2.57 (t, 1H), 2.74 (t, 2H), 3.47 (t, 1H), 3.50 (t, 1H), 4.12 (q, 2H), 4.48 (s, 1H), 4.49 (s, 1H), 7.25-7.37 (m, 5H).

Step 8:

With potassium hydroxide (192g 3mol) adds to 4-{[4-(2-benzyl oxygen base) ethyl] cyclohexyl }-(346.2g in EtOH 1.0mol) (2000mL) solution, stirs the mixture that obtains and refluxed 3 hours 4-ketobutyric acid ethyl ester.Behind 0 ℃ of adding 5N HCl (making pH reach 2), mixture is extracted with EtOAc (4000mL).Water layer extracts with EtOAc (1000mL), and the salt water washing of the organic layer of merging through dried over mgso and concentrating under reduced pressure, obtains brown solid.With solid suspension in Et ₂O-hexane (1: 4) filters collection and obtains trans-4-{[4-(2-benzyl oxygen base) ethyl] cyclohexyl }-the 4-ketobutyric acid, be light yellow solid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.90-1.02(m，2H)，1.22-1.45(m，3H)，1.54(dt，2H)，1.80-1.94(m，4H)，2.32(tt，1H)，2.62(t，2H)，2.76(t，2H)，3.50(t，2H)，4.49(s，2H)，7.26-7.36(m，5H)。

Step 9:

To (S)-(+)-phenyl glycinol (16.4g adds trans-4-{[4-(2-benzyl oxygen base) ethyl in toluene 0.12mol) (450mL) stirred solution] cyclohexyl }-the 4-ketobutyric acid (38.0g, 0.12mol).Adopt Dean-Rodney Stark equipment to be heated in the mixture that obtains and refluxed 5 hours, constantly remove simultaneously and anhydrate.Mixture is concentrated, and the residue that obtains is through silica gel chromatography, obtain trans-(3S, 7aS)-7a-[4-(benzyl oxygen base ethyl) cyclohexyl]-also [2,1-b] oxazole-5-ketone is colorless solid to 3-phenyl Pyrrolidine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.67-0.84(m，2H)，1.06-1.21(m，2H)，1.30-1.52(m，4H)，1.73-1.93(m，4H)，1.96(dt，1H)，2.43(ddd，1H)，2.58(ddd，1H)，2.75(dt，1H)，3.47(t，2H)，4.06(dd，1H)，4.48(s，2H)，4.64(t，1H)，5.19(t，1H)，7.19-7.23(m，2H)，7.24-7.36(m.8H)。

Step 10:

To the anhydrous AlCl of refrigerative (0 ℃) ₃(6.30g, (5.95g 157mmol), stirs 10min with the mixture that obtains down in uniform temp slowly to add lithium aluminum hydride in THF 47mmol) (300mL) mixture.In 30 minutes, in stirring that obtains and refrigerative (65 ℃) THF mixture, add the trans-(3S that is dissolved in THF (150mL), 7aS)-7a-[4-(benzyl oxygen base ethyl) cyclohexyl]-3-phenyl Pyrrolidine also [2,1-b] oxazole-5-ketone (22.0g, 52mmol).The mixture that obtains was stirred 2 hours down in uniform temp, be warmed to room temperature then, restir 1 hour.The mixture that obtains is cooled to 0 ℃, by adding Na carefully ₂SO ₄-10H ₂The O cancellation, restir is 30 minutes under room temperature.Filter insolubles, the filtrate vacuum concentration, obtain crude product trans-(S)-2-{ (R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine-1-yl-the 2-phenylethyl alcohol, it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.94-1.13(m，4H)，1.35-1.88(m，12H)，2.20-2.29(m，1H)，2.58-2.63(m，1H)，2.86-2.94(m，1H)，3.52(t，2H)，3.61-3.66(m，1H)，3.95-4.04(m，2H)，4.51(s，2H)，7.14-7.18(m，2H)，7.28-7.52(m.8H)。

Step 11:

To anhydrous formic acid ammonium (15.8g, 0.25mol) and trans-(S)-and 2-{ (R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine-1-yl }-2-phenylethyl alcohol (20.5g, 0.050mol) MeOH (200mL) mix in the liquid and to add 10% palladium carbon (1.00g), the mixture that obtains was stirred 2 hours in nitrogen environment, under room temperature, stirred 3 hours in 35 ℃ then.Filter reaction mixture, filtrate concentrates.The crude product residue is dissolved in 1N HCl, with extracted with diethyl ether to remove styroyl alcohol.Water layer adopts dichloromethane extraction by adding the 2.5NNaOH neutralization.The organic layer salt water washing that merges, through dried over mgso, filter and concentrated obtain crude product trans-(R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine.To crude product trans-(R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] add in EtOH (65mL) mixture of tetramethyleneimine L-tartrate (7.60g, 0.050mol).The mixture that obtains is warmed to 60 ℃, slowly cools to room temperature then.Filtering precipitate, with other washing with alcohol, obtain trans-(R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] the tetramethyleneimine tartrate, be the canescence crystallization.This tartrate is dissolved in the 1NNaOH aqueous solution, uses CH ₂Cl ₂Extraction, organic layer is through dried over mgso, filter and evaporation obtain pure trans-(R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.86-1.05(m，4H)，1.09-1.19(m，1H)，1.21-1.43(m，2H)，1.51(dt，2H)，1.60-1.94(m，7H)，2.62(dt，1H)，2.80(ddd，1H)，2.99(ddd，1H)，3.50(t，2H)，4.49(s，2H)，7.22-7.36(m.5H)。

Embodiment L: trans-N-[2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-ylmethyl]-N-[3,5-two (trifluoromethyl) benzyl] preparation of (2-methyl-2H-tetrazolium-5-yl) amine

Step 1:

With 2-chloro-6,7-difluoro-quinoline-3-formaldehyde (8.30g, 36mmol), trans-(R)-2-[4-(benzyl oxygen base ethyl) cyclohexyl] tetramethyleneimine (10.5g, 36mmol) and salt of wormwood (7.60g, toluene 55mmol) (90mL) and water (12mL) suspension stirred 4 hours down in refluxing.Reaction mixture is cooled to room temperature, then with the 1N HCl aqueous solution and ethyl acetate dilution.The saturated NaHCO of organic layer ₃The aqueous solution, salt water washing, through dried over mgso, filter and concentrate and obtain 2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-formaldehyde, be yellow soup compound, it can need not to be further purified direct use.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.77-1.00(m，2H)，1.07-1.20(m，2H)，1.30-1.43(m，1H)，1.49(dt，2H)，1.51-1.88(m，6H)，1.91-2.04(m，3H)，3.18-3.24(m，1H)，3.48(t，2H)，3.69(dt，1H)，4.49(s，2H)，4.66-4.73(m，1H)，7.24-7.35(m，5H)，7.40-7.47(m，2H)，8.31(s，1H)，10.12(s，1H)。

Step 2:

With crude product 2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-formaldehyde is dissolved among ethanol-THF (120mL/20mL), adopt sodium borohydride (1.33g, 36mmol) in 5 ℃ of processing, the mixture that obtains is stirred 30min down in uniform temp, after adding the saturated NH4Cl aqueous solution and ethyl acetate, with the mixture partial concentration to remove ethanol.Mixture is extracted with EtOAc, use the salt water washing,, filter and concentrate through dried over mgso.The crude product product is through silica gel chromatography, obtain [2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-yl] methyl alcohol, be yellow soup compound.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.74-0.92(m，2H)，0.98-1.13(m，2H)，1.26-1.39(m，1H)，1.45(dt，2H)，1.55-1.82(m，7H)，1.90-2.04(m，2H)，2.44-2.49(m，1H)，3.26-3.33(m，1H)，3.45(t，2H)，3.60(dt，1H)，4.47(s，2H)，4.61-4.67(m，1H)，4.72(dd，1H)，4.87(d，1H)，7.23-7.33(m，5H)，7.37(dd，1H)，7.48(dd，1H)，7.93(s，1H)。

Step 3:

In 5 ℃, with methylsulfonyl chloride (5.5mL, 71mmol) drop to [2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-yl] methyl alcohol (13.7g, 28.5mmol) and N, N-diisopropylethylamine (DIPEA, 12.4mL, in toluene 71mmol) (150mL) mixture, reaction mixture was stirred under room temperature 2 hours.In mixture, add entry and ethyl acetate, organic layer is with saturated sodium bicarbonate aqueous solution, salt water washing, through dried over mgso, filter and vacuum concentration obtains crude product 2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-3-(chloro methyl)-6,7-difluoro-quinoline.In 5 ℃ to 2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-3-(chloro methyl)-6,7-difluoro-quinoline and N-[3,5-two (trifluoromethyl) benzyl]-N-(2-methyl-2H-tetrazolium-5-yl) amine (13.9g, add in DMF 43mmol) (120mL) mixture potassium tert.-butoxide (4.80g, 43mmol).The mixture that obtains was stirred 1 hour down in uniform temp.Add saturated NH ₄Behind the Cl aqueous solution, with the mixture ethyl acetate extraction.The organic layer water, the salt water washing that merge through dried over mgso, are filtered and are concentrated.The mixture that obtains is through silica gel chromatography, obtain trans-N-[2-((R)-2-{4-[2-(benzyl oxygen base) ethyl] cyclohexyl } tetramethyleneimine-1-yl)-6,7-difluoro-quinoline-3-ylmethyl]-N-[3,5-two (trifluoromethyl) benzyl] (2-methyl-2H-tetrazolium-5-yl) amine, be yellow amorphous substance.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：0.69-0.93(m，2H)，0.97-1.11(m，2H)，1.25-1.38(m，1H)，1.43-1.54(m，3H)，1.60-1.76(m，6H)，1.82-1.93(m，1H)，1.95-2.05(m，1H)，3.18-3.24(m，1H)，3.46(t，2H)，3.45-3.54(m，1H)，4.20(s，3H)，4.47(s，2H)，4.54(d，1H)，4.56(d，1H)，4.58-4.66(m，1H)，4.78(d，1H)，4.99(d，1H)，7.22(dd，1H)，7.26-7.34(m，5H)，7.47(dd，1H)，7.56(s，1H)，7.63(s，2H)，7.72(s.1H)。

Embodiment M:N-[3-(bromomethyl) quinoxaline-2-yl]-preparation of N-(cyclopentyl-methyl) ethamine

Step 1:

With 2-chloro-3-methyl-quinoxaline (500mg, 2.8mmol), N-(ring penthyl methyl)-N-ethamine (900mg, 7.1mmol), (970mg, toluene 7.0mmol) (2.5mL) suspension stirred 14 hours in 150 ℃ salt of wormwood.Reaction mixture is cooled to room temperature, water and ethyl acetate dilution.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.The crude product product obtains N-(3-methyl-quinoxaline-2-yl)-N-(cyclopentyl-methyl) ethamine through reversed-phase HPLC purifying (0.1%TFA is to acetonitrile).

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.15-1.20(m，2H)，1.19(t，3H)，1.45-1.73(m，8H)，2.21(m，1H)，2.69(s，3H)，3.37(d，2H)，3.39(q，2H)，7.47(ddd，1H)，7.55(ddd，1H)，7.79(dd，1H)，7.86(dd，1H)。

Step 2:

With N-(3-methyl-quinoxaline-2-yl)-N-(cyclopentyl-methyl) ethamine (160mg, 0.59mmol), N-bromosuccinimide (130mg, 0.73mmol) and 2, the CCl of 2 '-Diisopropyl azodicarboxylate (10mg) ₄Mixture stirs and refluxed 1 hour.Reaction mixture obtains N-[3-(bromomethyl) quinoxaline-2-yl through silica gel chromatography]-N-(cyclopentyl-methyl) ethamine.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.10-1.25(m，2H)，1.22(t，3H)，1.45-1.73(m，8H)，2.22(m，1H)，3.42(d，2H)，3.49(q，2H)，4.73(s，2H)，7.51(ddd，1H)，7.62(ddd，1H)，7.81(dd，1H)，7.94(dd，1H)。

Embodiment N:{5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-yl } preparation of methyl alcohol

Step 1:

With 2-chloro-6-methyl-5-nitro cigarette nitrile (997mg, 5.05mmol), N-(cyclopentyl-methyl)-N-ethamine (770mg, 6.05mmol) and K ₂CO ₃(1.7g, toluene 12.3mmol) (20mL) mixture is in 110 ℃ of heating.Stir after 3 hours, filter reaction mixture is to remove the throw out of generation.Filtrate is adopted ethyl acetate dilution, water and salt water washing.Organic layer is through dried over sodium sulfate and vacuum concentration.Residue through silica gel chromatography, is obtained 2-[N-(cyclopentyl-methyl)-N-ethylamino]-6-methyl-5-nitro cigarette nitrile, be orange.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.30(t，3H)，1.22-1.33(m，2H)，1.55-1.64(m，2H)，1.65-1.76(m，2H)，1.75-1.85(m，2H)，2.32(ddt，1H)，2.78(s，3H)，3.77(d，2H)，3.88(dd，2H)，8.54(s，1H)。

Step 2:

To 2-[N-(cyclopentyl-methyl)-N-ethylamino]-6-methyl-5-nitro cigarette nitrile (1.22g adds N in DMF 4.23mmol) (10mL) mixture, and the dinethylformamide diethyl acetal (1.09mL, 6.35mmol).Behind 85 ℃ of stirring 30min, reaction mixture is cooled to room temperature, add H then ₂O.Mixture is extracted with EtOAc, through dried over sodium sulfate and vacuum concentration.The solid methanol wash that obtains obtains orange solids.Solid is dissolved in MeOH (200mL) and EtOAc (200mL), and (Pd/C (en) 470mg) handles with palladium on activated carbon quadrol mixture.Mixture was stirred 2.5 hours in hydrogen environment, under room temperature.Filter reaction mixture, the filtrate vacuum concentration.Residue is dissolved in the EtOAc/ hexane, filters by silicagel pad.With the mixture vacuum concentration that obtains, residue is dissolved in DMF (10mL).In 0 ℃ in this mixture, add NaH (0.54g, 13.5mmol), behind the 30min, add methyl iodide (0.28mL, 4.50mmol).Stir after 1 hour the cancellation of reactant water.Mixture is extracted with EtOAc, use the salt water washing.Organic layer is through dried over sodium sulfate and vacuum concentration.Residue through silica gel chromatography, is obtained 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.19(t，3H)，1.16-1.26(m，2H)，1.44-1.55(m，2H)，1.56-1.66(m，2H)，1.67-1.75(m，2H)，2.24(ddt，1H)，3.46(d，2H)，3.58(dd，2H)，3.76(s，3H)，6.47(d，1H)，7.31(d，1H)，7.76(s，1H)。

Step 3:

With 5-[N-(cyclopentyl-methyl)-N-ethylamino]-(0.30g, methyl cellosolve 1.06mmol) (6mL) solution adopt the 5N NaOH aqueous solution (6mL) to handle to 1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN.Reaction mixture stirred 60 hours in 130 ℃.After being cooled to room temperature, mixture is adopted the 1NHCl acidifying.With mixture CH ₂Cl ₂Extraction is through dried over sodium sulfate and vacuum concentration.Under room temperature, in THF (5mL) solution of the residue that obtains, add triethylamine (0.14mL, 1.00mmol) and chloro ethyl formate (0.10mL, 1.00mmol).After stirring 1h, the precipitation that filtering separation produces, filtrate vacuum concentration.In 0 ℃ of EtOH (3mL) solution, add to residue sodium borohydride (41mg, 1.08mmol).After stirring 1h, reactant adopts shrend to go out.The mixture ethyl acetate extraction, the salt water washing.Organic layer is through dried over sodium sulfate and vacuum concentration.Residue through silica gel chromatography, is obtained { 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-yl } methyl alcohol, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.08(t，3H)，1.14-1.23(m，2H)，1.42-1.50(m，2H)，1.71-1.79(m，2H)，2.01-2.10(m，2H)，3.12-3.22(m，4H)，3.78(s，3H)，4.87(s，2H)，5.98(s，1H)，6.60(d，1H)，7.21(d，1H)，7.42(s，1H)。

Embodiment O:{5-[N-(cyclopentyl-methyl) ethylamino]-1,3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-6-yl } preparation of methyl alcohol

Step 1:

In 0 ℃, to 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN (105mg, add in DMF 0.37mmol) (2mL) mixture N-bromosuccinimide (NBS, 66mg, 0.37mmol).After stirring 30min, add entry, reaction mixture extracts with EtOAc.Organic layer is through dried over sodium sulfate, concentrates and through silica gel chromatography, obtains 3-bromo-5-[N-(cyclopentyl-methyl)-N-ethylamino]-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN, be yellow solid.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.26(t，3H)，1.20-1.30(m，2H)，1.48-1.54(m，2H)，1.58-1.67(m，2H)，1.68-1.79(m，2H)，2.31(ddt，1H)，3.57(d，2H)，3.68(d，2H)，3.74(s，3H)，7.32(s，1H)，7.73(s，1H)。

Step 2:

In 0 ℃, with 3-bromo-5-[N-(cyclopentyl-methyl)-N-ethylamino]-(1.05g is 2.91mmol) with [1,1-two (diphenylphosphino) ferrocene] dichloro-palladium (II) methylene dichloride mixture (PdCl for 1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN ₂(dppf)-CH ₂Cl ₂, 0.24g, THF 0.29mmol) (20mL) mixture adopt methyl-magnesium-bromide (the THF solution of 0.93M, 7.8mL) processing.Reaction mixture stirred 22 hours in 75 ℃.After being cooled to room temperature, add entry, reaction mixture extracts with EtOAc.The saturated NaHCO of organic layer ₃With the salt water washing, through dried over sodium sulfate and concentrated.Residue through silica gel chromatography, is obtained 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1,3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN is colorless oil.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.23(t，3H)，1.19-1.29(m，2H)，1.46-1.52(m，2H)，1.58-1.65(m，2H)，1.66-1.77(m，2H)，2.22-2.33(m，4H)，3.49(d，2H)，3.60(dd，2H)，3.68(s，3H)，7.09(s，1H)，7.68(s，1H)。

Step 3:

According to the embodiment N (method of step 3), 5-[N-(cyclopentyl-methyl) ethylamino] and-1,3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-6-yl } methyl alcohol employing 5-[N-(cyclopentyl-methyl)-N-ethylamino]-1,3-dimethyl-1H-pyrrolo-[3,2-b] pyridine-6-formonitrile HCN preparation.

¹H-NMR(400MHz，CDCl ₃)，δ(ppm)：1.09(t，3H)，1.13-1.23(m，2H)，1.42-1.51(m，2H)，1.51-1.63(m，2H)，1.68-1.79(m，2H)，.1.99-2.10(m，1H)，2.33(s，3H)，3.12-3.19(m，4H)，3.70(s，3H)，4.85(s，2H)，6.98(s，1H)，7.32(s，1H)。

General UPLC (Ultra Performance Liquid Chromatography) condition:

Post: Waters ACQUITY UPLC BEH C18,1.7 μ M

Moving phase: CH ₃CN/H ₂O (0.1%TFA).

Claims

1. formula (I) compound that exists with free form or salt form or its salt:

Wherein:

Unsubstituted with ring B condensed ring A representative or replace carbocyclic aromatic group or heterocyclic aromatic group unsubstituted or that replace;

Wherein Ar represents carbocyclic aromatic group unsubstituted or that replace;

R ₁For group-C (=O)-R ₃,-C (=O)-O-R ₃,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅), m under any circumstance is integer 0,1 or 2, perhaps R ₁Be Z,

R ₄And R ₅Independent each other hydrogen, alkyl or cycloalkyl represent, described alkyl is replaced by the substituting group that one or more is selected from following groups: the unsubstituted or cycloalkyl that replaces, unsubstituted or the cycloalkenyl group and the heterocyclic group unsubstituted or replacement that replace;

R ₄And R ₅Together for the unsubstituted or alkylidene group that replaces or wherein be inserted with O, NR ₃' or S unsubstituted or the alkylidene group that replaces; R ₃' be R ₃Or-C (=O)-OR ₃And

M is an integer 0,1 or 2;

X is CR ₆Or N, Y is N; Or X is N, and Y is CR ₆

Wherein aryl moiety be unsubstituted or the aralkyl that replaces, heterocyclic radical partly for unsubstituted or heterocyclic radical-alkyl of replacing in, carbocyclic aromatic group or heterocyclic aromatic group or heterocyclic group or ring A or Ar are each other independently for unsubstituted or replaced by one or more substituting group that is selected from following groups: halogen, NO ₂, CN, OH, alkyl, alkoxyl group-alkyl, hydroxyl-alkyl, halo-alkyl, alkoxyl group, alkoxyl group-alkoxyl group, halogenated alkoxy ,-C (=O)-R ₃,-C (=O)-O-R ₃,-N (R ₄) (R ₅) ,-C (=O)-NR ₄R ₅,-S (O) _m-R ₃,-S (O) _m-N (R ₄) (R ₅) ,-NR ₃-S (O) _m-N (R ₄) (R ₅) and alkyloyl, m under any circumstance is integer 0,1 or 2; Unsubstituted or the cycloalkyl that replaces, the unsubstituted or cycloalkenyl group that replaces; Wherein aryl moiety be unsubstituted or the aralkyl that replaces and wherein heterocyclic radical partly be heterocyclic radical-alkyl unsubstituted or that replace.

2. the compound or its salt of claim 1 has formula (IA) or (IB):

Wherein X is N, and Y is CH or N;

R ₁For being selected from the heterocycle of following groups:

They under any circumstance are unsubstituted or are selected from the substituting group N of following groups or C-replaces: C ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, hydroxyl-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl-, (R ₄) (R ₅) N-C ₁-C ₇-alkyl-,-N (R ₄) (R ₅) and phenyl-C ₁-C ₇-alkyl-;

R ₉And R ₁₀Independent each other is hydrogen, halogen, NO ₂, CN, OH, C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, pyridyl-C ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkoxyl group, naphthyl-C ₁-C ₇-alkoxyl group, pyridyl-C ₁-C ₇-alkoxyl group, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkoxyl group, halo-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, carboxyl, C ₁-C ₇-alkoxyl group-carbonyl, C ₁-C ₇-alkyl-S (O) _m-, phenyl-C ₁-C ₇-alkyl-S (O) _m, naphthyl-C ₁-C ₇-alkyl-S (O) _m, pyridyl-C ₁-C ₇-alkyl-S (O) _m, halo-C ₁-C ₇-alkoxyl group and C ₂-C ₇-alkyloyl (oxygen base), m under any circumstance is integer 0,1 or 2; C ₃-C ₇-cycloalkyl, C ₃-C ₇-cycloalkenyl group; Wherein phenyl moiety is phenyl-C unsubstituted or that replace ₁-C ₇-alkyl and wherein pyridyl partly be unsubstituted or pyridyl-C of replacing ₁-C ₇-alkyl; And

Wherein p is 0 or 1 or 2 or 3;

Wherein n is 0 or 1 or 2 or 3;

R ₁₁Be C ₁-C ₇-alkyl;

The substituting group that connects in Z independently is selected from the substituting group of following groups for hydrogen or one or more each other: halogen, OH, NH ₂, carbonyl (=O), C ₁-C ₇-alkyl, C ₃-C ₇-cycloalkyl, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl-, C ₃-C ₇-cycloalkyl oxy-C ₁-C ₇-alkyl-, phenyl-C ₁-C ₇-alkoxyl group-, C ₃-C ₇-cycloalkyl-C ₁-C ₇-alkoxyl group-, halo-C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxyl group-, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group-, carboxyl-, C ₁-C ₇-alkoxyl group-carbonyl-, C ₁-C ₇-alkyl-S (O) _m-, phenyl-C ₁-C ₇-alkyl-S (O) _m-, halo-C ₁-C ₇-alkoxyl group and C ₂-C ₇-alkyloyl-, C ₁-C ₇-alkoxy-C ₃-C ₇-cycloalkyl-, phenyl-C ₁-C ₇-alkoxy-C ₃-C ₇-cycloalkyl-, hydroxyl-C ₃-C ₇-cycloalkyl-, hydroxyl-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, formyl radical-C ₃-C ₇-cycloalkyl-, formyl radical-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, carboxyl-C ₃-C ₇-cycloalkyl-, carboxyl-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-, H ₂NC (=O)-C ₃-C ₇-cycloalkyl-, H ₂NC (=O)-C ₁-C ₇-alkyl-C ₃-C ₇-cycloalkyl-.

3. the compound or its salt of claim 1 has formula (IC):

Wherein X is N, and Y is CH or N;

R ₁Be 2-C ₁-C ₇-alkyl-2H-tetrazolium-5-base;

R ₉Be one or two substituting group that is selected from following groups: hydrogen ,-CN, C ₁-C ₇-alkyl-, C ₁-C ₇-alkoxyl group, (C ₁-C ₇-alkyl) (C ₁-C ₇-alkyl-) amine-, halo-C ₁-C ₇-alkyl or halogen;

R ₄Be (C ₁-C ₄) alkyl-or (C ₃-C ₅) cycloalkyl-; And

4. formula (II) compound or its salt:

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (III):

R wherein ₆Be (C ₁-C ₄) alkyl-or (C ₃-C ₅) cycloalkyl-; Rb is-(CH ₂) _n-Rc; N is 0 or 1 or 2 or 3; Rc is carboxyl, hydroxyl, (C ₁-C ₄)-alkoxyl group or (C ₁-C ₄)-alkoxy carbonyl.

5. the compound or its salt of claim 4 has formula (II):

Wherein p is 0 or 1 or 2;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (IIIA):

6. formula (II) compound or its salt:

Wherein p is 0 or 1 or 2 or 3;

Ra is halogen or (C ₁-C ₄)-alkoxyl group or halo-(C ₁-C ₄) alkyl;

R ₁₂And R ₁₃Independent is halogen or halo-(C ₁-C ₄) alkyl;

R ₂Be formula (IV):

Wherein Rb is-(CH ₂) _n-Rc; N is 0 or 1 or 2 or 3; Rc is carboxyl, hydroxyl, formyl radical, (C ₁-C ₄)-alkoxyl group, H ₂NC (=O)-, H ₂NC (=O)-(C ₁-C ₄) alkyl, (C ₁-C ₄)-alkoxy carbonyl or halo-(C ₁-C ₄)-alkoxy carbonyl.

7. the compound or its salt of claim 6, wherein R ₂Be formula (IVA):

8. the compound of claim 7 or its pharmacy acceptable salt, wherein p is 1 or 2; Ra is a halogen; R ₁₂And R ₁₃Be halo-(C ₁-C ₄) alkyl; Rb is-(CH ₂) _n-Rc, wherein n is 0 or 1; Rc is carboxyl or (C ₁-C ₄)-alkoxy carbonyl or halo-(C ₁-C ₄)-alkoxy carbonyl.

9. be selected from following compound:

Numbering ??Rn ??R ₇ ??23 ??7-F ₂ ??CF ₃ ??24 ??6，7-F ₂ ??CF ₃ ??25 ??5，7-F ₂ ??CF ₃

Numbering ??Rn ??R2’ ??R ₇ ??26 ??5，7-F ₂ ??-(CH ₂) ₂OH ??CF ₃ ??27 ??5，7-F ₂ ??-(CH ₂) ₂OCH ₃ ??CF ₃ ??28 ??5，7-F ₂ ??-(CH ₂) ₂N(CH ₃) ₂ ??CF ₃

Numbering ??Rn ??Rb ??R ₇

??29 ??7-F ??-CH ₂OH ??CF ₃ ??30 ??7-F ??-CH ₂OH ??Cl ??31 ??6，7-F ₂ ??-CH ₂OH ??CF ₃ ??32 ??6，7-F ₂ ??-CH ₂OH ??Cl ??33 ??7-F ??-(CH ₂) ₂OH ??CF ₃ ??34 ??7-F ??-(CH ₂) ₂OH ??Cl ??35 ??6，7-F ₂ ??-(CH ₂) ₂OH ??CF ₃ ??36 ??6，7-F ₂ ??-(CH ₂) ₂OH ??Cl ??37 ??7-F ??-CHO ??CF ₃ ??38 ??7-F ??-CHO ??Cl ??39 ??6，7-F ₂ ??-CHO ??CF ₃ ??40 ??6，7-F ₂ ??-CHO ??Cl ??41 ??7-F ??-CH ₂CHO ??CF ₃ ??42 ??7-F ??-CH ₂CHO ??Cl ??43 ??6，7-F ₂ ??-CH ₂CHO ??CF ₃ ??44 ??6，7-F ₂ ??-CH ₂CHO ??Cl ??45 ??7-F ??-CO ₂H ??CF ₃ ??46 ??7-F ??-CO ₂H ??Cl ??47 ??6，7-F ₂ ??-CO ₂H ??CF ₃ ??48 ??6，7-F ₂ ??-CO ₂H ??Cl ??49 ??7-F ??-CH ₂CO ₂H ??CF ₃ ??50 ??7-F ??-CH ₂CO ₂H ??Cl ??51 ??6，7-F ₂ ??-CH ₂CO ₂H ??CF ₃ ??52 ??6，7-F ₂ ??-CH ₂CO ₂H ??Cl ??53 ??6，7-F ₂ ??-C(＝O)NH ₂ ??CF ₃ ??54 ??6，7-F ₂ ??-CH ₂C(＝O)NH ₂ ??CF ₃

Perhaps, under any circumstance, their salt.

10. the compound or its pharmacy acceptable salt that are used for the treatment of among the claim 1-9 of the mankind or animal each.

11. medicinal compositions, this medicinal compositions contain among the claim 1-9 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.

12. with each compound or its pharmacy acceptable salt among the claim 1-9 of the combined utilization that is selected from following activeconstituents:

(i) HMG-Co-A reductase inhibitor or its pharmacy acceptable salt,

(ii) angiotensin II receptor antagonists or its pharmacy acceptable salt,

(iv) calcium channel blocker or its pharmacy acceptable salt,

(v) aldosterone synthetase inhibitors or its pharmacy acceptable salt,

(vi) aldosterone antagonists or its pharmacy acceptable salt,

(viii) endothelin antagonist or its pharmacy acceptable salt,

(ix) renin inhibitor or its pharmacy acceptable salt,

(x) diuretic(s) or its pharmacy acceptable salt,

(xi) ApoA-I stand-in, and

(xii) DGAT inhibitor.

13. each compound is in production is used for preventing or treatment is obviously relevant with CETP disease or delay the purposes of the medicine of its development (described disease is hyperlipidaemia for example among the claim 1-11, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc.), described medicine also is used for the treatment of schistosomicide (or ovum embryo) especially as the prevention or the medicine of hyperlipidaemia or arteriosclerotic disease.

14. the disease that prevention or treatment and CETP are obviously relevant or delay the method for its development (described disease is hyperlipidaemia for example, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyperlipemia, high beta-lipoproteinemia, tangier's disease, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, coronary heart disease, coronary artery disease, coronary vessels diseases, stenocardia, local asphyxia, cardiac ischemia, thrombosis, coronary embolism forms for example myocardial infarction, apoplexy, peripheral vascular disease, reperfusion injury, postangioplasty restenosis, hypertension, congestive heart failure, diabetes are type ii diabetes for example, diabetic vascular complications, obesity or endotoxemia etc.), described medicine is especially as the prevention or the medicine of hyperlipidaemia or arteriosclerotic disease, also be used for the treatment of schistosomicide (or ovum embryo), described method comprises compound or its pharmacy acceptable salt that gives among the claim 1-9 that Mammals comprises human significant quantity each.