CN1942467A

CN1942467A - 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease

Info

Publication number: CN1942467A
Application number: CNA2005800118430A
Authority: CN
Inventors: J·C·巴罗; G·B·麦戈伊; P·G·南特梅特; H·A·拉亚帕克斯; H·G·塞尔尼克; S·R·斯陶费尔; J·P·瓦卡; S·J·斯塔彻尔; C·A·科伯恩; M·G·斯坦顿
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 2004-04-20
Filing date: 2005-04-20
Publication date: 2007-04-04

Abstract

The present invention is directed to 2, 4, 6-substituted pyridyl derivative compounds which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Description

Be used for as β-short Secretase inhibitors Alzheimer treatment 2,4, the pyridine derivative compound that 6-replaces

The related application of cross reference

60/653,037 the right of priority that the application enjoys according to 35 U.S.C.119 (e) request that the U.S. Provisional Application series number of submitting on April 20th, 2,004 60/563,612 and 15,60/630,539 and 2005 on the February of submitting on November 23rd, 2004 submit to.

Technical field

The present invention relates to a class new 2,4, the pyridine derivative compound that 6-replaces, they are effective β-short Secretase inhibitors and are applicable to and wherein involve the β-disease of short Secretases (secretase) such as the treatment of Alzheimer.

Background technology

Alzheimer is characterised in that the abnormal deposition of amyloid in brain forms neurofibrillary tangles in extracellular plaque and the cell.The speed that amyloid is accumulated is the function that forms, assembles and fail speed outside brain.People are generally accepted to be that the main composition of amyloid plaque is that (β A4 is also referred to as A β to the 4kD amyloid protein; Beta-protein matter and β AP), it is a kind of very large protein hydrolysate of size of precursor protein.Amyloid precursor protein (APP or A β; PP) has acceptor spline structure and have big ectodomain, stride diaphragm area and short cytoplasmic tail.A beta structure territory comprises a plurality of parts of the outer and membrane spaning domain of the born of the same parents of APP, thereby so its release mean that the existence of two kinds of different proteolysis incidents produces its NH ₂-and the COOH-end.At least exist two kinds to discharge APP and produce the APP (APP of solubility, COOH-butt form from film _s) secretion matrix.Proteolytic enzyme and the film forming fragment of structure thereof that discharges APP is called " short Secretases ".Most APP _sBe to be discharged by the α that infers-short Secretases, it is separated in a matter implosion and discharges α-APP _sAnd stoped the release of complete A β.The APP of small part _sBe to be discharged by β-short Secretases (" β-short Secretases "), it is at the NH of APP ₂Near-terminal cracking also produces the COOH-terminal fragment (CTFs) that contains whole A beta structures territory.

Therefore, the activity of β-short Secretases or β-site amyloid precursor protein-lyase (" BACE ") causes the unusual cracking of APP, produce A β, with amyloid-beta plaque accumulating in brain, it is characterized in that Alzheimer (referring to R.N.Rosenberg, Arch.Neurol., vol.59, Sep 2002, pp.1367-1368; H.Fukumoto etc., Arch.Neurol., vol.59, Sep 2002, pp.1381-1389; J.T.Huse etc., J.Biol.Chem., vol 277, No.18, May 3,2002 publishes pp.16278-16284; K.C.Chen and W.J.Howe, Biochem.Biophys.Res.Comm, vol.292, pp 702-708,2002).So, can suppress the therapeutical agent of β-short Secretases or BACE and can effectively treat Alzheimer.

Compound of the present invention prevents the formation of insoluble A β thus by suppressing the active effectively treatment Alzheimer of β-short Secretases or BACE; With the generation that stops A β.

Summary of the invention

The present invention relates to as 2,4 of β-short Secretase inhibitors, the pyridyl derivative compound that 6-replaces, and be used for the treatment of the disease that wherein relates to β-short Secretases, for example Alzheimer.The invention still further relates to the pharmaceutical composition that contains these compounds and these compounds and composition and relate to application in the disease of β-short Secretases in treatment.

Detailed Description Of The Invention

The present invention relates to the compound of formula (I):

Wherein: X is selected from group

R wherein ¹¹And R ¹²Be independently selected from

(a) hydrogen,

(b)-C _1-10Alkyl,

(c) C _2-10Alkenyl,

(d) C _2-10Alkynyl group,

(e)-C _3-12Cycloalkyl and

(f) be selected from the aryl of phenyl and naphthyl;

This alkyl wherein, cycloalkyl, alkenyl, alkynyl group or aryl are not substituted or are replaced by one or more following groups

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl and

(vi)-O-C _1-10Alkyl,

Y ¹Be N, and Y ²And Y ³Be respectively CH, or

Y ²Be N, and Y ¹And Y ³Be respectively CH, or

Y ³Be N, and Y ¹And Y ²Be respectively CH;

A is selected from group

(1) hydrogen,

(2)-C _1-10Alkyl and

(3)-C _2-10Alkenyl,

Wherein this alkyl or alkenyl are not replace or replaced by one or more following groups

(a) halogen,

(b)-C _3-12Cycloalkyl,

(c)-OH，

(d)-CN，

(e)-O-C _1-10Alkyl,

(f) phenyl, or

(g) heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, furyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl,  azoles base, different  azoles base, thiazolyl, the  di azoly, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, indoles alkynyl (indynyl) and benzoxazol base

With this phenyl and heteroaryl be not replace or replaced by one or more following groups

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _1-10Alkyl, or

(vi)-C _3-12Cycloalkyl;

Q is-C _0-3Alkyl, wherein this alkyl is not replace or replaced by one or more following groups

(1) halogen,

(2)-C _3-12Cycloalkyl,

(3)-OH，

(4)-CN，

(5)-O-C _1-10Alkyl and

(6)-C _1-10Alkyl;

R ¹Be the aryl that (1) is selected from phenyl and naphthyl,

(2) heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, furyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl,  azoles base, different  azoles base, thiazolyl, the  di azoly, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, indoles alkynyl and benzoxazol base

(3)-C _1-10Alkyl and

(4) C _3-8Cycloalkyl, this cycloalkyl randomly with C _6-10It is aryl-condensed,

This alkyl wherein, cycloalkyl, aryl or heteroaryl are not replace or replaced by one or more following groups

(a) halogen,

(b)-C _1-10Alkyl, wherein this alkyl is not replace or replaced by halogen,

(c)-OH，

(d)-CN，

(e)-O-C _1-10Alkyl,

(f)-C _3-12Cycloalkyl and

(g)-NR ⁸R ⁹；

R ²Be selected from

(1)-OH and

(2)-NR ⁸R ⁹, R wherein ⁸And R ⁹Be selected from

(a) hydrogen,

(b) C _1-10Alkyl and

(c) C0-6 alkyl-C _6-10Aryl,

Or work as R ²Be NR ⁸R ⁹, and R ⁸When being hydrogen with A, Q then, R ¹And R ⁹Formation-CH can link together ₂CH ₂CH ₂-, work as R ²Be NR ⁸R ⁹The time, then Q, R ¹Can link together with A constitutes 4 or 5 carbon alkyl chains, and wherein the one or more carbon atoms in the alkyl chain can be used N, O or S atom, or SO ₂Group substitutes;

R ⁴Be selected from group

(1)-C _1-10Alkyl, or

(2)-C _3-12Cycloalkyl, wherein this alkyl and cycloalkyl are not substituted or are replaced by one or more following groups

(a) halogen,

(b)-OH，

(c)-CN，

(d)-O-C _1-10Alkyl,

(e)-C _1-10Alkyl,

(f)-C _3-12Cycloalkyl,

(g) be selected from the aryl of phenyl and naphthyl, or

(h) heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, furyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl,  azoles base, different  azoles base, thiazolyl, the  di azoly, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, indoles alkynyl and benzoxazol base

With this aryl and heteroaryl be not replace or replaced by one or more following groups

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl, or

(vi)-C _1-10Alkyl;

R ⁷Be selected from group

(1) hydrogen,

(2)-C _1-10Alkyl and

(3) be selected from the aryl of phenyl and naphthyl;

Wherein this alkyl and aryl are not replace or replaced by one or more following groups

(a) halogen,

(b)-OH，

(c)-CN，

(d)-O-C _1-10Alkyl,

(e)-C _3-12Cycloalkyl,

(f) be selected from the aryl of phenyl and naphthyl, or

(g) heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, furyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl,  azoles base, different  azoles base, thiazolyl,  di azoly, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, indoles alkynyl and benzoxazol base;

This cycloalkyl wherein, aryl or heteroaryl are not replace or replaced by one or more following groups

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl, or

(vi) be selected from the aryl of phenyl and naphthyl;

Or R ⁴And R ⁷Formation-CH can link to each other ₂CH ₂CH ₂-;

R ⁵And R ⁶Be independently selected from

(1) hydrogen,

(2)-C _1-10Alkyl,

(3)-C _2-10Alkenyl,

(4)-C _2-10Alkynyl group and

(5)-C _1-10Alkyl-C _3-12Cycloalkyl;

This alkyl wherein, cycloalkyl, alkenyl or alkynyl group are not replace or replaced by one or more following groups

(a) halogen,

(b)-OH，

(c)-CN，

(d)-C _1-10Alkyl

(e)-C _3-12Cycloalkyl,

(f)-O-C _1-10Alkyl,

(g) heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, furyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl,  azoles base, different  azoles base, thiazolyl, the  di azoly, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, indoles alkynyl and benzoxazol base

Wherein this heteroaryl can not replace or be replaced by halogen;

(h) phenyl, or

(i)-NR ⁸R ⁹；

Or R ⁵And R ⁶The continuous 4-6 person of formation encircles with the nitrogen-atoms that they connected, and it does not replace or is replaced by one or more following groups

(a)-C _1-10Alkyl,

(b)-C _3-12Cycloalkyl,

(c)-(CH ₂) positive phenyl,

(d)-C _2-10Alkenyl, or

(e)-C _2-10Alkynyl group, this alkyl wherein, alkenyl and alkynyl group are not replace or replaced by one or more following groups

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl, or

(v)-C _3-12Cycloalkyl;

With this cycloalkyl and phenyl be not replace or replaced by one or more following groups

(i) halogen,

(ii)-C _1-10Alkyl,

(iii)-OH，

(iv)-CN，

(v)-C _3-12Cycloalkyl, or

(vi)-O-C _1-10Alkyl;

N is 0,1,2,3 or 4;

With its pharmaceutically acceptable salt, with and each enantiomer and diastereomer.

In a preferred embodiment, Y ¹Be N and Y ²And Y ³Be respectively CH.

In one embodiment, the compound that the present invention relates to formula (I) R wherein ¹Be preferably CH of the phenyl that do not replace or replace and Q ₂Preferably, R ¹It is unsubstituted phenyl.

In other embodiments, R ¹It is heteroaryl.Preferred R ¹Heteroaryl comprises pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), thienyl (preferred 2-thienyl or 3-thienyl), thiazole and indoles alkynyl.

In other embodiments, R ¹Be C _1-12Alkyl or C _3-8Cycloalkyl.Preferred C _1-12Alkyl R ¹Group comprises C _1-6Alkyl (preferred unsubstituted C _1-6Alkyl comprises methyl and sec.-propyl).Preferred C _3-8Cycloalkyl comprises cyclopropyl, and cyclopentyl and cyclohexyl are preferably unsubstituted.The ring carbon atom of two cycloalkyl can link to each other and constitute C _6-12Aryl.The isomery example of this embodiment condenses group and is:

In another embodiment, the compound that the present invention relates to formula (I) R wherein ²Be NR ⁸R ⁹, and preferred R ⁸And R ⁹Be hydrogen.

In another embodiment of formula (I) compound, work as R ²Be NR ⁸R ⁹And R ⁸When being hydrogen respectively with A, Q then, R ¹And R ⁹Formation-CH can link together ₂CH ₂CH ₂-, constitute the pyrrolidyl pyrrolidyl thus.

In another embodiment of formula (I) compound, work as R ²Be NR ⁸R ⁹, Q then, R ¹Constitute 4 or 5 carbon alkyl chains together with the A connexon, wherein the one or more carbon atoms in this alkyl chain can be by N, O or S atom, or by SO ₂Group substitutes.

In another embodiment of formula (I) compound, R ²Be OH.

In another embodiment of formula (I) compound, A is the C that does not replace or replace (preferably not replacing) _1-10Alkyl, the C of preferred (preferably not the replacing) that does not replace or replace _1-6Alkyl and especially more preferably methyl.

In another embodiment, A can be a hydrogen.

In another embodiment of formula (I) compound, R ⁵And R ⁶With the continuous formation of its nitrogen-atoms that connects simultaneously pyrrolidine ring.

In another embodiment of formula (I) compound, R ⁴And R ⁷Be C _1-10Alkyl, preferred C _1-6Alkyl.More preferably, R ⁴Be methyl or sec.-propyl and R ⁷It is methyl.

In an embodiment of formula (I) compound, X is that the  diazole is selected from

In another embodiment of formula (I) compound, X is that the  azoles is selected from

In another embodiment of formula (I) compound, X is that thiazole is selected from

At another embodiment of formula (I) compound, X is 1,2, the 4-triazine

Furans

Pyrazoles

Pyrimidine

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

A wherein, X, Y ¹, Y ², Y ³, Q, R ¹, R ², R ⁴, R ⁵And R ⁷Define as above, and R ¹⁰Be hydrogen or C _1-6Alkyl and its pharmaceutically acceptable salt and its each enantiomer and diastereomer.

At a preferred implementation of the compound of formula (II), Y ¹Be N and Y ²And Y ³Be respectively CH.In an embodiment of formula (II) compound, R ¹Be that phenyl and Q are CH ₂Preferably, R ¹It is unsubstituted phenyl.

In another embodiment, the compound that the present invention relates to formula (II) R wherein ²Be NR ⁸R ⁹And preferred R ⁸And R ⁹Be hydrogen simultaneously.

In another embodiment of formula (II) compound, R ²Be OH.

In another embodiment of formula (II) compound, R ¹⁰Be hydrogen.In another embodiment, R ¹⁰Be C _1-6Alkyl, preferable methyl, ethyl or sec.-propyl.

In another embodiment of formula (II) compound, A is C _1-10Alkyl, preferred C _1-6Alkyl, more preferably methyl.

In another embodiment of formula (II) compound, R ⁴And R ⁷Be C _1-10Alkyl, preferred C _1-6Alkyl.More preferably, R ⁴Be methyl or sec.-propyl and R ⁷It is methyl.

In another embodiment of formula (II) compound, R ⁵Be hydrogen or, C _1-10Alkyl, wherein C _1-10Alkyl is replaced by one or more following groups or does not replace:

(1) halogen (preferred fluorine),

(2)-OH，

(3)-CN，

(4) phenyl,

(5)-OC _1-10Alkyl, or

(6)-NR ⁸R ⁹(preferred R ⁸And R ⁹Be respectively C _1-10Alkyl).

In the compound of formula (II), preferred R ⁵Group comprises hydrogen, methyl, benzyl and-C _1-10Alkyl-NR ⁸R ⁹, R wherein ⁸And R ⁹Be respectively C _1-10Alkyl.

In an embodiment of formula (II) compound, X is that the  diazole is selected from

In another embodiment of formula (II) compound, X is that the  azoles is selected from

In another embodiment of formula (II) compound, X is that thiazole is selected from

In another embodiment of formula (II) compound, X is 1,2, the 4-triazine

Furans

Pyrazoles

Pyrimidine

Work as R ¹⁰When being hydrogen, formula (II) compound of a preferred enantiomorph configuration is to have trans-S on methyl-cyclopropyl-methyl moiety, the compound of S configuration, shown in (IIA):

In another embodiment, the present invention relates to the compound of formula (III)

A wherein, X, Q, R1, R ², R ⁴, R ⁵, R ⁶And R ⁷Define as above, and R ¹⁰Be hydrogen or C _1-6Alkyl and its pharmaceutically acceptable salt and its each enantiomer and diastereomer.

Another embodiment of the present invention comprises the compound of the title compound that is selected from the following example and its pharmaceutically acceptable salt.

So used, term " alkyl " itself or as another substituent integral part is meant saturated straight chain or branched hydrocarbyl (for example, C with defined amount carbon atom _1-10Alkyl is meant the alkyl with 1-10 carbon atom).The preferred alkyl that the present invention uses is C _1-6Alkyl has 1-6 carbon atom.The example alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.

So used, term " alkenyl " itself or as another substituent integral part is meant straight or branched alkyl (for example, the C that has a carbon-to-carbon double bond and specify carbonatoms _2-10Alkenyl is meant the alkenyl with 2-10 carbon atom).The preference chain thiazolinyl that the present invention uses is C _2-6Alkenyl has 2-6 carbon atom.The example chain thiazolinyl comprises vinyl and propenyl.

So used, term " cycloalkyl " itself or as another substituent integral part is meant to have the saturated monocycle of specifying carbonatoms, encircle or bridged cyclic hydrocarbon group (for example, C more _3-12Cycloalkyl is meant the cycloalkyl with 3-12 carbon atom).Preferred cycloalkyl comprises C _3-8Cycloalkyl, especially C _3-8Monocyclic cycloalkyl.The example monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Example bridged ring alkyl comprises adamantyl and norcamphyl.

So used, term " aryl " itself or as another substituent integral part is meant to have aromatics or cyclic group (for example, the C that specifies carbonatoms _6-10Aryl is meant the aryl with 6-10 carbon atom).The preferred aryl groups that the present invention uses comprises phenyl and naphthyl.

Term " halo " or " halogen " comprise fluorine, chlorine, bromine and iodine.

So used, term " heteroaryl " itself or as another substituent integral part is meant have at least one ring hetero atom aromatics cyclic group of (O, N or S).The example heteroaryl that the present invention uses comprises furyl, pyranyl, benzofuryl, isobenzofuran-base, chromenyl, thienyl, the benzo thiophenyl, pyrryl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, indazolyl, benzimidazolyl-, quinolyl and isoquinolyl.

When the heteroaryl of this paper definition is substituted, this substituting group can with the ring carbon atom bonding of heteroaryl, or be positioned on the ring hetero atom (that is, nitrogen, oxygen or sulphur), they have and allow the valency that replaces.Preferably, this substituting group bonding ring carbon atom.Similarly, when heteroaryl was defined herein as substituting group, tie point can be on the ring carbon atom of heteroaryl, or on ring hetero atom (that is, nitrogen, oxygen or sulphur), and they have and allow the valency that replaces.Preferably, connection can be positioned at ring carbon atom.

Compounds more of the present invention have at least one asymmetric center.May there be additional asymmetric neutrality in character according to different substituents on the molecule.Compound with asymmetric center produces enantiomer (optical isomer); Diastereomer (conformer) or both and scope of the present invention comprise the possible enantiomer and the diastereomer of all miscellanys and purifying and partial purification compound.The present invention includes all these type of isomeric form of these compounds.

The independence of enantiomerism or diastereo-isomerism enrichment compound is synthetic, or its chromatographic separation, can obtain by suitable improvement method disclosed herein according to methods known in the art.Its absolute stereo chemistry can be measured by the X-radiocrystallgraphy of crystalline product and deutero-crystal intermediate, if necessary, adopts the reagent of the asymmetric center that contains known absolute configuration.

If wish that the racemize miscellany of described compound can separate, thereby isolates single enantiomer.This separation can be undertaken by method well known in the art, for example the coupling of the compound of the racemize miscellany of described compound and enantiomer-pure forms the diastereomer miscellany, subsequently by standard method for example fractional crystallization and the single diastereomer of chromatographic separation.Linked reaction utilizes the acid of enantiomer-pure or alkali to form salt usually.The diastereomer derivative can be converted into pure enantiomer by the additional chirality residue of cracking.The racemize miscellany of described compound can also directly utilize chiral solid phase to separate by chromatographic process, and this method is well known in the art.

In addition, any enantiomer of compound can utilize the optical purity starting raw material of configuration known or reagent to obtain by method well known in the art by stereospecific synthesis.

In the compound of formula (I)-(III), with R ², A and Q bonding carbon atom remove and be chiral carbon.So can there be racemic modification in the compound of formula (I)-(III), perhaps with pure (R) of stereochemistry or (S) form.The isomer of formula (I) compound is as follows:

(be generally (R) configuration, for example work as A is CH to preferred above-mentioned first configuration ₃, R ²Be NH ₂, Q is-CH ₂-and R ¹When being phenyl).

Compound of the present invention can be according to following universal method and specific embodiment 1-94 preparation (route plan 1-25).

At route plan, the amino acid derivative of 1 type is converted into corresponding diazanyl acid amides 3 through two step programs.For the amino acid derivative that obtains to be purchased, can adopt two step alkylated reactions of glycine Schiff's base 4.The Schiff's base deprotection, Boc protection and ester hydrolysis provide another approach that obtains compound 2.Be used for synthetic 5 with 4 alkylated reaction can with the enantioselectivity mode according to the described method of document carry out (referring to K.Maruoka etc., J.Am.Chem.Soc.2000,122,5228-5229 and M.North etc., Tetrahedron Lett.2003,44,2045-2048).

Route plan 1

In route plan 2, the amino acid 2 of N-protected is converted into carboxylic acid amides 6a (with thiocarboxamide 6b), and subsequent dewatering obtains nitrile 7.7 use NH ₂OH-HCl handles under weak basic condition and obtains oxyamide thing 8.

Route plan 2

In route plan 3, the amino acid/11 BH that generates on the spot ₃Reduction obtains corresponding amino alcohol, and this compound can be obtained compound 9 by N-protected subsequently.9 oxidation generates aldehyde 10, and it can be converted into imines 11 subsequently under mild conditions.

Route plan 3

The alcohol of amino alcohol 12 is shown in route plan 4.10 epoxidation reaction is opened with ammonia subsequently and is obtained amino alcohol 12.

Route plan 4

Route plan 5 illustrates the preparation of regional isomer amino alcohol 13: the Ellman derivative of aldehyde 10 synthetic, and the Ge Shi addition of vinyl, ozone decomposes and reduction is handled, and removes the Ellman assistant agent subsequently.

Route plan 5

Route plan 6 has been described the preparation of bromoketone 14 processes derived from two azo ketone of acid 2.

Route plan 6

Route plan 7 has been described the preparation of intermediate 15-18, is used to modify different heterocycles.In addition, after heterocycle X has formed (intermediate 15 '-18 '), can stay next complete cl radical so that R is introduced in the back ⁵R ⁶N.Note, if desired, also can form back quilt-(R at heterocycle X by the residual second complete down cl radical ⁷) N-SO ₂R ⁴Substitute.

Route plan 7

Route plan 8-21 has described the preparation of different heterocyclic X.1,3 of 19 types, the synthetic of 4- diazole can dewater with Burgess reagent ring subsequently, and the Boc deprotection be finished (route plan 8) by with acid 15 and 3 couplings of diazanyl acid amides.

Route plan 8

In addition, acyl group-hydrazides can be directly derived from the acid of 15 types so that can be incorporated into subsequently in the  diazole ring by the different aminoacids derivative.Last R ¹Introducing subsequently of group can be carried out (route plan 8A) by the Schiff's base of 45 types.

Route plan 8A

Two kinds possible 1,2, a kind of synthetic shown in route plan 9 in the 4- diazole.Acid 15 and 11 couplings of oxyamide thing, ring dehydration and Boc deprotection obtain  diazole 20 under alkaline condition subsequently.

Route plan 9

The synthetic of 1,2, the 4  diazole that other are possible can be obtained by nitrile 17.Reaction sequence is similar to aforesaid method and obtains  diazole 21 (route plan 10).

Route plan 10

1,2,4-triazoles 22 is described in route plan 11.Nitrile 17 transforms to corresponding inferior amine salt under alkaline condition, obtains required heterocycle with 3 backflows of diazanyl acid amides and Boc deprotection subsequently.

Route plan 11

Imidazoles 24 is according to route plan 12 described preparations.12 with formic acid coupling and oxidation, closed loop obtains imidazoles 23 subsequently.Bromide 16 is converted into corresponding boric acid through the lithium halogen exchange, has palladium mediatedly finished this reaction process with coupling imidazoles 23 and Boc deprotection, obtains compound 24.

Route plan 12

1,2,3-triazoles 26 synthetic as described in the route plan 13.The two azo  intermediates that obtain via aniline 8 form aromatic yl azide, obtain 25 with the cycloaddition of suitable short of electricity alkynes subsequently.The formation of Ellman sulfinyl imines, nucleophilic addition, synthesizing subsequently by chirality assistant agent cracking realization 26.

Route plan 13

Synthesizing shown in route plan 14 of  azole 27, thiazoles 28 and imidazoles 29.Acid 15 reduction is oxidized to aldehyde, epoxidation reaction, and epoxide is opened with ammonia, subsequently the amino alcohol of gained and sour 2 couplings and oxidation is obtained general intermediate ketone group acid amides.The ring dehydration generates 27,28 or 29 under the described conditions.

Route plan 14

The regional isomerism  azoles of second series and thiazoles can be synthetic according to route plan 15 described methods by aromatic bromide 16.Crosslinked, the asymmetric amination of Sharpless and obtain general midbody acid amide-aldehyde with sour 2 couplings.Adopt above-mentioned condition to obtain  azoles 30, thiazole 31, and another obtains the approach of imidazoles 29.

Route plan 15

The another way of route plan 16 expression preparation heterocycle 29-31.Acid 15 is converted into corresponding bromoketone through intermediate two azo ketone.Substitute and cyclisation with carboxylic acid amides 6a, remove Boc subsequently and obtain  azoles 30.Substitute and cyclisation with thiocarboxamide 6b, remove Boc subsequently and obtain thiazole 31.Substitute and cyclisation in the presence of the ammonia source with acid 2, remove Boc subsequently and obtain imidazoles 29.

Route plan 16

Following route plan 17 is described regional isomerism  azole 32, thiazoles 33 and imidazoles 34 synthetic of the 3rd series.Acid 15 and amino alcohol 12 couplings, ring dehydration under proper condition, the Boc deprotection obtains required compound subsequently.

Route plan 17

Synthesizing shown in route plan 18 of the  azole 35 in the 3rd possibility XiLin, thiazoles 36.Amino alcohol 13 obtains general intermediate aldehydes-acid amides with the EDC coupling of acid 15.The ring dehydration obtains required 5-membered heterocycles under proper condition.

Route plan 18

The mode of the another kind of preparation of route plan 19 expressions heterocycle 34-36.Bromoketone 14 usefulness acid 15 substitutes, and cyclisation in the presence of the ammonia source is removed Boc subsequently and obtained imidazoles 34.Substitute and cyclisation with carboxylic acid amides 37, remove Boc subsequently and obtain  azoles 35.Substitute and cyclisation with thiocarboxamide 38, remove Boc subsequently and obtain thiazole 36.

Route plan 19

The different  azole of 40 types can be according to route plan 20 described method preparations.Aromatic bromide 16 obtains 39 with the cross-coupling and the deprotection of TMS acetylene.The cycloaddition of the nitrile oxide derivative made from oxidation 11 on the spot, the Boc deprotection obtains 40 subsequently.

Route plan 20

The second different  azoles regional isomer synthetic can utilize and be similar to route plan 20 described flow processs and finish.Aldehyde 10 can utilize the Corey-Fuchs method to be processed as alkynes 41.The acid reduction, the formation of oxidation and hydroxyl imide salt obtains 42.Generate nitrile oxide and cycloaddition on the spot by 41, remove Boc subsequently and obtain different  azoles 43.

Route plan 21

Route plan 22 has been described the preparation of intermediate 49, is used to prepare the  diazoles compound of 50 types.Carboxylic acid 48 also can be used for preparing the multiple heterocyclic compound of above-mentioned route plan.

Route plan 22

Route plan 23 expressions have the preparation method of the The compounds of this invention of pyrazoles or pyrimidine X group.

Route plan 23

Route plan 24 has been described the preparation of intermediate 54, is used to prepare the  diazoles compound of 55 types.Carboxylic acid 54 also can be used to modify the multiple heterocyclic compound described in the above-mentioned multiple route plan.

Route plan 24

Route plan 25 has been described compound synthetic of 58 types.Be purchased the diazotization and the iodate of 2-chloro-4-amino-6-chloropyridine, obtain Furan Aldehydes 56 by the Suzuki cross-coupling subsequently.The Ge Shi addition obtains intermediate ethanol 57 with rear oxidation and organo-metallic addition subsequently.Above-mentioned R ⁴And R ⁷Introducing, Ritte reaction subsequently, R ⁵And R ⁶Assembling and trinitride reduction obtain 58 compounds of final structure.

Route plan 25

Term " pure substantially " is meant by analytical technology known in the art and measures, and purity is at least 90% and preferred purity 95% and the special more preferably separate substance of purity 99%.

Term " pharmaceutically acceptable salt " is meant the salt that can be accepted nontoxic alkali or acid preparation by pharmacy, comprises inorganic or organic bases and inorganic or organic acid.Compound Ke Yishi one, two of the present invention or three salt depend on the acid functionality's who exists in this compound free alkali number.Free alkali and comprise aluminium by mineral alkali deutero-salt, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salt, inferior manganese, potassium, sodium, zinc etc.Preferred especially ammonium, calcium, magnesium, potassium and sodium salt.May there be more than a kind of crystalline structure in the salt of solid form and can also be the form of hydrate.The salt that can accept organic nontoxic alkali derived from pharmacy comprises primary, the salt of the second month in a season and tertiary amine comprises natural substitutional amine-group, cyclic amine and deacidite, arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl ethylidene-diamines, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, thanomin, ethylene diamine, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, hydrab amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, the purine class, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.When compound of the present invention was alkalescence, salt can be accepted the non-toxic acid preparation by pharmacy, comprises inorganic and organic acid.This type of acid comprises acetate, trifluoroacetic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid is pounced on acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Special optimization citric acid, Hydrogen bromide, hydrochloric acid, trifluoroacetic acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartrate.

The present invention relates to compound disclosed herein as β-short secretase activity or the active inhibitor of β-site amyloid precursor protein-lyase (" BACE ") in for example application in the Mammals of this inhibiting patient of needs or object, comprise the described compound of using significant quantity.Term " β-short Secretases ", " β-site amyloid precursor protein-lyase " and " BACE " can exchange use in this manual.Except the mankind, many other Mammalss can be handled according to method of the present invention.

The invention further relates to and prepare the medicine or the method for compositions that contain The compounds of this invention and pharmaceutical carriers or thinner that is used for suppressing human body and animal β-short secretase activity.

Compound of the present invention has utilizability in the danger of treatment, improvement, control or reduction Alzheimer.For example, described compound can be used to prevent the dementia of Alzheimer type, and be used for the Alzheimer type early stage, mid-term or late period dementia.Described compound can also be used for the treatment of, improves, controls or reduce danger and other illnesss that can pass through inhibition β-short Secretases treatment or divide of the disease that unusual cracking mediated (being also referred to as APP) of amyloid precursor protein.This type of illness comprises mild cognitive damage, Trisomy 21 (mongolism), brain amyloid blood vessel disease, sex change dementia, hereditary cerebral hemorrhage are followed Dutch type amyloidosis (HCHWA-D), Creutzfeld-JakobShi disease, prion disease, amyotrophic lateral sclerosis is benumbed on the carrying out property nuclear, head trauma, apoplexy, mongolism, pancreatitis, embedding gonosome myositis, other periphery amyloid, diabetes and atherosclerosiss.

Object that The compounds of this invention is used or patient generally are the mankind that wherein wish to suppress β-short secretase activity, sex, but also can comprise other Mammalss, dog for example, cat, mouse, rat, ox, horse, sheep, rabbit, monkey, chimpanzee or other apes or primates wherein need to suppress β-short secretase activity or treat above-mentioned disease.

Compound of the present invention can be united with one or more other drugs and is used for disease or the treatment of conditions that The compounds of this invention is suitable for, and the coupling of its Chinese traditional medicine keeps away that it is separately safe in utilization or more effective.In addition, compound of the present invention can or reduce the side effect or the toxic medication combined use of The compounds of this invention with one or more other treatments, prevention, control, improvement.This type of other drug can be by certain approach and with its usual amounts and The compounds of this invention administration simultaneously or sequentially.So pharmaceutical composition of the present invention comprises those that contain one or more other activeconstituentss except that The compounds of this invention.The calcium cooperative programs can be used as the integral part administration of a unit dosage joint product, and perhaps as cover box or treatment plan administration, wherein one or more medications are to separate a part of administration of formulation as treatment plan.

The cooperative programs example of the unit dosage of The compounds of this invention and other drug or cover box-like formula comprises the cooperative programs that contain the Kang Aercihaimoshi medicine, for example other β-short Secretase inhibitors or γ-short Secretase inhibitors; The tau phosphorylation inhibitor; The retarding agent that the A beta oligomers forms; The p25/CDK5 inhibitor; The HMG-CoA reductase inhibitor; The NK1/NK3 receptor antagonist; NSAID class medicine comprises Ibuprofen BP/EP; Vitamin-E; Anti-amyloid antibody; Anti-inflammatory compound, for example (R)-flurbiprofen; CB-1 receptor antagonist or CB-1 receptor inverse agonists; Antibody is doxycycline and Rifampin for example; N-methyl-D-aspartate (NMDA) receptor antagonist, for example Memantine hydrochloride; Anticholinesterase is lycoremine for example, and thunder department replaces bright, solely Buddhist nun's inferior and tacrine; The tethelin succagoga is ibutamoren for example, methylsulfonic acid ibutamoren, and capromorelin; Histamine H ₃Antagonist; The AMPA agonist; PDE IV inhibitor; The GABAA inverse agonist; Neuronal nicotinic sample agonist; P-450 inhibitor, for example ritonavir; Or other raising The compounds of this invention that influence acceptor or enzyme are tired, security, accessibility or reduce adverse side effect or toxic medicine.The above-mentioned catalogue of cooperative programs only is to illustrate and qualification never in any form.

Term used herein " composition " comprises the product of the specific components that contains predetermined amount or ratio, and any product that is directly or indirectly obtained by the cooperative programs of the specific components of specified quantitative.This term relevant with pharmaceutical composition comprised the product of the carrier that contains one or more activeconstituentss and choose wantonly, described carrier comprises inert fraction, and it is any directly or indirectly by the associating of two or more components arbitrarily, compound or assemble the product that obtains, perhaps by other reactions of one or more components or the product that reacts to each other and obtain.Usually, pharmaceutical composition closely makes activeconstituents and liquid vehicle or absorption solid financial group or two kinds combine to prepare by all even, and subsequently, if necessary, is required preparation with this product shaping.Active target compound is enough to exist the process of disease or the amount of situation generation predictive role in pharmaceutical composition.So pharmaceutical composition of the present invention comprises any composition by The compounds of this invention and pharmaceutical acceptable carrier cyclisation are made.

The pharmaceutical composition that orally uses can contain one or more reagent that are selected from sweeting agent, correctives, tinting material and sanitas according to the preparation of the method for pharmaceutical compositions known in the art and this based composition provides pharmaceutically attractive in appearance and good to eat preparation.Tablet contains the activeconstituents mixed mutually with the pharmaceutical acceptable excipient that is fit to the preparation tablet.These vehicle can be for example, inert diluent, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, starch for example, gelatin, polyvinylpyrrolidone or gum arabic, and lubricant, for example, Magnesium Stearate, stearic acid or talcum powder.Tablet is dressing not, and perhaps they can also obtain slow releasing function for more time with its dressing with the disintegration and the absorption of delay in gi tract thus by known technology.

The preparation that orally uses also can be used as hard gelatin capsule and exists, and wherein activeconstituents and inert solid diluent are mixed, and this inert solid diluent for example is lime carbonate, calcium phosphate or kaolin; Or as the soft gelatin capsule existence, wherein this activeconstituents and water or oil medium such as peanut oil, whiteruss or sweet oil are mixed.

The other drug composition comprises aqueous suspension, and it contains and the mixed active substance of vehicle that is fit to the preparation aqueous suspension.In addition, oil-based suspension can for example be prepared in the whiteruss by activeconstituents being suspended in vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois or being suspended in mineral oil.Oil-based suspension can contain different vehicle.Pharmaceutical composition of the present invention can also be an O/w emulsion, and it also can contain vehicle for example sweeting agent and correctives.

This pharmaceutical composition can be the form of sterilization injectable water or oil-based suspension, and it can be prepared according to methods known in the art, perhaps can use with the form of rectal administration suppository.

Compound of the present invention also can be by sucking, utilize suction apparatus administration well known by persons skilled in the art, perhaps by the transdermal patch administration.

So-called " pharmacy can be accepted " be meant carrier, thinner or vehicle must with other component compatibility of preparation and harmless to the recipient.

Term " is used " and " administration " should be understood to be meant compound of the present invention is offered in the individuality that needs treatment being incorporated into the intravital form of individual machine with treatment useful form and treatment significant quantity, includes, but are not limited to oral dosage form, tablet for example, capsule, syrup, suspensoid etc.; Injectable dosage formulations, IV for example, IM, or IP etc.; The transdermal formulation comprises creme, frozen glue, powder or patch; Through buccal dosage form; Suck powder, sprays, suspensoid etc.; And rectal suppository.

Term " significant quantity " or " treatment significant quantity " are meant the active compound that is searched out by researchist, animal doctor, clinician and other clinical positions person of described compound or medicament produces biology or medical response in tissue, system, animal or human's body amount.So used, term " treatment " is meant above-mentioned treatment of conditions, particularly in the patient of the symptom that has been proved disease or illness.

So used, term " treatment " or " processing " is meant and uses compound of the present invention and comprise that (1) suppresses this disease (promptly in experience or performance remove the animal of the pathology of disease or symptom, stop further developing of pathology and/or symptom), or (2) improve disease (that is, reversing this pathology and/or symptom) in experience or performance remove the animal of the pathology of disease or symptom.

Term " control " comprises preventative processing, elimination, improvement or reduces the seriousness of controlled illness.

The composition that contains The compounds of this invention generally exists with unit dosage and can prepare by the method that pharmaceutical field is known.Term " unit dosage " is meant that wherein all active and non-active ingredients are combined into the single formulation of a suitable system, the patient can open a container or packing maybe for this medicament administration patient's people and wherein contains all dosage thus, and does not need any composition in two or more containers or the packing mixed.The representative instance of unit dosage is the tablet or the capsule of oral administration, the single dose bottle of injection, or the suppository of rectal administration.The above-mentioned catalogue of unit dosage limits never in any form, and only is the existing representative instance of unit dosage.

The composition that contains The compounds of this invention can be used as the cover box usually and exists, two or more components thus, it can be activity or inactive component, carrier, thinner etc., offers the patient or gives the people of patient's drug administration with the specification sheets of reagent preparation formulation.This type of cover box can contain and material and the component that is necessary be provided, or they can comprise and using or preparation patient or need the material that can independently obtain or the specification sheets of composition for the people of patient's drug administration.

When pointing out with compounds for treating of the present invention, improvement, control or reducing Alzheimer or other diseases dangerous, can obtain gratifying result when usually The compounds of this invention is with the per daily dose administration of the about 100mg/kg per weight of about 0.1mg-, preferably as single per daily dose administration or with separate doses administration every day 2-6 time, or take the slowly-releasing form.Total per daily dose is the about 2000mg of about 1.0mg-, the about 20mg/kg body weight of preferably about 0.1mg-.In the adult situation of 70kg, total per daily dose generally is that about 7mg-is about 1,400mg.This dosage can be adjusted to produce nearest therapeutic response.Described compound can adopt 1-4 time scheme administration every day, preferred every day 1 or 2 times.

Concrete dosage The compounds of this invention or its pharmaceutically acceptable salt comprises 1mg, 5mg, 10mg, 30mg, 80mg, 100mg, 150mg, 300mg and 500mg.Pharmaceutical composition of the present invention can provide to contain the 0.5mg-1000mg formulations of active ingredients of having an appointment; More preferably contain the 0.5mg-500mg activeconstituents of having an appointment; Or 0.5mg-250mg activeconstituents; Or 1mg-100mg activeconstituents.The certain drug composition that is used for the treatment of can contain the 1mg that has an appointment, 5mg, 10mg, 30mg, 80mg, 100mg, 150mg, the activeconstituents of 300mg and 500mg.

Yet, should understand the concrete dosage level of any particular patient and administration and can change this moment and should depend on multiple factor, comprise the activity of used specific compound, the time length of metabolic stability and compound effects, age, body weight, whole body health, sex, diet, mood and administration time, excretion rate, the therapy medication combined, that the seriousness of particular disorder and host carry out.

The compounds of this invention can confirm by methods known in the art as the practicality of β-short secretase activity inhibitor.Enzyme inhibition is measured as follows.

The ECL analytical method: evenly terminal point electrochemiluminescence (ECL) analysis is adopted biotinylation BACE substrate.The Km of substrate is greater than 100 μ M and owing to the restriction of this unit solubleness can't be measured.Type reaction contains the 0.1nM enzyme of having an appointment, the substrate of 0.25M, and damping fluid (50mM NaOAc, pH4.5,0.1mg/ml BSA, 0.2% CHAPS, 15mM EDTA and 1mM Deferoxamine) and total reaction volume are 100 μ l.Reaction process is 30 minutes, adds the 1M Tris-HCL of 25 μ L subsequently, and pH8.0 ends.Gained enzyme product is analyzed by adding rutheniumization (ruthenylated) antibody, and this antibodies specific is discerned the C-end of this product.Join the magnetic bead of streptavidin coating in this solution and sample carries out M-384 (Igen Inc., Gaithersburg MD) analyze.Under these conditions, handle with BACE 1 less than 10% substrate.Used enzyme dissolves in the human protein in (do not comprise membrane spaning domain and kytoplasm stretch) baculovirus expression system in these researchs.For the inhibition of measuring compound is tired, contain the solution (inhibitor of 12 kind concentration be by 100M begun preparation and carried out three times serial dilutions) of inhibitor in DMSO in the reaction mixture (the DMSO final concentration is 10%).All tests at room temperature utilize above-mentioned standard reaction condition to carry out.For measuring the IC of compound ₅₀, four parameter formula are used for fitting of a curve.The error of reproducing dissociation constant is generally less than 2 times.

The HPLC test: evenly (tonka bean camphor-CO-REVNFEVEFR), its cracking under BACE 1 effect discharges the N-terminal fragment that is connected with tonka bean camphor to terminal point HPLC test employing substrate.The Km of this substrate is greater than 100 μ M and owing to the restriction of this unit solubleness can't be measured.Type reaction contains the 2nM enzyme of having an appointment, and the substrate of 1.0 μ M and damping fluid (50mM NaOAc, pH4.5,0.1mg/ml BSA, 0.2% CHAPS, 15mM EDTA and 1mM deferoxamine) and cumulative volume are 100 μ l.This reaction was carried out 30 minutes and by adding the 1M Tris-HCL of 25 μ L, pH8.0 ends.The gained reaction mixture is carried on the HPLC and product separates with substrate with 5 development linear gradients.Under these conditions, carry out BACE 1 less than 10% substrate.Used enzyme dissolves in the human protein in (do not comprise membrane spaning domain and kytoplasm stretch) baculovirus expression system in these researchs.For the inhibition of measuring compound is tired, contain the solution (inhibitor of 12 kind concentration be by 100M begun preparation and carried out three times serial dilutions) of inhibitor in DMSO in the reaction mixture (the DMSO final concentration is 10%).All tests at room temperature utilize above-mentioned standard reaction condition to carry out.For measuring the IC of compound ₅₀, four parameter formula are used for fitting of a curve.The error of reproducing dissociation constant is generally less than 2 times.

Particularly, the compound of the following example has the activity of inhibition β-short Secretases, the IC that generally has in one or both above-mentioned tests ₅₀Be about 1nM-100 μ M.This type of result is the index of used inhibitor as the intrinsic activity of β-short secretase activity inhibitor.

The Several Methods of preparation The compounds of this invention is in route plan and the embodiment illustrated of this paper.Starting raw material is according to methods known in the art or in this method that exemplifies preparation.Provide the following example to understand the present invention more comprehensively.These embodiment should not limit the present invention for example by any way.

Intermediate compound I: R-N-(tert-butoxycarbonyl)-Alpha-Methyl phenylalanine hydrazi acid amides (route plan 1)

Steps A: Boc protection

To D-Alpha-Methyl phenylalanine (1.00g, 5.58mmol) add in the slurries in 20mL two  alkane 3N NaOH (7.4mL, 22.32mmol) and Boc2O (1.28g, 5.86mmol).Make this reaction carry out 14 hours.Reduce pH by dripping 1N HCl, dilute with water, and water extracts with EtOAc (3x).The organism Na that merges ₂SO ₄Drying is filtered and is concentrated and obtains expecting product, and it is a white foam.This material just need not to be further purified and can use. ¹H?NMR(d ₄-MeOH)δ7.25-7.17(m，3H)，7.12(d，J＝6.6Hz，2H)，3.27(d，J＝13.4Hz，1H)，3.15(d，J＝13.4Hz，1H)，1.45(s，9H)，1.39(s，3H)。LCMS[(M-Boc)+H] ⁺＝180

Step B: the formation of diazanyl acid amides

(1.50g is 5.37mmol) at 25mL CH to the R-N-Boc-of steps A Alpha-Methyl phenylalanine ₃Add in the solution among the CN EDC (1.75g, 9.13mmol), add subsequently hydrazine (0.421mL, 13.43mmol).Generate white precipitate at once, this solution became clarification gradually in 1 hour.Make this reaction at room temperature spend the night, add saturated NaHCO ₃The aqueous solution is ended it, dilutes with EtOAc.Separate each layer, water layer washs with fresh EtOAc (3x).The organic layer Na that merges ₂SO ₄Drying is filtered and is concentrated and obtains white foam, and it need not to be further purified and can use. ¹H?NMR(d ₄-MeOH)δ7.27-7.20(m，3H)，7.11(d，J＝7.7Hz，2H)，3.30(d，J＝13.5Hz，1H)，3.02(d，J＝13.5Hz，1H)，1.46(s，9H)，1.31(s，3H)。LCMS[[(M-Boc)+H] ⁺＝194

Intermediate II: R-N-(tert-butoxycarbonyl)-Alpha-Methyl phenylalanine amides (route plan 2)

(2.04g is 7.30mmol) at 26mL CH to N-Boc-D-Alpha-Methyl phenylalanine ₂Cl ₂In solution in add EDC (1.54g, 8.03mmol), add subsequently HOAt (0.845g, 6.21mmol).After following 30 minutes of the room temperature, adding 15mL DMF, this reaction is cooled to～and 10 ℃, in this reaction, be blown into ammonia 50 minutes.This reaction is by adding saturated NaHCO ₃The aqueous solution is ended and is diluted with EtOAc.Separate each layer, water layer washs with new EtOAc (2x).The organism that merges is used Na with the 3M LiCl aqueous solution and salt water washing ₂SO ₄Drying is filtered and is concentrated.This resistates is by normal-phase chromatography purifying (0-＞6% MeOH/CH ₂Cl ₂) obtain the white solid of required carboxylic acid amides. ¹H?NMR(d ₄-MeOH)δ7.96(br?s，1H)，7.28-7.13(m，3H)，7.12(d，J＝7.4Hz，2H)，6.39(br?s，1H)，5.81(br?s，1H)，3.32(d，J＝13.7Hz，1H)，3.10(d，J＝13.7Hz，1H)，1.44(s，9H)，1.40(s，3H)。LCMS[(M-Boc)+H] ⁺＝179。

Intermediate III: (3R-amino-1-benzyl-2RS-hydroxyl-1-methyl-propyl) t-butyl carbamate (route plan 3,4)

Steps A: reduction

To D-Alpha-Methyl-phenylalanine (1.74g, 9.71mmol) in the solution in 30mL THF in room temperature property adding next time NaBH4 (0.92g 24.27mmol).This solution is cooled to 0 ℃.Drip in 30 minutes the iodine be present among the 5mL THF (2.46g, 9.71mmol).Behind reinforced the finishing, should react reflux 2 days.This reaction is cooled to 0 ℃ and end until stopping bubbling by adding methyl alcohol subsequently.This reaction mixture is acidified to pH1 by adding 6N HCl, stirs 30 minutes down and vacuum concentration at 50 ℃.Utilize ion-exchange chromatogram purification (SCX box) to obtain the white solid of 2R-amino-2-methyl-3-phenyl third-1-alcohol I. ¹H NMR (400MHz, CDCl ₃) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4Hz, 1H), 3.31 (B of AB, d, J=10.4Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H).

Step B:Boc protection

With 2R-amino-2-methyl-3-phenyl third-1-alcohol (4.14g, 25mmol) and tert-Butyl dicarbonate (7.1g, 32.5mmol) solution at room temperature stirred 16 hours, concentrate and to obtain (1-benzyl-2R-hydroxyl-1-methylethyl) t-butyl carbamate), it is a white solid. ¹HNMR (400MHz, CDCl ₃) δ 7.35-7.15 (m, 5H), 4.48 (br s, 1H), 4.17 (br s, 1H), 3.76-3.62 (m, 2H), 3.19 (A of AB, d, J=13.6Hz, 1H), 2.81 (B of AB, d, J=13.6Hz, 1H), 1.47 (s, 9H), 1.07 (s, 3H).

Step C: oxidation

To (1-benzyl-2R-hydroxyl-1-methylethyl) t-butyl carbamate (6.7g, 25.2mmol) add in the solution in DCM (100mL) and DMSO (25mL) triethylamine (10.5mL, 75.7mmol) and sulphur trioxide-pyridine (10g, 63.1mmol).This reaction mixture at room temperature stirred 3.5 hours, with the EtOAc dilution, used 10% KHSO ₄, saturated NaHCO ₃, water, salt solution and LiCl solution washing, use dried over sodium sulfate, vacuum concentration and obtain the white solid of (1-benzyl-1-methyl-2R-oxoethyl) t-butyl carbamate by purification by flash chromatography (silica gel, 0-20% EtOAc/ hexane). ¹H NMR (400MHz, CDCl ₃) δ 9.53 (s, 1H), 7.35-7.22 (m, 3H), 7.12-7.00 (m, 2H), 4.84 (br s, 1H), 3.17 (A of AB, d, J=13.6Hz, 1H), 3.08 (B of AB, d, J=13.6Hz, 1H), 1.51 (s, 9H), 1.27 (s, 3H).

Step D: epoxidation reaction

To N-((1-benzyl-1-methyl-2R-oxoethyl) t-butyl carbamate (and 1g 3.80mmol) adds 6 and drips in the solution in acetonitrile (15mL), trimethyl sulfonium iodide (775mg, 3.80mmol) and potassium hydroxide (511mg, 9.11mmol).This is reflected at 60 ℃ of lower seals stirred 1.5 hours, add additional trimethyl sulfonium iodide (775mg, 3.80mmol) and potassium hydroxide (511mg 9.11mmol) and stirring under should react 60 ℃, seals and reaches 3 hours.Reaction mixture is diluted with EtOAc, use saturated NaHCO ₃The aqueous solution, salt water washing obtain the oil of (1-methyl isophthalic acid-oxyethane-2R-base-2-phenylethyl) t-butyl carbamate with dried over sodium sulfate and vacuum concentration.MS(ES，M+H)278。

Step e: the open loop of epoxide

(986mg is 3.56mmol) at EtOH (35mL) and NH with (1-methyl isophthalic acid-oxyethane-2R-base-2-phenylethyl) t-butyl carbamate ₄Solution among the OH (35mL) stirred 16 hours at 60 ℃ of lower seals, vacuum concentration and by purification by flash chromatography (silica gel, 0-30% (10%NH ₄OH/MeOH)/CH ₂Cl ₂) obtain the viscous crude of (3R-amino-1-benzyl-2RS-hydroxyl-1-methyl-propyl) t-butyl carbamate. ¹H NMR (400MHz, CD ₃OD, 1: 1 non-enantiomer mixture) δ 7.30-7.14 (m, 5H), 4.01 (br d, J=9.2Hz, 0.5H), 3.54 (dd, J=10.0,2Hz, 0.5H), 3.39 (br s, 0.5H), 3.36 (br s, 0.5H), 2.94-2.56 (m, 4H), 1.47 (s, 9H), 1.03 (s, 1.5H), 0.99 (s, 1.5H).

Intermediate compound IV: amino N 2-[(tert-butoxycarbonyl)]-2-methyl-3-pyridin-4-yl propionic acid (route plan 1)

Steps A: the formation of Schiff's base

(10.0g is 71.6mmol) at 100mL CH to the alanine methyl ester hydrochloride ₂Cl ₂In solution in add benzophenone imines (12.0mL, 71.6mmol).Make this reaction at room temperature carry out 15 hours, this solution engenders white precipitate.This reaction H ₂O and CH ₂Cl ₂Dilution separates each layer, and Na is used in the salt water washing of this organic layer ₂SO ₄Drying is filtered and the concentrated viscous oil that obtains N-(phenylbenzene methylene radical) alanine methyl ester, and it need not to be further purified and can use. ¹HNMR(CDCl ₃，400MHz)δ7.62(m，2H)，7.47-7.29(m，7.19-7.16(m，2H)，4.16(q，J＝6.8Hz，1H)，3.7(s，3H，1.40(d，J＝6.8Hz，3H)。

Step B: alkylation

(9.78g 36.6mmol) adds two (trimethyl silyl) ammonification sodium at THF (45.72mL, 45.72mmol) the 1M solution in down and in 20 minutes in 0 ℃ in the solution in 60mL DMF to the N-of steps A (phenylbenzene methylene radical) alanine methyl ester.In 30 minutes, in 20 minutes, add 4-picoline villaumite hydrochlorate (3.00g, 18.29mmol) solution in 40mL DMF through sleeve pipe to this reaction.Make this reaction rise to room temperature and stirred 5 hours.The saturated NH of this reaction ₄The Cl aqueous solution is ended and is extracted with EtOAc (3x).The organic layer that merges is new with 3MLiCl (2x) and salt solution, uses Na ₂SO ₄Drying is filtered vacuum concentration.Obtain 2-[(phenylbenzene methylene radical by silica gel chromatography purifying (0-40% EtOAc/ hexane)) amino]-white solid (5.28g, 81%) of 2-methyl-3-pyridin-4-yl methyl propionate.LCMS[M+H]＝359.2。 ¹HNMR (d ₄-MeOH) δ 8.51 (dd, J=4.5,1.5Hz, 2H), 7.56 (dd, J=8.4,1.4Hz, 2H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.10-7.07 (m, 2H), 3.33 (A of AB, d, J=13.0Hz, 1H), 3.27 (s, 3H), 3.18 (B of AB, d, J=12.9Hz, 1H), 1.32 (s, 3H).

Step C: the removing of Schiff's base

To the 2-[(of step B phenylbenzene methylene radical) amino]-2-methyl-3-pyridin-4-yl methyl propionate (5.28g, 14.73mmol) at 75mL 1: adding 6NHCl in the suspension among the 1MeOH/THF (3.68mL, 22.10mmol).At room temperature stir after 1.5 hours and should react vacuum concentration.Utilize ion-exchange chromatogram purification (SCX box) to obtain 2-amino-2-methyl-3-pyridin-4-yl methyl propionate, it is yellow oil (2.76g, 97%).LCMS[M+H]＝195.3。 ¹H NMR (d ₄-MeOH) δ 8.43 (dd, J=4.6,1.6Hz, 2H), 7.24 (dd, J=4.6,1.5Hz, 2H), 3.70 (s, 3H), 3.09 (A of AB, d, J=12.9Hz, 1H), 2.90 (B of AB, d, J=13.0Hz, 1H), 1.39 (s, 3H).

Step D:Boc protection

To the 2-of step C amino-2-methyl-3-pyridin-4-yl methyl propionate (2.76g, 14.21mmol) in the suspension in 70mL THF in 0 ℃ add down tert-Butyl dicarbonate (4.03g, 18.47mmol).After 30 minutes, this reaction is risen to room temperature and makes it spend the night.This reaction is with the EtOAc dilution and use saturated NH ₄The Cl aqueous solution, water and salt water washing.Organic layer Na ₂SO ₄Drying is filtered and vacuum concentration.At silica gel chromatography (0-60%EtOAc/CH ₂Cl ₂) purifying obtains the 2-[(tert-butoxycarbonyl) amino]-yellow solid (3.22g, 77%) of 2-methyl-3-pyridin-4-yl methyl propionate.LCMS[M+H]＝295.2。 ¹H NMR (400MHz, d4-MeOH) δ 8.43 (d, J=5.1Hz, 2H), 7.21 (d, J=5.9Hz, 2H), 3.73 (s, 3H), 3.44 (A of AB, d, J=13.2Hz, 1H), 3.12 (B of AB, d, J=13.2Hz, 1H), 1.46 (s, 9H), 1.30 (s, 3H).

Step e: saponification

To the 2-[(of step D tert-butoxycarbonyl) amino]-2-methyl-3-pyridin-4-yl methyl propionate (0.25g, 0.85mmol) at 4.25mL 1: adding 3NNaOH in the solution among the 1MeOH/THF (0.43mL, 1.27mmol).This is reflected at carried out under 50 ℃ 1 hour, this moment with its be cooled to room temperature and with 6N HCl (0.21mL, 1.27mmol).To react vacuum concentration and generate the 2-[(tert-butoxycarbonyl) amino]-white solid of 2-methyl-3-pyridin-4-yl propionic acid NaCl.LCMS[M+H]＝281.3。 ¹H NMR (400MHz, d4-MeOH) δ 8.44 (d, J=5.3Hz, 2H), 7.28 (d, J=5.9Hz, 2H), 3.43 (A of AB, d, J=12.6Hz, 1H), 3.33 (B of AB, d, J=12.3Hz, 1H), 1.47 (s, 9H), 1.41 (s, 3H).

Intermediate V:N-(tert-butoxycarbonyl)-2,5-dimethyl remove first leucine (route plan 1)

It is to be prepared according to the described method of preparation intermediate compound IV by iodate Trimethylmethane and L-Ala Schiff's base that N-(tert-butoxycarbonyl)-2,5-dimethyl remove the first leucine.

Intermediate A: N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine

Steps A: coupling

In the 2L flask with trans-nicotinic acid (15.0g, 174mmol), benzylamine (20.5g, 192mmol) and DIPEA (36.7g 192mmol) is dissolved in the 700mL methylene dichloride.Under the room temperature in this solution gradation add solid EDC-HCl (36.7g, 192mmol) and stir and spend the night.Reaction mixture is inclined to 10%KHSO ₄(250mL) aqueous solution.Separate each layer and use 10%KHSO once more ₄The washing 1 this.Organic layer is with H successively ₂Na is used in O (200mL), salt solution (150mL) washing ₂SO ₄Dry and be concentrated into the dried crystallization that obtains white (2E)-N-benzyl but-2-enamides: ¹HNMR (400MHz, CDCl ₃) δ 7.28 (m, 5H), 6.85 (sext, J=6.8Hz, 1H), 5.78 (dd, J=15.2,1.6Hz, 2H), 4.47 (d, J=5.6Hz, 2H), 1.82 (dd, J=7.2,1.6Hz, 3H).

Step B: cyclisation

Containing Et under the room temperature ₂Under vigorous stirring, in 5 minutes, drip in the Erlenmeyer flask of the O (300mL) and the 40% KOH aqueous solution (111mL) 1-methyl-3-nitro-1-nitrosoguanidine (11.1g, 67mmol).Stop stirring and water layer is freezing under-78 ℃ of baths behind reinforced the finishing.The ether layer is decanted among the Erlenmeyer that contains the KOH sheet.Content was placed 5 minutes., curve to the three respectively contain in the flask of KOH sheet and with hypsokinesis to the Et that contains (2E)-N-benzyl but-2-enamides (3.0g, 17.1mmol derive from steps A) ₂On the O/THF solution (200mL/50mL).Add subsequently Pd (OAc) 2 (180mg, 0.9mmol) and make this reaction rise to room temperature and stirred 1 hour.Be blown into nitrogen 10 minutes to this reaction.This miscellany H ₂O (150mL) washing.Separate organic layer and use Na subsequently ₂SO ₄Dry.Remove desolvate and by flash chromatography at SiO ₂(EtOAc/ hexane) purifying obtains N-benzyl-trans-2-methyl cyclopropane carboxylic acid amides (83%): ¹H NMR (400MHz, CDCl ₃) δ 7.28 (m, 5H), 5.81 (br s, 1H), 4.43 (dd, J=5.6,2.4Hz, 2H), 1.37 (m, 1H), 1.17 (m, 1H), 1.07 (d, J=6.0Hz, 3H), 1.04 (overlapping m, 1H), 0.56 (m, 1H).

Randomly be prepared chirality HPLC obtain preferred enantiomer trans-S, S.In following intermediate and embodiment, no matter be preferred enantiomer trans-S, S or trans-S, S and trans-R, the racemic mixture of R need not to identify and can use.In order to simplify, this methyl-cyclopropyl-methyl moiety is plotted as trans-racemize.

Step C: reduction

In the 500mL flask, add the N-benzyl-trans-2-methyl cyclopropane carboxylic acid amides be contained among the THF (80mL) (derive from step B, 3.9g, 20.6mmol).Drip BH through dropping funnel ₃-THF (1.0M, 105mL, 105mmol).Reinforced finishing back (10 minutes.), this miscellany was refluxed 5 hours.Make this miscellany be cooled to room temperature and carefully use MeOH (15mL) to end.This miscellany is concentrated into dried, is dissolved in methylene dichloride and washs with 3M KOH.Separate organic layer, use the salt water washing, use Na subsequently ₂SO ₄Dry and be concentrated into dried.Thick material was handled 1 hour under 50 ℃ in two  alkane with 1N HCl.This miscellany is concentrated the white solid that obtains hydrochloride.This solid is dissolved in saturated NaHCO ₃The aqueous solution (80mL) is also used CHCl ₃(2 * 150mL) extractions.Na is used in the organic layer salt water washing that merges ₂SO ₄Dry and remove through rotary evaporation and to desolvate, obtain the cream-coloured semisolid (quant.) of N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine after the vacuum-drying: ¹H NMR (400MHz, CDCl ₃) δ 7.28 (m, 5H), 3.80 (s, 2H), 2.50 (d, J=6.8Hz, 2H), 2.4 (br s, 1H), 1.02 (d, J=6.0Hz, 3H), 0.69 (m, 1H), 0.52 (m, 1H), 0.23 (m, 2H).

Intermediate B: N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine

In N-benzyl-1-(2-trans-methyl cyclopropyl) solution of methylamine (8g, 45.6mmol, intermediate A) in DCE (240mL) and MeOH (120mL), add formaldehyde (34mL, 456mmol, 37% aqueous) and NaBH (OAc) ₃(19.3g, 91mmol).Reaction mixture was at room temperature stirred 1 hour, use saturated NaHCO ₃The aqueous solution is handled, and concentrates near doing, and dilute with water is also with EtOAc (3x) extraction.Dried over sodium sulfate is used in the organic layer salt water washing that merges, with HCl (50mL, 50mmol, 1M Et ₂O) handle, and vacuum concentration obtains the hydrochloride of N-benzyl-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine, it is at 20%Pd (OH) ₂Hydrogenation 2 hours under 60 ℃ and the 1atm H2 in EtOH (400mL) under the existence of/C (616mg).Filter and vacuum concentration obtains the hydrochloride of N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine. ¹HNMR(400MHz，CD ₃OD)δ2.88(d，J＝7.3Hz，2H)，2.69(s，3H)，1.09(d，J＝5.7Hz，3H)，0.78-0.70(m，2H)，0.52-0.50(m，1H)，0.50-0.40(m，1H)。

Intermediate C:2-{ benzyl [2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] Yi Yansuan (route plan 7)

Steps A: the introducing of sulphonamide

With 2; 6-dichloro-isonicotinic acid methyl esters (5.0g; 24.3mmol), methyl (methyl sulphonyl) amine (3.18g; 29.12mmol), potassiumphosphate (7.22g; 34.0mmol), Xantphos (0.87g; 1.50mmol) and three (dibenzylidene ketone), two palladiums (0.68g, 0.51mmol) join drying, be blown in the flask of argon gas.Add two  alkane (195mL), this solution is reflected at 100 ℃ of following heating 16 hours with argon-degassed and this.This reaction is cooled to room temperature, through diatomite filtration and vacuum-evaporation.Flash chromatography (silica gel, 0-50%EtOAc/CH ₂Cl ₂) obtain 2-chloro-6-[methyl (methyl sulphonyl) amino] iso methyl nicotinate, it is a yellow oil: ¹H NMR (400MHz, CDCl ₃) δ 7.88 (s, 1H), 7.68 (s, 1H), 3.96 (s, 3H), 3.44 (s, 3H), 3.11 (s, 3H).

Step B: hydrolysis

To 2-chloro-6-[methyl (methyl sulphonyl) amino] and iso methyl nicotinate (2g, 7.18mmol) 1: 1THF: adding NaOH in the solution among the MeOH (60mL) (9.3mL, 9.3mmol, 1N).Reaction mixture was at room temperature stirred 0.5 hour, is acidified to pH3-4,, obtain 2-chloro-6-[methyl (methyl sulphonyl) amino with dried over sodium sulfate and vacuum concentration with methylene dichloride (x2) extraction with 1N HCl] white solid of Yi Yansuan. ¹H?NMR(400MHz，CD ₃OD)δ7.88(s，1H)，7.63(s，1H)，3.39(s，3H)，3.13(s，3H)。

Step C: amination

With 2-chloro-6-[methyl (methyl sulphonyl) amino] Yi Yansuan (1.2g; 4.53mmol), intermediate A (1.85g; 10.55mmol), potassiumphosphate (3.18g; 15.1mmol) and two (tri-butyl phosphine) palladium (0.13g, 0.25mmol) suspension in degassing DMA (10mL) is sealed in the Glass tubing and is heated to 130 ℃ and reaches 4 hours.Reaction mixture water and salt solution dilution are acidified to pH3-4 with 1N HCl, with dichloromethane extraction and vacuum concentration.This resistates is dissolved in EtOAc, with LiCl (x3) solution washing, at Na ₂SO ₄Last dry, vacuum concentration and by purification by flash chromatography (silica gel, 2-7% (1% AcOH is in MeOH)/CH ₂Cl ₂) obtain 2-{ benzyl [(2-methyl cyclopropyl) methyl] amino-6-[methyl (methyl sulphonyl) amino] oil of Yi Yansuan. ¹HNMR (400MHz, CDCl ₃) δ 7.35-7.15 (m, 5H), 7.06 (s, 1H), 7.03 (s, 1H), 4.59-4.28 (m, 2H), 3.55 (A of ABX, dd, J=14.8,5.6Hz, 1H), 3.29 (B of ABX, dd, J=14.8,7.2Hz, 1H), 3.28 (s, 3H), 2.87 (s, 3H), 0.97 (d, J=6.4Hz, 3H), 0.84-0.74 (m, 1H), 0.66-0.56 (m, 1H), and 0.40-0.31 (m, 1H), 0.29-0.21 (m, 1H).

Intermediate D:2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] Yi Yansuan (route plan 7)

2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] Yi Yansuan is by 2-chloro-6-[methyl (methyl sulphonyl) amino] Yi Yansuan and N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine utilization is similar to the method preparation described in the step C of intermediate C preparation. ¹HNMR (400MHz, CD ₃OD) δ 7.02 (s, 1H), 6.96 (s, 1H), the 3.55 (A of ABX, dd, J=14.4,6.0Hz, 1H), the 3.29 (B of ABX, dd, J=14.4,7.2Hz, 1H), 3.35 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 1.03 (d, J=6.0Hz, 3H), 0.82-0.66 (m, 2H), 0.48-0.41 (m, 1H), 0.28-0.22 (m, 1H).

Intermediate E: N-(4-(acetyl bromide)-6-{ methyl (2-methyl cyclopropyl) methyl } amino) pyridine-2-yl)-N-methyl Toluidrin (route plan 16)

To intermediate D (250mg, 0.76mmol) being cooled in THF (3mL) drip in-78 ℃ the solution N-methylmorpholine (0.088mL, 0.8mmol) and tetryl formate (0.104mL, 0.8mmol), with ℃ down stirring 0.5 hour of this reaction mixture-78.Reaction mixture filters on diatomite, uses ether rinse.Filtrate and washings are cooled to-20 ℃ and with two azomethanes (3.5mL, Et ₂O solution is by 150mL Et ₂O, the 40mL 40% KOH aqueous solution and 13.2g 1-methyl-3-nitro-1-nitrosoguanidine are made) handle.Stirring is after 1.5 hours down at-20 ℃, and this reaction mixture rises to room temperature, adds 5mL two azomethane solution and this reaction mixture is at room temperature stirred 0.5 hour vacuum concentration (room temperature bath and HOAc are in trap).This resistates is dissolved in Et ₂O and EtOAc, water, salt solution are new, with dried over sodium sulfate and vacuum concentration.This resistates is dissolved in Et ₂O (5mL) is cooled to-20 ℃, handles with 62% HBr (0.25mL), stirs 0.3 hour down at-20 ℃, uses Et ₂The O dilution, water, saturated NaHCO ₃The aqueous solution, salt solution are new, obtain thick N-(4-(acetyl bromide)-6-(methyl [(2-methyl cyclopropyl) methyl] amino) pyridine-2-yl)-N-methyl Toluidrin with dried over sodium sulfate and vacuum concentration, and it is a yellow oil. ¹H NMR (400MHz, CDCl ₃) δ 6.96 (s, 1H), 6.80 (s, 1H), 4.40 (s, 2H), 3.52 (A of ABX, dd, J=14.8,6.4Hz, 1H), 3.36 (B of ABX, dd, J=14.8,6.8Hz, 1H), 3.39 (s, 3H), 3.12 (s, 3H), 3.11 (s, 3H), 1.03 (d, J=6.0Hz, 3H), 0.78-0.62 (m, 2H), and 0.44-0.38 (m, 1H), 0.31-0.26 (m, 1H).

Intermediate F:N-(4-(2-amino-1-hydroxyethyl)-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 14)

Steps A: reduction

(815mg, 2.49mmol) being cooled in THF (10mL) adds BH in 0 ℃ the solution to intermediate D ₃-THF (7.5mL, 7.5mmol, 1M THF) and this reaction mixture at room temperature stirred 2.5 hours carefully ends with MeOH, ends with 1N HCl subsequently, with the EtOAc dilution, with 1N HCl, saturated NaHCO ₃The aqueous solution, salt water washing, use dried over sodium sulfate, vacuum concentration and obtain the viscous crude of N-(4-(hydroxymethyl)-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin by purification by flash chromatography (silica gel, 25-70% EtOAc/ hexane). ¹H NMR (400MHz, CDCl ₃) δ 6.51 (s, 1H), 6.38 (s, 1H), 4.63 (d, J=6.0Hz, 2H), 3.50 (A of ABX, dd, J=14.4,6.4Hz, 1H), 3.33 (s, 3H), 3.31 (B of ABX, dd, J=14.4,6.8Hz, 1H), 3.10 (s, 3H), 3.07 (s, 3H), 1.84 (t, J=6.0Hz, 1H), 1.02 (d, J=5.6Hz, 3H), 0.77-0.60 (m, 2H), and 0.42-0.35 (m, 1H), 0.27-0.21 (m, 1H).

Step B: oxidation

To N-(4-(hydroxymethyl)-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (480mg, 1.53mmol) add in the solution in methylene dichloride (10mL) and DMSO (2.5mL) triethylamine (1.07mL, 7.66mmol) and SO ₃-pyridine (975mg, 6.13mmol).This reaction mixture was at room temperature stirred 0.5 hour, with the EtOAc dilution, with 1N HCl, saturated NaHCO ₃Dried over sodium sulfate is used in the aqueous solution, salt water washing, vacuum concentration and obtain N-(4-formyl radical-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin by purification by flash chromatography (silica gel, 25-50% EtOAc/ hexane). ¹HNMR (400MHz, CDCl ₃) δ 9.94 (s, 1H), 6.92 (s, 1H), 6.72 (s, 1H), 3.53 (A of ABX, dd, J=14.8,6.4Hz, 1H), 3.40 (s, 3H), 3.36 (B of ABX, dd, J=14.8,6.8Hz, 1H), 3.15 (s, 3H), 3.13 (s, 3H), 1.04 (d, J=6.0Hz, 3H), 0.78-0.62 (m, 2H), and 0.45-0.37 (m, 1H), 0.31-0.24 (m, 1H).

Step C: the open loop of epoxidation reaction and epoxide

To N-(4-formyl radical-6-(methyl [(2-methyl cyclopropyl) methyl] amino) pyridine-2-yl)-N-methyl Toluidrin (435mg; 1.40mmol) add 5 in the solution in acetonitrile (5mL) and drip; trimethyl sulfonium iodide (342mg; 1.68mmol) and potassium hydroxide (188mg, 3.35mmol).This is reflected at 65 ℃ of lower seals stirred 3 hours,, use saturated NaHCO with the EtOAc dilution ₃The aqueous solution, salt water washing use dried over sodium sulfate and vacuum concentration to obtain N-methyl-N-(6-{ methyl [(2-methyl cyclopropyl) methyl] amino }-4-oxyethane-2-yl pyridines-2-yl) Toluidrin, are used for the step down.(440mg is 1.35mmol) at EtOH (10mL) and NH for Toluidrin with N-methyl-N (6-{ methyl [(2-methyl cyclopropyl) methyl] amino }-4-oxyethane-2-yl pyridines-2-yl) ₄Solution among the OH (15mL) stirred 16 hours at 60 ℃ of lower seals, vacuum concentration and by purification by flash chromatography (silica gel, 5-15% (10%NH ₄OH/MeOH)/CH ₂Cl ₂) obtain the viscous crude of N-(4-(2-amino-1-hydroxyethyl)-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin. ¹H NMR (400MHz, CD ₃OD) δ 6.52 (s, 1H), 6.47 (s, 1H), the 4.58 (X ' of A ' B ' X ', dd, J=7.6,4.0Hz, 2H), the 3.54 (A of ABX, dd, J=14.4,6.4Hz, 1H), the 3.35 (B of ABX, dd, J=14.4,6.8Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 3.08 (s, 3H), 3.86 (A ' of A ' B ' X ', dd, J=13.2,4.0Hz, 1H), 2.76 (B ' of A ' B ' X ', dd, J=13.2,7.6Hz, 1H), 1.02 (d, J=6.0Hz, 3H), 0.80-0.65 (m, 2H), 0.46-0.39 (m, 1H), 0.25-0.18 (m, 1H).

Intermediate G:N-(tert-butoxycarbonyl)-N-(2-oxo-2-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-{ methyl (methyl sulphonyl) amino] pyridin-4-yl }-α-D-aminomethyl phenyl alanimamides (route plan 14)

Steps A: coupling

With intermediate F (330mg, 096mmol), N-Boc-D-Alpha-Methyl phenylalanine (323mg, 1.16mmol), EDC (240mg, 1.25mmol), HOAt (157mg, 1.16mmol) and diisopropylethylamine (0.34mL, 1.93mmol) solution in DMF (9mL) at room temperature stirred 16 hours.Reaction mixture dilutes with EtOAc; water and salt water washing; use dried over sodium sulfate; vacuum concentration and by purification by flash chromatography (silica gel; 30-65% EtOAc/ hexane) obtain N-(tert-butoxycarbonyl)-N-(2-hydroxyl-2-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl) ethyl)-the light yellow foam of D-Alpha-Methyl phenyl alanimamides, it directly carries out oxidation step.

Step B: oxidation

To N-(tert-butoxycarbonyl)-N-(2-hydroxyl-2-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] the pyridin-4-yl ethyl)-D-Alpha-Methyl phenyl alanimamides (458mg; 0.76mmol) add triethylamine (0.53mL in the solution in DCM (6mL) and DMSO (1.5mL); 3.79mmol) and sulphur trioxide-pyridine (483mg, 3.03mmol).Reaction mixture at room temperature stirred 1.5 hours, with the EtOAc dilution, used 10% KHSO ₄, saturated NaHCO ₃With the salt water washing, use dried over sodium sulfate, vacuum concentration and obtain N-(tert-butoxycarbonyl)-N-(2-oxo-2-{2-{ methyl [(2-5 by purification by flash chromatography (silica gel, 0-50% EtOAc/ hexane)

The methyl cyclopropyl) methyl] amino-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl } ethyl)-orange oil of D-Alpha-Methyl phenyl alanimamides. ¹H NMR (400MHz, CDCl ₃) δ 7.38-7.10 (m, 5H), 6.91 (s, 1H), 6.75 (s, 1H), 4.82 (br s, 1H), 4.78-4.62 (m, 2H), 3.53 (A of ABX, dd, J=14.7,6.7Hz, 1H), 3.43 (A of AB, d, J=14.4Hz, 1H), 3.38 (s, 3H), 3.36 (B of ABX, dd, J=14.7,6.6Hz, 1H), 3.16 (s, 3H), 3.15 (B of AB, d, J=14.4Hz, 1H), 3.13 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H), 1.04 (d, J=6.0Hz, 3H), 0.80-0.62 (m, 2H), 0.46-0.38 (m, 1H), 0.31-0.24 (m, 1H).

Intermediate H:[1R-benzyl-1-methyl-3-(the 2-{ methyl [(2-methyl cyclopropyl) methylamino }-6-[methyl (methyl sulphonyl) amino] different nicotinoyl amino)-the 2-oxopropyl] t-butyl carbamate (route plan 17)

[1R-benzyl-1-methyl-3-; ({ 2-; (methyl [; (2-methyl cyclopropyl) methyl] amino }-the 6-[methyl; (methyl sulphonyl) amino] different nicotinoyl amino)-the 2-oxopropyl] t-butyl carbamate is by intermediate III and intermediate D) coupling and utilize tert-butoxycarbonyl subsequently with preparation N-)-N-; (2-oxo-2-{2-{ methyl [; (2-methyl cyclopropyl) methyl] amino }-the 6-[methyl; (methyl sulphonyl) amino] pyridin-4-yl) ethyl)-D-Alpha-Methyl phenyl alanimamides; the hydroxyl oxidize method that (intermediate G) is identical. ¹H NMR (400MHz, CDCl ₃) δ 7.36-7.22 (m, 3H), 7.13-7.08 (m, 2H), 6.88 (br s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.74 (br s, 1H), 4.68-4.58 (m, 1H), 4.44-4.34 (m, 1H), 3.53 (A of ABX, dd, J=14.0,6.0Hz, 1H), 3.38 (s, 3H), 3.40-3.30 (A of AB and the B of ABX, m, 2H), 3.14 (s, 3H), 3.11 (s, 3H), 3.05 (B of AB, d, J=13.6Hz, 1H), 1.49 (s, 9H), 1.32 (s, 3H), 1.04 (d, J=6.0Hz, 3H), 0.78-0.62 (m, 2H), 0.44-0.36 (m, 1H), 0.29-0.22 (m, 1H).

Intermediate J:2-{ methyl [(2-methyl cyclopropyl) methyl l amino]-6-[methyl (methyl sulphonyl) amino] pyridine-4-carboxylic imidic acid ethyl ester (route plan 7,11)

Steps A: the preparation of nitrile (route plan 7)

With intermediate D (250mg, 0.76mmol), ammonium chloride (204mg, 3.82mmol), EDC (176mg, 0.92mmol), HOAt (104mg, 0.76mmol) and diisopropylethylamine (0.67mL, 3.82mmol) suspension in DMF (10mL) at room temperature stirred 16 hours.Reaction mixture dilutes with EtOAc, water, 10%KHSO ₄, saturated NaHCO ₃The aqueous solution, LiCl solution washing are with dried over sodium sulfate and vacuum concentration.This resistates is dissolved in THF (5mL), with Burgess reagent (219mg, 0.92mmol) handle and 80 ℃ of following microwaves (Smith synthesizer) irradiation 5 minutes, vacuum concentration and obtain N-(4-cyano group-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin by purification by flash chromatography (silica gel, 0-30% EtOAc/ hexane). ¹H NMR (400MHz, CDCl ₃) δ 6.73 (s, 1H), 6.48 (s, 1H), the 3.47 (A of ABX, dd, J=14.8,6.4Hz, 1H), 3.37 (s, 3H), 3.33 (B of ABX, dd, J=14.8,6.8Hz, 1H), 3.13 (s, 3H), 3.09 (s, 3H), 1.04 (d, J=5.6Hz, 3H), 0.78-0.62 (m, 2H), 0.45-0.37 (m, 1H), 0.32-0.25 (m, 1H).

Step B: the preparation of inferior amine salt

(180mg, 0.58mmol) being cooled in EtOH (10mL) is blown into HCL (g) in 0 ℃ the solution and reaches 10 minutes to N-(4-cyano group-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin.With the reaction mixture sealing, rise to room temperature and stirring 3 hours.Nitrogen is blown into this reaction mixture 10 minutes and with this reaction mixture vacuum concentration.Obtain 2-{ methyl [(2-methyl cyclopropyl) methyl] amino with ether development }-6-[methyl (methyl sulphonyl) amino] hydrochloride and the glassy yellow solid of pyridine-4-azomethine acetoacetic ester. ¹H NMR (400MHz, CD ₃OD) δ 6.96 (s, 1H), 6.88 (s, 1H), 4.63 (q, J=7.2Hz, 2H), 3.60 (A of ABX, dd, J=14.8,6.4Hz, 1H), 3.44 (B of ABX, dd, J=14.8,6.8Hz, 1H), 3.38 (s, 3H), 3.18 (s, 3H), 3.16 (s, 3H), 1.61 (t, J=7.2Hz, 3H), 1.03 (d, J=6.0Hz, 3H), 0.84-0.68 (m, 2H), and 0.50-0.43 (m, 1H), 0.29-0.23 (m, 1H).

Intermediate K:(2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amine

Steps A: coupling

In the 500-mL flask with difluoroacetic acid (0.78g, 8.2mmol), N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine (1.3g, 7.42mmol) and DIPEA (4.2g 32.6mmol) is dissolved in the methylene dichloride of 100mL.Gradation at room temperature adds BOP (3.3g, solid 7.42mmol) and stirring 1 hour in this solution.Should react vacuum concentration and pass through the acid amides that flash column chromatography purifying (silica gel, 0-10% ethyl acetate/hexane) obtains 1.45g (77%), it is a clarified oil: ¹HNMR (400MHz, CDCl ₃) δ 7.31 (m, 5H), 6.19 (td, J=51,20Hz, 1H), 4.75 (m, 2H), 3.24 (m, 2H), 0.99 (t, J=5.5Hz, 3H), 0.62 (m, 2H), 0.31 (m, 2H); LCMS[M+H] ⁺=254.1.

Step B: reduction

In round-bottomed flask with N-benzyl-2,2-two fluoro-N-{[-2-methyl cyclopropyl methyl]-methyl (1.45g 5.7mmol) is dissolved in the anhydrous THF of 75mL to ethanamide.In this solution, add BH ₃-THF (18.9mmol, the 1M THF solution of 18.9mL).Should react according to reflux exchanger and reflux 16 hours.Make this reaction be cooled to 0 ℃ and by adding methyl alcohol, adding dense HCl (5mL) subsequently and end.The gained mixture at room temperature stirred 16 hours.With crude mixture vacuum concentration and between 10% NaOH/ ethyl acetate, distributing subsequently.The organism dried over sodium sulfate is filtered and vacuum-evaporation.Flash column chromatography purifying (silica gel, 0-10% ethyl acetate/hexane) obtains the amine of 1.25g (91%), and it is a clarified oil: ¹H NMR (400MHz, CDCl ₃) δ 7.31 (m, 5H), 5.75 (tt, 56.5,4.5Hz, 1H), 3.78 (d, J=13.7Hz, 1H), 3.73 (d, J=13.7Hz, 1H), 2.92 (td, J=15,3.8Hz, 2H), 2.56 (dd, J=13.2,6.0Hz, 1H), 2.37 (dd, J=13.2Hz, 7.0Hz, 1H), 1.03 (d, J=6.0Hz, 3H), 0.54 (m, 2H), 0.25 (t, J=6.2Hz, 2H); LCMS[M+H] ⁺=240.2.

Step C: hydrogenation

With N-benzyl-2,2-two fluoro-N-[(2-methyl cyclopropyl) methyl] ethamine (1.25g, 5.2mmol) and the solution of hydrochloric acid (5.7mmol, the 4M two  alkane solution of 1.44mL) in ethanol (50mL) handle with the nitrogen degassing and with palladium hydroxide (125mg).This reaction placed under the nitrogen atmosphere and vigorous stirring 1 hour.This reaction obtains the light yellow oil of (2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amine through diatomite filtration with methanol wash and vacuum concentration: ¹H NMR (400MHz, CD ₃OD) δ 6.35 (tt, 48,3Hz, 1H), 3.56 (td, J=15.6,3.1Hz, 2H), 3.03 (m, 2H), 1.11 (d, J=5.9Hz, 3H), 0.83 (m, 2H), 0.60 (m, 1H), 0.50 (m, 1H).

Intermediate L:N, N-dimethyl-N-[(2-methyl cyclopropyl) methyl] the third-1, the 3-diamines

Steps A: coupling

The 100-mL flask with vinylformic acid (0.17g, 2.4mmol), N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine (0.5g, 2.4mmol) and DIPEA (0.64g 4.9mmol) is dissolved in the 20mL methylene dichloride.(0.68g, solid 3.5mmol) also stirred 15 hours at room temperature to drip EDC in this solution.Making this be reflected between 1M HCl and the methylene dichloride distributes.The organism dried over sodium sulfate is filtered, vacuum concentration and the crude product that carries out the next step.

Step B:Michael addition

In the 50-mL flask, acrylamide (crude product of steps A) is handled with dimethyl amine (4.5mmol, the 2M methanol solution of 2.2mL) at methyl alcohol (10mL).Should react and at room temperature stir 1 hour, subsequently vacuum concentration.This resistates obtains the 0.47g N in (75% liang of step) by flash column chromatography purifying (2.5-15%MeOH/ methylene dichloride) ¹-benzyl-N ³, N ³-dimethyl-N ¹The clarified oil of-[(2-methyl cyclopropyl)-methyl]-β-alanimamides: ¹H NMR (400MHz, CDCl ₃) δ 7.24 (m, 5H), 4.68 (m, 2H), 3.21 (m, 2H), 2.67 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 0.97 (m, 3H), 0.58 (m, 2H), 0.29m, 2H).LCMS[M+H] ⁺＝275.4。

Step C: reduction

At round-bottomed flask with N ¹-benzyl-N ³, N ³-dimethyl-N ¹-(0.47mg 1.7mmol) is dissolved among the anhydrous THF of 10mL [(2-methyl cyclopropyl)-methyl]-β-alanimamides.Add BH to this solution ₃-THF (5.1mmol, the 1M THF solution of 5.1mL).This reaction was installed back flow condenser and reflux 16 hours.Make this reaction be cooled to 0 ℃ and with methyl alcohol, use dense HCl (5mL) to end subsequently.The gained mixture heating up was refluxed 16 hours.With crude mixture vacuum concentration and between 10% NaOH/ ethyl acetate, distributing after this.This organism dried over sodium sulfate is filtered and vacuum-evaporation.Obtain the N of 0.42g (49%) by the reverse-phase chromatography purifying ¹-benzyl-N ³, N ³-dimethyl-N ¹-[(2-methyl cyclopropyl)-methyl] the third-1, the clarified oil of 3-two ammoniums two (trifluoroacetate): LCMS[M+H] ⁺=261.5.

Step D: hydrogenation

With N ¹-benzyl-N ³, N ³-dimethyl-N ¹-[(2-methyl cyclopropyl)-methyl] the third-1,3-two ammoniums two (trifluoroacetate) (0.42g, 0.86mmol) handle with the nitrogen degassing with palladium hydroxide (75mg) by the solution in ethanol (50mL).This reaction placed under the nitrogen atmosphere and vigorous stirring 1 hour.This reaction obtains N with methanol wash and vacuum concentration, N-dimethyl-N-[(2-methyl cyclopropyl through diatomite filtration) methyl] the third-1, the light yellow oil of 3-two ammoniums two (trifluoroacetate).

Intermediate M:(2-fluoro ethyl) [(2-methyl cyclopropyl) methyl] amine

Be similar to the described method preparation of intermediate K by gifblaar poison, utilization. ¹HNMR(400MHz，CDCl ₃)δ9.79(bs，1H)，4.98(bd，J＝46.3，2H)，3.42(m，2H)，3.03(bs，2H)，1.12(bs，3H)，1.01(bs，1H)，0.87(bs，1H)，0.66(bs，1H)，0.50(bs，1H)。

Intermediate N:(2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine

Be similar to the described method preparation of intermediate K by the methoxyacetic acid utilization. ¹HNMR(400MHz，CDCl ₃)δ7.98(bs，1H)，3.64(bs，2H)，3.38(bs，3H)，3.27(bs，2H)，3.00(bs，2H)，1.06(d，J＝5.3Hz，3H)，0.79(bs，2H)，0.51(m，2H)。

Intermediate O:N, N-dimethyl-N-[(2-methyl cyclopropyl) methyl] second-1, the 2-diamines

By N, the N-N-methylsarcosine adopts and is similar to the described method preparation of intermediate K. ¹HNMR(400MHz，CD ₃OD)δ3.49(m，4H)，2.98(m，2H)，2.96(s，6H)，1.09(d，J＝5.8Hz，3H)，0.83(m，2H)，0.61(m，1H)，0.49(m，1H)。

Intermediate P:{ (1S)-[(1S, 2S)-2-methyl cyclopropyl] ethyl } amine

Steps A. (2E)-1,1-diethoxy but-2-ene

With crotonaldehyde (23.64mL, 285.35mmol), triethyl orthoformate (57.02mL, 342.42mmol) and ammonium nitrate (2.28g 28.54mmol) mixes in 60mL EtOH.After following 22 hours of the room temperature, should react with EtOAc dilution (60mL) and with saturated sodium bicarbonate solution (40mL) and wash.Water layer is used EtOAc (20mL) extraction once more.The organism that merges is used Na with salt water washing (40mL) ₂SO ₄Drying is filtered and vacuum concentration obtains 1 of 36.5g (89%), 1-diethoxy but-2-ene. ¹H?NMR(CDCl ₃，400MHz)5.84(m，1H)；5.54(m，1H)；4.82(d，J＝5.7Hz，1H)；3.64(m，2H)；3.49(m，2H)；1.73(m，3H)；1.21(m，6H)。

Step B. (4S, 5S)-2-[(lE)-third-1-thiazolinyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester

With (2E)-1,1-diethoxy but-2-ene (32.20g, 223.27mmol), D-tartrate (-)-diisopropyl ester (64.64mL, 245.60mmol) and toluenesulphonic acids pyridine  (2.24g, 8.93mmol) solution in the 100mL phenyl ester is heated to 95 ℃, distillation removes desolvates and generates EtOH.95 ℃ after following 7 hours, this reaction is cooled to room temperature and vacuum concentration.By normal-phase chromatography purifying (10-＞30% EtOAc/ hexane) obtain 35.37g (55%) (4S, 5S)-2-[(1E)-third-1-thiazolinyl]-1,3-dioxolane-4, the orange oil of 5-dicarboxylic acid diisopropyl ester. ¹H?NMR(CDCl ₃，400MHz)6.03(m，1H)；5.86(m，2H)；5.12(m，2H)；4.71(d，J＝3.84Hz，1H)；4.63(d，J＝3.84Hz，1H)；1.78(m，3H)；1.30(d，J＝6.23Hz，12H)；LC/MS[M+H] ⁺＝287。

Step C. (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester

To intermediate (4S, 5S)-2-[(1E)-third-1-thiazolinyl]-1,3-dioxolane-4, the 5-diisopropyl ester (4.10g, 14.32mmol) add in 20 ℃ of solution in the 60mL hexane 1M be present in zinc ethyl in the hexane (42.96mL, 42.96mmol).Drip methylene iodide (6.92mL, 85.92mmol) and vigorous stirring.-20 ℃ after following 1 hour, this is reflected at-5 ℃ freezing down.-5 ℃ after following 17 hours, this is reflected at 0 ℃ continues down to stir 5 hours and used cold saturated ammonium chloride solution (100mL) to end and use Et subsequently ₂O (100mL * 3) extraction.The organism that merges filters with sodium thiosulfate solution (100mL) and salt solution (100mL) washing, uses Na ₂SO ₄Drying is filtered and vacuum concentration once more.By normal-phase chromatography purifying (10-＞30%EtOAc/ hexane) obtain 3.85g (89%) (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester, it is a yellow oil. ¹H?NMR(CDCl ₃，400MHz)5.12(m，2H)；4.78(d，J＝6.41Hz，1H)；4.66(d，J＝4.21Hz，1H)；4.57(d，J＝4.22Hz，1H)；1.30(m，12H)；1.09(d，J＝5.68Hz，3H)；0.94(m，2H)；0.67(m，1H)；0.39(m，1H)；LC/MS[M+H] ⁺＝301。

Step D.2-methyl-N-{ (1E)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical) third-2-sulfenimide

To (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl l-1,3-dioxolane-4, (0.450g is 1.50mmol) at 5mL CH for 5-dicarboxylic acid diisopropyl ester ₂Cl ₂/ 200 μ L H ₂Adding tosic acid in the solution among the O (0.071g, 0.38mmol).This is reflected at 50 ℃ of following reflux., 50 ℃ after following 16 hours, this reaction is cooled to room temperature.Remove the water droplet that generates at this reaction top.Add cuprous sulfate (II) (0.507g, 2.85mmol) and R-(+)-tertiary butyl thionyl amines (0.173g, 1.43mmol).After following 5.5 hours of the room temperature, this reaction is filtered through Celite pad.This diatomite CH ₂Cl ₂(200mL) washing and this filtrate vacuum concentration.By normal-phase chromatography purifying (0-＞50%EtOAc/ hexane) generate 2-methyl-N-{ (1E) of 0.245g (92%)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical) the colourless resistates of clarification of third-2-thionyl amines. ¹H?NMR(CDCl ₃，400MHz)7.46(d，J＝7.69Hz，1H)；1.62(m，1H)；1.25(m，2H)；1.10(m，12H)；0.82(m，1H)；LC/MS[M+H] ⁺＝188。

Step e .2-methyl-N-{ (1S)-1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } third-2-thionyl amines

To 2-methyl-N-{ (1E)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical (0.300g is 1.60mmol) at 5mL CH for third-2-thionyl amines ₂Cl ₂In-78 ℃ of solution in add 3M and be present in Et ₂Methyl-magnesium-bromide among the O (1.07mL, 3.20mmol).-78 ℃ after 2 hours, this reaction rises to room temperature.After following 1 hour of the room temperature, this reaction is ended with saturated ammonium chloride solution (15mL) and is extracted with EtOAc (30mL * 2).The organism that merges is used Na with salt water washing (15mL) ₂SO ₄Drying is filtered and vacuum concentration.Generate methyl-N-{ (1S)-1-[(1S of 0.224g (69%) by normal-phase chromatography purifying (0-＞80% EtOAc/ hexane), 2S)-2-methyl cyclopropyl] ethyl } the colourless resistates of clarification of third-2-thionyl amines. ¹H?NMR(CDCl ₃，400MHz)2.77(m，1H)；1.31(d，J＝6.50Hz，3H)；1.21(s，9H)；1.03(d，J＝5.77Hz，3H)；0.54(m，3H)；0.30(m，1H)；LC/MS[M+H] ⁺＝204。

Step F. (1S)-1-[(1S, 2S)-2-methyl cyclopropyl] the ethane chlorination ammonium

To 2-methyl-N-{ (1S)-1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } (0.210g 1.03mmol) adds 2M and is contained in Et third-2-thionyl amines in 0 ℃ of solution in 4mL MeOH ₂HCl among the O (0.52mL, 1.03mmol).This is reflected at 0 ℃ stirred 18 hours down and vacuum concentration subsequently.The gained material is dissolved in Et ₂O (4mL) and vacuum concentration obtain (1S)-1-[(1S 2 times, 2S)-2-methyl cyclopropyl] white solid of ethane chlorination ammonium. ¹H?NMR(CDCl ₃，400MHz)2.60(m，1H)；1.37(d，J＝6.59Hz，3H)；1.08(d，J＝6.04Hz，3H)；0.77(m，1H)；0.64(m，2H)；0.42(m，1H)；LC/MS[M+H] ⁺＝100。

Intermediate Q:{ (1R)-1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } amine

S-(+)-uncle's butane thionyl imide that adopts the described method of intermediate P and improve among the step D prepares.LC/MS[M+H] ⁺＝100。

Intermediate R:{ (1S)-1-[(1S, 2S)-2-methyl cyclopropyl] propyl group } amine

Adopt the described scheme of intermediate P, and improve the used ethylmagnesium bromide of step e.LC/MS[M+H] ⁺＝114。

Intermediate S:(1S)-2-methyl isophthalic acid-((1S, 25)-2-methyl cyclopropyl) third-1-amine

By the described scheme of intermediate P, and the used sec.-propyl bromination magnesium of improvement step e prepares.LC/MS[M+H] ⁺＝128。

The intermediate T:(2-tertiary butyl (dimethyl) silyl) oxygen base } (2-methyl cyclopropyl)-methyl] amine

Be similar to the described method preparation of intermediate B by (tertiary butyl (dimethyl) siloxy-) ethamine, utilization. ¹H?NMR(400MHz，CD ₃OD)δ3.74(t，J＝5.3Hz，2H)，2.76(m，2H)，2.52(m，2H)，1.04(d，J＝6.0Hz，3H)，0.90(s，9H)，0.68(m，1H)，0.55(m，1H)，0.29(m，1H)，0.24(m，1H)，0.07(s，6H)。

Intermediate a:2-{ (2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amino)-and 6-[methyl (methyl sulphonyl) amino] Yi Yansuan

Be similar to the described method preparation of intermediate C by intermediate K utilization.LCMS[M+H] ⁺＝378.3。

Intermediate b:2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] Yi Yansuan

Be similar to the described method preparation of intermediate C by intermediate N utilization.LCMS[M+H] ⁺＝372.3。

Intermediate c:2-{ (2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] Yi Yansuan

Be similar to the described method preparation of intermediate C by intermediate K and (sec.-propyl alkylsulfonyl) methylamine utilization. ¹H?NMR(400MHz，CDCl ₃)δ7.09(s，1H)，7.01(s，1H)，6.08(td，J＝56.4，4.2Hz，1H)，3.93(m，2H)，3.46(m，1H)，3.44(s，3H)，3.32(dd，J＝15.0，6.6Hz，1H)，1.41(d，J＝6.8Hz，6H)，1.06(d，J＝5.7Hz，3H)，0.74(m，2H)，0.45(m，1H)，0.35(m，1H)。LCMS[M+H] ⁺＝406.5。

Intermediate d:2-{ (2-fluoro ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] Yi Yansuan

Be similar to the method preparation of intermediate C by intermediate M and (sec.-propyl alkylsulfonyl) methylamine utilization.LCMS[M+H] ⁺＝388.0。

Intermediate: (methyl) amino 2-[(sec.-propyl alkylsulfonyl)]-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino) Yi Yansuan

Be similar to the described method preparation of intermediate C by intermediate N and (sec.-propyl alkylsulfonyl) methylamine utilization. ¹H?NMR(400MHz，CDCl ₃)δ7.01(s，1H)，6.98(s，1H)，3.99(m，1H)，3.75(m，1H)，3.59(m，1H)，3.47(m，1H)，3.44(s，3H)，3.36(s，3H)，3.34(m，1H)，1.40(d，J＝3.3Hz，6H)，1.05(d，J＝5.8Hz，3H)，0.74(m，2H)，0.43(m，1H)，0.29(m，1H)。LCMS[M+H] ⁺＝400.5。

Intermediate f:2-{[2-(dimethylamino) ethyl] [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] Yi Yansuan

Being similar to the described mode of intermediate C by intermediate O and (sec.-propyl alkylsulfonyl) methylamine utilization prepares. ¹H?NMR(400MHz，CDCl ₃)δ6.95(s，1H)，6.85(s，1H)，4.00(m，2H)，3.88(m，1H)，3.44(m，2H)，3.43(s，3H)，3.34(d，J＝5.9Hz，2H)，2.95(bs，6H)，1.38(d，J＝7.0Hz，6H)，1.03(d，J＝5.7Hz，3H)，0.70(m，2H)，0.45(m，1H)，0.31(m，1H)。LCMS[M+H] ⁺＝413.3。

Intermediate g:2-{[3-(dimethylamino) propyl group] [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] Yi Yansuan

Be similar to the described method preparation of preparation intermediate C by intermediate L and (sec.-propyl alkylsulfonyl) methylamine utilization.LCMS[M+H] ⁺＝427.4。

Intermediate h:[1-(5-{2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1,3,4- diazole-2-yl)-1R-methyl-2-phenylethyl] t-butyl carbamate (route plan 8)

Steps A. coupling

To 2-chloro-6-[methyl (methyl sulphonyl) amino) Yi Yansuan (0.200g, 0.76mmol) add in the solution in 3mL DMF triethylamine (0.13mL, 0.91mmol); intermediate compound I (0.222g, 0.76mmol), HOAt (0.123g; 0.91mmol) and EDC (0.174g, 0.91mmol).After following 17 hours of the room temperature, this reaction with saturated sodium bicarbonate solution (30mL) and salt solution (30mL) washing, is used Na with EtOAc dilution (60mL) ₂SO ₄Drying is filtered and vacuum concentration.Obtain the colourless resistates of clarification of the acyl group hydrazides of 0.544g (99%) by normal-phase chromatography purifying (20-＞80% EtOAc/ hexane).NMR(CDCl ₃，400MHz)7.71(s，1H)；7.53(s，1H)；7.29(m，3H)；7.15(d，J＝6.59Hz，2H)；3.50(d，J＝13.55Hz，1H)；3.42(s，3H)；3.11(s，3H)；3.05(d，J＝13.73Hz，1H)；1.47(s，9H)；1.43(s，3H)；LC/MS[M-C4H7]+＝484。

Step B. cyclodehydration

To the acyl group hydrazides of steps A (0.550g, 1.02mmol) add in the solution in 5mL DCE Burgess reagent (0.971g, 4.07mmol).This be reflected at 120 ℃ of microwave treatment 10 minutes and directly by normal-phase chromatography purifying (0-＞50% EtOAc/ hexane) obtain (1R)-1-(5-{2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl t-butyl carbamate, it is a white foam.NMR(CDCl ₃，400MHz)7.89(s，1H)；7.72(s，1H)；7.29(m，3H)；7.08(m，2H)；3.60(d，J＝13.55Hz，1H)；3.46(s，3H)；3.38(d，J＝13.55Hz，1H)；3.15(s，3H)；3.15(s，3H)；1.70(s，3H)；1.42(s，9H)；[M+H] ⁺＝522。

Intermediate i.{1-[5-(2-chloro-6-{ methyl (2-methyl cyclopropyl) methyl } base of aminopyridine-4-))-1,3,4- diazole-2-yl]-1R-methyl-2-phenylethyl } t-butyl carbamate

Steps A: nucleophilicity amination

With 2, the 6-dichloro-isonicotinic acid (0.25g, 1.3mmol), methyl-[(methyl cyclopropyl) methyl] salt acid amide (0.53g, 3.9mmol) and cesium carbonate (1.25g, 6.5mmol) in the solution in 5mL DMF in 120 ℃ of lower seal pipes the heating 72 hours.This is reflected between 1M HCl and the ethyl acetate and distributes.Dried over sodium sulfate is used in this organism water (4x), salt water washing, filters and vacuum-evaporation obtains thick 2-chloro-6-{ methyl [(the 2-methyl cyclopropyl) methyl] amino of 0.3g (90%) } the nucleic acid oil of Yi Yansuan: LCMS (M+H)=255.0.

Step B: coupling

2-chloro-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } Yi Yansuan (0.33g, 1.3mmol), N-(tert-butoxycarbonyl)-D-Alpha-Methyl phenylalanine hydrazi acid amides (alaninhydrazamid) (0.38g, 1.3mmol) and diisopropylethylamine (0.17g, 1.3mmol) (0.57g 1.3mmol) handles with BOP for solution in the 10mL methylene dichloride.Stir under the room temperature should react after 1 hour with additional hydrazi acid amides (0.19g, 0.65mmol) and BOP (0.29g, 0.65mmol).After 1 hour, this reaction vacuum-evaporation and obtain { 1-benzyl-2-oxo-2-[2-(2-chloro-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } different nicotinoyl of 0.224g (33%) by anti-phase LC purifying) diazanyl]-the 1R-methylethyl orange solids of the amino acid tert-butyl ester: LCMS (M+H)=530.3.

Step C: cyclodehydration

With the different nicotinoyl of 1-benzyl-2-oxo-2-[2-(2-chloro-6-{ methyl [(2-methyl cyclopropyl) methyl] amino)) diazanyl]-the 1R-methylethyl) t-butyl carbamate (0.22g; 0.42mmol) (0.22g 0.93mmol) handles with Burgess reagent for solution in 2mLTHF.Should react sealing and ℃ reach 5 minutes at microwave reactor internal heating to 130.Add additional 2 normal Burgess reagent and this container sealed once more and reheat 5 minutes.Should react vacuum-evaporation and by flash column chromatography purifying (25-40% ethyl acetate: hexane) obtain { 1-[5-(2-chloro-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridin-4-yl)-1,3,4- diazole-2-yl]-1R-methyl-2-phenylethyl } the aminobutyric acid tert-butyl ester, it is a yellow oil: ¹H NMR (400MHz, CDCl ₃) δ 7.28 (m, 3H), 7.06 (m, 2H), 7.00 (s, 2H), 3.57 (m, 2H), 3.39 (m, 2H), 3.15 (s, 3H), 1.73 (s, 3H), 1.56 (s, 9H), 1.05 (d, J=5.7Hz, 3H), 0.72 (m, 2H), 0.45 (m, 1H), 0.29 (m, 1H).LCMS(M+H)＝512.2。

Intermediate k:1-(2-{2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1,3- azoles-5-yl)-1R-methyl-2-phenylethyl] t-butyl carbamate

Steps A. coupling

To 2-chloro-6-[methyl (methyl sulphonyl) amino] Yi Yansuan (1.80g, 6.79mmol) add in the solution in 10mL DMF triethylamine (1.14mL, 8.15mmol); intermediate compound IV (2.00g, 8,15mmol); HOAt (1.11g, 8.15mmol) and EDC (1.56g, 8.15mmol).After following 3.5 hours of the room temperature, this reaction with saturated sodium bicarbonate solution (50mL) and salt solution (50mL) washing, is used Na with w/EtOAc (100mL) dilution ₂SO ₄Drying is filtered and vacuum concentration.By normal-phase chromatography purifying (0-＞70% EtOAc/ hexane and 0-7%MeOH/CH ₂Cl ₂) generate the white solid of (1R)-1-benzyl-3-({ 2-chloro-6-[methyl (methyl sulphonyl) amino] different nicotinoyl } amino)-2-hydroxyl-1-methyl-propyl t-butyl carbamate of 3.18g (87%).NMR(CDCl ₃，400MHz)7.66(d，J＝2.58Hz，1H)；7.50(d，J＝4.58Hz，1H)；7.31(m，3H)；7.18(m，2H)；4.05(m，1H)；3.84(m，1H)；3.59(m，1H)；3.43(s，3H)；3.23(d，J＝13.92Hz，1H)；3.09(s，3H)；2.68(d，J＝13.55Hz，1H)；1.45(s，9H)；1.21(s，3H)；LC/MS[M+H] ⁺＝541。

Step B. oxidation

({ 2-chloro-6-[methyl (methyl sulphonyl) amino] different nicotinoyl } amino)-(0.400g is 0.74mmol) at 8mLCH for 2-hydroxyl-1-methyl-propyl t-butyl carbamate to (1R)-1-benzyl-3- ₂Cl ₂Adding triethylamine in-20 ℃ of solution the among/4mL DMSO (0.41mL, 2.96mmol).After 5 minutes, (0.471g, 2.96mmol) solution in 3mL DMSO adds through conduit with the pyridine sulphur trioxide.After following 16 hours of the room temperature, Et is ended and used to this reaction with salt solution (10mL) ₂O (15mL) extraction.Water layer is used Et once more ₂O (10mL * 2) extraction.The organism that merges is used Na with 10% sodium bisulfite (10mL) and salt solution (10mL) washing ₂SO ₄Drying is filtered and vacuum concentration.Obtain the white solid of (1R)-1-benzyl-3-({ 2-chloro-6-[methyl (methyl sulphonyl) amino] different nicotinoyl } amino)-1-methyl-2-oxopropyl t-butyl carbamate of 0.335g (84%) by normal-phase chromatography purifying (20-＞70% EtOAc/ hexane).NMR(CDCl ₃，400MHz)7.69(d，J＝1.01Hz，1H)；7.51(d，J＝0.92Hz，1H)；7.31(m，3H)；7.12(m，2H)；4.62(m，1H)；4.41(m，1H)；3.44(s，3H)；3.11(s，3H)；1.48(s，9H)；1.31(s，3H)；LC/MS[M-C4H7]+＝483。

Step C. cyclodehydration

To (1R)-1-benzyl-3-({ 2-chloro-6-[methyl (methyl sulphonyl) amino] different nicotinoyl } amino)-1-methyl-2-oxopropyl t-butyl carbamate (0.190g; 0.35mmol) add in the solution in 2mL toluene Burgess reagent (0.504g, 2.12mmol).This is reflected at 130 ℃ of following microwave treatment 30 minutes.With the clarification of this reaction mixture yellow upper strata vacuum concentration and by normal-phase chromatography purifying (0-＞50% EtOAc/ hexane) obtain (1R)-1-(2-{2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl-1,3- azoles-5-yl)-1-methyl-2-phenylethyl t-butyl carbamate.NMR(CDCl ₃，400MHz)7.86(s，1H)；7.69(s，1H)；7.28(m，3H)；7.04(m，3H)；3.45(s，3H)；3.13(m，4H)；1.60(s，3H)；1.42(s，9H)；LC/MS[M+H] ⁺＝521。

Intermediate l:N-(4-(diazanyl carbonyl)-6-{ methyl [(2-methyl cyclopropyl) methyl I amino pyridine-2-yl)-N-methyl Toluidrin

Steps A; Coupling

To intermediate D (1.95g, 5.96mmol) and the Boc-hydrazine (0.866g, 6.55mmol) add in the solution in 25mLDMF EDC (1.37g, 7.15mmol) and HOAt (0.080g, 0.596mmol).Make this reaction carry out 15 hours, add subsequently that 3M LiCl ends and dilute with EtOAc.Separate each layer, water layer washs with EtOAc (2x).The organism that merges is used Na with 3MLiCI (2x) and salt water washing ₂SO ₄Drying is filtered and is concentrated.This resistates obtains required coupling adducts by normal-phase chromatography purifying (15-＞65% EtOAc/ hexane), and it is a white foam. ¹H?NMR(CDCl ₃，400MHz)δ8.17(br?s，1H)，6.74(s，1H)，6.70(s，1H)，6.23(br?s，1H)，3.50(dd，J＝14.5，6.4Hz，1H)，3.33(s，3H)，3.30(dd，J＝14.5，8.3Hz，1H)，3.08(s，3H)，3.06(s，3H)，1.48(s，9H)，1.00(d，J＝5.9Hz，3H)，0.74-0.60(m，2H)，0.37(m，1H)，0.23(m，1H)；LCMS[M+H] ⁺＝442。

Step B; Deprotection

(2.50g is 5.662mmol) at 100mLCH under 0 ℃ HCl to be blown into the product of steps A ₂Cl ₂In solution in reach 10 minutes.This solution changes glassy yellow.This reaction rises to room temperature and reaches 30 minutes, concentrates subsequently and obtains yellow solid, and it need not to be further purified and can use. ¹HNMR(CDCl ₃，400MHz)δ7.55(s，1H)，7.35(s，1H)，3.44(m，2H)，3.34(s，3H)，3.22(s，3H)，3.15(s，3H)，0.92(d，J＝5.8Hz，3H)，0.72(m，1H)，0.63(m，1H)，0.40(m，1H)，0.23(m，1H)；LCMS[M+H] ⁺＝342。

Intermediate m:N-{4-(5-{ (1-((phenylbenzene methylene radical) amino) ethyl)-1,3,4- diazole-2-yl)-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin

To N-(4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-6-I methyl [(2-methyl cyclopropyl) methyl] amino pyridine-2-yl)-N-methyl Toluidrin (embodiment 22 for 0.544g, 1.26mmol) is at 10mL CH ₂Cl ₂In solution in add benzophenone imines (0.25mL, 1.51mmol).In reaction process, generate white precipitate gradually.(0.160mL in the time of 0.894mmol), makes this reaction carry out 15 hours when the benzophenone imines that adds another equal portions.After 24 hours, this reaction H ₂O and EtOAc dilution separate each layer.Water layer washs with EtOAc (2x), and Na is used in the salt water washing of the organism of merging ₂SO ₄Drying is filtered and is concentrated.This resistates by normal-phase chromatography purifying (2-＞35% EtOAc/ hexane) obtain N-(4-(5-{1-[(phenylbenzene methylene radical) amino] ethyl-1,3,4- diazole-2-yl)-and 6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-the yellow foam of N-methyl Toluidrin. ¹H?NMR(CDCl ₃，400MHz)δ7.63(m，4H)，7.54-7.50(m，4H)，7.48(m，2H)，7.05(s，1H)，6.99(s，1H)，4.95(q，J＝6.5Hz，1H)，3.52(dd，J＝14.3，6.2Hz，1H)，3.38(s，3H)，3.34(dd，J＝14.3，6.3Hz，1H)，3.14(s，3H)，3.12(s，3H)，1.67(d，J＝6.6Hz，3H)，1.01(d，J＝6.0Hz，3H)，0.74(m，1H)，0.65(m，1H)，0.40(m，1H)，0.25(m，1H)；LCMS[M+H] ⁺＝559。

Intermediate n:((2E)-and 1-benzyl-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1-methyl-4-oxo but-2-ene-1-yl) t-butyl carbamate (route plan 24)

Steps A: the preparation of Weinreb acid amides

To intermediate C (1.0g 2.23mmol) adds N in the solution in the 10mL methylene dichloride, the O dimethyl hydroxylamine hydrochloride (226mg, 2.32mmol), diisopropylethylamine (574L, 3.48mmol), EDC (577mg, 3.01mmol), and HOAt (347mg, 2.55mmol).Gained solution at room temperature stirred 16 hours, with hypsokinesis to 0.3N HCl (20mL) with ethyl acetate extraction (3 * 50mL).The organism that merges is with sodium bicarbonate aqueous solution (75mL) washing, uses salt solution (75mL) washing subsequently and with dried over sodium sulfate and concentrated.By automatic purification by flash chromatography (silica gel box; about 20 minutes of 0-100% ethyl acetate/hexane) obtain 2-{ benzyl [(2 methyl cyclopropyl) methyl] amino-6-[(sec.-propyl alkylsulfonyl) (methyl) amino]-N-methoxyl group-N methyl Isonicotinamide, it is a yellow oil.LCMS[M+H]＝475.1。

Step B: the preparation of methyl ketone

To the 2-{ of steps A benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino]-N-methoxyl group-N-methyl Isonicotinamide (860mg; 1.81mmol) add methyl-magnesium-bromide (3.62mL in-78 ℃ of solution in the 6mL dry THF; 10.8mmol 3M solution is in Anaesthetie Ether).Make reaction mixture slowly rise to 0 ℃ in 1 hour, incline it to the saturated ammonium chloride of 20mL and use ethyl acetate extraction (3 * 30mL) this moment.The organism that merges is used dried over sodium sulfate and concentrated with salt water washing (30mL).Obtain the glassy yellow solid of N-(4-ethanoyl-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide by automatic purification by flash chromatography (silica gel box, about 35 minutes of 0-100% ethyl acetate/hexane).LCMS[M+H]＝430.1。

Step C: aldol withdrawal

To the N-of step B (4-ethanoyl-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (100mg; 0.23mmol) add two (trimethyl silyl) lithamide (244L in-78 ℃ of solution in the 1.5mL dry THF; 0.49mmol; the THF solution of 2M), and with the gained mixture stirred 15 minutes.Add (1R)-1-benzyl-1-methyl-2-oxoethyl t-butyl carbamate (61mg, 0.23mmol is according to preparing the method preparation of intermediate III to step C) to this mixture and be dissolved in the 1mL dry THF.This solution slowly rises to room temperature and continue to stir subsequently 16 hours, ends with the saturated solution (15mL) of ammonium chloride this moment and with ethyl acetate extraction (2 * 25mL).The organism that merges is used dried over sodium sulfate and is concentrated.Obtain (1R by the reverse-phase chromatography purifying; 2E)-1-benzyl-4-{2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] pyridin-4-yl)-1-methyl-4-oxo but-2-ene aminocarbamic acid tert-butyl ester; intermediate n, it is an orange oil.LCMS[M+H]＝675.3。

Embodiment 1

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-(benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 8)

Steps A: coupling

To intermediate C (100mg, 0.25mmol) and intermediate compound I (87mg, 0.30mmol) add in the solution in DMF (5mL) HOAt (37mg, 0.27mmol) and EDC (57mg, 0.30mmol).Reaction mixture at room temperature stirred 2 hours, handled with N-(tert-butoxycarbonyl)-D-Alpha-Methyl phenylalanine hydrazi acid amides (20mg, 0.07mmol, intermediate compound I), stirred 1 hour under the room temperature, and with the EtOAc dilution, Na is used in water, LiCl (x3) washing ₂SO ₄Dry; vacuum concentration and by purification by flash chromatography (silica gel, 10-50% EtOAc/ hexane) obtain [1R-benzyl-2-oxo-1-methyl-2-(2-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] different nicotinoyl diazanyl) ethyl] white foam of t-butyl carbamate. ¹HNMR (400MHz, CDCl ₃) δ 9.35 (br s, 1H), 8.64 (br s, 1H), 7.38-7.14 (m, 10H), 6.79 (s, 2H), 4.88 (A of AB, d, J=17.2Hz, 1H), 4.83 (B of AB, d, J=17.2Hz, 1H), 4.66 (s, 1H), 3.60-3.48 (m, 2H), 3.36-3.24 (m, 1H), 3.28 (s, 3H), the 3.07 (B of AB, d, J=14.0Hz, 1H), 2.84 (s, 3H), 1.50 (s, 9H), 1.45 (s, 3H), 0.98 (d, J=6.0Hz, 3H), 0.86-0.76 (m, 1H), 0.65-0.55 (m, 1H), 0.39-0.31 (m, 1H), 0.30-0.23 (m, 1H).

Step B: dehydrocyclization and Boc remove

Will [1R-benzyl-2-oxo-1-methyl-2-(2-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] different nicotinoyl } diazanyl) ethyl] t-butyl carbamate (140mg; 0.21mmol) and methoxycarbonyl amino-sulfonyl-triethyl ammonium hydroxide (197mg; 0.83mmol; Burgess reagent) solution in THF (5mL) is microwave (Smith synthesizer) and 120 ℃ of following irradiations 10 minutes; vacuum concentration and by purification by flash chromatography (silica gel; the 0-30%EtOAc/ hexane) obtain [1-(5-{2-{ benzyl [(2-methyl cyclopropyl) methyl] amino } }-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-1-methyl-2-phenylethyl] t-butyl carbamate.The EtOAc solution saturated with HCl (g) contacts 0.5 hour to remove Boc, concentrate and by the dry N-(4-[5-(1-amino-1-methyl-2-phenylethyl)-1 that obtains of two  alkane/water-cooled freeze-drying, 3,4- diazole-2-yl]-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-hydrochloride of N-methyl Toluidrin. ¹H?NMR(400MHz，CD ₃OD)δ7.33-7.18(m，8H)，7.08-7.02(m，3H)，6.94(d，J＝2.8Hz，1H)，4.98-4.82(m，2H)，3.74-3.66(m，1H)，3.48-3.36(m，1H)，3.41(s，3H)，3.34-3.26(m，2H)，2.96(s，3H)，1.82(s，3H)，0.98(d，J＝6.0Hz，3H)，0.91-0.81(m，1H)，0.73-0.62(m，1H)，0.48-0.39(m，1H)，0.29-0.19(m，1H)。HRMS (ES, M+H) calculated value: C ₃₀H ₃₆N ₆O ₃S:561.2643, measured value: 561.2655.

Use preferred enantiomer among the intermediate A step B trans-S, thereby S prepares the pure S of preferred mapping, S, R example.

Embodiment 2

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-([(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin

Will [1-(5-{2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 1R-methyl-2-phenylethyl] t-butyl carbamate (94mg; 0.14mmol; derive from embodiment 1) EtOH (10mL) and TFA (0.011mL, 0.14mmol) in solution with 20% Pd (OH) ₂/ C (20mg) hydrogenation 3 hours under 40 ℃ and 1atm H2.Filter and concentrate, Boc removes (the saturated EtOAc of HCl (g)) subsequently, concentrates and at Et ₂Development obtains N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{[(2-methyl cyclopropyl) methyl among the O] amino } pyridine-2-yl)-light yellow solid of N-methyl Toluidrin hydrochloride. ¹H?NMR(400MHz，CD ₃OD)δ7.35-7.30(m，3H)，7.11-7.05(m，2H)，6.99(d，J＝1.2Hz，1H)，6.93(d，J＝1.2Hz，1H)，3.45(br?s，2H)，3.37(s，3H)，3.28-3.20(m，2H)，3.19(s，3H)，1.82(s，3H)，1.06(d，J＝6.0Hz，3H)，0.90-0.80(m，1H)，0.73-0.65(m，1H)，0.47-0.41(m，1H)，0.31-0.24(m，1H)。HRMS (ES, M+H) calculated value C ₂₃H ₃₀N ₆O ₃S:471.2173, measured value: 471.2175.

Embodiment 3

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin

By 2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] Yi Yansuan and N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine adopts and is similar to embodiment 1 described method preparation.HRMS (ES, M+H) calculated value C ₂₄H ₃₂N ₆O ₃S:485.2330, measured value: 485.2355.

Embodiment 4

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide

By 2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (sec.-propyl alkylsulfonyl) amino] Yi Yansuan (being similar to the method for preparing intermediate C) and N-(tert-butoxycarbonyl)-D-Alpha-Methyl phenylalanine hydrazi imines, adopt and be similar to embodiment 1 described method preparation by methyl (sec.-propyl alkylsulfonyl) amine.HRMS (ES, M+H) calculated value C ₃₂H ₄₀N ₆O ₃S:589.2955, measured value: 589.2920.

Embodiment 5

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{[(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide

Be similar to embodiment 2 described methods preparations by embodiment 4 employings.HRMS (ES, M+H) calculated value C ₂₅H ₃₄N ₆O ₃S:499.2486, measured value: 499.2499.

Embodiment 6

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-((2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate P utilization.HRMS[M+1]+calculated value=535.2298, measured value=535.2288.

Embodiment 7

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate Q utilization.HRMS[M+1]+calculated value=529.2592, measured value=529.2591.

Embodiment 8

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate R utilization.HRMS[M+1]+calculated value=563.2611, measured value=562.2603.

Embodiment 9

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2-fluoro ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate S utilization.HRMS[M+1]+calculated value=545.2705, measured value=545.2727.

Embodiment 10

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (route plan 8)

Utilize the mode that is similar to embodiment 1 to prepare by intermediate T.HRMS[M+1]+calculated value=557.2905, measured value=557.2900.

Embodiment 11

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{[2-(dimethylamino) ethyl] [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate U utilization.LCMS[M+H] ⁺＝570.4。

Embodiment 12

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-([3-(dimethylamino) propyl group] [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide (route plan 8)

Be similar to embodiment 1 described method preparation by intermediate V utilization.HRMS[M+1]+calculated value=584.3378, measured value=584.3382.

Embodiment 13

N-[4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-(1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } amino) pyridine-2-yl]-N-methyl Toluidrin (route plan 8, the 2 hurdles)

Steps A .Pd coupling

To (1S)-1-[(1S; 25)-and 2-methyl cyclopropyl] ethane chlorination ammonium (ethanaminiumchloride) (intermediate P; 0.045g; 0.33mmol) and (1R)-1-(5-{2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-(intermediate h, 0.173g 0.33mmol) add K in the solution in 1mL DMF to 1R-methyl-2-phenylethyl t-butyl carbamate ₃PO ₄(0.352g, 1.66mmol) and Pd (PtBu ₃) ₂(0.025g, 0.05mmol).The 110 ℃ of down heating 12 hours and filtering with EtOAc dilution (30mL) and through Celite pad subsequently that are reflected at sealing.This diatomite washs with EtOAc (100mL).With the filtrate vacuum concentration with by normal-phase chromatography purifying (0-＞50% EtOAc/ hexane), anti-phase subsequently LC purifying.The gained material washs with EtOAc dilution (40mL) and with saturated sodium bicarbonate solution (20mL).Water layer is used EtOAc (20mL) extraction once more.The organism that merges is used Na with salt water washing (40mL) ₂SO ₄Dry; filter and vacuum concentration obtain (1R)-1R-methyl isophthalic acid of 0.030g (16%)-(5-{2-((1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethyl } amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 2-phenylethyl t-butyl carbamate, it is a yellow residue.NMR(CDCl ₃，400MHz)7.27(m，3H)；7.03(m，3H)；6.79(s，1H)；3.55(d，J＝13.46Hz，1H)；3.43(m，2H)；3.37(s，3H)；3.15(s，3H)；1.71(s，3H)；1.42(s，9H)；1.29(d，J＝6.41Hz，3H)；1.07(d，J＝5.77Hz，3H)；0.67(m，2H)；0.50(m，1H)；0.26(m，1H)；LC/MS[M+H] ⁺＝585。

Step B.Boc removes

With HCl (g) be blown into (1R)-1-methyl isophthalic acid-(5-{2-((1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethyl } amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-(0.030g is 0.05mmol) at 1mL CH for 2-phenylethyl t-butyl carbamate ₂Cl ₂In 0 ℃ of solution reach 5 minutes.0 ℃ after following 10 minutes, should react vacuum concentration and be dissolved in DMF.By anti-phase LC purifying; with postlyophilization generate 0.008g (27%) (2R)-2-(5-{2-((1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethyl } amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl-1; 3,4- diazole-2-yl)-white solid of 1-phenyl third-2-trifluoroacetic acid ammonium.NMR(CDCl ₃，400MHz)7.31(m，3H)；7.05(m，2H)；6.91(d，J＝1.1Hz，1H)；6.84(d，J＝1.1Hz，1H)；3.55(m，1H)；3.40(s，2H)；3.16(s，3H)；1.83(s，3H)；1.28(d，J＝6.4Hz，3H)；1.06(d，J＝5.7Hz，3H)；0.67(m，2H)；0.53(m，1H)；0.21(m，1H)；LC/MS[M+H] ⁺＝485。

Wherein X is that the other compound of  diazole is according to the described preparation of table 1.Method A and B are respectively with reference to the method A of route plan 8 and the method B of route plan 8.

Table I- diazole embodiment

Embodiment 39

N-(4-[2-(1R-amino-I-methyl-2-phenylethyl)-1,3- azoles-5-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 16)

With intermediate E (100mg, 0.25mmol) and intermediate II (103mg, 0.37mmol) solution in DMF (0.5mL) is 120 ℃ of down heating 1 hour.Crude product is by preparation HPLC purifying (5-＞95%CH ₃CN/H ₂O; add 0.1% TFA; C18 PRO YMC 20 * 150mm) obtain [the 1R-methyl isophthalic acid-(4-{2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl-1,3- azoles-2-yl)-the 2-phenylethyl] t-butyl carbamate.Boc removes (the saturated EtOAc of HCl (g)), concentrates and by preparation HPLC purifying (5-＞95% CH ₃CN/H ₂O, add 0.1% TFA, C18 PRO YMC 20 * 150mm) obtain N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3- azoles-5-yl]-tfa salt of 6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin. ¹HNMR(400MHz，CD ₃OD)δ8.58(s，1H)，7.32-7.26(m，3H)，7.02-6.96(m，2H)，6.92(d，J＝0.8Hz，1H)，6.84(d，J＝0.8Hz，1H)，3.62-3.53(m，1H)，3.43-3.26(m，3H)，3.33(s，3H)，3.14(s，3H)，3.11(s，3H)，1.81(s，3H)，1.03(d，J＝6.0Hz，3H)，0.81-0.66(m，2H)，0.48-0.41(m，1H)，0.27-0.21(m，1H)。HRMS (ES, M+H) calculated value C ₂₅H ₃₃N ₅O ₃S:484.2377, measured value: 484.2400.

Embodiment 40

N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3- azoles-5-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 14)

With intermediate G (25mg, 0.04mmol) and Burgess reagent (40mg, 0.17mmol) solution in THF (0.5mL) is in microwave (Smith synthesizer) and 80 ℃ irradiation 25 minutes down, under N2, concentrate and by purification by flash chromatography (silica gel, 0-40% EtOAc/ hexane).Remove Boc (1mL with HCl, 4mmol, 4M is in two  alkane), with postlyophilization obtain N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3- azoles-5-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] amino pyridine-2-yl)-tfa salt of N-methyl Toluidrin. ¹H?NMR(400MHz，CD ₃OD)δ7.84(s，1H)，7.32-7.26(m，3H)，7.04-6.97(m，2H)，6.92(s，1H)，6.81(s，1H)，3.70-3.57(m，1H)，3.50-3.36(m，1H)，3.42(s，2H)，3.38(s，3H)，3.18(s，6H)，1.84(s，3H)，1.04(d，J＝6.0Hz，3H)，0.84-0.706(m，2H)，0.54-0.44(m，1H)，0.34-0.26(m，1H)。HRMS (ES, M+H) calculated value C ₂₅H ₃₃N ₅O ₃S:484.2377, measured value: 484.2390.

Embodiment 41

N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3-thiazoles-5-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 14)

With intermediate G (50mg, 0.08mmol) and Lawson ' s reagent (134mg, 0.33mmol) irradiation 15 minutes and 90 ℃ of 15 minutes (Boc also can utilize same reaction to remove) of irradiation down down of 85 ℃ in the inherent microwave of solution in acetonitrile (0.8mL) (Smith synthesizer), flow down at N2 and to concentrate and by preparation HPLC purifying (5-＞95% CH ₃CN/H ₂O, add 0.1% TFA, C18PRO YMC 20 * 150mm) obtain N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3-thiazoles-5-yl]-tfa salt of 6-(methyl [(2 methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin.MS(ES，M+H)500。

Embodiment 42

N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3-imidazoles-5-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 14)

With intermediate G (50mg, 0.08mmol) and ammonium acetate (64mg, mixture 0.83mmol) is 150 ℃ of down fusings 15 minutes (loss part Boc).Make reaction mixture be cooled to room temperature, use saturated NaHCO ₃Dilution is with EtOAc (x3) extraction.Na is used in the organic layer salt water washing that merges ₂SO ₄Drying and vacuum concentration.The TFA (5mL, 10% TFA is in DCM) that is used on the DCM removes Boc, and vacuum concentration is by preparation HPLC purifying (5-＞95% CH ₃CN/H ₂O, add 0.1%TFA, C18 PRO YMC 20 * 150mm) and lyophilize obtain the tfa salt of N-(4-[2-(1R-amino-1-methyl-2-phenylethyl)-1,3-imidazoles-5-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] aminopyridine-2-yl)-N-methyl Toluidrin. ¹H NMR (400MHz, CD ₃OD) δ 7.76 (s, 1H), 7.29-7.21 (m, 3H), 7.06 (s, 2H), 6.92-6.86 (m, 2H), and 3.66-3.56 (m, 1H), 3.48-3.35 (m, 1H), the 3.41 (A of AB, d, J=13.6Hz, 1H), 3.34 (s, 3H), the 3.26 (B of AB, d, J=13.6Hz, 1H), 3.18 (s, 3H), 3.16 (s, 3H), 1.74 (s, 3H), 1.04 (d, J=5.7Hz, 3H), 0.85-0.70 (m, 2H), 0.51-0.45 (m, 1H), 0.31-0.25 (m, 1H).HRMS (ES, M+H) calculated value C ₂₅H34N ₆O2S:483.2537, measured value: 483.2548.

Embodiment 43

N-(4-[5-(1R-amino-I-methyl-2-phenylethyl)-1,3- azoles-2-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl) N-methyl Toluidrin (route plan 17)

Embodiment 43 adopts the described method of preparation that is similar to embodiment 7 to make by intermediate H. ¹H NMR (400MHz, CD ₃OD) δ 7.32-7.26 (m, 3H), 7.22 (s, 1H), 7.14 (s, 1H), and 7.06-6.99 (m, 3H), 3.62 (A of ABX, dd, J=14.4,6.2Hz, 1H), 3.45 (A of AB, d, J=13.7Hz, 1H), 3.43 (B of ABX, dd, J=14.4,2.3Hz, 1H), 3.39 (s, 3H), 3.26 (B of AB, d, J=13.7Hz, 1H), 3.18 (s, 3H), 3.16 (s, 3H), 1.73 (s, 3H), 1.04 (d, J=6.2Hz, 3H), 0.86-0.70 (m, 2H), 0.52-0.44 (m, 1H), 0.30-0.24 (m, 1H).HRMS (ES, M+H) calculated value C ₂₅H ₃₃N ₅O ₃S:484.2377, measured value: 484.2374.

Embodiment 44

N[4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3- azoles-2-yl]-6-(1-[(1S, 2S)-2-methyl cyclopropyl] ethyl) amino) pyridine-2-yl]-N-methyl Toluidrin

Steps A .Pd coupling

To (1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethane chlorination ammonium (intermediate P; 0.039g; 0.29mmol) and (1R)-1-(2-(2-chloro-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl)-1; 3- azoles-5-yl)-1-methyl-2-phenylethyl t-butyl carbamate (intermediate k; 0.050g, 0.10mmol) add K in the solution in 1mL DMF ₃PO ₄(0.122g, 0.58mmol) and Pd (PtBu ₃) ₂(0.007g, 0.01mmol).After following 16 hours of the room temperature, with sealed reaction 110 ℃ down heating 8.5 hours and with after Celite pad filter.This diatomite is washed with EtOAc (60mL).Be dissolved in DMF and pass through anti-phase LC purifying with the filtrate vacuum concentration and with the gained resistates.The gained material washs with EtOAc dilution (40mL) and with saturated sodium bicarbonate solution (20mL).Water layer is used EtOAc (20mL) extraction once more.The organism that merges is used Na with salt water washing (20mL) ₂SO ₄Dry; filter and vacuum concentration obtain (1R)-1-methyl isophthalic acid of 0.028g (50%)-(2-{2-((1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethyl } amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3- azoles-5-yl)-and 2-phenylethyl t-butyl carbamate, it is a yellow residue.(CDCl ₃，400MHz)7.28(m?3H)；7.06(d，J＝0.91Hz，1H)；7.03(m，2H)；6.93(s，1H)；6.76(s，1H)；3.50(m，1H)；3.36(m，4H)；14(m，4H)；1.60(s，3H)；1.42(s，9H)；LC/MS[M+H] ⁺＝584。

Step B.Boc removes

With HCl (g) be blown into (1R)-1-methyl isophthalic acid-(2-{2-((1S)-1-[(1S; 2S)-and 2-methyl cyclopropyl] ethyl } amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1; 3- azoles-5-yl)-(0.028g is 0.05mmol) at 1mL CH for 2-phenylethyl t-butyl carbamate ₂Cl ₂In 0 ℃ of solution in reach 5 minutes.0 ℃ following 10 minutes, should react vacuum concentration and be dissolved in DMF.By anti-phase LC purifying; obtain (2R)-2-(2-(2-(((1S)-1-[(1S with postlyophilization; 25)-and 2-methyl cyclopropyl] ethyl) amino)-6-[methyl (methyl sulphonyl) amino] pyridin-4-yl }-1,3- azoles-5-yl)-white solid of 1-phenyl-propane-2-ammonium.(CDCl ₃，400MHz)7.27(m，3H)；7.19(s，1H)；7.01(m，3H)；6.89(d，J＝0.92Hz，1H)；3.53(m，1H)；3.45(d，J＝13.37Hz，1H)；3.33(s，3H)；3.24d，J＝13.55Hz，1H)；3.14(s，3H)；1.71(s，3H)；1.27(d，J＝6.41Hz，3H)；1.94(d，J＝5.67Hz，3H)；0.66(m，2H)；0.53(m，1H)；0.20(m，1H)；LC/MS[M+H] ⁺＝484。

Other  oxazole derivatives are according to following table 3 described preparations.

Table 3- oxazole derivatives

Embodiment 49

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3-thiazoles-2-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 17)

Embodiment 49 is by intermediate H, utilizes the described method preparation of the preparation that is similar to embodiment 8. ¹H NMR (400MHz, CD ₃OD) δ 7.55 (s, 1H), 7.26-7.20 (m, 3H), 7.05-7.00 (m, 2H), 6.99 (d, J=1.2Hz, 1H), 6.90 (d, J=1.2Hz, 1H), 3.59 (A of ABX, dd, J=14.4,6.4Hz, 1H), 3.42 (B of ABX, dd, J=14.4,6.8Hz, 1H), 3.37 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 3.09 (s, 2H), 1.60 (s, 3H), 1.04 (d, J=6.0Hz, 3H), 0.85-0.68 (m, 2H), 0.50-0.42 (m, 1H), 0.29-0.21 (m, 1H).HRMS (ES, M+H) calculated value C ₂₅H ₃₃N ₅O ₂S ₂: 500.2149, measured value: 500.2149.

Embodiment 50

N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-4H-1,2,4-triazole-3-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 11)

With intermediate compound I (17mg, 0.06mmol), intermediate J (20mg, 0.05mmol) and diisopropylethylamine (0.013mL, 0.08mmol) solution in EtOH (1mL) sealing and 150 ℃ of heating 2 days down.With the reaction mixture vacuum concentration and by preparation HPLC purifying (5-＞95%CH ₃CN/H2O, the 0.1%TFA that adds, C18 PRO YMC 20 * 150mm) obtain N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-4H-1,2,4-triazole-3-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] amino pyridine-2-yl)-tfa salt of N-methyl Toluidrin. ¹HNMR(400MHz，CD ₃OD)δ7.30-7.22(m，3H)，7.13(s，1H)，7.04(s，1H)，7.02-6.96(m，2H)，3.65-3.56(m，1H)，3.48-3.42(m，1H)，3.38(s，3H)，3.36(s，2H)，3.18(s，3H)，3.17(s，3H)，1.78(s，3H)，1.04(d，J＝6.0Hz，3H)，0.86-0.70(m，2H)，0.52-0.44(m，1H)，0.30-0.23(m，1H)。

Embodiment 51

N-(4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] amino) pyridine-2-yl)-N-methyl Toluidrin (another route plan 8)

Steps A: coupling

(0.610g is 1.614mmol) with N-Boc-L-Ala (0.336g, 1.78mmol) adding HunigShi alkali (0.564mL in the solution in 10mL DMF to intermediate 1,3.23mmol), EDC (0.371g, 1.94mmol) and HOAt (0.025g, 0.161mmol).After 15 hours, this reaction separates each layer with 3M LiCl and EtOAc dilution.Water layer washs with EtOAc (2x), and the organism of merging is used Na with 3M LiCl (2x) and salt water washing ₂SO ₄Drying is filtered and is concentrated.This resistates obtains required coupling adducts by normal-phase chromatography purifying (35-＞90% EtOAc/ hexane), and it is yellow foam. ¹H?NMR(CDCl ₃，400MHz)δ9.11(br?s，1H)，8.97(br?s，1H)，8.00(s，1H)，6.76(s，1H)，6.69(s，1H)，5.09(d，J＝7.5Hz，1H)，3.47(dd，J＝14.5，6.2，1H)，3.32(s，3H)，3.29(dd，J＝14.5，7.0Hz，1H)，3.07(s，3H)，2.93(s，3H)，1.43(s，9H)，1.41(d，J＝7.5Hz，3H)，1.00(d，J＝5.7Hz，3H)，0.68(m，1H)，0.62(m，1H)，0.36(m，1H)，0.23(m，1H)；LCMS[M+H] ⁺＝513。

Step B: dehydration

To the product of steps A (0.763g, 1.49mmol) at 7mL 1, add in the solution in the 2-ethylene dichloride Burgess reagent (1.42g, 5.95mmol).These slurries are 120 ℃ of following microwave treatment 10 minutes, directly incline subsequently to being used for positive purifying (10-＞55% EtOAc/ hexane) to the top of silicagel column.Obtain expecting product, it is yellow foam. ¹H?NMR(CDCl ₃，400MHz)δ7.01(s，1H)，6.93(s，1H)，5.12(m，1H)，3.52(dd，J＝14.5，6.3Hz，1H)，3.38(s，3H)，3.33(dd，J＝14.5，7.0Hz，1H)，3.15(s，3H)，3.11(s，3H)，1.63(d，J＝6.8Hz，3H)，1.44(s，9H)，1.01(d，J＝4.9Hz，3H)，0.73(m，1H)，0.67(m，1H)，0.41(m，1H)，0.26(m，1H)；LCMS[M+H] ⁺＝495。

Step C: deprotection

(0.532g, 1.08mmol) solution in 15mLEtOAc reaches 5 minutes HCl to be blown into the product of step B under 0 ℃.Bright yellow solution was risen to room temperature 1 hour, concentrate subsequently and obtain N-(4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-6-{ methyl [(2-methyl cyclopropyl) methyl] aminopyridine-2-yl)-N-methyl Toluidrin, it is yellow foam, and it need not to be further purified and can use. ¹H?NMR(d ₄-MeOH，400MHz)87.15(s，1H)，7.05(s，1H)，4.95(q，J＝7.0Hz，1H)，3.61(dd，J＝14.5，8.1Hz，1H)，3.43(dd，J＝14.5，6.9Hz，IH)，3.38(s，3H)，3.16(s，3H)，3.15(s，3H)，1.79(d，J＝7.0Hz，3H)，1.01(d，J＝5.8Hz，3H)，0.82-0.75(m，2H)，0.47(m，1H)，0.25(m，1H)；LCMS[M+H] ⁺＝395。

Embodiment 52

N (4-[5-(1-amino-1-methyl-2-pyridin-4-yl ethyl)-1,3,4- diazole-2-yl]-6-{[(2 methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (another route plan 8)

N-(4-[5-(1-amino-1-methyl-2-pyridin-4-yl ethyl)-1,3,4- diazole-2-yl]-6-([(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin is to be similar to embodiment 70 described method preparations by intermediate III and intermediate compound I utilization. ¹H?NMR(d ₄-MeOH)δ8.77(d，J＝6.0Hz，2H)，7.78(d，J＝6：4Hz，2H)，6.96(d，J＝l?1.7Hz，2H)，3.78(app?ABX，JAB，JAX，JBx＝13.5Hz，2H)，3.37(s，3H)，3.24(d，J＝6.8Hz，2H)，3.16(s，3H)，1.94(s，3H)，1.06(d，J＝6.0，3H)，0.87-0.81(m，1H)，0.72-0.66(m，1H)，0.43(dt，J＝8.7，4.6Hz，1H)，0.26(dt，J＝8.6，4.8Hz，1H)。HRMS (ES, M+H) calculated value C ₂₂H ₂₉N ₇O ₃S:472.2126, measured value: 472.2163.

Table IV- oxadiazole derivative

Embodiment 87

N-(4-[5-(1-amino-1-methyl-2-(4-fluorophenyl) ethyl)-1,3,4- diazole-2-yl]-6-(methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (another route plan 8, the 2 hurdles)

(0.051g 0.091mmol) adds down 1M in 0 ℃ in the solution in 0.80mL DMF and is contained in NaHMDS among the THF (0.13mL, 1.30mmol), this reaction becomes blueness to intermediate m.After 5 minutes, (0.180mL, 0.180mmol), behind reinforced finishing, this reaction becomes yellow to add the 1M solution of 4-luorobenzyl bromination thing in DMF with syringe.After 30 minutes, add 0.125mL H ₂O and 0.025mL 1H HCl.1.5 after hour, add 0.125mL 1N HCl, this reaction was carried out 15 hours, be carried in the SCX ion exchange column subsequently, use the MeOH wash-out, subsequently with the 2M NH3 wash-out that is contained among the MeOH.Separate impure required product by alkaline cut, it is further by preparation HPLC purifying (5-＞95% CH ₃CN/H ₂O, about 30min, 0.1% TFA that adds, obtain after C18 PRO YMC 20 * 150mm) lyophilizes N-(4-{5-[1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4- diazole-2-yl }-6-{ methyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-the cotton-shaped yellow solid of N-methyl Toluidrin. ¹HNMR (d ₄-MeOH, 400MHz) δ 7.12-7.03 (m, 5H), 6.91 (s, 1H), 3.59 (dd, J=14.8,6.2Hz, 1H), 3.43-3.39 (m, 3H), 3.31 (s, 3H), 3.16 (s, 3H), 3.15 (s, 3H), 1.84 (s, 3H), 1.02 (d, J=6.0Hz, 3H), 0.80-0.70 (m, 2H), 0.46 (m, 1H), 0.26 (m, 1H); High resolution mass spectrometry (FT/ICR) calculated value M+H=503.2235 measured value 503.2279.

Other  oxadiazole derivatives are according to following table 5 described method preparations.

Table 5- oxadiazole derivative

Embodiment 91

Steps A: with 4-amino 2, the 6-dichloropyridine (2.0g 12.2mmol) is suspended in the toluene (50mL), to wherein add phenyl aldehyde (6.24mL, 30.7mmol).This reacts reflux 12 hours and collects water with Dean-Stark equipment.Solvent removed in vacuo subsequently.This resistates is dissolved in ethanol (25mL) and is heated to 50 ℃.Dropping NaBH4 (1.86g, 61mmol).This reaction postheating reaches 2 hours for 75 ℃.Solvent removed in vacuo adds entry (100mL) and (3 * 100mL) extract with EtOAc with this solution.The organic layer that merges salt water washing (1 * 100mL), use MgSO ₄Drying is filtered and is concentrated.Obtain this benzylaniline (2.93g, 94%) by silica gel chromatography purifying (20%EtOAc/Hex).LCMS[M+H]＝253。 ¹H?NMR(CDCl ₃)δ7.40-7.14(m，5H)，6.46(s，2H)，4.35(d，J＝5.5Hz，2H)

Step B: to the aniline of steps A (0.079g, 0.31mmol) add in the solution in the brooethyl cyclopropane (0.05g, 0.37mmol), add subsequently NaH (60% dispersion, 0.014g, 0.37mmol).This solution at room temperature stirred 30 minutes, used H subsequently ₂O ends.(3 * 30mL) extract this solution, after this organic layer MgSO of He Binging with EtOAc ₄Drying is filtered and is concentrated.Obtain cyclopropyl monomethylaniline (0.078g, 81%) by silica gel chromatography purifying (15% EtOAc/Hex).

LCMS[M+H]＝307.1

¹H?NMR(CDCl ₃)δ7.36-7.13(m，5H)，6.51(s，2H)，4.64(s，2H)，3.29(d，J＝6.6Hz，2H)，1.08-1.6(m，1H)，0.60-0.55(m，2H)，0.24-0.21(m，2H)

Step C: with the dichloropyridine of step B (0.078g, 0.25mmol), N-methyl sulphonamide (0.033g, 0.30mmol), K ₃PO ₄(0.075g, 0.35mmol), and Xanphos (0.01g, two  alkane solution (2mL) 0.17mmol) outgased with being blown into argon gas in 15 minutes.Add Pd2 (dba) ₃G, 0.05mmol) and this solution is heated to 100 ℃ reaches 12 hours.Cool off this solution and use H ₂O (30mL) dilution.This solution is with EtOAc (3 * 30mL) extractions and the organic layer MgSO that merge ₄Drying is filtered and is concentrated.Obtain required sulphonamide (0.034g, 35%) by silica gel chromatography purifying (20% EtOAc/Hex).

LCMS[M+H]＝380.3

¹H?NMR(CDCl ₃)δ7.35-7.19(m，3H)，7.16(d，J＝7.1Hz，2H)，6.68(s，1H)，6.46(s，1H)，4.62(s，2H)，3.31(d，J＝6.5Hz，2H)，3.29(s，3H)，2.93(s，3H)，1.12-1.08(m，1H)，0.58-0.55(m，2H)，0.24-.21(m，2H)。

Step D: (0.17g 1.45mmol), adds Pd (PPh subsequently to add zinc cyanide in the solution of sulphonamide in DMF (4mL) of step C ₃) ₄(0.017g, 0.15mmol).This solution is heated to 85 ℃ reaches 48 hours.With reaction mixture H ₂O (30mL) dilution and with EtOAc (3, * 30mL) extract.The organic layer that merges salt water washing (1 * 50mL), use MgSO ₄Drying is filtered, and concentrates.Obtain this cyanopyridine (0.27g, 81%) by silica gel chromatography purifying (30% EtOAc/Hex).

LCMS[M+H]＝371.1

¹H?NMR(CDCl ₃)δ7.36-7.26(m，3H)，7.15(d，J＝7.2Hz，2H)，6.87(s，1H)，6.82(s，1H)，4.68(s，2H)，3.36(d，J＝6.5Hz，2H)，3.30(s，3H)，2.92(s，3H)，1.12-1.09(m，1H)，0.61(d，J＝7.6Hz，2H)，0.27(d，J＝4.9Hz，2H)。

Step e: (0.15g is 0.41mmol) 9: 1EtOH/H to the cyanopyridine of step D ₂Adding solid KOH in the solution among the O (10mL) (0.26g, 4.1mmol).This solution is heated to 85 ℃ reaches 16 hours.Cool off this solution, use 1N HCl acidifying, and (3 * 30mL) extract with EtOAc.The organic layer that merges salt water washing (1 * 50mL), use MgSO ₄Drying is filtered and is concentrated.This resistates need not to be further purified and can use.In the solution of this carboxylic acid in DCM (5mL), add the diazanyl phenylalanine (0.16g, 0.59mmol), DIPEA (0.023g, 1.78mmol) and bop reagent (0.25g, 0.59mmol).This reaction was at room temperature stirred 1 hour, obtained diketo hydrazine (0.30g, 77%) by silica gel chromatography purifying (5%MeOH/ chloroform) subsequently

LCMS[M+H]＝665.1

¹H?NMR(CDCl ₃)δ7.41-7.16(m，11H)，6.83(s，1H)，4.72(s，2H)，3.57(d，J＝14Hz，1H)，3.39(d，J＝6.6Hz，2H)，3.35(s，3H)，3.10(d，J＝14Hz，1H)，2.91(s，3H)，1.50(s，9H)，1.45(s，3H)，1.13-1.10(m，1H)，0.59-0.55(m，2H)，0.25(d，J＝5.0Hz，2H)。

Step F: to the diketo hydrazine of step e (0.30g, 0.46mmol) 1, add in the 2-dichloroethane solution (3mL) burgess reagent (0.33g, 1.4mmol).With this solution 120 ℃ of following microwave treatment 8 minutes.Obtain required  diazole (0.29g, 62%) by the silica gel chromatography purifying.

LCMS[M+H]＝647.1

¹H?NMR(CDCl ₃)δ7.39-7.04(m，11H)，6.75(s，1H)，4.73(s，2H)，3.54-3.48(m，2H)，3.41(d，J＝6.6Hz，2H)，3.34(s，3H)，3.03(s，3H)，1.72(br?s，3H)，1.41(br?s，9H)，1.24-1.13(m，1H)，0.60(q，J＝7.9Hz，2H)，0.26(q，J＝5.3Hz，2H)。

Step G: (add TFA (1.5mL) in the 0.027g, methyl alcohol 0.05mmol) (5mL) solution, add the Pd (OH) of catalytic amount subsequently to the  of step F diazole ₂Place H2 atmosphere to assign 20 minutes through balloon this solution.This solution obtains the aminopyridine of complete deprotection through diatomite filtration and vacuum concentration.

LCMS[M+H]＝457.1

¹H?NMR(CD ₃OD)δ7.31-7.21(m，3H)，7.21(s，1H)。7.08(m，2H)，6.69(s，1H)，3.46(d，J＝4.8Hz，2H)，3.36(s，3H)，3.17(s，3H)，3.08(d，J＝7.0Hz，2H)，1.87(s，3H)，1.14-1.08(m，1H)，0.59(d，J＝7.0Hz，2H)，0.30(d，J＝5.1Hz，2H)。

Embodiment 92

N-(4-(5-[(1R)-1-amino-1-methyl-2-phenylethyl]-the 1H-pyrazole-3-yl)-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide

To intermediate n (62mg, 0.09mmol) add in the solution in 0.5mL DMF anhydrous hydrazine (14L, 0.46mmol).The gained mixture was 90 ℃ of following reflux 18 hours and be cooled to room temperature subsequently.To wherein adding 2mL water and 3mL ethyl acetate.Separate organic layer, use the salt water washing, use dried over sodium sulfate and be concentrated into dried.By the reverse-phase chromatography purifying obtain (1R)-1-(3-(2-(benzyl [(2-methyl cyclopropyl) methyl] amino)-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] pyridin-4-yl }-1H-pyrazoles-5-yl)-1-methyl-2-phenylethyl t-butyl carbamate, it is dissolved in the methylene dichloride that 1mL contains 20% TFA.After 1 hour, this solution concentration is obtained title compound, N-(4-(5-[(1R)-1-amino-1-methyl-2-phenylethyl]-the 1H-pyrazole-3-yl)-6-(benzyl [(2-methyl cyclopropyl) methyl] amino) pyridine-2-yl)-N-methyl-prop-2-sulphonamide.

1H?NMR(400MHz，d4-MeOH)δ7.31-7.19(m，9H)，7.01-6.99(m，2H)，6.76(s，1H)，6.71(s，1H)，6.61(s，1H)，4.96-4.76(m，2H)，3.81-3.74(m，1H)，3.69-3.63(m，1H)3.39(s，3H)，3.35-3.22(m，4H)，1.70(s，3H)，1.14(d，J＝6.8Hz，6H)，0.94(d，J＝6Hz，3H)，0.87-0.84(m，1H)，0.66-0.60(m，1H)，0.42-0.38(m，1H)，0.26-0.21(m，1H)；LCMS[M+H]＝587.2。

Embodiment 93

N-(4-(6-[(1R)-1-amino-1-methyl-2-phenylethyl] pyrimidine-4-yl }-6-{ benzyl [(2-methyl cyclopropyl) methyl] aminopyridine-2-yl)-N-methyl-prop-2-sulphonamide

Steps A: condensation

The suspension of 69mg (1.01mmol) sodium ethylate in 1mL DMA is added drop-wise in the solution of 81mg (1.01mmol) amitraz hydrochloride in 1mL DMA, and with this miscellany vigorous stirring 5 minutes.(68mg, 0.10mmol) drips of solution in 1mL DMA is added in the single mixture, and gained mixture heating up to 110 ℃ is reached 30 minutes with intermediate n.Make it be cooled to room temperature subsequently.Add entry (10mL) and this miscellany ethyl acetate extraction (3 * 15mL).The organism were washed with 3M aq.LiCI that merges (3 * 25mL), with salt water washing (25mL), with dried over sodium sulfate and concentrated.Obtain (1R)-1-(6-{2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[(sec.-propyl alkylsulfonyl) (methyl) amino by the reverse-phase chromatography purifying] pyridin-4-yl }-3; 4-dihydro-pyrimidin-4-yl)-and 1-methyl-2-phenylethyl t-butyl carbamate, it is a yellow oil.LCMS[M+H]＝701.3

Step B: oxidation and deprotection

To (the 1R)-1-of above-mentioned steps A (6-(2-(benzyl [(2-methyl cyclopropyl) methyl] amino)-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] pyridin-4-yl-3; 4-dihydro-pyrimidin-4-yl)-1-methyl-2-phenylethyl t-butyl carbamate (49mg; 0.07mmol) add in the solution in 2mL toluene dichloro dicyano quinone (24mg, 0.11mmol).Gained solution was heated 30 minutes down at 120 ℃, be cooled to room temperature subsequently and be concentrated into dried.Obtain (1R)-1-(6-(2-(benzyl [(2-methyl cyclopropyl) methyl] amino)-6-[(sec.-propyl alkylsulfonyl) (methyl) amino] pyridin-4-yl } pyrimidine-4-yl)-1-methyl-2-phenylethyl t-butyl carbamate by the reverse-phase chromatography purifying, make it be dissolved in the methylene dichloride that 1mL contains 20%TFA.Make this miscellany place 1 hour, concentrate and obtain this title compound N-(4-{6-[(1R)-1-amino-1-methyl-2-phenylethyl] pyrimidine-4-yl }-6-{ benzyl [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl-prop-2-sulphonamide. ¹H?NMR(400MHz，d4-MeOH)δ9.29(s，1H)，7.66-7.65(m，1H)，7.31-7.21(m，8H)，7.02-7.01(m，2H)，6.96-6.93(m，2H)，4.98-4.60(m，2H)，3.83-3.66(m，2H)，3.38(s，3H)，3.35-3.25(m，4H)，1.81(s，3H)，1.16(d，J＝6.8Hz)，0.96(dd，J＝6Hz，J＝1.8Hz，3H)0.90-0.82(m，1H)，0.70-0.62(m，1H)，0.45-0.40(m，1H)，0.28-0.24(m，1H)；LCMS[M+H]＝599.1。

Embodiment 94

N (2-(5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-6-[(cyclopropyl methyl) (methyl) amino] pyridin-4-yl }-N-methyl Toluidrin

Steps A: will contain 6.52g (40.0mmol) 4-amino-2 in the 200mL pyridine, the solution of 6-dichloropyridine is handled with 22.8g (200mmol) methylsulfonyl chloride and was heated 72 hours down at 60 ℃.Cooling reaction mixture and evaporating solvent.The gained resistates is dissolved in the methylene dichloride of 200mL again and uses NaHCO ₃(50mL), water (3 * 50mL) and salt solution (50mL) washing.Organic phase MgSO ₄Drying is filtered and is concentrated.Obtain the disulfonic acid amide that required sulphonamide (5.30g, 55%) and 3.44g (27%) do not expect by silica gel chromatography purifying (20% EtOAc/ hexane).LCMS[M+H]＝241.1

Step B: the solution of 5.00g (20.7mmol) sulphonamide that will in 12.5g (176mmol) cyclopropylamine, contain steps A under 125 ℃ at the sealed tube internal heating.After 72 hours, cool off this reaction mixture and evaporate the brown resistates, obtain required aminopyridine (3.42g, 60%) by silica gel chromatography purifying (60% EtOAc/ hexane).LCMS[M+H]＝276.1

Step C: in 0 ℃ of solution of aminopyridine that in 15mL DMF, contains 1.00g (3.62mmol) step B and 1.13g (7.98mmol) methyl iodide, add 191mg (7.98mmol) sodium hydride.This solution is at room temperature stirred months 17 hours and end with 5mL water.With reaction mixture with 100mL ether dilution and water (6 * 10mL), use salt solution (10mL) washing subsequently.Organic phase MgSO ₄Drying is filtered and is concentrated.Obtain this aminopyridine that methylates (1.00g, 91%) by silica gel chromatography purifying (30% EtOAc/Hex).LCMS[M+H]＝304.1

Step D: (773mg 6.58mmol), adds Pd (PPh3) 4mg, 0.658mmol) subsequently to obtain adding in the solution zinc cyanide to the chloropyridine that contains 1.00g (3.29mmol) step C in 15mL DMF.This solution heated 24 hours down at 90 ℃, made this reaction mixture cooling subsequently and with ether dilution (100mL), used H subsequently ₂O (6 * 10mL) washings.Organic phase MgSO ₄Drying is filtered and is concentrated.Obtain required cyanopyridine (2.66g, 81%) by silica gel chromatography purifying (30% EtOAc/Hex).LCMS[M+H]＝295.2

Step e: at 9: 1 EtOH/H ₂Contain among the O (10mL) in steps the cyanopyridine of D (add in the 150mg, solution 0.51mmol) solid KOH (286mg, 5.1mmol).This solution is heated to 85 ℃ reaches 16 hours.The cooling reaction mixture is used 3N HCl acidifying, and (3 * 30mL) extract with EtOAc.The organic layer that merges salt water washing (1 * 50mL), use MgSO ₄Drying is filtered and is concentrated.Resistates need not to be further purified and can use.In the solution of this carboxylic acid in DCM (5mL), add the hydrazides intermediate compound I (140mg, 0.48mmol), DIPEA (186mg, 1.43mmol) and bop reagent (212mg, 0.48mmol).This reaction was at room temperature stirred 1 hour and directly was carried in silicagel column (50%EtOAc/ hexane) and obtains required hydrazides (150mg, 53%) LCMS[M+H]=589.1

Step F: to the hydrazides of step e (150mg, 0.255mmol) 1, add in the 2-dichloroethane solution (3mL) Burgess reagent (182mg, 0.764mmol).With this solution 140 ℃ of following microwave treatment 8 minutes.Obtain required  diazole (90mg, 62%) by the silica gel chromatography purifying.LCMS[M+H]＝571.1?H?NMR(CDCl ₃)δ7.29-7.19(m，5H)，7.05(m，2H)，6.79(s，1H)，5.23(bs，1H)，3.54-3.41(m，4H)，3.38(s，3H)，3.17(s，3H)，2.92(s，3H)，1.76(m，3H)，1.41(br?s，9H)，1.24-1.13(m，1H)，0.50(m，2H)，0.26(m，2H)。

Step G: (add TFA (1.5mL) in the 50mg, DCM 0.083mmol) (5mL) solution to the  of step e diazole.This solution stirring 30 is placed and concentrated.Obtain 50mg (100%) required compound with the ether development, it is a tfa salt.LCMS[M+H]＝471.1

¹H?NMR(CD ₃OD)δ7.41(s，1H)，7.37-7.25(m，3H)，7.05(m，2H)，6.75(s，1H)，3.54-3.41(m，4H)，3.38(s，3H)，3.17(s，3H)，2.94(s，3H)，1.86(m，3H)，1.24-1.13(m，1H)，0.50(m，2H)，0.26(m，2H)。

Following abbreviation is applicable in full:

Me: methyl

Bu: butyl

I-Bu: isobutyl-

T-Bu: the tertiary butyl

Et: ethyl

Pr: propyl group

I-Pr: sec.-propyl

Ar: aryl

Ph: phenyl

Py: pyridine

Ac: ethanoyl

EDC: ethyl-3-(3-dimethylaminopropyl)-carbodiimide

HOAt:1-hydroxyl-7-azepine-benzotriazole

HOBt: hydroxybenzotriazole

DMF:N, N '-dimethyl formamide

THF: tetrahydrofuran (THF)

DMSO: dimethyl sulfoxide (DMSO)

EDTA: ethylenediamine tetraacetic acid (EDTA)

Boc: tert-butoxycarbonyl

BOP: benzotriazole-1-base oxygen base-three (dimethylamino) 

CHAPS:3-[(3-chloro-acid amide base propyl group) Dimethyl Ammonium]-2-hydroxyl-1-and sulfonate

TEA: triethylamine

TFA: trifluoroacetic acid

NaHMDS: hexamethyldisilazane

The NCS:N-chloro-succinimide

DCE: ethylene dichloride

DIPEA: diisopropylethylamine

DCM: methylene dichloride

DIC:N, N '-DIC

DCA:1, the 2-ethylene dichloride

DMA:N, the N-N,N-DIMETHYLACETAMIDE

Aq: moisture

Rt: room temperature

HPLC: high efficiency liquid chromatography

Though the present invention describes and explanation with reference to some embodiments, it will be understood by those skilled in the art that many adaptations, change, modification, the method that substitutes, omits and add and scheme can obtain not breaking away under aim of the present invention and the scope.So, of the present invention be service by claims limit and these type of claims as much as possible from broadly carrying out reasonable dismissal.

Claims

1. the compound of formula (I):

Wherein: X is selected from group

R wherein ¹¹And R ¹²Be independently selected from

(a) hydrogen,

(b)-C _1-10Alkyl,

(c) C _2-10Alkenyl,

(d) C _2-10Alkynyl group,

(e)-C _3-12Cycloalkyl and

(f) be selected from the aryl of phenyl and naphthyl;

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl and

(vi)-O-C _1-10Alkyl,

Y ¹Be N, and Y ²With Y4 be respectively CH, or

Y ²Be N, and Y ¹And Y ³Be respectively CH, or

Y ³Be N, and Y ¹And Y ²Be respectively CH;

A is selected from group

(1) hydrogen,

(2)-C _1-10Alkyl and

(3)-C _2-10Alkenyl,

(a) halogen,

(b)-C _3-12Cycloalkyl,

(c)-OH，

(d)-CN，

(e)-O-C _1-10Alkyl,

(f) phenyl, or

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _1-10Alkyl, or

(vi)-C _3-12Cycloalkyl;

(1) halogen,

(2)-C _3-12Cycloalkyl,

(3)-OH，

(4)-CN，

(5)-O-C _1-10Alkyl and

(6)-C _1-10Alkyl;

R ¹Be the aryl that (1) is selected from phenyl and naphthyl,

(3)-C _1-10Alkyl and

(a) halogen,

(b)-C _1-10Alkyl, wherein this alkyl is not replace or replaced by halogen,

(c)-OH，

(d)-CN，

(e)-O-C _1-10Alkyl,

(f)-C _3-12Cycloalkyl and

(g)-NR ⁸R ⁹；

R ²Be selected from

(1)-OH and

(2)-NR ⁸R ⁹, R wherein ⁸And R ⁹Be selected from

(a) hydrogen,

(b) C _1-10Alkyl and

(c) C0-6 alkyl-C _6-10Aryl,

R ⁴Be selected from group

(1)-C _1-10Alkyl, or

(a) halogen,

(b)-OH，

(c)-CN，

(d)-O-C _1-10Alkyl,

(e)-C _1-10Alkyl,

(f)-C _3-12Cycloalkyl,

(g) be selected from the aryl of phenyl and naphthyl, or

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl, or

(vi)-C _1-10Alkyl;

R ⁷Be selected from group

(1) hydrogen,

(2)-C _1-10Alkyl and

(3) be selected from the aryl of phenyl and naphthyl;

(a) halogen,

(b)-OH，

(c)-CN，

(d)-O-C _1-10Alkyl,

(e)-C _3-12Cycloalkyl,

(f) be selected from the aryl of phenyl and naphthyl, or

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl,

(v)-C _3-12Cycloalkyl, or

(vi) be selected from the aryl of phenyl and naphthyl;

Or R ⁴And R ⁷Formation-CH can link to each other ₂CH ₂CH ₂-;

R ⁵And R ⁶Be independently selected from

(1) hydrogen,

(2)-C _1-10Alkyl,

(3)-C _2-10Alkenyl,

(4)-C _2-10Alkynyl group and

(5)-C _1-10Alkyl-C _3-12Cycloalkyl;

(a) halogen,

(b)-OH，

(c)-CN，

(d)-C _1-10Alkyl

(e)-C _3-12Cycloalkyl,

(f)-O-C _1-10Alkyl,

Wherein this heteroaryl can not replace or be replaced by halogen;

(h) phenyl, or

(i)-NR ⁸R ⁹；

(a)-C _1-10Alkyl,

(b)-C _3-12Cycloalkyl,

(c)-(CH ₂) positive phenyl,

(d)-C _2-10Alkenyl, or

(i) halogen,

(ii)-OH，

(iii)-CN，

(iv)-O-C _1-10Alkyl, or

(v)-C _3-12Cycloalkyl;

(i) halogen,

(ii)-C _1-10Alkyl,

(iii)-OH，

(iv)-CN，

(v)-C _3-12Cycloalkyl, or

(vi)-O-C _1-10Alkyl;

N is 0,1,2,3 or 4;

2. the compound of claim 1, wherein Y ¹Be N and Y ²And Y ³Be respectively CH.

3. the compound of claim 1, wherein R ¹Be that phenyl and Q are CH ₂

4. the compound of claim 1, wherein R ²Be-NR ⁸R ⁹

5. the compound of claim 1, wherein A is C _1-6Alkyl.

6. the compound of claim 1, wherein R ⁴And R ⁷Be C _1-10Alkyl.

7. the compound of claim 1, wherein X is that the  diazole is selected from

8. the compound of claim 1, wherein X is that the  azoles is selected from

9. the compound of claim 1, wherein X is that thiazole is selected from

10. the compound of claim 1, it is the compound of formula (II)

A wherein, X, Y ¹, Y ², Y ³, Q, R ¹, R ², R ⁴, R ⁵And R ⁷As the definition of above-mentioned claim 1, and its pharmaceutically acceptable salt, with and each enantiomer and diastereomer.

11. the compound of claim 10, wherein Y ¹Be N and Y ²And Y ³Be respectively CH.

12. the compound of claim 10, wherein R ¹Be that phenyl and Q are CH ₂

13. the compound of claim 10, wherein R ²Be NR ⁸R ⁹

14. the compound of claim 10, wherein X is that the  diazole is selected from

15. the compound of claim 10, wherein X is that the  azoles is selected from

16. the compound of claim 10, wherein X is that thiazole is selected from

17. the compound of claim 10, wherein R ⁵Be hydrogen or C _1-10Alkyl, wherein this C _1-10Alkyl does not replace or is replaced by one or more following groups:

(1) halogen,

(2)-OH，

(3)-CN，

(4) phenyl,

(5)-OC _1-10Alkyl, or

(6)-NR ⁸R ⁹。

18. the compound of claim 17, wherein R ⁵Be C _1-10Alkyl, wherein this C _1-10Alkyl does not replace or is replaced by one or more halogens.

19. the compound of formula (III)

A wherein, X, Q, R ¹, R ², R ⁴, R ⁵, R ⁶And R ⁷As the definition of above-mentioned claim 1, with and pharmaceutically acceptable salt and its each enantiomer and diastereomer.

20. the compound of claim 1, it is selected from group

21. pharmaceutical composition wherein contains compound or its pharmaceutically acceptable salt and the pharmaceutical acceptable carrier of the claim 1 for the treatment of significant quantity.

22. the method for a treatment Alzheimer in its patient of needs comprises compound or its pharmaceutically acceptable salt to the claim 1 of this patient's administering therapeutic significant quantity.