CN103221413A - Triazolopyrimidine derivative and preparation method and use thereof - Google Patents

Abstract

The present invention relates to triazolopyrimidine derivatives and a preparation method and a use thereof. In particular, the present invention relates to triazolopyrimidine derivatives as shown in general formula (I), and the use thereof as a therapeutic agent, especially as a P2Y12 receptor antagonist, wherein the definition of each substituent in general formula (I) is the same as the definition in the description.

Description

Triazolo pyrimidine analog derivative, Its Preparation Method And Use

Triazolo pyrimidine analog derivative, Its Preparation Method And Use technical field

The present invention relates to a kind of novel triazolopyrimidines analog derivative, the pharmaceutical composition containing the derivative, its preparation method and its it is used as purposes of the therapeutic agent especially as P2Y12 receptor antagonists.Background technology

Signal transduction is the various bioelectric detecting processes that extracellular information transmission to intracellular process is participated in cell, by the information enhancement of acquisition, breaks up, integrates and pass to downstream sensors, so as to realize various biological effect processes.Signal transduction is transmitted by film surface receptor, and G G-protein linked receptors are current maximum film surface receptor families, take part in numerous signal transduction process.

The G-protein species that g protein coupled receptor (GPCRs) is coupled according to downstream is divided into three classes:Gs albumen, Gi albumen, four kinds of G-protein hypotypes of Gq albumen and G12/13 albumen mediate signal to transmit.At present, only find that g protein coupled receptor is present in eucaryote.The part of g protein coupled receptor, which can be combined, includes telergone, neurotransmitter, polypeptide, micromolecular compound etc..G G-protein linked receptors take part in the formation of numerous diseases, therefore be important drug targets, and about 30% medicine is all to be used as target using g protein coupled receptor currently on the market.

Gq/Gi coupled receptors have numerous subfamilies, just include among these：（1) purinoceptor family (Purinergic receptor), member includes PI, P2;(2) adenosine receptor family (Adenosine receptor), member includes Al, A2A, A2B, A3, and they are the classes in purinoceptor family PI subtribes.Purinoceptor family plays key effect in terms of regulation myocardial oxygen consumption, coronary flow, anti-inflammatory, vascular reactivity, natural death of cerebral cells, cytokine secretion.

P2 subtribes can be divided into five phenotypes again according to pharmacological characteristic and Tissue distribution：The Τ of 2 Ζ, P2U standing grain Β Ρ of P2X, P2Y, Ρ 2.The wherein Χ of Ρ 2 and the Ζ of Ρ 2 belong to ion channel receptor, and the Τ of P2Y, P2U and Ρ 2 belongs to g protein coupled receptor.

The Υ receptor families of Ρ 2 for the coupled G proteins having found include 9 kinds of (Υ 1 of Ρ 2,2,4,6,11-14) hypotypes, it is distributed widely in various kinds of cell and tissue, homology is very low between hypotype, so different hypotypes is very high to the selectivity of part.The wherein Υ 1,2,6,14 of Ρ 2 combine Gq and activate PLC approach；P2Y12,13 combine Gi and suppress adenyl cyclase activity；P2Y4 is coupled two kinds of G-proteins of Gq/Gi；P2Y11 is coupled two kinds of G-proteins of Gq/Gs.A series of receptor-mediated biological effects of P2Y include platelet aggregation, immunological regulation, smooth muscle cell proliferation etc..

Thrombus is formed in coagulation process by platelet aggregation, and the thrombus formed in the case of non-damaging can reduce VPV or even block tail vein to cause the diseases such as necrosis, athero- artery sclerosis, myocardial infarction.Hematoblastic activation has number of ways and mechanism such as the collagen of exposure, tissue factor, endogenous stimulus factors A DP in blood vessel.

It is indispensable that P2Y1 and P2Y12 acceptors are activated during platelet aggregation jointly.P2Y1 acceptors discharge Ca by activating PBK approach²⁺So as to cause blood platelet deformation to be assembled.P2Y1 gene knockout types are small Mouse will not react [Fabre JE et al., Nat Med 5 for the ADP platelet aggregations triggered and deformation: 1199-1202 (1999)].

P2Y12 acceptors were cloned [Hollopeter G et al., Nature 409 first in 2001:202-207 (2001)].Research shows that P2Y12 acceptors participate in the processes such as fibrinogen deceptor activation, thrombosis, thromboxane A2 generation, the platelet aggregation of wound initiation.The P2Y12 acceptors of the mankind are made up of 342 amino acid, are distributed mainly in blood platelet and brain tissue, are the targets of antithrombotic thiophene pyridine compounds and their.The endogenous stimulus factor such as ADP etc. combines P2Y12 by paths such as cognition activation PBK and then activation Raplb, Akt, ER path causes the activation binding fiber proteinogen of fibrinogen deceptor to trigger thrombosis or platelet aggregation jointly.This process must can just be realized in the case where P2Y1 acceptors are activated simultaneously.It is worth noting that by PAR-1 acceptors（PAR-1 acceptors belong to extracellular N-terminal portion in g protein coupled receptor family, structure and are cut off and activated by itself by serine stretch protein enzyme such as fibrin ferment, and then play hemoglutination）The activation of P2Y12 acceptors must also be relied on and be amplified signal by G12/13 paths by activating the Akt Pathway Activations triggered.P2Y12 acceptors are blocked to significantly inhibit the platelet aggregation and thrombosis by ADP and the initiation such as PAR-1 activating peptides SFLLR, collagen of other stimulating factors.

The patent application of the P2Y12 receptor antagonists of series is disclosed at present, including WO1999005143, WO2000034283 and WO200103642.

Although the P2Y12 receptor antagonists of the diseases such as a series of platelet aggregation and thrombus have been disclosed at present, the new compound with more preferable drug effect of exploitation is stilled need, by being continually striving to, present invention design has formula（I the compound of the structure shown in), and find that the compound with this class formation shows excellent effect and effect.The content of the invention

It is an object of the invention to provide the novel triazolopyrimidines analog derivative shown in a kind of formula ω or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt,

Its towel：

- it is singly-bound or double bond；

R¹Selected from cycloalkyl or heteroaryl；

Work as R¹During selected from cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced, or R¹Selected from aryl or heteroaryl-condensed cycloalkyl, wherein described with aryl or heteroaryl-condensed Cycloalkyl optionally further by it is one or more be selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R⁷、 -C(0)0R⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

Work as R¹During selected from heteroaryl, the heteroaryl is optionally further selected from alkyl, halogen, hydroxyl, alkoxy, nitro, cyano group ,-C (0) R by one or more⁷ -C(0)OR⁷ -S(0)_mR⁷ -NR⁸R⁹、 -C(0)NR⁸R⁹ -NR⁸C(0)R⁹ -NR⁸S( )_mR⁹Or-S ()_mNR⁸R⁹Substituent replaced；

R²Selected from alkyl, the alkyl is optionally further replaced by one or more substituents selected from cycloalkyl;When=be singly-bound when, R³Selected from halogen, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced；Or R³And R⁴- play formation=0 or alkenyl；When=be double bond when, R³It is not present, and meets valence bond theory；

When=be singly-bound when, R⁴Selected from hydrogen atom or alkyl, or R³And R⁴- formation=0 or alkenyl are played, wherein the alkenyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, alkoxy, nitro or cyano group；Or R⁴With R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory；When¹When ^ is double bond, R⁴Selected from hydrogen atom；

R⁵Selected from hydrogen atom, alkyl, hydroxyl or halogen；When¹When ^ is singly-bound, R⁵With R⁴Optionally into cycloalkyl, and cyclization meets valence bond theory；

Condition is to work as R²Selected from unsubstituted alkyl, R³Selected from alkoxy or hydroxyl, wherein alkoxy is replaced by a hydroxyl, R⁴Selected from hydrogen atom, R⁵During selected from hydrogen atom, R¹It is not the C being substituted by phenyl₃〜C₈Cycloalkyl；

R⁶Selected from aryl or heteroaryl, wherein the aryl or heteroaryl are optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R-C (0) 0R by one or more independently of one another⁷ -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

R⁷、 R⁸And R⁹It is each independently selected from hydrogen atom, alkyl, cycloalkyl, hydroxyalkyl, heterocyclic radical, aryl or heteroaryl；

M is 0,1 or 2.In a preferred embodiment in accordance with this invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt described in a kind of logical formula (I), it is the compound or pharmaceutically acceptable salt thereof shown in a kind of formula (Π)： Wherein： ^〜11⁵Described in the definition for being as defined above mutual-through type (I).In a preferred embodiment in accordance with this invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt described in a kind of logical formula (I), it is a kind of formula (Π Ι) institute salt：

Wherein： ^〜11⁵Described in the definition for being as defined above mutual-through type (I).In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), wherein R¹Selected from cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced； R⁶It is as defined above mutual-through type（I described in definition).In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic structure body, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), wherein , R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl or halogen independently of one another.In another preferred embodiment of the present invention, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt of a kind of logical formula (I) depicted, wherein R³Selected from halogen, hydroxyl, alkyl or alkoxy, the alkyl, alkoxy are independently of one another optionally further by one or more hydroxyls, OR⁷Or halogen is replaced.In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures shown in a kind of logical formula (I) and its Officinal salt, wherein：

R¹Selected from cycloalkyl or heteroaryl；

Work as R¹During selected from cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced, or R¹Selected from aryl or heteroaryl-condensed cycloalkyl, wherein described with aryl or heteroaryl-condensed cycloalkyl is optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

Work as R¹During selected from heteroaryl, the heteroaryl is optionally further selected from alkyl, halogen, hydroxyl, alkoxy, nitro, cyano group ,-C (0) R by one or more⁷ -C(0)OR⁷ -S(0)_mR⁷ -NR⁸R⁹、 -C(0)NR⁸R⁹ -NR⁸C(0)R⁹ -NR⁸S( )_mR⁹Or-S ()_mNR⁸R⁹Substituent replaced；

R²Selected from alkyl, the alkyl is optionally further replaced by one or more cycloalkyl；

When=it is singly-bound, R⁵Selected from alkyl, hydroxyl or halogen, or and R⁴Optionally into cycloalkyl, and cyclization is when meeting valence bond theory：

R³Selected from halogen, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are further selected from hydroxyl, halogen, cycloalkyl, OR by least two independently of one another⁷Or the substituent of heterocyclic radical is replaced；

R⁴Selected from hydrogen atom, or and R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory；

When=it is singly-bound, R⁵During for hydrogen atom：

R³For alkoxy, wherein the alkoxy is further replaced by least two substituents for being each independently selected from hydroxyl, halogen, cycloalkyl, hydroxyalkyl or heterocyclic radical；

R⁴For hydrogen atom；

When=be double bond when： R³It is not present, and meets valence bond theory； R⁴ 、 R⁵Selected from hydrogen atom；

R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹ -NR⁸C(0)R⁹ -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

R⁷、 R⁸And R⁹It is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;M is 0,1 or 2.In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), it is a kind of logical formula (IV) salt：

( IV ) Its towel：

R³Selected from ^ elements, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced； R⁴Selected from alkyl, hydrogen atom, or and R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory； R⁵Selected from alkyl, hydroxyl or halogen, or and R⁴Optionally into cycloalkyl, and cyclization meets valence bond theory； R⁷Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；

R R²Described in the definition for being as defined above mutual-through type ω.In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), it is a kind of logical formula (V) institute salt：

(V)

Its towel：

R³Selected from halogen, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are further selected from hydroxyl, halogen, cycloalkyl, OR by least two independently of one another⁷Or the substituent of heterocyclic radical is replaced；

R⁷Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；

R R²Described in the definition for being as defined above mutual-through type ω.In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), it is salt used in a kind of logical formula (VI)：

( VI )

Wherein： ^〜11²Described in the definition for being as defined above mutual-through type (I).In another preferred embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures shown in a kind of logical formula (I) and its Officinal salt, it is a kind of formula (ν π) salt:

( VH

Its towel：

R²Selected from alkyl, the alkyl is further replaced by one or more cycloalkyl；

R³Selected from ^ elements, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced； R⁷Selected from hydrogen atom, alkyl, cycloalkyl, hydroxyalkyl, heterocyclic radical, aryl or heteroaryl；

R¹Described in the definition for being as defined above mutual-through type ω.In another embodiment of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I), wherein further, preferably：

R¹For cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced； R²Selected from alkyl, the alkyl is further replaced by one or more cycloalkyl, and the cycloalkyl is preferably cyclopropyl；

R³Selected from alkoxy or hydroxyl, wherein the alkoxy is optionally further replaced by one or more substituents selected from hydroxyl or halogen；

R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more independently of one another⁷、 -C(0)0R⁷、 -S(0)_MR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_MR⁹Or-S (0)_MNR⁸R⁹Substituent replaced；Preferably ^ is for phenyl.The typical compound of the present invention includes, but are not limited to:

^HN、^YY^F

Η Ο ^ Ν, J Shang

Eight people^s、

HO OH

(1S, 2 3R, 5-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [[(lR, 2-2- (3,4- difluorophenyls）Cyclopropyl] amino] triazol [4,5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol

HO N Shang 11

HO Ώ OH

(lR, 2R, 35,5R)-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [[(lR, 2-2- (3,4- difluorophenyls) cyclopropyl] amino] triazol [4,5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol

(1S, 2 3R, 5-3- { 7- [[(lR, 2R)-2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol

^ΗΟFly^Ν' eight

(1S, 2 3WR) -3- (2- hydroxyl-oxethyls) -5- [7- (indanyl -2- bases amino) -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl] cyclopenta -1,2- glycol

HO OH (1S, 2 3S, 4-5- { 7- [[(lR, 2R)-2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta-1,2,3,4- tetrols

HON. Jl

Η⁰ Γ N ^S〜

HO OH

(1S, 23 4R) -5- 7- [[(lR, 2^-2- (3,4- difluorophenyl) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] -3- bases } cyclopenta -1,2,3,4- tetrols

(lR, 2S, 3S, 4S, 5S) -4- 7- [[(lR, 25) -2- (3,4- difluorophenyl) cyclopropyl] amino] -5- propyl group sulfydryl-triazol-d] the fluoro- cyclopenta -1,2 of pyrimidin-3-yl 5-, 3- triols

(1S, 2 3^^, 5R) -3- { 7- [[(lR, 2^-2- (3,4- difluorophenyls) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } the fluoro- 5- of -4- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol

(15,25,35,5R) -3- (2- hydroxyl-oxethyls) -5- { 7- [[(lR, 2R) -2- (4- methylthiazol -5- bases) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta -1,2- glycol

HO OH (1S, 2 3R, 5^-3- { 7- [[(lR, 2^-2- (3,4- difluorophenyl) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } -5- (2,3- dihydroxy propoxyl group) cyclopenta -1,2- glycol

(S, 2S, 3S, 4R, 5S) -3- { 7- [[(R, 2S) -2- (3,4- difluorophenyls) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls）Cyclopenta -1,2,4- triols

(lS, 2S, 3S, 5R) -3- (2- hydroxyl-oxethyls）- 5- { 5- propyl group sulfydryls -7- [(lR, 2S/lS, 2R) -2- (3- pyridine radicals) cyclopropylamino] triazol [4,5-d] pyrimidine -3- bases } pentamethylene -1,2- glycol

(1S, 23 4R, 5R) -3- (7- ((lR, 2^-2- (3,4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) the fluoro- 5- of -4- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol

(1R, 23 4S, 5R) -4- (7- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazole [4,5-d] pyrimidin-3-yl) -5- fluorine pentamethylene -1,2,3- triols

(S, 2S, 3R, 5S) -3- (7- ((R, 2S) -2- (3,4- difluorophenyls）Cyclopropylamino) -5- (rosickyite Base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -5- (the fluoro- 3- hydroxy propyloxy groups of 2-) pentamethylene -1,2- glycol

s〜

ΗΟ ΟΗ

(15,2R, 5R) -5- (7- ((lR, 25) -2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazole-d] pyrimidin-3-yl) amyl- 3- alkene -1, the 2- glycol of ring

(15,25,35,5R) -3- (2,2- difluoroethoxy) -5- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene -1,2- glycol

(lR, 2R, 3^4R, 5-4- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3^ [1,2,3] triazol [4,5-^] pyrimidin-3-yl) two ring simultaneously [3.1.0] hexane-2,3- glycol of-1- (methylol)

N- J Shang Η Ο Ο Η

(1S, 2 3R, 5^-3- (7- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -5- fluorine pentamethylene -1,2- glycol

ΗΟ、' ΟΗ

(1^2R, 5R)-5- (7- (((lR, 2-2- (3,4- difluorophenyl) cyclopropyl) amino)-5- (rosickyite

Thing form and its officinal salt.The present invention relates to the compound described in a kind of logical formula (I) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its preparation method of officinal salt, it comprises the following steps：

( IA )

Formula (IA) compound and 1^ Ν Η₂Reaction, optionally further sloughs the protection group Ρ and Ρ ' of hydroxyl, obtains logical formula (I) compound；

Wherein：L is leaving group, preferably halogen；

Ρ and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or Ρ and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy;

R R²〜R⁵Described in the definition for being as defined above mutual-through type (I). The invention further relates to the compound shown in a kind of formula (Π) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its preparation method of officinal salt, it comprises the following steps：

Formula (Π Α) compound and 1^ Ν Η₂Reaction, optionally further sloughs the protection group Ρ and Ρ ' of hydroxyl, obtains formula (Π) compound；

Wherein：L is leaving group, preferably halogen；

Ρ and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or Ρ and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy;

R R²-R⁵Described in the definition for being as defined above mutual-through type (I).Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt and pharmaceutically acceptable carrier, diluent and excipient shown in the logical formula (I) of therapeutically effective amount.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in formula (I), or purposes of the pharmaceutical composition comprising it in the medicine for preparing P2Y12 receptor antagonists.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in formula (I), or the pharmaceutical composition comprising it is preparing the purposes in treating or preventing miocardial infarction, embolic breaking-out, Transient ischemic attacks, peripheral vascular disease or anginal medicine.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in formula (I), or purposes of the pharmaceutical composition comprising it in the medicine for treating or preventing the disorderly disease of platelet aggregation is prepared.Detailed description of the invention

Unless stated to the contrary, the term used in the specification and in the claims has following implications.

" alkyl " refers to the aliphatic hydrocarbon group of saturation, it is the straight chain and branched group for including 1 to 20 carbon atom, preferably comprise the alkyl of 1 to 12 carbon atom, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propylenes Base, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- ethyl -2- methyl-propyls, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyls, 1,3- dimethylbutyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its various branched chain isomers etc.；Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent can preferably be independently selected by one or more from following substituent group on any workable tie point：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base ,-C (0) R⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms, preferably comprises 3 to 12 carbon atoms, and more preferably cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..The non-limiting examples of polycyclic naphthene base include the cycloalkyl of loop coil, condensed ring and bridged ring.

" spiro cycloalkyl group " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic moiety of a carbon atom (title spiro-atom), it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spiro cycloalkyl groups or many spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring, is preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting examples of spiro cycloalkyl group include：

" cycloalkyl " refers to the full carbon polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in 5 to 20 yuan, system, and wherein one or more rings can contain one or more double bonds, but not have One ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring alkyl can be divided into according to the number of composition ring, preferably bicyclic or three rings,.The non-limiting examples of cycloalkyl include：

" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, and it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.Bridge ring alkyl it is non-

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being cycloalkyl with the ring that precursor structure links together, non-limiting examples include indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be optionally substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base ,-NR⁸R⁹、 -C(0)NR⁸R⁹ -NR⁸C(0)R⁹ -NR⁸S(0)_mR⁹、 -S(0)_mNR⁸R⁹、 -C(O)R¹⁰ -C(0)OR¹⁽⁾Or-S (O)_mR¹⁰。

" alkenyl " refers to the alkyl as defined above being made up of at least two carbon atoms and at least one carbon-to-carbon double bond.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl.Alkenyl can be substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) R⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" block base " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are constituted.Such as second block base, third piece of base of 1-, third piece of base of 2-, 1-, 2- or 3- fourth block base.Block base can be substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, -C(0)R'、 -C(0)OR\ -S(0)_mR\ -NR ^y、 -C(0)NR ^y、 -NRT(0)R^y -NR⁸S(0)_mR^yOr-S (0)_mNR⁸R⁹。

" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)_m(wherein m is integer 0 to 2), but do not include -0-0-, -0-S- or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 14 are hetero atoms, more preferably heterocyclic ring includes 3 to 10 annular atoms.The non-limiting examples of monocyclic heterocycles base include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..The non-limiting examples of multiring heterocyclic include the heterocyclic radical of loop coil, condensed ring and bridged ring.

" spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)_m(wherein m is integer 0 to 2), remaining annular atom is carbon.It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring, is preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.Spiro heterocyclic radical it is non-limiting

" condensed hetero ring base " refers to 5 to 20 yuan, the polycyclic heterocyclic group of each ring and shared a pair of the atoms adjoined of other rings in system in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)_m(wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 can be divided into according to the number of composition ring.The non-limiting examples of condensed hetero ring base include：

" bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)_m(wherein m is integer 0 to 2), remaining annular atom is Carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical, preferably bicyclic, three rings or Fourth Ring, more preferably bicyclic or three rings can be divided into according to the number of composition ring.The non-limiting examples of bridge heterocyclic radical include：

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring being connected to precursor structure includes for heterocycle non-limiting examples： With

Deng.Heterocyclic radical can be optionally substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base ,-C (0) R⁷、 -C(0)OR⁷ -S(0)_mR⁷ -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, polycyclic (i.e. its ring for the carrying phase adjacency pair carbon atom) group of pi-electron system with conjugation, preferably 6 to 10 yuan, such as phenyl and naphthyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, and ring together is aryl rings, and non-limiting examples include：

Aryl can be substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) R⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom are selected from oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan, more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical.The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is heteroaryl ring, non-limiting examples include：

Heteroaryl can be optionally substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) R⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" alkoxy " refers to-o- (base of washing) and-o- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limiting examples include methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxy can be optionally substituted or unsubstituted, when substituted, preferably be independently selected by one or more from following substituent group：Alkyl, alkenyl, block base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (0) R⁷、 -C(0)OR⁷ -S(0)_mR⁷ -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹。

" haloalkyl " refers to alkyl and replaced by one or more halogens.

" hydroxyl " refers to-OH groups.

" hydroxyalkyl " refers to alkyl and is optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH₂。

" cyano group " refers to-CN.

" nitro " refers to-N0₂。

" benzyl " refers to-CH₂- phenyl.

" oxo base " refers to=0.

" carboxylic acid group " refers to-C (0) OH.

" carboxylic acid ester groups " refers to-C (0) 0 (alkyl) or-C (0) 0 (cycloalkyl), and wherein alkyl, cycloalkyl is as defined above.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substitution " refers to one or more of group hydrogen atom, and preferably at most 5, more preferably 13 hydrogen atoms are replaced by the substituent of respective number independently of one another.Self-evident, substituent is only in theirs Possible chemical position, those skilled in the art can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.

" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically/officinal salt or pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.

" officinal salt " refers to the salt of the compounds of this invention, and this kind of salt has security and validity when being used in mammal body, and with due bioactivity.

R⁷〜R⁹Definition as described in general formula compound, m is 0,1 or 2.The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention uses following synthetic technology scheme：

A kind of formula（I the preparation method of the compound or pharmaceutically acceptable salt thereof described in), it includes：

( IE ) ( I )

General formula compound (IB) carries out aromatic nucleophilic substitution reaction in a solvent with general formula compound (IC), obtains general formula compound (ID);General formula compound (ID) is dissolved in solvent, adds natrium nitrosum, is reacted under condition of ice bath, is obtained general formula compound (IA);General formula compound (IA) is reacted in the basic conditions with R^NH^, obtains general formula compound (IE);General formula compound (IE) further sloughs the protection group P and P' of hydroxyl, obtains general formula compound（I) o reaction dissolvents include but is not limited to ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, DMF or its mixed solvent；

Go back original reagent includes but is not limited to iron powder；

The reagent for providing alkalescence condition includes but is not limited to organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, potassium tert-butoxide, described inorganic base include but is not limited to sodium hydride, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus or cesium carbonate；

Reaction temperature is controlled at -80 °C to 200 °C, preferably 0 °C to 100 °C;Reaction time general control was at 1 minute to 72 hours, preferably 15 minutes to 24 hours； Its towel：

Ri〜R⁵Definition such as formula (；I described in)；

L and L' is leaving group, preferably halogen；

P and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or P and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy.56 wherein described circle heterocycles bases optionally react in acid condition, slough protection group, obtain general formula compound (1).Described in a kind of logical formula (VI)

H₂N

(IB)

General formula compound (IB) carries out aromatic nucleophilic substitution reaction in a solvent with general formula compound (VIA), obtains general formula compound (VIB);General formula compound (VIB) is dissolved in solvent, adds natrium nitrosum, is reacted under condition of ice bath, is obtained general formula compound (VIC);General formula compound (VIC) is reacted in the basic conditions with R^NH^, obtains general formula compound (VID);General formula compound (VID) reacts in the presence of triphenylphosphine and azoformic acid diester (being preferably diisopropyl azodiformate), obtains general formula compound (VIE);General formula compound (VIE) further sloughs the protection group P and P' of hydroxyl, obtains general formula compound (VI).

Reaction dissolvent includes but is not limited to ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, DMF or its mixed solvent；

Go back original reagent includes but is not limited to hydrogen, iron powder or zinc powder；

The reagent for providing alkalescence condition includes but is not limited to organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, potassium tert-butoxide, described inorganic base include but is not limited to sodium hydride, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus or cesium carbonate；

Reaction temperature is controlled at -80 °C to 200 °C, preferably 0 °C to 100 °C;Reaction time general control was at 1 minute to 72 hours, preferably 15 minutes to 24 hours；

Its towel：

Ri〜R²Definition such as formula (；I described in)；

L and L' is leaving group, preferably halogen； P and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or P and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy.

(IVA) (IVE) (IV) general formula compound (IVB) carries out aromatic nucleophilic substitution reaction in a solvent with general formula compound (IVC), obtains general formula compound (IVD);General formula compound (IVD) is dissolved in solvent, and nitro is reduced in acid condition, obtains general formula compound (IVF);General formula compound (IVF) is dissolved in solvent, adds natrium nitrosum, is reacted under condition of ice bath, is obtained general formula compound (IVA);General formula compound (IVA) is reacted in the basic conditions with R^NH^, obtains general formula compound (IVE);General formula compound (IVE) further sloughs the protection group P and P' of hydroxyl, obtains general formula compound (IV).

Reaction dissolvent includes but is not limited to ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, DMF or its mixed solvent；

Go back original reagent includes but is not limited to iron powder；

The reagent for providing alkalescence condition includes but is not limited to organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, potassium tert-butoxide, described inorganic base include but is not limited to sodium hydride, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus or cesium carbonate；

Reaction temperature is controlled at -80 °C to 200 °C, preferably 0 °C to 100 °C;Reaction time general control was at 1 minute to 72 hours, preferably 15 minutes to 24 hours；

Its towel：

Ri〜R⁵Definition such as formula (；I described in)；

L and L' is leaving group, preferably halogen；

P and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or P and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy.Embodiment It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the scope of the present invention.

The experimental method of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to the condition proposed by raw material or commodity manufacturer.The unreceipted reagent specifically originated, is the conventional reagent of market purchase.

The structure of compound is determined by nuclear magnetic resonance (1H NMR) and/or mass spectrum (MS).IHNMR displacements (δ) are provided with the unit of hundred a ten thousandths (ppm).1H NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated methanol (CD₃OD), deuterochloroform (CDC1₃), hexadeuterated dimethyl sulfoxide (OMSO-d₆), inside it is designated as tetramethylsilane (TMS).

MS measure is with FINMGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model： Finnigan LCQ advantage MAX).

HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (the 150x4.6mm chromatographic columns of Sunfire C 18) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18 150x4.6mm chromatographic columns）.

IC₅The measure of o values NovoStar ELIASAs (German BMG companies）.

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography

(TLC) specification that the silica gel plate used is used is the mm of 0.15 mm 0.2, and the silica gel plate specification that thin-layer chromatography isolates and purifies product use is the mm of 0.4 mm 0.5.

Silicagel column is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200 300.

Alkali alumina post is carrier with the mesh alkali aluminas of FCP200 300 typically using traditional Chinese medicines chromatography.

The known initiation material of the present invention can be used or synthesized according to methods known in the art, or can be in

The splendid remote chemistry scientific and technological (Accela ChemBio Inc) of ABCR GmbH ＆ Co. KG, Acros Organics, Aldrich Chemical Company and up to the purchase of the companies such as auspicious chemicals.

Without specified otherwise in embodiment, reaction is carried out under nitrogen or argon atmospher.

Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of about 1 L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of about 1 L volume.

Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS types hydrogenation instrument.

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature, preferably 20 °C 30 °C.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), there is the system of solvent used in reaction：Dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, acetone system, the volume ratio of solvent are adjusted according to the polarity difference of compound.

The system of the eluant, eluent for the column chromatography that purifying compound is used and the system of the solvent of thin-layered chromatography include：

A:Dichloromethane and methanol system, B:N-hexane and ethyl acetate system, C:Dichloromethane and acetone system,

D:Methanol system, E:Petroleum ether and ethyl acetate system, F:Ethyl acetate and methanol system, the volume of solvent It is adjusted than the polarity difference according to compound, the acid reagents such as the alkalescence such as a small amount of triethylamine or acetic acid can also be added and be adjusted.

Embodiment 1

(the ＆ S' of 1S, 2 ＆ 3)-5- 7- [[(lR, 2-2- (3,4- difluorophenyl) cyclopropyl] amino]-5- propyl group sulfydryl-triazol

[4,5-d] -3- bases } cyclopenta -1,2,3,4- tetrols

The first step

The chloro- l- of 2- (3,4- difluorophenyl) ethyl ketone

Alchlor (26.3 g, 197 mmol) is added into 1,2- difluorobenzenes (25 g, 219 mmol), 50 °C is heated to, chloracetyl chloride C17.5 mL, 219 mmol is slowly added dropwise), stirred 1 hour at 50 °C.Reaction solution is slowly added to 100 g ice, in the mixed solution of 25 mL water and 38 mL concentrated hydrochloric acids, keeping temperature is less than 60 °C, after completion of dropping, mixed liquor is heated to 60 °C, layering, organic phase is washed with saturated nacl aqueous solution (25 mLx2), anhydrous sodium sulfate drying, filtering, Jian Ya Nong Shrink, obtain the chloro- 1- (3 of title product 2-, 4- difluorophenyls) ethyl ketone la (37 g, yellow solid), yield： 88.7%.

GC-MS m/z： 190.0 [M⁺]

Second step

(the chloro- 1- of 1^-2- (3,4- difluorophenyl) ethanol

By (^- diphenyl-pyrrolidin-2-yl-methanol (1.8 g, 6.8 mmol) it is dissolved in 45 mL toluene, add trimethylborate (1 g, 9.6 mmol), reacted 1.5 hours under 40 °C, maintain the temperature at 35 °C of 45 °C of addition dimethyl sulphide borines, reacted 1 hour at 40 °C, maintain the temperature at 35 °C 45 °C and add the chloro- 1- (3 of 75 mL 2-, 4- difluorophenyls) ethyl ketone la (26 g, 136 mmol) toluene solution, continue 40 °C react 1 hour.Reaction solution is cooled to 10 °C, keeping temperature is less than 35 °C, adds 25 mL methanol, and reaction solution is cooled into 20 °C, stirs 30 minutes.Jian Ya Nong Shrink reaction solutions, residue is washed (100 mLx4) with 10% acetic acid, extracted with toluene (50 mL), merge organic phase, washed with water (50 mL), anhydrous sodium sulfate drying, filtering, relief portion Fen Nong Shrink obtain the chloro- 1- (3 of the 1^1-2- of crude title product 60,4- difluorophenyls) ethanol lb (26.3g) toluene solution, directly carry out next step reaction.

GC-MS m/z： 192.0 [M⁺]

3rd step

(lR, 2R) -2- (3,4- difluorophenyls) ethylene-acetic acid ethyl ester is by 60% sodium hydride (10.9 g, 273 mmol) it is suspended in 100 mL toluene, it is heated to 40 °C, 60 mL (diethoxy-phosphate)-ethyl acetate (33.7 g are added dropwise, 150 mmol) toluene solution, 40 °C are reacted 1 hour, the chloro- 1- (3 of 60 mL (lS) -2- are added less than 60 °C, 4- difluorophenyls) ethanol lb (26.3 g, 137 mmol) toluene solution, 60 °C stir 12 hours.150 mL water are added into reaction solution, layering, organic phase anhydrous sodium sulfate drying, filtering, Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (lR, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid ethyl ester lc (13.8 g, faint yellow solid), yield： 44.7%.

MS m/z (ESI): 227.0 [M+l]

4th step

(lR, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid

By (lR, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid ethyl ester lc (13.8 g, 61 mmol) it is dissolved in 90 mL methanol, add 30% sodium hydroxide C4.39g, 109 mmol) solution, 65 °C are reacted 2 hours.Subtract the dense Shrink of pressure, add 100 mL toluene and 100 mL water, layering, with 35% salt acid for adjusting pH≤7, layering, with toluene (500 MLx2) extract, merge organic phase, with anhydrous sodium sulfate drying, filtering, Jian Ya Nong Shrink obtain crude title product (lR, 2R) -2- (3,4- difluorophenyls) ethylene-acetic acid Id (12.1 g, yellow liquid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 197.0[M-1]

5th step

(lR, 2R) -2- (3,4- difluorophenyl) cyclopropyl carboxamide

By (lR, 2R) -2- (3,4- difluorophenyls) ethylene-acetic acid Id (12.1 g, 61 mmol) is dissolved in 100 mL toluene, adds thionyl chloride (5.4 mL, 73.9 mmol), 35 °C are reacted 6 hours, and Jian Ya Nong Shrink add 28% ammoniacal liquor (14.9 g less than 10 °C into residue, 244 mmol) 35 mL water and 100 mL ethyl acetate, react 1 hour.With 35% salt acid for adjusting pH≤7, layering is extracted with ethyl acetate (100 mL), merge organic phase, washed, anhydrous sodium sulfate drying with water (100 mL), filtering, Jian Ya Nong Shrink add 300 mL n-hexanes, mashing, filtering, solid vacuum drying, obtain title product (lR, 2R) -2- (3,4- difluorophenyl) cyclopropyl carboxamide le (9.8 g, white solid), yield： 81.7%.

MS m/z (ESI): 198.0 [M+l]

6th step

(lR, 2^-2- (3,4- difluorophenyl) cyclopropylamine

By (lR, 2R) -2- (3,4- difluorophenyls) cyclopropyl carboxamide le (9 g, 45.64 mmol) add to 30% sodium hydroxide (16.43 g, 411 mmol) in solution, 20 25 °C are heated to, 13% sodium hypochlorite (8.49 g are added dropwise, 114 mmol) solution, is stirred 1 hour at 60 °C or so.Reaction solution is cooled down to 5 °C, with 37% salt acid for adjusting pH to 8.5 9.5,55 mL isopropyl acetates and 30 mL methanol are added, stirring, layering, is extracted with isopropyl acetate (30 mLx2), merges organic phase, Jian Ya Nong Shrink, obtain crude title product (lR, 2-2- (3,4- difluorophenyl) cyclopropylamine If (7.29 g, dark red solution), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 170.1 [M+l]

7th step

(lR, 2^-2- (3,4- difluorophenyls) cyclopropylamine L- (+)-tartrate is by (1R, 2-2- (3,4- difluorophenyls) cyclopropylamine If (7.29 g, 43.1 mmol) is dissolved in 100 mL ethyl acetate and methanol (V/V=7:3) in the mixed solvent, stirring is lower to add L- (+)-tartaric acid (3.88 g, 25.9 mmol), stirs 12 hours, there is solid precipitation.Filtering, solid is isolated and purified with silica gel column layer chromatography with eluant, eluent system D, obtains title product (1R, 2-2-03,4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (3.70 g, yellow solid), yield： 44.8%.

MS m/z (ESI): 170.1 [M+l]

1H NMR (400 MHz, DMSO-d₆) δ 7.29 (dd, 1H), 7.19 (dd, 1H), 6.91-7.08 (m, 1H), 4.00 (s, 2H), 2.65-2.78 (m, 1H), 2.21-2.37 (m, 1H), 1.27-1.43 (m, 1H), 1.07-1.21 (m, 1H)

8th step

[(3aR, 4R, 6R, 6aR) -6- methoxyl group -2,2- dimethyl -3a, 4,6,6a- tetrahydrofurans simultaneously [3,4-] [1,3] dioxole -4- yls] methanol

1 M methanol hydrochloride solutions (90 mL, 90 mmol) and trimethyl orthoformate (90 mL, 0.82 mol) are dissolved In 70 mL acetone, addition 30 mL (3R, 4S, 5R) -5- (methylol) tetrahydrofuran -2,3,4- triols lh (22.5g, 150 mmol) acetone soln, 70 °C are reacted 5 hours.Add 6 mL pyridines and reaction is quenched, Jian Ya Nong Shrink, residue is dissolved in 500 mL ethyl acetate, saturation sulfuric acid ketone solution (60 mL X 3) is used successively, water (60 mL) and saturated nacl aqueous solution (60 mL X 2) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product [(3aR, 4R, 6R, 6aR) -6- methoxyl groups -2, 2- dimethyl -3a, 4, 6, 6a- tetrahydrofurans simultaneously [3, 4-d] [l, 3] Dioxol-4 -yl] methanol li (15.5 g, light brown grease), yield： 50.6%.

1H NMR (400 MHz, CDC1₃) δ 4.09 (s, 1H), 4.81 (d, 1H), 4.56 (d, 1H), 4.38-4.42 (m, 1H), 3.67 (dd, 1H), 3.59 (dd, 1H), 3.41 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H)

9th step

(3aS, 4^6R, 6aR) -4- (iodomethyl) -6- methoxyl group -2,2- dimethyl -3a, 4,6,6a- tetrahydrofurans simultaneously [3,4-d] [1,3] dioxole

By [(3aR, 4R, 6R, 6aR) -6- methoxyl group -2,2- dimethyl -3a, 4,6,6a- tetrahydrofurans simultaneously [3,4-d] [1,3] dioxole -4- yls] methanol li (15.5 g, 76 mmol) is dissolved in 300 mL toluene and acetonitrile (V/V=1:1) in the mixed solvent, sequentially adds triphenylphosphine (24 g, 91 mmol) and imidazoles (7.75 g, 1 14 mmol), and iodine (23 g, 91 mmol), back flow reaction 5 minutes are added portionwise under stirring.It is cooled to room temperature, Jian Ya Nong Shrink, add 400 mL ether, saturated sodium thiosulfate solution (60 mL X 2) is used successively, water (60 mL) and saturated nacl aqueous solution (60 mL X 2) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 3a^^, 6R, 6aR) -4-0i allusion quotations methyl) -6- methoxyl groups -2, 2- dimethyl -3a, 4, 6, 6a- tetrahydrofurans simultaneously [3, U] [1, 3] dioxole lj (22.2 g, yellow oil yield： 93.3%.

Tenth step

(4R, 5R) -2,2- methyl -5- vinyl -1,3- dioxolane -4- formaldehyde will（3aS, 4 6R, 6aR) -4- (iodomethyls）- 6- methoxyl group -2,2- dimethyl -3a, 4,6,6a- tetrahydrofurans simultaneously [3, U] [1,3] dioxole lj (83 g, 264 mmol) it is dissolved in 500 mL isopropanols, add and acetic acid (26.4 g are added under zinc powder (25.7 g, 396 mmol), ice bath, 462 mmol), 30 °C are reacted 4 hours.Add saturated sodium bicarbonate solution, adjust pH≤7, Jian Ya Nong Shrink, add 400 mL ethyl acetate, filtering, filter cake is washed with ethyl acetate (100 mL X 2), merge organic phase, water (60 mL) is used successively, saturated sodium bicarbonate solution (60 mL) and saturated nacl aqueous solution (60 mL X 2) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (4R, 5R) -2, 2- dimethyl -5- vinyl -1, 3- dioxolane -4- formaldehyde lk (31 g, colorless oil yield： 75.3%.

1H NMR (400 MHz, CDC1₃) δ 9.54 (d, 1H), 5.70-5.79 (m, 1H), 5.43-5.48 (m, 1H), 5.29-5.32 (m, 1H), 4.82-4.86 (m, 1H), 4.40 (dd, 1H), 1.61 (s, 3H), 1.43 (s, 3H)

11st step

L- [(4WR) -2,2- dimethyl -5- vinyl -1,3- dioxolane -4- bases] the small alcohol of propyl- 2- alkene is by (4R, 5R) -2,2- dimethyl -5- vinyl -1,3- dioxolane -4- formaldehyde lk (30 g, 192 mmol) is dissolved in 50 mL tetrahydrofurans, -78 °C rapidly join 1 M vinyl magnesium bromides tetrahydrofuran solution (550 ML, 384 mmol), kept for -78 °C react 1 hour, be warmed to room temperature, continue to react 30 minutes.Add 120 mL saturated ammonium chloride solutions, add silica gel, filtering, filter cake is washed with ethyl acetate (200 mL X 4), merges organic phase, washed successively with water (60 mL) and saturated nacl aqueous solution (60 mL X 2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product

1- [(4S, 5R) -2,2- dimethyl -5- vinyl -1,3- dioxolane -4- bases] propyl- 2- alkene -1- alcohol lm (20 g, colorless oil), yield： 56.7%.

12nd step

O 4R, 6aR) -2,2- dimethyl -4,6a- dihydro -3aH- cyclopentas M [l, 3] dioxole -4- alcohol is by two (tricyclohexyl phosphine) benzal chloride rutheniums（444 mg, 0.54 mmol) add in reaction bulb, syringe adds 100 mL l- [(4S, 5R) -2,2- dimethyl -5- vinyl -1,3- dioxolane -4- bases] the small alcohol lm of propyl- 2- alkene (10 g, 54 mmol) chloroformic solution, react 2 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (3a^, 4R, 6aR) -2,2- dimethyl -4,6a- dihydro -3aH- cyclopentas [l, 3] dioxole -4- alcohol In (4.5 g, light brown grease), yield： 53.2%.

13rd step

2- (0 4 6＆-2,2- dimethyl-4,6＆- dihydro-3＆^ cyclopentas [[1,3] Dioxol-4 -yl) isoindoline-1,3- diketone

By (3aS, 4R, 6aR) -2,2- dimethyl -4,6a- dihydro -3aH- cyclopenta M [l, 3] dioxole -4- alcohol In (936 mg, 6 mmol), phthalimide (1.32 g, 9 mmol) and triphenylphosphine (2.36 g, 9 mmol) it is dissolved in tetrahydrofuran, 10 mL diisopropyl azodiformates (1.9 mL, 9 mmol) tetrahydrofuran solution is added, 20 °C are reacted 24 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (3aR, 4R, 6a-2,2- dimethyl-4,6a- dihydro-3aH- cyclopentas M [l, 3] Dioxol-4 -yl) isoindoline-1,3- diketone lo (1.4 g, white solid), yield： 82.3%.

1H NMR (400 MHz, CDC1₃) δ 7.85-7.87 (m, 2H), 7.75-7.77 (m, 2H), 6.18 (d, 1H), 5.69 (d, 1H), 5.62 (d, 1H), 5.36 (br, 1H), 4.90 (d, 1H), 1.50 (s, 3H), 1.40 (s, 3H)

14th step

2- (3aR, 4S, 56 6a -4,5- dihydroxy -2,2- dimethyl tetrahydro -3aH- cyclopentas M [l, 3] dioxole -6- bases) isoindoline -1,3- diketone

By 2- (3aR, 4R, 6a -2,2- dimethyl -4,6a- dihydro -3aH- cyclopentas M [l, 3] dioxole -4- bases) isoindoline -1,3- diketone lo (500 mg, 1.75 mmol) it is dissolved in 10 mL tetrahydrofurans, the osmium tetroxide of 1 catalytic amount is added, is reacted 24 hours at room temperature.10 mL water will be added in reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (10 mL X 3), the organic phase anhydrous sodium sulfate drying of merging, overnight, decompression Xia Nong Shrink, obtain crude title product 2- (3aR, 4S, 56 6a -4,5- dihydroxy -2,2- dimethyl tetrahydro -3aH- cyclopentas [d] [l, 3] dioxole -6- bases) isoindoline -1,3- diketone lp (558 mg, colorless oil), product is not purified directly to carry out next step reaction.

15th step

2- ((3aS, 3M, 6aS, 7a^-2,2, and 5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4-if | connection ([1,3] dioxa Cyclopentene) -7- bases) isoindoline -1,3- diketone

By 2- (3aR, 4S, 56 6a -4,5- dihydroxy -2,2- dimethyl tetrahydro -3aH- cyclopenta M [l, 3] dioxole -6- bases) isoindoline -1,3- diketone lp (558 mg, 1.75 mmol) is dissolved in 10 mL acetone, is added one and is hydrated p-methyl benzenesulfonic acid (4 mg, 0.02 mmol), it is heated to 50 °C and reacts 24 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- ((3aS, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4-if | connection ([1,3] dioxole) -7- bases) isoindoline -1,3- diketone lq (230 mg, white solid), yield： 36.6%.

16th step

(tetramethyl tetrahydrochysene -3aH- the cyclopentas [1,2- of 3aS, 3M, 6aS, 7a -2,2,5,5-:3,4- '] ([1,3] dioxole) -7- amine is joined

By the 2- ((tetramethyl tetrahydrochysene -3aH- cyclopentas [1,2- of 3aS, 3M, 6aS, 7a -2,2,5,5-:3,4- '] ([1,3] dioxole) -7- bases are joined) isoindoline -1,3- diketone lq (220 mg, 0.61 mmol) is dissolved in 10 mL ethanol, adds hydrazine hydrate（0.36 mL, 6.12 mmol), it is heated to 70 °C and reacts 2.5 hours.Reaction solution is cooled to room temperature, and filtering, filtrate decompression Nong Shrink Jiang Nong Shrink residue is dissolved with dichloromethane, filters, filtrate decompression Nong Shrink, obtain crude title product (3a^, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4- ^ connection ([1,3] dioxole) -7- amine lr (130 mg, weak yellow liquid), yield： 93.1%. 1H NMR (400 MHz, CDC1₃) δ 4.61-4.59 (m, 1H), 4.59-4.51 (m, 1H), 4.41-4.36 (m, 1H) 4.36-4.31 (m, 1H), 3.26-3.21 (m, 1H), 1.47 (s, 3H), 1.45 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H)

17th step

The chloro- 2- of 6- (propyl group sulfydryl)-N⁴- [(tetramethyl tetrahydrochysene -3aH- the cyclopentas of 3aS, 3M, 6aS, 7a -2,2,5,5-

[1,2- (1:3,4- (1'] connection (；[1,3] dioxole) -7- bases] pyrimidine -4,5- diamines is by 4, chloro- 2- propyl group mercapto-pyrimidine -5- amine Is (162 mg of 6- bis-, 0.68 mmol, is prepared using known method " special standing grain lj WO2001092263 ") and (3aS, 3bS, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4-if | connection ([1,3] dioxole) -7- amine lr (130 mg, 0.57 mmol) it is dissolved in 5 mL ethylene glycol, it is heated to 100 °C and reacts 24 hours.30 mL ethyl acetate are added in reaction solution, washed successively with water (10 mL X 3) and saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of title product 6- (propyl group sulfydryl)-N⁴- ((3aS, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [1,2- 3,4- ^ connection ([1,3] dioxole) -7- bases) pyrimidine -4,5- diamines It (80 mg, yellow solid), yield： 32.6%.

MS m/z (ESI): 431.0 [M+l]

18th step

The chloro- 5- of 7- (propyl group sulfydryl) -3- [(tetramethyl tetrahydrochysene -3aH- cyclopentas of 3aS, 3M, 6aS, 7a -2,2,5,5-

[l, 23,4] joins ([1,3] dioxole) -7- bases] under -3H- [1,2,3] triazol [4,5-d] pyrimidine ice bath, by the chloro- 2- of 6- (propyl group sulfydryl)-N⁴- ((3aS, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4-^ connection ([1,3] dioxole) -7- bases) pyrimidine -4,5- diamines It (80 mg, 0.19 mmol) is dissolved in 1.5 mL acetic acid and water (V/V=2:1) in the mixed solvent, adds natrium nitrosum (12 mg, 0.20 ), mmol 0 °C is reacted 5 minutes.15 mL ethyl acetate and 10 mL saturated sodium carbonate solutions are added into reaction solution, stirring 10 minutes, divide liquid, it is extracted with ethyl acetate (10 mL X 2), merges organic phase, washed successively with saturated sodium carbonate (10 mL), saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain the chloro- 5- of crude title product 7- (；Propyl group sulfydryl) -3- (3aS, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 2-i:3,4] ([1,3] dioxole) -7- bases are joined) -3H- [1,2,3] triazol [4,5-d] pyrimidine lu (82 mg, brown oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 442.1 [M+l]

19th step

N- [(lR, 2-2- (3,4- difluorophenyl) cyclopropyl]-5- (propyl group sulfydryl)-3- [(3aS, 3M, 6aS, 7a-2,2,5,5- tetramethyl tetrahydrochysene-3aH- cyclopentas [l, 23,4] ([1 is joined, 3] dioxole]-7- bases)-3H- [1,2,3] triazol

[4,5-d] pyrimidine -7- amine

By the chloro- 5- of 7- (propyl group sulfydryl) -3- ((3a^, 3M, 6aS, 7a -2, 2, 5, 5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23, 4- ^ connection ([1, 3] dioxole) -7- bases) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidine lu (82 mg, 0.19 mmol) and (1R, 2-2- (3, 4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (83 mg, 0.26 mmol) it is dissolved in 10 mL acetonitriles, add triethylamine (0.09 mL, 0.67 mmol), reaction 24 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product N- { [(lR, 2^-2- (3,4- difluorophenyl) cyclopropyl] -5- (propyl group sulfydryl) -3- [(3aS, 3M, 6aS, 7a -2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [l, 23,4] join ([1,3] dioxole] -7- bases } -3^ [1,2,3] triazol [4,5-d] pyrimidine -7- amine lv (80 mg, yellow oil yield： 73.4%.

MS m/z (ESI): 575.1 [M+l]

20th step

(1 2^^, -5- 7- [[(lR, 2^-2- (3,4- difluorophenyl) cyclopropyl] amino] -5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } cyclopenta -1,2,3,4- tetrols

By N- { [(lR, 2-2- (3,4- difluorophenyls）Cyclopropyl] -5- (propyl group sulfydryl) -3- [(3aS, 3M, 6aS, 7a^-2,2,5,5- tetramethyl tetrahydrochysene -3aH- cyclopentas [1,2- 3,4- ^ connection ([1,3] dioxole] -7- bases } -3H- [1,2,3] triazol [4,5-d] pyrimidine -7- amine lv (80 mg, 0.14 mmol) is dissolved in 3 mL methanol, adds 5 M hydrochloric acid (0.3 mL, 1.5 mmol), react 48 hours.Add saturated sodium carbonate solution, adjust ρ Η=8, stirring 5 minutes, Jian Ya Nong Shrink are extracted with ethyl acetate (10 mL X 5), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with high performance liquid preparative chromatography method purify gained residue, obtain title product (- the 5- of 1 2^3 4 7- [[(1 2-2- (；3,4- difluorophenyls) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta -1,2,3,4- tetrol l (18 mg, white solid), yield： 25.7%.

MS m/z (ESI): 495.1 [M+l]

1H NMR (400 MHz, CDC1₃) δ 7.26-7.05 (m, 3H), 5.31-5.26 (m, 1H), 5.12-5.08 (m, 1H) 4.55-4.50 (m, 1H), 4.15-4.09 (m, 2H), 3.16-3.10 (m, 1H), 3.10-2.92 (m, 2H), 2.20-2.10 (m, 1H), 1.65-1.39 (m, 4H), 0.92 (t, 3H) Embodiment 2 and embodiment 3

(1R, 2R, 3 5R)-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [[(lR, 2-2- (3,4- difluorophenyls) cyclopropyl] amino] triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1, (1 2 3R of 2- glycol 2,5-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [[(lR, 2-2- (3,4- difluorophenyl) cyclopropyl] amino] three

- d] pyrimidin-3-yl } -5- (2- hydroxyl -1,2- glycol 3

〇 0 '

(lake

The first step

N- hydroxy carbamic acid benzyl esters

By azanol (7.65 g, 0.11 mol) and sodium acid carbonate C58.8 g, 0.70 mol) it is dissolved in 630 mL tetrahydrofurans and water (V/V=1:1) in the mixed solvent, is slowly added dropwise benzyl chloroformate (33.8 mL, 0.10 mol), reacts at room temperature 12 hours.Jian Ya Nong Shrink major part tetrahydrofurans, add 500 mL water, extracted with ethyl acetate (200 mIX3), merge organic phase, washed with saturated nacl aqueous solution (300 mL), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, residue is dissolved in 270 mL dichloromethane and n-hexane (V/V=5.5 in 45 °C:8) in the mixed solvent, stands cooling crystallization, obtains title product N- hydroxy carbamic acid benzyl esters 2a (15.48 g, white solid), yield： 92.6%.

MS m/z (ESI): 168.1 [M+l]

Second step

(1R, 41 4R) -2- oxygen -3- azabicyclos [2.2.1] heptane -5- alkene -3- benzyl formates are by N- hydroxy carbamic acid benzyl ester 2aC20.4 g, 0.12 mol) it is dissolved in 800 mL first alcohol and waters (V/V=3:1) cyclopentadiene (22.98 g, 0.35 mol) and sodium metaperiodate (25.3 g, 0.12 mol) are added under in the mixed solvent, ice bath, is reacted 10 minutes between being maintained at 0 °C 5 °C, is reacted at room temperature 2 hours.0 °C 5 °C are cooled to, cyclopentadiene (16.5 g, 0.25 mol) and sodium metaperiodate (14.9 g, 0.07 mol) is added, reacted at room temperature 12 hours.Jian Ya Nong Shrink major part methanol, adds 500 mL water, is extracted with ethyl acetate (300 mLx3), merge organic phase, washed, anhydrous sodium sulfate drying with saturated nacl aqueous solution (300 mL), filtrate decompression Nong Shrink, vacuum drying, are obtained To crude title product（1R, 4S/1 4R) -2- oxygen -3- azabicyclos [2.2.1] heptane -5- alkene -3- benzyl formates 2b (32.39 g, dark oil thing), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 232.0 [M+l]

3rd step

(1 4R, 6S/1R, 6R) -5, 6- dihydroxy -2- oxygen -3- azabicyclos [2.2.1] heptane -3- benzyl formates are by crude product (1R, 41 4R) -2- oxygen -3- azabicyclos [2.2.1] heptane -5- alkene -3- benzyl formates 2b (32.39 g, 0.12mol) it is dissolved in 600mL tetrahydrofurans, add N- methyl morpholine oxides (57.2 g, 0.24mol) with osmium tetroxide (lOOmg, 0.39 mmol), reaction 1.5 hours, add sodium dithionite (63.7 g, 0.37 mol), reaction 30 minutes.Jian Ya Nong Shrink parts tetrahydrofuran, add 500 mL water, extracted with ethyl acetate (200 mIX3), merge organic phase, washed with saturated nacl aqueous solution (400 mL), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, drying, obtain crude title product C, 4R, 6S/1R, 6R) -5,6- dihydroxy -2- oxygen -3- azabicyclos [2.2.1] heptane -3- benzyl formate 2c (31.73g, yellow oil), product is not purified directly to carry out next step reaction.

1HNMR (400 MHz, CDC1₃) δ 7.44-7.28 (m, 5H), 5.25-5.11 (m, 2H), 4.49-4.47 (m, 1H), 4.47-4.44 (m, 1H), 4.05 (br, 2H), 2.14 (d, 1H), 1.86-1.69 (m, 1H)

4th step

(4 7 7＆5/3＆ of 3＆ 47 7＆ -2,2- dimethyl dihydros -3＆^4,7- methylene [1,3] dioxole simultaneously [4,5-d] [l, (the 4H benzyl formates of 2] oxazines -6

By crude product (1S, 4R, 6S/1R, 6R) -5,6- dihydroxy -2- oxygen -3- azabicyclos [2.2.1] heptane -3- benzyl formates 2c (31.73 g, 0.12 mol) are dissolved in 150 mL acetone, are added one and are hydrated p-methyl benzenesulfonic acid (300 mg, 1.58 mmol), 30 °C are reacted 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the 7aR of 047 7＆ of title product/3＆ 4 7) -2,2- dimethyl dihydros -3aH-4,7- methylene [1,3] dioxole simultaneously [4,5-d] [l, 2] oxazines -6 (4H benzyl formates 2d (27.8 g, white solid), yield： 76.1%.

1H NMR (400 MHz, CDC1₃) δ 7.42-7.28 (m, 5H), 5.23 (d, 1H), 5.18 (d, 1H), 4.64-4.59 (m, 2H), 4.35-4.29 (m, 2H), 2.19 (d, 1H), 1.77-1.66 (m, 1H), 1.43 (s, 3H), 1.28 (s, 3H)

5th step

(3& 4 6 6&5>3＆^^, 6 6＆ -6- amino -2,2- dimethyl tetrahydro -3＆ cyclopentas [^] [1,3] dioxole -4- alcohol

By (the 7＆ -2 of 47 7＆5/3＆ of 3＆ 47,2- dimethyl dihydros -3＆^4,7- methylene [1,3] dioxole simultaneously [4,5-^] [1, (4H benzyl formates 2d (27.8 g of 2] oxazines -6,91.06 mmol) it is dissolved in 400 mL methanol, adding palladium/carbon, (10%, 1.4 g), hydrogen is replaced three times, is reacted 40 hours in 50 °C.Filtering, filtrate decompression Nong Shrink, obtain the 6aR 6- amino -2 of 046 6＆ of crude title product/3＆ 46,2- dimethyl tetrahydro -3aH- cyclopentas [[l, 3] dioxole -4- alcohol 2e (16.8 g, yellow solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 174.1 [M+l]

6th step N- [(3a5,4R, 65,6aR/3aR, 45,6R, 6a5) -6- hydroxyl -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases] benzyq carbamate is by crude product (3aR, 4^6R, 6a5>3a^4R, 6 6aR) -6- amino -2,2- dimethyl 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] dioxole -4- alcohol 2e (16.8 g, 91.06 mmol) be dissolved in 195 mL 4- methyl -2- pentanones and water (； V/V = 3 :1) in the mixed solvent, adds potassium carbonate (22.65 g, 163.9 mmol), and benzyl acyl chlorides (27 mL, 0,87 mol) is added dropwise, and reacts at room temperature 12 hours.Divide liquid, aqueous phase is extracted with 4-methyl-2 pentanone (50 mLx2), merge organic phase, washed with saturated nacl aqueous solution (100 mLx2), anhydrous magnesium sulfate is dried, 200 mL n-hexanes and dichloromethane (V/V=20 are added in filtrate decompression Nong Shrink, residue:1) mixed solvent, is beaten, filtering, vacuum drying, obtains title product N- [(3aS, 4R, 6 6aR/3aR, 45,6R, 6a5)-6- hydroxyls-2,2- dimethyl 4,5,6,6a- tetrahydrochysene-3aH- cyclopentas [^] [1,3] Dioxol-4 -yls] benzyq carbamate 2f (18.82 g, off-white powder), yield： 77.3%.

MS m/z (ESI): 308.1 [M+l]

7th step

2- ((3＆^^, 6＆ -6- (the benzyloxycarbonyl aminos -2 of 6 6＆^3＆ 46, 2- dimethyl tetrahydro -3＆11- cyclopentas W] [l, 3] Dioxol-4 -yl) ethoxyacetic acid ethyl ester is by N- [(3aS, 4R, 6 6aR/3aR, 4S, 6R, 6aS) -6- hydroxyls -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] benzyq carbamate 2f (2 g, 6.51 mmol) it is dissolved in 100 mL tetrahydrofurans, the dry ice bath is cooled to less than -22 °C (interior temperature), insulation 30 minutes, add 10 mL potassium tert-butoxides (3.65 g, 9.76 mmol) tetrahydrofuran solution, 30 minutes (interior temperature) is incubated in less than -22 °C, in less than -10 °C, stirring 30 minutes, bromoethyl acetate (1.09 mL are added dropwise, 9.76 mmol) tetrahydrofuran solution (10 mL), after 1 hour being incubated below -22 °C, it is increased to room temperature reaction 12 hours.Reaction solution Nong Shrink under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- ((3aS, 4R, 6 6aR/3aR, 4S, 6R, 6a-6- (benzyloxycarbonyl aminos-2,2- dimethyl tetrahydro-3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl) ethoxyacetic acid ethyl ester 2g (2.16 g, pale yellow oil), yield： 84.4%. MS m/z (ESI): 394.3 [M+l]

8th step

(3aS, 4R, 6 6aR/3aR, 4^6R, 6aS) -6- (2- hydroxy ethoxies) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl] benzyq carbamate is by 2- ((3aS, 4R, 6 6aR/3aR, 4S, 6R, 6aS) -6- (benzyloxycarbonyl aminos -2, 2- dimethyl tetrahydro -3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl) ethoxyacetic acid ethyl ester 2g (8 g, 20.34 mmol) it is dissolved in 60 mL tetrahydrofurans, add tetrahydro boron lithium (887 mg, 40.7 mmol), it is stirred overnight at room temperature.Reaction solution is poured into 150 mL water, extracted with ethyl acetate (60 mIX3), merge organic phase, washed successively with saturated sodium bicarbonate solution (100 mL) and saturated nacl aqueous solution (100 mL), anhydrous magnesium sulfate is dried, filtrate decompression Nong Shrink, obtain title product N- [(3aS, 4R, 6 6aR/3aR, 45, 6R, 6a5) -6- (2- hydroxy ethoxies) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 2h (6.82 g, colourless thick liquid), yield 49.7%. MS m/z (ESI): 352.1 [M+l]

9th step

2- { [(3aR, 4^6R, 6aS/3a^4R, 6 6aR) -6- amino -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas

M [l, 3] dioxole-⁴- yl] epoxide } ethanol

By N- [(3aS, 4R, 6 6aR/3aR, 4S, 6R, 6a-6- (2- hydroxy ethoxies)-2,2- dimethyl 4,5,6,6a- tetrahydrochysene-3aH- cyclopentas [l, 3] Dioxol-4 -yl] benzyq carbamate 2hC6.8 g, 19.35 mmol) it is dissolved in 150 mL methanol, add palladium/carbon (10%, 600 mg), hydrogen is replaced three times, is stirred at room temperature 12 hours.Filtering, filtrate decompression Nong Shrink obtain crude title product 2- { [(3aR, 4S, 6R, 6aS/ 3aS, 4R, 6 6aR)-6- amino-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol 2i (4.43 g, weak yellow liquid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 218.1 [M+l]

1H NMR (400 MHz, CDC1₃) δ 4.68 (d, 1H), 4.46 (d, 1H), 3.92 (d, 1H), 3.73-3.68 (m, 2H), 3.67-3.62 (m, 1H), 3.63-3.57 (m, 1H), 3.39 (d, 1H), 2.35 (br, 3H), 2.16 (ddd, 1H), 1.84 (d, 1H), 1.44 (s, 3H), 1.31 (s, 3H)

Tenth step

2- (Cvclopropvlmethvl sulfydryl) pyrimidine -4,6- glycol

By 2- mercaptopyrimidines -4,6- glycol 2j (10.0 g, 69.3 mmol) it is dissolved in 30 mL water, add sodium hydroxide (6.4 g, 160 mmol), stir 40 min, 20 mL water are added, 1- methylpyrrole -2- ketone (20.6 g, 207.9 mmol) bromomethyl cyclopropane (9.6 g are sequentially added, 71.4 mmol), 20 °C of 12 h of stirring, add the M hydrochloric acid of 30 mL 1 and then add the M hydrochloric acid of 15 mL 6, stir 12 h, filtering, successively through water（10 mLx4)-ethanol (10 mL)-water washing (10 mLx2), dry, obtain title product 2- (Cvclopropvlmethvl sulfydryl) pyrimidine -4,6- glycol 2k (12.0 g, white solid), yield： 87.6%.

MS m/z (ESI): 199.0 [M+l]

11st step

2- (Cvclopropvlmethvl sulfydryl) -5- toluene nitrine) pyrimidine -4,6- glycol is by 4- methylanilines (6.7 g, 62 mmol) and 36% hydrochloric acid (18.7 mL, 224 mmol) it is dissolved in 20 mL water, 20 mL sodium nitrite solutions (4.5 g, 65 mmol), completion of dropping are added dropwise under ice bath, it is maintained under condition of ice bath, solution for standby.

2- (Cvclopropvlmethvl sulfydryl) pyrimidine -4,6- glycol 2k (10 g, 50 mmol) is dissolved in 100 mL water and ethanol (V/V=1:1) in the mixed solvent, sequentially adds and the solution of above-mentioned preparation is added dropwise in reaction solution under sodium hydroxide (1.92 g, 48 mmol) and sodium acetate (20.83 g, 254 mmol), ice bath, reacts at room temperature 24 hours.Add 15 mL concentrated hydrochloric acids, adjust pH=l, there is solid precipitation, filtering, filter cake is washed with water (100 mL), is dried in vacuo, obtain title product 2- (Cvclopropvlmethvl sulfydryl) -5- (toluene nitrine) pyrimidine -4,6- glycol 2m (14.1 g, yellow solid), yield： 78.4%.

MS m/z (ESI): 305.1 [M+1]

12nd step

(E)-[4,6- bis- chloro- 2- (Cvclopropvlmethvl sulfydryl) pyrimidine -5- bases]-toluene) hydrazine By 2- (Cvclopropvlmethvl sulfydryl) -5- toluene nitrine) pyrimidine -4,6- glycol 2m (12.2 g, 39 mmol) is suspended in 40 mL toluene, and 70 °C add pyridine C6 mL, 77 mmol), keep below 94 °C be added dropwise POCl3s (；44 mL, 482 mmol), react 4.5 hours.Reaction solution is cooled to room temperature, is poured slowly into 400 mL frozen water, is stirred at room temperature 1 hour, uses ethyl acetate（100 mIX3) extraction, merge organic phase, washed, anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution (200 mL) successively, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (E)-[4,6- bis- chloro- 2- (Cvclopropvlmethvl sulfydryl) pyrimidine -5- bases] toluene) hydrazine 2n (9.5 g, red solid), yield： 69.9%.

MS m/z (ESI): 353.0[M+1]

13rd step

4,6- bis- chloro- 2- (Cvclopropvlmethvl sulfydryl) pyrimidine -5- amine

By (E)-[4,6- bis- chloro- 2- (；Cvclopropvlmethvl sulfydryl) pyrimidine -5- bases]-(toluene) hydrazine 2n (9.5 g, 27 mmol) it is dissolved in 190 mL ethyl acetate, add palladium/carbon (10%, 2.56 g), hydrogen is replaced three times, under 3atm pressure, react at room temperature 9 hours.Filtering reacting liquid, 40 ° of C Nong Shrink to 34 mL, washed with 3 M hydrochloric acid (30 mL X 2), with 3 M salt acid for adjusting pH=1.5 2, the dense Shrink of filtrate decompression, obtained crude title product 4,6- bis- chloro- 2- (Cvclopropvlmethvl sulfydryl) pyrimidine -5- amine 2p (6.5 g, dark red oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 251.9 [M+l]

14th step

2- { [(3aR, 4^6R, 6aS/3aS, 4R, 6 6aR)-6- [[the chloro- 2- of 5- amino-6- (Cvclopropvlmethvl sulfydryl) pyrimidine-4- bases] amino]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol

By chloro- 2- (the Cvclopropvlmethvl sulfydryls of 4,6- bis-）Pyrimidine-5- amine 2p (700 mg, 2.8 mmol) and 2- { [(3aR, 45,6R, 6a5/3a5,4R, 65,6aR)-6- amino-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol 2i (500 mg, 2.3 mmol) it is dissolved in 15 mL ethylene glycol, 100 °C are reacted 7 hours.50 mL ethyl acetate and 50 mL water are added in reaction solution, washed successively with water (10 mL X 3) and saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 2- { [6＆ -6- of 46 6＆^3＆ of 3＆ 46 [[the chloro- 2- of 5- amino -6- (Cvclopropvlmethvl sulfydryl) pyrimidine-4-yl] amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 2q (250 mg, dark red oil), yield： 25.2%.

MS m/z (ESI): 431.1 [M+l]

15th step

2- { [(3aR, 4^6R, 6aS/3a^4R, 6 6aR)-6- [the chloro- 5- of 7- (Cvclopropvlmethvl sulfydryl) triazol [4,5-d] pyrimidin-3-yl]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol

Under ice bath, by 2- { [(3aR, 4S, 6R, 6aS/3aS, 4R, 6 6aR) -6- [[5- amino -6- chloro- 2- (Cvclopropvlmethvl mercaptos Base) pyrimidine-4-yl] amino]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol 2q (250 mg, 0.58 mmol) it is dissolved in 1 mL acetic acid, natrium nitrosum (42 mg, 0.61 mmol) is added, 0 °C is reacted 20 minutes.10 mL ethyl acetate and 50 mL saturated sodium carbonate solutions are added in reaction solution, point liquid uses ethyl acetate（50 mL X 2) extraction, merge organic phase, washed successively with saturated sodium carbonate (50 mL) and saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained solid, obtain crude title product 2- { [(3aR, 4^6R, 6aS/3aS, 4R, 6 6aR) -6- [the chloro- 5- of 7- (Cvclopropvlmethvl sulfydryl) triazols [4, 5-d] pyrimidine -3- bases] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 2r (212 mg, pale yellow oil), yield： 82.8%.

MS m/z (ESI): 442.1 [M+l]

16th step

2- { [((3aR, 4 6R, 6aS/3aS, 4R, 6 6aR) -6- [5- (Cvclopropvlmethvl sulfydryl) -7- [[(lR, 2^-2- (3, 4- difluorophenyls) cyclopropylamino] triazol [4, 5-d] pyrimidin-3-yl] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl] epoxide } ethanol is by 2- { [(3aS, 4^6R/3aR, 4^6R) -6- [the chloro- 5- of 7- (Cvclopropvlmethvl sulfydryl) triazols [4, 5-d] pyrimidine -3- bases] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 2r (212 mg, 0.48 mmol) and (lR, 2-2- (3, 4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (207 mg, 0.65 mmol) it is dissolved in 15 mL acetonitriles, add triethylamine（170 mg, 1.68 mmol), react 24 hours.Reaction solution Jian Ya Nong Shrink, add 50 mL ethyl acetate and 50 mL water, add 2.5 M hydrochloric acid regulation ρ Η<4, divide liquid, aqueous phase is extracted with ethyl acetate (300 mL X 2), merge organic phase, washed with saturated aqueous common salt (50 mL X 2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained solid, obtain the title product 2- { [(6＆ -6- of 46 6＆ of 3＆/3＆ 46 [5- (Cvclopropvlmethvl sulfydryl) -7- [[(lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino] triazol [4, 5-d] pyrimidin-3-yl] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 2s (225 mg, faint yellow solid), yield： 81.5%.

MS m/z (ESI): 575.3 [M+l]

17th step

(1R, 2R, 3 5R/ lS, 2^3R, 5^-3- { 5- (Cvclopropvlmethvl sulfydryl) -7- [(lR, 2S) -2- (3, 4- difluorophenyls) cyclopropylamino] triazol [4, 5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) cyclopenta -1, 2- glycol is by 2- { [(3aR, 4S, 6R, 6aS/3aS, 4R, 6 6aR) -6- [5- (Cvclopropvlmethvl sulfydryl) -7- [[(lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino] triazol [4, 5-d] pyrimidin-3-yl] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] Dioxol-4 -yl] epoxide } ethanol 2s (225 mg, 0.39 mmol) it is dissolved in 15 mL methanol, add 2.5 M hydrochloric acid (4.5 mL, 1 1.25 mmol), reaction 24 hours.Saturation sodium hydroxide solution is added, regulation ρ Η >=7 add 60 mL ethyl acetate and 20 mL water, stirring 15 minutes, divide liquid, aqueous phase is extracted with ethyl acetate (300 mL X 2), merges organic phase, paint is washed with saturated aqueous common salt (50 mL X 2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with 4.7 mL Gossypol recrystallized from chloroform, silicon is used Glue column chromatography purifies gained solid with eluant, eluent system B, obtained raceme product (1R, 2R, 3 5R/ 1 2^3R, 5S) -3- { 5- (Cvclopropvlmethvl sulfydryl) -7- [(lR, 2S) -2- (3,4- difluorophenyls) cyclopropylamino] triazol [4,5-d] pyrimidin-3-yl } -5- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol 2s (149 mg, colorless oil), yield： 71.5%.

MS m/z (ESI):535.3 [M+l]

1H NMR (400 MHz, DMSO-d₆) 9.37 (d of δ, 1H), 7.21-7.38 (m, 2H), 7.00-7.10 (m, 1H), 5.10 (dd, 1H), 5.05 (d, 1H), 4.96 (q, 1H), 4.56-4.62 (m, 1H), 4.49-4.56 (m, 1H) 3.90-3.97 (m, 1H), 3.70-3.82 (m, 1H), 3.41-3.57 (m, 4H), 3.11-3.21 (m, 1H), 2.84-2.95 (m, 1H), 2.71-2.81 (m, 1H), 2.56-2.69 (m, 1H), 2.07-2.14 (m, 1H), 1.94-2.07 (m, 1H), 1.50-1.61 (m, 1H), 1.31-1.42 (m, 1H), 1.20-1.26 (m, 1H), 1.08-1.20 (m, 1H), 0.95-1.06 (m, 1H), 0.35-0.59 (m, 1H), 0.03-0.14 (m, 1H)

18th step

(1 23 5-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [(1 2-2- (3,4- difluorophenyls) cyclopropylamino] triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1, (- the 3- of 1 2^3 5 { 5- (Cvclopropvlmethvl sulfydryl)-the 7- [(1 2-2- (3 of 2- glycol 2,4- difluorophenyls) cyclopropylamino] triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol 3 is by non-enantiomer mixture（1R, 2R, 3 5R 12 3R, 5-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino] triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol 2s (149mg, colorless oil), by using HPLC methods, separated with the chiral isomers of chiral column, obtain title product（LR, 2R, 3WR)-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino] triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol 2 (61.8 mg, colorless oil), yield： 41.5%;(1 2 3R, 5-3- { 5- (Cvclopropvlmethvl sulfydryl)-7- [(lR, 25)-2- (3,4- difluorophenyls）Cyclopropylamino] and triazol [4,5 pyrimidine -3- bases } -5- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol 3 (61.5 mg, colorless oil), yield： 41.3%. 2: MS m/z (ESI):535.3 [M+l]

3: MS m/z (ESI):535.3 [M+l] embodiments 4

(1 2^3R, 5-3- { 7- [(lR, 2R)-2- (the chloro- 2- thienyls of 5-) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } -5- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol

4th step

The first step

The chloro- 2- thienyls of the chloro- l-O of 2-) ethyl ketone

By 2- chloracetyl chlorides (22.5 g, 0.2 mol) it is dissolved in 100 mL dichloromethane, add alchlor (24 g, 0.18 mol), it is stirred at room temperature, 150 mL 2- chlorothiophenes (23.72 g, 0.2 mol) dichloromethane solution is added dropwise, reacts 3.5 hours.125 mL frozen water and 35 mL concentrated hydrochloric acid mixed liquors are added in reaction solution, stirring 30 minutes, divide liquid, organic phase is washed with saturated nacl aqueous solution (150 mL X 2), anhydrous sodium sulfate drying, Jian Ya Nong Shrink obtain the chloro- 1- of crude title product 2- (the chloro- 2- thienyls of 5-) ethyl ketone 4a (32 g, yellow oil), product is not purified directly to carry out next step reaction.

1H NMR (400 MHz, CDC1₃) δ 7.58 (d, /=4.12 Hz, 1H), 7.00 (d, /=4.12 Hz, 1H), 4.52 (s, 2H)

Second step

(the chloro- l- of 1-2- (the chloro- 2- thienyls of 5-) ethanol

By S)-diphenyl-pyrrolidin-2-yl-methanol（2.08 g, 8.2 mmol) it is dissolved in 45 mL toluene, trimethylborate (1.1 g, 11.5 mmol) is added, is reacted 1.5 hours in 40 °C, is kept for 35 °C 45 °C be added dropwise two Dimethyl sulfide borine (65.5 mL, 131 mmol), reacts 1 hour in 40 °C, is kept for 35 °C 45 °C, the chloro- 1- of 150 2- (the chloro- 2- thienyls of 5-) ethyl ketone 4＆ (32 was added dropwise in 1.5 hours_§, 0.16 mol) toluene solution, react 12 hours.Reaction solution is kept for less than 35 °C, 30 mL methanol are added dropwise, it is cooled to 20 °C, stirring 30 minutes, reaction solution Jian Ya Nong Shrink, remove methanol and trimethylborate, washed with 10% acetic acid (100 mL X 4), merge aqueous phase, extracted with toluene (60 mL), saturated nacl aqueous solution (150 mL) washing , Nong Shrink, obtain crude title product (the chloro- 1- of 1-2- (the chloro- 2- thienyls of 5-) ethanol 4b (32.3 g, yellow oil).

MS m/z (ESI): 196.0 [M-l]

3rd step

(lR, 2R) -2- (the chloro- 2- thienyls of 5-) ethylene-acetic acid ethyl esters are by 60% sodium hydride (13.12 g, 0.33 mol) it is suspended in 50 mL toluene, it is heated to 40 °C, 2- diethoxy phosphonoacetic acid ethyl esters (40.5 g are added dropwise, 0.18 mol) toluene solution, reacted 1 hour in 40 °C, (the chloro- 1- of 1-2- (the chloro- 2- thienyls of 5-) ethanol 4b (32.3 g are added dropwise, 0.16 mol) solution, 60 °C are stirred 12 hours, add 150 mL water, divide liquid, it is organic to be added to anhydrous sodium sulfate drying, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (lR, 2R) -2- (the chloro- 2- thienyls of 5-) ethylene-acetic acid ethyl ester 4c (10.9 g, yellow liquid), yield： 28.8%.

1H NMR (400 MHz, CDC1₃) δ 6.69 (d, J=3.76 Hz, 1H), 6.58 (dd, J=0.72,3.76 Hz, 1H), 4.19-4.14 (m, 2H), 2.60-2.56 (m, 1H), 1.91-1.86 (m, 1H), 1.60-1.55 (m, 1H), 1.28 (t, /=7.14 Hz, 3H), 1.28-1.23 (m, 1H)

4th step

(lR, 2R) -2- (the chloro- 2- thienyls of 5-) ethylene-acetic acid

By (lR, 2R) -2- (the chloro- 2- thienyls of 5-) ethylene-acetic acid ethyl ester 4c (10.9 g, 0.047 mol) it is dissolved in 80 mL ethanol, add 30% sodium hydroxide solution (3.4 g, 0.085 mol), stirring 4.5 hours, Jian Ya Nong Shrink major part ethanol, add 100 mL water and 100 mL toluene, concentrated hydrochloric acid is added dropwise, adjust pH≤7, layering, aqueous phase is extracted with toluene (100 mL X 2), merge organic phase, washed with saturated nacl aqueous solution (150 mL), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, obtain title product (lR, 2R) -2- (the chloro- 2- thienyls of 5-) ethylene-acetic acid 4d (7.8 g, yellow liquid), yield： 81.6%.

MS m/z (ESI):201.0 [M-l]

5th step

(lR, 2R) -2- (the chloro- 2- thienyls of 5-) Cyclopropyl carbonyl chloride

By (lR, 2R) the chloro- 2- thienyls of -2-0) ethylene-acetic acid 4d (3.24 g, 16 mmol) it is dissolved in 10 mL toluene, thionyl chloride (3.04 g are added dropwise, 25.6 mmol), it is stirred below 24 hours in 25 °C, reaction solution Jian Ya Nong Shrink, remove thionyl chloride, obtain the mL (lR of crude title product 5,2R) -2- (the chloro- 2- thienyls of 5-) Cyclopropyl carbonyl chloride 4e (3.53 g) toluene solution, product is not purified directly to carry out next step reaction.

6th step

(lR, 2R) -2- (the chloro- 2- thienyls of 5-) ring the third formyl nitrine

By sodium azide (1.0 g, 16.8 mmol), sodium carbonate (0.76 g, 7.2 mmol) and normal-butyl ammonium bromide (0.16 g, 0.48 mmol) it is dissolved in 10 mL water, it is cooled to 0 °C, mL (lR, the 2R) -2- of crude product 15 (chloro- 2- are added dropwise Thienyl) Cyclopropyl carbonyl chloride 4e (3.53 g, 16 mmol) toluene solution, 0 °C it is stirred below reaction 3 hours, 10 mL frozen water are added into reaction solution, layering, aqueous phase is extracted with toluene (20 mL), merge organic phase, washed successively with frozen water (25 mL) and saturated nacl aqueous solution (20 mL), with anhydrous sodium sulfate drying, obtain the mL (lR of crude title product 35, 2R) -2- (the chloro- 2- thienyls of 5-) ring the third formyl nitrine 4f toluene solution, product is not purified directly to carry out next step reaction.

7th step

(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamine

20 mL toluene are placed in 250 mL three-necked bottles, it is heated to 100 °C, crude product (the lR of 35 mL above-mentioned steps is added dropwise, 2R) -2- (the chloro- 2- thienyls of 5-) ring the third formyl nitrine 4f toluene solution, reacted 1 hour in 100 °C, it is cooled to room temperature, solution for standby.

By 2.5 M hydrochloric acid (19.2 mL, 48 mmol) it is heated to 80 °C, kept for 80 °C to be added dropwise in above-mentioned stock solution, mixed solution reacts 1.5 hours in 80 °C, add 45 mL water, it is cooled to room temperature, divide liquid, discard toluene layer, aqueous phase adjusts pH-12 with saturation sodium hydroxide solution, extracted with ethyl acetate (35mL X 2), organic phase is washed with water (45mL X 2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, obtain title product (lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamine 4g (715 mg, yellow oil), yield： 25.8%.

1H NMR (400 MHz, CDC1₃) δ 6.66 (d, J=3.76 Hz, 1H), 6.46 (d, J=3.72 Hz, 1H), 2.54-2.5 l (m, 1H), 1.96-1.92 (m, 1H), 1.71 (br, 2H), 1.07-1.02 (m, 1H), 0.96-0.91 (m, 1H)

8th step

2-{[(3& 4 6 6& /3&^^,6 6＆ -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] Dioxol-4 -yl] oxygen } ethanol is by 2- { [(3aR,4S,6R,6aS/3aS,4R,6 6aR) -6- amino -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas W] [l,3] Dioxol-4 -yl] epoxide } ethanol 2i (1.95 g,9 mmol) it is dissolved in 30 mL ethylene glycol,Add 4,Chloro- 2- propyl group mercapto-pyrimidine -5- amine ls (2.6 g of 6- bis-,10.8 mmol) and triethylamine (4.5 g, 45 mmol),Reacted 12 hours in 100 °C,It is cooled to room temperature,Add 150 mL ethyl acetate and 150 mL saturated nacl aqueous solutions,Stirring 20 minutes,Divide liquid,Aqueous phase is extracted with ethyl acetate (50 mL X 2),Merge organic phase,Washed with saturated nacl aqueous solution (200 mL),Anhydrous sodium sulfate drying,Filtrate decompression Nong Shrink,With silica gel column chromatography with eluant, eluent system B purify gained residue,Obtain title product 2- { [(3aR,4S,6R,6aS /3aS,4R,6 6aR) -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] Dioxol-4 -yl] oxygen } ethanol 4h (1.8 g,Pale tan oil),Yield： 47.6%.

MS m/z (ESI):419.2 [M+l]

9th step

2- { [(6＆-the 6- of 46 6＆ of 3＆/3＆ 46 (the chloro- 5- propyl group sulfydryl-3^ [1 of 7-, 2,3]-triazol [4,5-^] pyrimidin-3-yl)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yl] epoxide) ethanol

Under ice bath, by 2- { [(3aR, 4S, 6R, 6aS/3aS, 4R, 6 6aR) -6- [(chloro- 2- propyl group sulfydryls of 5- amino -6--phonetic Pyridine -4- bases) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] oxygen } ethanol 4h (1.8 g, 4.3 mmol) it is dissolved in 7.2 mL acetic acid, by natrium nitrosum (310 mg, 4.5 mmol) it is dissolved in 3 mL water, it is added dropwise in batches in above-mentioned solution, stirring adds 60 mL ethyl acetate after 30 minutes, then 30 mL unsaturated carbonate potassium solutions are added, reaction is quenched, divide liquid, aqueous phase is extracted with ethyl acetate (50 mL X 2), merge organic phase, washed successively with unsaturated carbonate potassium solution (80 mL) and saturated nacl aqueous solution (80 mL), anhydrous sodium sulfate drying, Lv Ye Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- { [(3aR, 4S, 6R, 6aS/3aS, 4R, 6 6aR) -6- (the chloro- 5- propyl group sulfydryl -3H- [1 of 7-, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 4j (1.27 g, faint yellow solid), yield： 69.0%

MS m/z (ESI):430.2 [M+l]

1H NMR (400 MHz, CDC1₃) δ 5.54-5.52 (m, 1H), 5.22-5.19 (m, 1H), 4.89-4.87 (d, the Hz of J=6.36, 1H), 4.06-4.03 (m, 1H), 3.64-3.54 (m, 3H), 3.52-3.48 (m, 1H), 3.21 (t, the Hz of /=7.08, 2H), 2.73-2.66 (m, 1H), 2.56-2.50 (m, 1H), 1.97 (br s, 1H), 1.87-1.79 (m, 2H), 1.55 (s, 3H), 1.37 (s, 3H), 1.09 (t, the Hz of /=7.36, 3H)

Tenth step

2- { [(3＆ 4^6 6＆/3＆^^, 6 6＆-6- [7- [[(1 2-2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentene

[d] [l, 3] Dioxol-4 -yl] oxygen } ethanol

By the 2- { [(6＆ -6- of 3＆ 4^6 6＆/3＆ 46 (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-,5- pyrimidine -3- bases) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] Dioxol-4 -yl] epoxide } ethanol 4j (215 mg,0.5 mmol) it is dissolved in 15 mL acetonitriles,Add (lR,2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamine 4g (117 g, 0.68 mmol),It is stirred below in 25 °C,Triethylamine (177.1 mg are added dropwise, 1.75 mmol),Stirred 12 hours in 25 °C,Jian Ya Nong Shrink major part acetonitriles,Add 30 mL water and 30 mL ethyl acetate,With 2.5 M hydrochloric acid regulation ρ Η -4,Divide liquid,Aqueous phase is extracted with ethyl acetate (20 mL),Merge organic phase,Washed with water (40mL X 2),Anhydrous sodium sulfate drying,Filtrate decompression Nong Shrink,With silica gel column chromatography with eluant, eluent system B purify gained residue,Obtain title product 2- { [OR,4S,6R,6aS /3aS,4R,6S,6aR)-6-[7-[[(lR,2R) -2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5- pyrimidin-3-yls] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentene M [l,3] Dioxol-4 -yl] oxygen } ethanol 4k (245 mg,Faint yellow solid),Yield： 86.6%

1H NMR (400 MHz, CDC1₃) δ 6.74-6.71 (m, 1H), 6.37-6.36 (m, 1H), 5.53-5.51 (m, 1H)_:5.17-5.16 (m, lH), 4.87 (d, J=5.96 Hz, 1H), 4.01-4.00 (m, 1H), 3.62-3.51 (m, 4H), 3.16-3.12 (m, 3H), 2.66-2.62 (m, 1H), 2.46-2.45 (m, 1H), 2.23-2.21 (m, 1H), 1.78-1.73 (m, 2H), 1.54 (s, 3H), 1.42-1.31 (m, 1H), 1.29-1.20 (m, 1H), 1.36 (s, 3H), 1.02 (t, /=7.28 Hz, 3H)

11st step

(1 2^3R, 5S/lR, 2R, 3^5R) -3- { 7- [[(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino] -5- propyl group sulfydryls -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl } -5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol By 2- { [(3aR, ^, 6R, 6aS/3aS, 4R, 6 6aR) -6- [7- [[(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentene W] [l, 3] Dioxol-4 -yl] oxygen } ethanol 4k (245 mg, 0.43 mmol) it is dissolved in 15 mL methanol, 20 °C of dropwise addition M hydrochloric acid of 5 mL 2.5, stirred 12 hours in 20 °C, reaction solution adjusts ρ Η -7 with saturation sodium hydroxide solution, it is extracted with ethyl acetate (35mL X 3), merge organic phase, washed with saturated nacl aqueous solution (40mL X 2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, 1.5 mL ethyl acetate are added in crude product, in stirring 10 minutes under 57 °C, add 2 mL n-hexanes, stirred 1 hour in 57 °C, it is cooled to room temperature, filtering, obtain title product（1^2S, 3R, 5S/lR, 2R, 3^5R) -3- { 7- [[(lR, 2R) -2- (chloro- 2- thienyls of 5-）Cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol 4m (190 mg, faint yellow solid), yield： 83.7%.

1H NMR (400 MHz, DMSO-J₆) 9.33 (d of δ, the Hz of J=6.36, 1H), 6.95 (d, the Hz of J=3.76, 1H), 6.78 (d, the Hz of J=3.72, 1H), 5.11 (d, the Hz of /=6.40, 1H), 5.05 (d, the Hz of J=4.08, 1H), 5.01-4.94 (m, 1H), 4.62-4.53 (m, 2H), 3.96-3.93 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.47 (m, 4H), 3.13-2.99 (m, 3H), 2.68-2.60 (m, 1H), 2.38-2.21 (m, 1H), 2.09-2.03 (m, 1H), 1.70-1.54 (m, 3H), 1.37-1.32 (m, 1H), 0.92 (t, the Hz of /=7.32, 3H)

12nd step

(1 2^3R, 5-3- { 7- [[(lR, 2R)-2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl }-5- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol general（1S, 2 3R, 5S/lR, 2R, 3^5R) -3- { 7- [[(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) pentamethylene -1, 2- glycol 4m (190 mg, 0.36 mol), by using HPLC methods, separated with the chiral isomers of chiral column, obtain title product (1 2^3R, 5-3- { 7- [[(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino] -5- propyl group sulfydryl-triazol [4, 5 pyrimidin-3-yl 5- (2- hydroxyl-oxethyls) cyclopenta -1, (52 mg of 2- glycol 4, yellow solid yield： 27.3%.

MS m/z (ESI): 527.1 [M⁺]

1H NMR (400 MHz, DMSO-J₆) 9.33 (d of δ, the Hz of J=6.36, 1H), 6.95 (d, the Hz of J=3.76, 1H), 6.78 (d, the Hz of J=3.72, 1H), 5.11 (d, the Hz of /=6.40, 1H), 5.05 (d, the Hz of J=4.08, 1H), 5.01-4.94 (m, 1H), 4.62-4.53 (m, 2H), 3.96-3.93 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.47 (m, 4H), 3.13-2.99 (m, 3H), 2.68-2.60 (m, 1H), 2.38-2.21 (m, 1H), 2.09-2.03 (m, 1H), 1.70-1.54 (m, 3H), 1.37-1.32 (m, 1H), 0.92 (t, the Hz of /=7.32, 3H) embodiments 5

(1 23 5R) -3- (2- hydroxyl-oxethyls) -5- { 7- (indanyl -2- bases amino) -5- propyl group sulfydryl-triazol [4,5- pyrimidin-3-yls } cyclopenta -1,2- glycol

(3aR4S6R6a^-6- amino -2,2- dimethyl -4566a- tetrahydrochysene -3aH- cyclopentas M [l 3] dioxole -4- alcohol L- (-)-dibenzoyl tartaric acid salt

By (the 7＆5 of 3＆ 47>3＆ 47 7＆ -22- dimethyl dihydro -3＆ 47- methylene [13] dioxole simultaneously [45-^] [(4H benzyl formates 2d (mmol of 20 g 65.5) is added in 400 mL methanol 12] oxazines -6, add palladium/carbon (l g 5%), hydrogen is replaced three times, reacted 24 hours in 50 °C, filtering, add L- (-)-dibenzoyl tartaric acid (mmol of 23.4 g 65.5), Jian Ya Nong Shrink, 262 mL acetonitriles and 43.7 mL water are added in crude product, stirred 1 hour in 60 °C, naturally cool to room temperature, it is slow to separate out solid, it is stirred at room temperature 12 hours, obtain title product (3aR4S6R6a^-6- amino -2, 2- dimethyl -4566a- tetrahydrochysene -3aH- cyclopentas M [l 3] dioxole -4- alcohol L+)-dibenzoyl tartaric acid salt 5a (11.8 g, off-white powder), yield： 33.9% MS m/z(ESI): 174.1 [M+l]

Second step

N- [(3aS4R6 6aR)-6- hydroxyls-2,2- dimethyl-4566a- tetrahydrochysene-3aH- cyclopentas M [l 3] Dioxol-4 -yl] benzyq carbamate

By (3aR ^6R6a -6- amino -2,2- dimethyl -4566a- tetrahydrochysene -3aH- cyclopentas M [l 3] dioxole -4- alcohol L-)-mmol of dibenzoyl tartaric acid salt 5aC11.8 g 22.2) it is dissolved in 195 mL tetrahydrofurans and water (V/V=10:3) in the mixed solvent, add potassium carbonate, benzyl chloroformate (mmol of 7.57 g 22.2) is slowly added dropwise, reacts at room temperature 12 hours, reaction solution Jian Ya Nong Shrink remove most of tetrahydrofuran, ethyl acetate extracts (50mLX3), merge organic phase, washed with saturated nacl aqueous solution (100 mL), anhydrous magnesium sulfate is dried, filtrate decompression Nong Shrink, residue 63mL n-hexanes and dichloromethane (V/V=20:1) mixed solvent mashing, filtering, filter cake vacuum drying obtains title product N- [(3aS4R6 6aR 6- hydroxyl -2,2- dimethyl -4566a- Tetrahydrochysene-3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl] benzyq carbamate 5b (6.51 g, white solid), yield： 95.4%.

MS m/z (ESI): 308.1 [M+1]

1H NMR (400 MHz, CDC1₃) δ 7.46-7.27 (m, 5H), 5.63 (br, 1H), 5.10 (s, 2H), 4.58 (d, 1H), 4.47 (d, 1H), 4.27 (d, 1H), 4.19 (t, 1H), 2.23 (m, 1H), 1.97 (br, 1H), 1.70 (d, 1H), 1.41 (s, 3H), 1.26 (s, 3H)

3rd step

2- [[(3aR, 4S, 6R, 6a -6- Benzyoxycarbonylamino -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas

M [l, 3] Dioxol-4 -yl] oxygen] ethyl acetate

By N- [(3aS, 4R, 6 6aR) -6- hydroxyls -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 5b (2 g, 6.51 mmol) it is dissolved in 20 mL tetrahydrofurans, potassium tert-butoxide (3.65 g are added dropwise under the dry ice bath, 9.76 mmol), drop finishes, less than -20 °C are reacted 1 hour, bromoacetate (1.63 g are added dropwise in less than -20 °C, 9.76 mmol), less than -20 °C are reacted 1 hour, warm naturally to room temperature, stirring 12 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- [[OR, 4S, 6R, 6a -6- Benzyoxycarbonylaminos -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] oxygen] ethyl acetate 5c (2.16 g, pale yellow oil), yield： 84.2%.

MS m/z (ESI): 394.3[M+1]

1H NMR (400 MHz, CDC1₃) δ 7.47-7.27 (m, 5H), 5.93 (d, 1H), 5.10 (s, 2H), 4.57 (s, 2H), 4.27-4.01 (m, 5H), 3.91 (d, 1H), 2.29-2.15 (m, 1H), 1.82 (d, 1H), 1.40 (s, 3H), 1.26 (s, 3H), 1.23 (t, 3H)

4th step

N- [(3aS, 4R, 6 6aR) -6- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas

W] [l, 3] Dioxol-4 -yl] benzyq carbamate

By 2- { [(3aR, 4^6R, 6a -6- benzyloxy-amides -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] oxygen } ethyl acetate 5c (8 g, 20.34 mmol) it is dissolved in 60 mL tetrahydrofurans, add lithium borohydride (887 mg, 40.67 mmol), stirring 12 hours, reaction solution is poured into 150 mL water, extracted with ethyl acetate (60 mL X 3), saturated nacl aqueous solution (100 mL) is washed, anhydrous magnesium sulfate is dried, filtrate decompression Nong Shrink, obtain crude title product N- [OS, 4R, 6 6aR) -6- (hydroxyl-oxethyl) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 5d (7.04 g, faint yellow thick liquid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 352.1 [M+1]

5th step

2- [(3aR, 4S, 6R, 6a^-6- amino-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol

By N- [(3aS, 4R, 6 6aR)-6- (2- hydroxyl-oxethyls)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 5d (.04 g, 20.03 mmol) is dissolved in 100 mL In methanol, palladium/carbon 350 mg, 5% are added), hydrogen is replaced three times, is stirred 12 hours, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- { [(3aR, 4^6R, 6a-6- amino-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas [l, 3] Dioxol-4 -yl] epoxide）Ethanol 5e (4.54 g, pale yellow oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 218.1 [M+1]

6th step

2-{[OR,4S,6R,6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas W] [l,3] Dioxol-4 -yl] epoxide } ethanol is by crude product 2- { [(3aR,45,6R,6a5) -6- amino -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] Dioxol-4 -yl] epoxide } ethanol 5e (1.5 g,6.9 mmol) it is dissolved in 25 mL ethylene glycol,Add triethylamine (3.49 g,34.5 mmol) and 4,The chloro- 2- propyl group mercapto-pyrimidine -5- amine ls of 6- bis- (l .98 g, 8.28 mmol),100 °C are reacted 12 hours,It is cooled to room temperature,Add 100 mL ethyl acetate and 100 mL saturated nacl aqueous solutions,Stirring 20 minutes,Divide liquid,Aqueous phase is extracted with ethyl acetate (50 mL X 3),Merge organic phase,Washed with saturated nacl aqueous solution (100 mL),Anhydrous sodium sulfate drying,Filtrate decompression Nong Shrink,With silica gel column chromatography with eluant, eluent system B purify gained residue,Obtain title product 2- { [(3aR,4S,6R,6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] Dioxol-4 -yl] epoxide）Ethanol 5f (1.6 g, yellow oil), yield： 55.4%.

MS m/z (ESI): 419.1 [M+1]

7th step

2- { [(3aR, 4S, 6R, 6a^-6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] epoxide } under ethanol ice bath, by 2- { [(3aR, 4 6R, 6a-6- [(the chloro- 2- propyl group mercapto-pyrimidine-4- bases of 5- amino-6-）Amino]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol 5f (1.6 g, 3.8 mmol) it is dissolved in 6.5 mL acetic acid, stir, 3 mL natrium nitrosums are added dropwise（277 mg, 4 mmol) solution, continue to stir 30 minutes under ice bath, add 50 mL ethyl acetate and 30 mL unsaturated carbonate potassium solutions, it is quenched, divide liquid, aqueous phase is extracted with ethyl acetate (50 mL X 3), merge organic phase, washed successively through unsaturated carbonate potassium solution (80 mL) and saturated nacl aqueous solution (80 mL), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- { [(3aR, 45, 6R, 6a5) -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-J] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 5gCU8 g, faint yellow thick liquid), yield： 72.4%.

MS m/z (ESI):430.1 [M+1]

8th step

2- { [(3aR, 4S, 6R, 6a-6- [7- (indanyl-2- bases amino)-5- propyl group sulfydryl-triazol [4,5-d] pyrimidine-3- bases]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol is by 2- { [(3aR, 4S, 6R, 6a-6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl)-2,2- dimethyl - 4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] Dioxol-4 -yl] epoxide } ethanol 5g (100 mg, 0.23 mmol) it is dissolved in 8 mL acetonitriles, add 2- aminoidans (418 mg, 0.31 mmol), stirring, triethylamine (82.2 mg are added dropwise, 0.81 mmol), it is stirred at room temperature 24 hours, 15 mL water are added in reaction solution, with 2.5 M hydrochloric acid regulation ρ Η -4, ethyl acetate (25 mL X 2) is extracted, merge organic phase, washed with saturated nacl aqueous solution (25 mL X 2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, obtain crude title product 2- { [(3aR, 45, 6R, 6a5) -6- [7- (indanyl -2- base amino）- 5- propyl group sulfydryl-triazol [4,5- pyrimidine-3- bases]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide } ethanol 5h (100 mg, faint yellow solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 527.2[M+1]

9th step

(1S, 23 5R) -3- (2- hydroxyl-oxethyls) -5- [7- (indanyl -2- bases amino) -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl] cyclopenta -1,2- glycol

By crude product 2- { [(3aS, 4R, 6 6aR) -6- [7- (indanyl -2- bases amino) -5- propyl group sulfydryls-triazol [4, 5-d] pyrimidin-3-yl] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] oxygen } ethanol 5h (100 mg, 0.19 mmol) it is dissolved in 5 mL methanol, hydrochloric acid (4 mL are added dropwise, 2.5 M), stirring 12 hours, saturation sodium hydroxide solution is added in reaction solution, adjust ρ Η -9, ethyl acetate (30 mL X 2) is extracted, merge organic phase, washed with saturated nacl aqueous solution (25 mL X 2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system F purify gained residue, obtain title product (lS, 2S, 3S, 5R) -3- (2- hydroxyl-oxethyls) -5- [7- (indanyl -2- bases amino) -5- propyl group sulfydryls-triazol [4, 5-d] pyrimidin-3-yl] cyclopenta -1, (75 mg of 2- glycol 5, white solid), yield： 81.2%.

MS m/z (ESI): 487.2[M+1]

1H NMR (400 MHz, DMSO-J₆) 7.25 (m of δ, 2H), 7.18 (m, 2H), 5.12-5.11 (m, 1H), 5.05-5.04 (m, 1H), 5.00-4.94 (m, 2H), 4.60-4.57 (m, 3H), 3.95 (m, 1H), 3.77 (m, 1H), 3.52-3.50 (m, 3H), 3.29-3.27 (m, 1H), 3.11-3.06 (m, 3H), 2.68-2.60 (m, 2H), 2.34 (s, 1H), 2.05-2.00 (m, 1H), 1.75-1.70 (m, 2H), 1.24 (s, 1H), 0.98 (t, the Hz of /=7.18, 3H) embodiments 6

(1^2S, 3 4-5- { 7- [[(lR, 2R)-2- (the chloro- 2- thienyls of 5-) cyclopropyl] amino]-5- propyl group sulfydryl-triazol

[4,5- -3- bases } cyclopenta -1,2,3,4- tetrols

The first step

5- nitro -2- propyl group mercapto-pyrimidine -4,6- glycol

Under ice-water bath, 2- propyl group mercapto-pyrimidine -4,6- glycol 6a (being prepared X8.0 g, 43 mmol using known method " patent WO2001092263 ") is dissolved in 35 mL fuming nitric aicds, 0 °C is reacted 1.5 hours.Reaction solution is poured into ice cube, it is stirred at room temperature 1 hour, has a small amount of solid to separate out, adds potassium carbonate to reaction solution pH=l 2, there are a large amount of solids to separate out, filtering, filter cake is washed with water (50 mLx2), is dried, obtain crude title product 5- nitro -2- propyl group mercapto-pyrimidine -4,6- glycol 6b (11.1 g, yellow powder solid), yield： 100%. 1H NMR (400 MHz, CDC1₃) (t, the 3H) of 53.27-3.17 (t, 2H), 1.90-1.74 (m, 2H), 1.1 1

Second step

4,6- chloro- 5- nitros -2- propyl group mercapto-pyrimidines

Crude product 5- nitro -2- propyl group mercapto-pyrimidine -4,6- glycol 6b (1.0 g, 4.3 mmol) are dissolved in POCl3 (8.4 g, 85.64 in mmol), add N, N- diethylanilines (1.12 g, 7.5 mmol).Back flow reaction 1.5 hours.Reaction solution is poured into ice cube, stirring 20 minutes, extracted with ether (40 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, Lv Ye Nong Shrink, obtain title product 4, the chloro- 5- nitros -2- propyl group sulfydryls of 6--pyridine of crowing_6c(0.45 g, orange), yield： 39%.

3rd step

0 6-2,2- dimethyl-6,6＆- dihydro-3＆^ cyclopentas [^] [1,3] dioxole-6- alcohol is by two (tricyclohexyl phosphine) benzal chloride ruthenium 6d (177 mg, 0.216 mmol) add in reaction bulb, syringe adds 40 mL l- [(4S, 5R)-2,2- dimethyl-5- vinyl-1,3- dioxolane-4- bases] small alcohol lm (2 g of propyl- 2- alkene, 10.8 mmol) chloroformic solution, react 2 hours.Reaction solution Jian Ya Nong Shrink, use silica gel column chromatography Gained residue is purified with eluant, eluent system B, title product (3aR, 6-2,2- dimethyl-6,6a- dihydro-3aH- cyclopentas W] [l, 3] dioxole-6- alcohol 6e C450 mg, brownish black grease), yield is obtained： 26.7%. 1H NMR (400 MHz, DMSO-J₆) δ 6.01-6.02 (m, 1H), 5.88-5.90 (m, 1H), 5.25-5.28 (m, 1H), 4.78 (m, 1H), 4.50-4.5 l (d, 1H), 2.23 (br, 1H), 1.39 (s, 3H), 1.34 (s, 3H)

4th step

(4R, 6aR) -2, 2- dimethyl -4, 6a- dihydro -3aH- cyclopenta M [l, 3] dioxole -4- amine is by triphenylphosphine (3.26 g, 12.43 mmol) it is dissolved in 30 mL tetrahydrofurans, -20 °C are added dropwise diisopropyl azodiformate (2.5 mL, 12.43 mmol), reacted 10 minutes in -20 °C, 20mL (3aR are added dropwise, 6-2, 2- dimethyl -6, 6a- dihydro -3aH- cyclopentas [[1, 3] dioxole -6- alcohol 6e (1.77 g, 11.3 mmol) tetrahydrofuran solution, reacted 30 minutes in -20 °C, it is warming up to 0 °C, diphenyl phosphate azide (3.73 g are added dropwise, 13.56 mmol), reacted 7 hours in 0 °C, add triphenylphosphine (3.26 g, 12.43 mmol), reacted 12 hours in 0 °C, add 5 mL water, reaction 8 hours, room temperature reaction 5 hours, reaction solution Jian Ya Nong Shrink, obtain crude title product (4R, 6aR) -2, 2- dimethyl -4, 6a- dihydro -3aH- cyclopenta M [l, 3] dioxole -4- amine 6f (1.7 g, colorless oil), product is not purified directly to carry out next step reaction.

1H NMR (400 MHz, CDC1₃) δ 6.15 (m, 1H), 5.87-5.89 (m, 1H), 5.22-5.26 (m, 1H), 4.58-4.60 (m, 1H), 4.39 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H)

5th step

N- [(3aR, 6R) -2,2- dimethyl -6,6a- dihydro -3aH- cyclopentas M [l, 3] dioxole -6- bases] benzyq carbamate

By C4R, 6aR) -2, 2- dimethyl -4, 6a- dihydro -3aH- cyclopentas M [1, 3] dioxole -4- amine 6f (1.7 g, 11 mmol) it is dissolved in 20 mL tetrahydrofurans, add 10 mL water and potassium carbonate (3.04 g, 22 mmol), benzyl chloroformate (4.5 mL are added dropwise, 13.2 mmol), reaction 12 hours, extracted with ethyl acetate (20 mLx2), merge organic phase, Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product N- [(3aR, 6R) -2, 2- dimethyl -6, 6a- dihydro -3aH- cyclopenta M [l, 3] dioxole -6- bases] benzyq carbamate 6g (570 mg, white solid), yield： 17.9%.

MS m/z (ESI): 288.3[M-1]

6th step

((3aS, 4R, 56 6aR)-5,6- dihydroxy-2,2- dimethyl tetrahydro-3aH- cyclopentas M [l, 3] Dioxol-4 -yl) benzyq carbamate

By N- [(3aR, 6R) -2,2- dimethyl -6,6a- dihydro -3aH- cyclopentas [l, 3] dioxole -6- bases] benzyq carbamate 6g (570 mg, 1.97 mmol) it is dissolved in 10 mL tetrahydrofurans, add N- methyl morpholine oxides (0.94 mL, 4 mmol) and osmium tetroxide（102 mg, 0.4 mmol), reaction 12 hours, add 30 mL water, ethyl acetate (60 mLx3) is extracted, merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aS, 4R, 56 6aR) -5, 6- dihydroxy -2, 2- dimethyl tetrahydro -3aH- cyclopenta M [l, 3] Dioxol-4 -yl) benzyq carbamate 6h (500 mg, colorless oil), yield： 78.0%.

MS m/z (ESI): 324.3[M+1] 1H NMR (400 MHz, CDC1₃) δ 7.31-7.36 (m, 5H), 5.42 (d, 1H), 5.29 (s, 2H), 5.11 (br, 2H), 4.54 (d, 1H), 4.48 (d, 1H), 4.30-4.40 (m, 1H), 4.17-4.2 l (m, 1H), 4.05-4.09 (m, 1H), 1.43 (s, 3H), 1.25 (s, 3H)

7th step

OR, 4S, 5 6R, 6a -6- amino -2,2- dimethyl tetrahydro -3aH- cyclopentas M [l, 3] dioxole

- 4,5- glycol

By (3aS, 4R, 56 6aR) -5, 6- dihydroxy -2, 2- dimethyl tetrahydro -3aH- cyclopenta M [l, 3] dioxole -4- yls) benzyq carbamate 6h (500 mg, 1.54 mmol) it is dissolved in 15 mL methanol, add palladium/carbon (150 mg, 10%), hydrogen is replaced three times, stirring 12 hours, add diatomite, filtering, filtrate decompression Nong Shrink, obtain crude title product OR, 4S, 5 6R, 6a -6- amino -2, 2- dimethyl tetrahydro -3aH- cyclopentas [d] [l, 3] dioxole -4, 5- glycol 6j (270 mg, colorless oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 190.2[M+1]

1H NMR (400 MHz, CDC1₃) δ 4.63 (d, 1H), 4.45 (d, 1H), 4.25-4.27 (m, 1H), 3.97 (d, 1H), 3.46 (d, 1H), 2.67 (m, 4H), 2.67 (br, 4H), 1.41 (s, 3H), 1.28 (s, 3H)

8th step

(3aR, 4S, 5 6R) -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4, 5- glycol is by OR, 4S, 5 6R, 6a^-6- amino -2, 2- dimethyl tetrahydro -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6j (270 mg, 1.42 mmol) it is dissolved in 15 mL ethanol, add triethylamine (0.4 mL, 2.84 mmol) standing grain B 4, chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (419 mg of 6-, 1.57 mmol), reaction 12 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aR, 4S, 5^6R) -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6kC390 mg, yellow solid), yield： 65.4%.

MS m/z (ESI): 421.1 [M+1]

9th step

OR, 4S, 5 6R, 6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -2,2- dimethyl

- 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4,5- glycol are by OR, 4S, 5 6R) -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-）Amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6k (390 mg, 0.93 mmol) it is dissolved in 10 mL acetic acid, add iron powder (260 mg, 4.64 mmol), reaction 12 hours, add 50 mL ethyl acetate, stirring, filtering, filter cake is washed (40 mLx2) with ethyl acetate, merge organic phase, it is washed with water (50 mLx2), merge aqueous phase, it is extracted with ethyl acetate (50 mLx3), organic phase Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aR, 4S, 5 6R, 6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6m (200 mg, brown solid), yield： 55%. MS m/z (ESI): 391.1 [M+1]

1H NMR (400 MHz, DMSO-J₆) δ 4.51-4.54 (m, 1H), 4.38-4.40 (m, 1H), 4.21-4.23 (m, 1H), 4.13-4.15 (m, 1H), 3.86-3.87 (m, 1H), 2.94 (t, 2H), 1.60-1.65 (m, 2H), 1.38 (s, 3H) 1.20 (s, 3H), 0.93-0.99 (m, 3H)

Tenth step

(3aR,4S,5 6R) -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l,3] dioxole -4,5- glycol is by OR, ^,5S,6R,6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] dioxole -4,5- glycol 6m (200 mg,0.51 mmol) it is dissolved in 4 mL acetic acid,Add 0.5 mL water,0.5 mL natrium nitrosums (38.9 mL are added dropwise,0.56 mmol) ice water solution,Stirring 5 minutes,Add 60 mL ethyl acetate,Successively through saturated sodium bicarbonate solution (10 mL),Water (20 mL) and saturated nacl aqueous solution (20 mL) washing,Anhydrous sodium sulfate drying,Jian Ya Nong Shrink,Obtain crude title product (3aR,4S,5^6R) -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-,5- pyrimidin-3-yls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] dioxole -4,5- glycol 6n (220 mg),Brown oil),Product is not purified directly to carry out next step reaction.

MS m/z (ESI): 402.1 [M+1]

11st step

(3aR, 4S, 5^6R) -6- { 7- [(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole

- 4,5- glycol

Will（3aR, 4S, 5^6R) -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6n (80 mg, 0.2 mmol) it is dissolved in 10 mL acetonitriles, add (lR, 2^-2- (3, 4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (58.8 mg, 0.28 mmol), stirring, triethylamine (0.1 mL is added dropwise, 0.7 mmol), reaction 12 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aR, 4S, 5S, 6R) -6- { 7- [(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamino] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6p (107 mg, pale yellow oil), yield 100%.

MS m/z (ESI): 540.1 [M+1]

12nd step

(1 23 4-5- 7- [(1 2-2- (the chloro- 2- thienyls of 5-) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } cyclopenta -1,2,3,4- tetrols

By (3aR, 4S, 5^6R) -6- { 7- [(lR, 2R) -2- (the chloro- 2- thienyls of 5-) cyclopropylamino] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl } -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 6p (107 mg, 0.2 mmol) it is dissolved in 8 mL methanol, add in the M hydrochloric acid of 2 mL 2, stirring 12 hours, with saturated sodium carbonate solution regulation ρ Η -8, Jian Ya Nong Shrink remove methanol, it is extracted with ethyl acetate (60 mLx3), anhydrous magnesium sulfate is dried, filtrate decompression Nong Shrink, further separated by HPLC preparative chromatographies, To title product (；1 2^3 4 -5- -[(；1 2 -2-(；The chloro- 2- thienyls of 5-) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta -1,2,3,4- tetrols 6 (45mg, white solid), yield： 45.2%. MS m/z (ESI): 499.1[M+1]

1H NMR (400 MHz, CD₃OD) δ 6.74-6.79 (m, 2H), 5.22-5.23 (m, 1H), 5.09 (m, 1H), 4.50-4.51 (m, 1H), 4.09-4.13 (m, 2H), 3.15-3.16 (m, 2H), 3.05-3.09 (m, 1H), 2.21-2.22 (m, 1H), 1.71-1.73 (m, 2H), 1.50-1.51 (m, 1H), 1.32-1.35 (m, 1H), 1.02-1.10 (m, 1H), 0.97 (t, 3H), 0.85-0.92 (m, 1H) embodiments 7

(lS, 2S, 3S, 4R) -5- 7- [(lR, 2] -5- propyl group sulfydryl-triazol [4,5-d]

The first step

06 6＆ -6- (methylol) -2,2- dimethyl-tetrahydrofurans simultaneously [3,4^] [1,3] dioxole -4- alcohol By (3R, 4S, 5R) -5- (methylol) tetrahydrofuran -2,3,4- triols lh (20 g, 133 mmol) is dissolved in 250 mL acetone, adds the 0.6 mL concentrated sulfuric acids, is reacted 4 hours at room temperature.Sodium bicarbonate solid is added in reaction solution until pH=7, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product (3aR, 6R, 6aR) -6- (methylol) -2,2- dimethyl-tetrahydrofurans simultaneously [3, U] [1,3] dioxole -4- alcohol 7a (17.8 g, colorless oil), yield 70.4%.

Second step

(R)-1-((4R, 5-2, 2- dimethyl -5- vinyl -1, 3- dioxolanes -4- bases) ethane -1, 2- glycol is by methyltriphenylphosphonium bromide (94.6 g, 265 mmol) it is suspended in 600 mL tetrahydrofurans, solution is cooled to 0 °C, add potassium tert-butoxide (32.9 g, 293 mmol), reacted 20 minutes at 0 °C, it is warmed to room temperature reaction 1 hour, 6＆-the 6- (methylol) -2 of 200 mL 06 are added dropwise, 2- dimethyl-tetrahydrofurans simultaneously [3, 4^] [1, 3] dioxole -4- alcohol 7a (18 g, 95 mmol) tetrahydrofuran solution, stir 12 hours at room temperature.150 mL water will be added in reaction solution, solid dissolving, divide liquid, it is extracted with ethyl acetate (100 mL X 4), the organic phase of merging is washed with saturated nacl aqueous solution (100 mL X 2), anhydrous sodium sulfate drying, filtering, decompression Xia Nong Shrink, obtain crude product (R)-l- ((4R, 5^-2,2- dimethyl -5- vinyl -1,3- dioxolanes -4- bases) ethane -1,2- glycol 7b (17.8 g, brownish red grease), product is not purified directly to carry out next step reaction.

3rd step

(4 5-2,2- dimethyl-5- vinyl-DOX-4- formaldehyde is by (R)-l- ((4R, 5-2,2- dimethyl-5- vinyl-1,3- dioxolanes-4- bases) ethane-1,2- glycol 7b (17 g, 90 mmol) is dissolved in 300 mL tetrahydrofurans, 200 mL sodium metaperiodates (29 g are added dropwise, 135 mmol) solution, 30 minutes completion of dropping, continuation reaction 30 minutes.200 mL water will be added in reaction solution, divide liquid, aqueous phase extracts (200 mL X 2), the organic phase anhydrous sodium sulfate drying of merging with dichloromethane, filtering, filtrate decompression Xia Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (5-2,2- dimethyl-5- vinyl-1,3- dioxolanes-4- formaldehyde 7c (7.5 g, colorless oil), yield 53.4%.

4th step

1- ((4R, 5-2,2- dimethyl-5- vinyl-1,3- dioxolanes-4- bases) the small alcohol general (4 5-2 of propyl- 2- alkene, 2- dimethyl-5- vinyl-1,3- dioxolanes-4- formaldehyde 7c (25 g, 160 mmol) it is dissolved in 300 mL tetrahydrofurans, solution is cooled to-78 °C, 1M vinyl magnesium bromide (320 mL are added dropwise, 320 mmol), reacted 1 hour under-78 °C after completion of dropping, rise to 0 °C and react 30 minutes.200 mL saturated ammonium chloride solutions are added in reaction solution, stirring divides liquid after 10 minutes, aqueous phase is extracted with ethyl acetate (200 mL X 2), the organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate decompression Xia Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product l- ((4R, 5-2,2- dimethyl-5- vinyl-1,3- dioxolanes-4- bases) propyl- 2- alkene-1- alcohol 7d C18 g, colorless oil), yield 61%.

5th step

04 6＆^-2,2- dimethyl -4,6＆- dihydro -3＆^ cyclopentas [^] [1,3] dioxole -4- alcohol is by two (tricyclohexyl phosphine) benzal chloride ruthenium (0.5 g, 0.63 mmol) add in 1000 mL single port bottles Syringe adds 450 mL l- ((4R, 5-2,2- dimethyl-5- vinyl-1,3- dioxolanes-4- bases) small alcohol 7d (11.5 g of propyl- 2- alkene, 62.5 mmol) chloroformic solution, react at room temperature 3.5 hours, reaction solution Jian Ya Nong Shrink, with silica gel chromatography with eluant, eluent system B purify gained residue, obtain title product（3aR, 4R, 6a -2,2- dimethyl -4,6a- dihydro -3aH- cyclopentas [^] [1,3] dioxole -4- alcohol 7e (3.2 g, shallow brownish black grease), yield 50%.

6th step

04 6＆^-4- benzyloxy -2,2- dimethyl -4,6＆- dihydro -3＆^ cyclopentas ^] [1,3] dioxole general（3aR, 4R, 6a -2, 2- dimethyl -4, 6a- dihydro -3aH- cyclopenta M [l, 3] dioxole -4- alcohol 7e (2.5 g, 16 mmol) it is dissolved in 30 mL DMF, 0 °C be added portionwise 60% sodium hydride (1.28 g, 32 mmol), room temperature reaction 30 minutes, add benzyl bromide a-bromotoluene (2.85 mL, 24 mmol), reaction 12 hours, plus reaction is quenched in methanol, reaction solution Jian Ya Nong Shrink, add 50 mL ethyl acetate, wash (20mLx2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the 6＆ -4- benzyloxies -2 of title product 04, 2- dimethyl -4, 6＆- dihydro -3＆^ cyclopentas ^] [1, 3] dioxole 7fC3.9g, colorless oil), yield： 100%.

7th step

(1 2 5-5- benzyloxy cyclopentene-3- alkene-1,2- glycol

By (3aR, ^, 6a -4- benzyloxies -2,2- dimethyl -4,6a- dihydro -3aH- cyclopenta M [l, 3] dioxole 7f (3.9 g, 16 mmol) it is dissolved in 20 mL methanol, the resin cations of Dowex 50 (3 g) are added, are stirred 12 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product benzyloxy cyclopentene -3- alkene -1,2- glycol 7g (2.2 g, pale yellow oil), yield： 66.6%.

8th step

(lR, 2R, 3^4R, 5R) -4- benzyloxies -6- oxabicyclos simultaneously [3 Shang 0] hexane -2, 3- glycol is by the (- 5- benzyloxy cyclopentene -3- alkene -1 of 1^2 5, 2- glycol 7g (2.2 g, 10.67 mmol) it is dissolved in 50mL dichloromethane, add metachloroperbenzoic acid (4.74 g, 19.2 mmol), reaction 24 hours, reaction solution Jian Ya Nong Shrink, silica gel column chromatography purifies gained residue with eluant, eluent system B, obtain title product (1R, 2R, 3 4R, 5R) -4- benzyloxies -6- oxabicyclos simultaneously [3 Shang 0] hexane -2, 3- glycol 7h (2.14 g, pale yellow oil), yield： 90.3%.

9th step

(1 23 4R, 5-3- azidos-5- benzyloxies-cyclopenta-1,2,4- triols will the (- 4- benzyloxy-6- oxabicyclos of 12 3^4 5 simultaneously [3 Shang 0] hexane-2,3- glycol 7h (2.14 g, 9.63 mmol) it is dissolved in 30 mL DMF and water (V/V=5:1) in the mixed solvent, add sodium azide (940mg, 14.5 mmol), reacted 16 hours in 80 °C, reaction solution Jian Ya Nong Shrink, residue is dissolved with ethyl acetate, wash (20mLx2), (10mLx2), anhydrous sodium sulfate drying is extracted with ethyl acetate, organic phase Jian Ya Nong Shrink, obtain crude title product (, 2^, 3S, 4R, 5-3- azidos-5- benzyloxies-cyclopenta-1,2,4- triols 7j (2.55 g, pale yellow oil), product is not purified directly to carry out next step reaction. Tenth step

(3aS, 4R, 5R, 6 6aS) -4- azido -6- benzyloxy -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas

M [l, 3] dioxole -5- alcohol

By (1 23 4R, 5S) -3- azidos -5- benzyloxies-cyclopenta -1, 2, 4- triols 7j (2.55 g, 9.63 mmol) it is dissolved in 20 mL acetone, add 2, 2- dimethoxy propane C2.36 mL, 19.3 mmol) and p-methyl benzenesulfonic acid (750 mg, 4.4 mmol), reaction 4 hours, reaction solution Jian Ya Nong Shrink, silica gel column chromatography purifies gained residue with eluant, eluent system B, obtain the 4R of title product 0, 5R, 6 6a -4- azido -6- benzyloxies -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentene M [l, 3] dioxole -5- alcohol 7k (1.78 g, white solid yield： 60.5%

11st step

(3aS, 4R, 5R, 6 6aS) -4- amino -6- benzyloxy -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol

By (3aS, 4R, 5R, 6 6a -4- azido -6- benzyloxies -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentene M [l, 3] dioxole -5- alcohol 7k (400 mg, 1.31 mmol) with triphenylphosphine (490 mg, 1.86 mmol) it is dissolved in 6 mL tetrahydrofurans, add 1.2 mL water, reacted 12 hours in 30 °C, reaction solution Jian Ya Nong Shrink, silica gel column chromatography purifies gained residue with eluant, eluent system A, obtain title product (3a^, 4R, 5R, 6S, 6a -4- amino -6- benzyloxies -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -5- alcohol 7m (340 mg, white solid), yield： 93%.

MS m/z (ESI): 280.1 [M+1]

1H NMR (400 MHz, DMSO-J₆) δ 7.45-7.30 (m, 5H), 4.77 (d, 1H), 4.64 (d, 1H), 4.52 (br, 1H), 4.35-4.25 (m, 1H), 3.90-3.79 (m, 2H), 3.20 (br, 1H), 1.53 (s, 3H), 1.34 (s, 3H)

12nd step

(3aR, 4S, 5R, 6R, 6a -6- amino -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4,5- glycol

By (3aS, 4R, 5R, 6 6a -4- amino -6- benzyloxies -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] dioxole -5- alcohol 7m (340 mg, 1.22 mmol) it is dissolved in 8 mL methanol, add palladium dydroxide (600 mg, 4.27 mmol), reacted 12 hours under l atm, reaction solution Jian Ya Nong Shrink, obtain crude title product (3aR, 4S, 5R, 6R, 6a -6- amino -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 7_n(230 mg, thick white shape solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 190.2[M+1]

13rd step

OR, 4S, 5R, 6R, 6a -6- [(;The chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol is by (3aR, 4S, 5R, 6R, 6a -6- amino -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, the η of 5- glycol 7 (230 mg, 1.22 mmol) and 4, chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (423.5 mg of 6-, 1.6 mmol) it is dissolved in 15 mL ethanol, triethylamine (0.34 mL is added dropwise, 2.44 mmol), Reaction 4 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain the 6＆ -6- of title product 0456 [(；The chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4,5- glycol 7p (310 mg, faint yellow solid), yield： 60.5%.

MS m/z (ESI): 421.1 [M+1]

14th step

C3aR,4S,5R,6R,6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] dioxole -4,5- glycol is by (3aR,4S,5R,6R,6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] dioxole -4,5- glycol 7p (310 mg,0.74 mmol) it is dissolved in 10 mL acetic acid,Add iron powder (207 mg, 3.7 mmol),Reaction 3 hours,Add 20 mL ethyl acetate,Stirring 5 minutes,Filtering,Filter cake is washed with a large amount of ethyl acetate,Filtrate is washed through water (20 mL X 2) and saturated sodium bicarbonate solution (20 mL X 2) successively,Merge aqueous phase,Extracted with ethyl acetate (20 mL X 2),Merge organic phase,Jian Ya Nong Shrink,Obtain title product C3aR,4WR,6R,6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l,3] dioxole -4,5- glycol 7q (210 mg,Yellow solid),Yield 93%.

MS m/z (ESI): 391.1 [M+1]

15th step

(3aR, 4S, 5R, 6R, 6a^-6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol is by OR, 4S, 5R, 6R, 6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 7q (270 mg, 0.7 mmol) it is dissolved in 4.5 mL acetic acid and water (V/V=2:1) in the mixed solvent, under ice bath, add natrium nitrosum (53.2 mg, 0.77 mL), reacted 5 minutes in 0 °C, add 20 mL ethyl acetate and 20 mL saturated sodium carbonate solutions, stirring 5 minutes, divide liquid, organic phase is washed with saturated sodium carbonate solution (10 mL) and saturated nacl aqueous solution (10 mL) successively, merge aqueous phase, it is extracted with ethyl acetate (10 mL X 2), anhydrous sodium sulfate drying, filtrate decompression Nong Shrink obtain crude title product OR, 4S, 5R, 6R, 6a -6- (;The chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidine -3- bases) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4,5- glycol 7r (281 mg, brown oil).

MS m/z (ESI): 402.2[M+1]

16th step

(3aR, 4S, 5R, 6R, 6a-6- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole

- 4,5- glycol

By (3aR, 4S, 5R, 6R, 6a -6- (the chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4,5- glycol 7r (281.3 mg, 0.7mmol) (1R, 2-2- (3, 4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (312.9 mg, 0.98 mmol) it is dissolved in 10 mL acetonitriles, triethylamine (0.34 mL is added dropwise, 2.45mmol), reaction 16 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aR, 45, 5R, 6R, 6a5) -6- { 7- [(lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazole [4, 5-d] pyrimidin-3-yl 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4, 5- glycol 7s (310 mg, white solid), yield： 83%.

MS m/z (ESI): 535.3[M+1]

17th step

(1S, 2 3S, 4R) -5- [7- [[(lR, 2^-2- (3,4- difluorophenyl) cyclopropyl] amino] -5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl] cyclopenta -1,2,3,4- tetrols

By (3aR, 4S, 5R, 6R, 6a -6- { 7- [(lR, 2^-2- (3,4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazole [4,5-d] pyrimidin-3-yl } -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4,5- glycol 7s (310 mg, 0.58 mmol) is dissolved in 10 mL first alcohol and waters (V/V=9:1) in the mixed solvent, add Dowex50 (300 mg), reaction 16 hours, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (1 23 4R) -5- { 7- [(lR, 25) -2- (3,4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta -1,2,3,4- tetrols 7 (260 mg, white solid), yield： 91%.

MS m/z (ESI): 495.2[M+1]

1H NMR (400 MHz, CD₃OD) δ 7.25-7.07 (m, 3H), 5.00-4.93 (m, 1H), 4.62-4.58 (m, 1H), 4.48-4.41 (m, 1H), 4.05-4.01 (m, 1H), 3.95-3.91 (m, 1H), 3.15-2.91 (m, 3H), 2.20-2.10 (m, 1H), 1.70-1.30 (m, 4H), 0.93 (t, 3H) embodiments 8

(lR, 2S, 3^4S, 5-4- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } the fluoro- cyclopenta -1,2 of -5-, 3- triols

The first step

(3a^4S, 5R, 6R, 6a -4- azidos -6- (benzyloxy) -2,2- dimethyl tetrahydro -3aH- cyclopentas M [1,3] dioxole -5- base triflates

By (3aS, 4R, 5R, 6 6a -4- azido -6- benzyloxy -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentene M [l, 3] dioxole -5- alcohol 7k (0.10 g, 0.33 mmol) are dissolved in 5 mL dichloromethane, sequentially add pyridine (39 mg, 0.50 mmol) and trifluoromethanesulfanhydride anhydride (113 mg, 0.40 mmol), react 1 hour.Add 5 mL saturated sodium bicarbonate solutions and 10 mL dichloromethane, divide liquid, organic phase is washed with saturated sodium bicarbonate solution (10 mL) and copper/saturated copper sulphate solution (10 mLx2) successively, dried, filtered, filtrate decompression Nong Shrink with anhydrous magnesium sulfate, obtain crude title product C3a^^, 5R, 6R, 6a -4- azidos -6- (；Benzyloxy) -2,2- dimethyl tetrahydro -3aH- cyclopentas M [l, 3] dioxole -5- base triflates 8a (145 mg, pale yellow oil), product is not purified directly to carry out next step reaction.

Second step

(3aS, 4R, 56 fluoro- 2, the 2- dimethyl -4,5 of 6a -6- azido -4- benzyloxies -5-, 6,6a- tetrahydrochysene -3aH- cyclopentas

M [l, 3] dioxole

Will（3aS, 4 5R, 6R, 6a -4- azidos -6- (benzyloxy) -2,2- dimethyl tetrahydro -3aH- cyclopentas W] [l, 3] dioxole -5- base triflates 8a (136 mg, 0.33 mmol) is dissolved in 5 mL tetrahydrofurans, the tetrahydrofuran solution of 0.5 mL lM tetrabutyl ammonium fluoride trihydrates is added, is reacted 3 hours.Power mouthful enters 10 mL water and 10 mL ethyl acetate, divide liquid, aqueous phase is washed with ethyl acetate (10 mLx2), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product（3a^, 4R, 56 fluoro- 2, the 2- dimethyl -4,5 of 6a -6- azido -4- benzyloxies -5-, 6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole 8b (0.10 g, colorless oil), yield： 99.0%. MS m/z (ESI): 308.1 [M+l]

3rd step

(3aS, 4R, 56 fluoro- 2, the 2- dimethyl -4,5 of 6a -4- benzyloxies -5-, 6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- amine

By (3aS, 4R, 56 fluoro- 2, the 2- dimethyl -4 of 6a -6- azido -4- benzyloxies -5-, 5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole 8b (0.60 g, 1.96 mmol) it is dissolved in 10 mL tetrahydrofurans, triphenylphosphine (0.66 g, 2.54 mmol) and 2 mL water are sequentially added, are reacted 48 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain crude title product (3aS, 4R, 56 6a -4- benzyloxies -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- amine 8c (0.60 g, colorless oil), product is not purified directly to carry out next step reaction. MS m/z (ESI): 282.2 [M+l]

4th step

N- [(3aS, 4R, 56 fluoro- 2, the 2- dimethyl -4,5 of 6a -4- benzyloxies -5-, 6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases] benzyq carbamate

By crude product (3aS, 4R, 5S, 6 fluoro- 2, the 2- dimethyl -4,5 of 6a -4- benzyloxies -5-, 6,6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- amine 8cC550 mg, 1.90 mmol) it is dissolved in 10 mL tetrahydrofurans and 3 mL water, potassium carbonate (525 mg, 3.80 mmol) is added, benzyl chloroformate (0.5 mL is added dropwise, 3 mmol), react 1 hour.Divide liquid, aqueous phase is extracted with ethyl acetate (10 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify obtained by residue, obtain title product N- [(3aS, 4R, 56 fluoro- 2, the 2- dimethyl -4 of 6a -4- benzyloxies -5-, 5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases] benzyq carbamate 8d (590 mg, colorless oil), yield： 75.0%. MS m/z (ESI): 416.1 [M+l]

5th step

(3aR, 4R, 56 ＆ 6a -6- amino-5-fluorine -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4- alcohol

By N- [(3aS, 4R, 56 6a -4- benzyloxies -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- bases] benzyq carbamate 8d (88 mg, 1.90 mmol) it is dissolved in 20 mL methanol, add palladium dydroxide/carbon (1.20 g, 7.83 mmol), hydrogen is replaced three times, is reacted 16 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3aR, 4R, 56 ＆ 6a -6- amino-5-fluorine -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4- alcohol 8e C270 mg, colorless oil yield： 72.0%. MS m/z (ESI): 192.35 [M+l]

6th step

OR, 4R, 56 6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] fluoro- 2,2- dimethyl of -5-

- 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4- alcohol will（3aR, 4R, 56 ＆ 6a -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4- alcohol 8e (0.08 g, 0.42 mmol) and chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (0.20 g of 4,6-, 0.75 mmol) it is dissolved in 10 mL ethanol, add triethylamine (88 mg, 0.84 mmol), reaction 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (3aR, 4R, 56 6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4- alcohol 8f (0.10 g, yellow solid), yield： 56.5%.

MS m/z (ESI): 423.1 [M+l]

7th step

OR, 4R, 56 6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] fluoro- 2,2- dimethyl of -5-

- 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4- alcohol is by OR, 4R, 5^6 6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] fluoro- 2,2- dimethyl -4 of -5-, 5,6,6a- tetrahydrochysene -3aH- cyclopentas [^] [1,3] dioxole -4- alcohol 8f (0.10 g, 0.24 mmol) it is dissolved in 5 mL acetic acid, iron powder (66 mg, 1.20 mmol) is added, is reacted 1.5 hours.Add 20 mL ethyl acetate, filtering, filtrate water (10 mLx3) is washed, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product OR, 4R, 56 6a -6- [the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 0 amino -6-) amino] -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4- alcohol 8g (93 mg, colorless oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 393.41 [M+l]

8th step

(3aR, 4R, 5^6^6a -6- (the chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidin-3-yl) fluoro- 2,2- dimethyl of -5-

- 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4- alcohol is by OR, 4R, 5^6 6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -4- alcohol 8g (93 mg, 0.43 mmol) is dissolved in 4 mL acetic acid and water (V/V=1:1) in the mixed solvent, natrium nitrosum (18 mg, 0.47 mnol) is added in 0 °C, is reacted 10 minutes.Add 15 mL ethyl acetate, then 10 mL saturated sodium carbonate solutions are added to reaction solution ρ Η=7, divide liquid, organic phase is washed with saturated sodium carbonate solution (10 mL) and saturated nacl aqueous solution (10 mL) successively, merge aqueous phase, extracted with ethyl acetate (10 mL), merge organic phase, dried with anhydrous magnesium sulfate, filtering, filtrate decompression Nong Shrink, obtain crude title product (3aR, 4R, 56 6a -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4- alcohol 8h (96 mg, colorless oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 404.1 [M+l]

9th step

(5^6 6＆-the 6- of 3＆ 4 { 7- [(1 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl 5- fluoro- 2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-4- alcohol

By crude product (3aR, 4R, 5S, 6 6a-6- (the chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidin-3-yl) fluoro- 2,2- dimethyl-4 of-5-, 5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-4- alcohol 8h (96 mg, 0.24 mmol) and (lR, 2-2- (3,4- difluorophenyl) cyclopropylamine L- (+)-tartrate lg (106 mg, 0.33 mmol) It is dissolved in 5 mL acetonitriles, triethylamine (86 mg, 0.85 mmol) is added dropwise, reacts 48 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (3aR, 4R, 5S, 6S, 6aS)-6- { 7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-fluoro- 2, the 2- dimethyl-4 of triazol [4,5-d] pyrimidin-3-yl 5-, 5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-4- alcohol 8i (0.10 g, white solid), yield： 78.7%.

MS m/z (ESI): 537.2 [M+l]

Tenth step

(lR, 2S, 3^4S, 5-4- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } the fluoro- cyclopenta -1,2 of -5-, 3- triols

By (3aR, 4R, 5 6^6a-6- { 7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } fluoro- 2, the 2- dimethyl-4,5 of-5-, 6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-4- alcohol 8 0.10 g, 0.19 mmol) be dissolved in 6 mL first alcohol and waters (； V/V = 5 :1) in the mixed solvent, adds the resin cations of Dowex 50 (0.15 g), reacts 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (1 234 5-4- [7- [[(1 2-2- (3,4- difluorophenyls) cyclopropyl] amino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl] the fluoro- cyclopenta-1,2 of-5-, (0.07 g of 3- triols 8, white solid), yield： 76.0%.

MS m/z (ESI): 497.44 [M+l]

1H NMR (400 MHz, CD₃OD) δ 7.25-7.00 (m, 3H), 5.33-5.27 (m, 1H), 5.20-5.14 (m, 1H), 5.13-5.02 (m, 1H), 4.26-4.16 (m, 2H), 3.18-3.12 (m, 1H), 3.08-3.00 (m, 1H), 2.95-2.85 (m, 1H), 2.18-2.12 (m, 1H), 1.65-1.35 (4H, m), 0.90 (t, 3H) embodiments 9

(1S, 2 3^4S, 5R)-3- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4,5-d] pyrimidin-3-yl } the fluoro- 5- of -4- (2- hydroxyl-oxethyls) cyclopenta -1,2- glycol

The first step

N- [fluoro- 6- hydroxyls-2, the 2- dimethyl-4,5 of (3aS, 4S, 5 6R, 6aR)-5-, 6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] benzyq carbamate

Will（3aR, 4R, 56 ＆ 6a -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -4- alcohol 8eC0.19 g, 1 mmol) it is dissolved in 10 mL methanol and 3 mL water, add potassium carbonate (276 mg, 2 mmol), benzyl chloroformate (0.24 g, 1.40 mmol) is added dropwise in 0 °C, reacts at room temperature 1 hour.Divide liquid, aqueous phase is extracted with ethyl acetate (10 mLx2), merge organic phase, dried, filtered, filtrate decompression Nong Shrink with anhydrous magnesium sulfate, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- [(3aS, 4S, 5 6R, 6aR) the fluoro- 6- hydroxyls-2 of-5-, 2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 9a (0.28 g, colorless oil), yield： 86.0%. MS m/z (ESI): 282.2 [M-43]

Second step

2- { [(3aS, 4R, 56 6a -6- benzyloxycarbonyl aminos -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] Dioxol-4 -yl] epoxide } ethyl acetate is by N- [(3aS, 4S, 5 6R, 6aR) the fluoro- 6- hydroxyls -2 of -5-, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] benzyq carbamate 9a (0.28 g, 0.86 mmol) it is dissolved in 10 mL tetrahydrofurans, the tetrahydrofuran solution C0.7 mL of 20% potassium tert-butoxide are added dropwise in 0 °C, 1.30 mmol), reaction 30 minutes.2- bromoacetates (217 mg, 1.30 mmol) are added dropwise, react 30 minutes.It is warmed to room temperature, reacts 16 hours.10 mL water are added in reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (10 mLx2), merge organic phase, dried, filtered, filtrate decompression Nong Shrink with anhydrous magnesium sulfate, obtain crude title product 2- { [(3aS, 4R, 56 fluoro- 2, the 2- dimethyl-4 of 6a-6- benzyloxycarbonyl aminos-5-, 5,6,6a- tetrahydrochysene-3aH- cyclopentas [d] [l, 3] Dioxol-4 -yls] epoxide } ethyl acetate 9b (0.36 g, colorless oil), product is not purified directly to carry out next step reaction. 3rd step

N- [(3aS, 4R, the 56 fluoro- 4- of 6a -5- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases] benzyq carbamate is by 2- { [(3aS, 4R, 56 6a -6- benzyloxycarbonyl aminos -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] epoxide } ethyl acetate 9b (354 mg, 0.86 mmol) it is dissolved in 10 mL tetrahydrofurans, add lithium borohydride C38 mg, 1.72 mmol), reaction 3 hours.5 mL water are added in reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (10 mLx3), merge organic phase, dried with anhydrous magnesium sulfate, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [(3aS, 4R, 5 6S, the fluoro- 4- of 6a^-5- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases] benzyq carbamate 9c (0.29 g, colorless oil), yield： 91.3%.

MS m/z (ESI): 326.2 [M-43]

4th step

2- [(3aS, 4R, 56 6a-6- amino-5-fluorine-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide）Ethanol

By N- [(the fluoro- 4- of 3aS, 4R, 5^6 6a -5- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases] benzyq carbamate 9c (0.29 g, 0.79 mmol) it is dissolved in 10 mL methanol, adding palladium/carbon, (10%, 0.30 g), hydrogen is replaced three times, is reacted 16 hours.Reacting liquid filtering, filtrate decompression Nong Shrink, obtain crude title product 2- [[0 4R, 56 6a-6- amino-5-fluorines-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide] ethanol 9d (185 mg, white solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 236.1 [M+l]

1H NMR (400 MHz, CDC1₃) 55.06-5.04 (m, 0.5H), 4.93-4.91 (m, 0.5H), 4.65-4.62 (m, 1H), 4.48-4.45 (m, 1H), 3.94-3.88 (m, 1H), 3.76-3.69 (m, 4H), 3.40-3.30 (m, 1H), 2.08 (s, 2H), 1.46 (s, 3H), 1.28 (s, 3H)

5th step

2- { [(3aS, 4R, 5^6 6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] epoxide } ethanol is by 2- { [(3aS, 4R, 56 6a -6- amino-5-fluorines -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9d (185 mg, 0.79 mmol) standing grain M, chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (315 mg of 6-, 1.18 mmol) it is dissolved in 10 mL ethanol, add triethylamine (0.16 g, 1.58 mmol), reaction 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product 2- { [C3aS, 4R, 5S, 6S, 6a-6- [(the chloro- 5- nitros-2- propyl group mercapto-pyrimidine-4- bases of 6-) amino]-5- fluoro- 2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9e (0.20 g, yellow oil), yield： 54.3%

MS m/z (ESI): 467.42 [M+l]

6th step 2- { [(3aS, 4R, 5^6 6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] epoxide } ethanol is by 2- { [0 4R, 5S, 6 6a -6- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9e (0.20 g, 0.43 mmol) it is dissolved in 6 mL acetic acid, add iron powder (123 mg, 2.20 mmol), reaction 2 hours.20 mL ethyl acetate are added, are filtered, filtrate water (10 mLx3) washing, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- 3aS, 4R, 56 6a-6- [(the chloro- 2- propyl group sulfydryl-pyrimidine-4-yls of 5- amino-6-) amino] fluoro- 2,2- dimethyl-4 of-5-, 5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide）Ethanol 9f (188 mg, yellow oil), product is not purified directly to carry out next step reaction. MS m/z (ESI): 437.1 [M+l]

7th step

2- { [(3aS, 4R, 56 6a -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] Dioxol-4 -yl] epoxide } ethanol is by 2- { [0 4R, 5S, 6 6a -6- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9f (188 mg, 0.43 1^^1) it is dissolved in 4.5 1^ acetic acid and water (^/$=2:1) in the mixed solvent.Natrium nitrosum (33 mg, 0.47 mmol) is added in 0 °C, is reacted 10 minutes.20 mL ethyl acetate are added in reaction solution, saturated sodium carbonate solution is added to reaction solution ρ Η=7, divide liquid, organic phase is washed with saturated sodium carbonate solution (10 mL) and saturated nacl aqueous solution (10 mL) successively, anhydrous magnesium sulfate is dried, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- { [(3aS, 4R, 56 6a -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9g (0.20 g, yellow oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 448.41 [M+l]

8th step

2- { [(3＆^^, 56 6＆ -6- [7- [(1 2^-2- (3,4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl] -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -4- yls] epoxide } ethanol

By 2- { [(3aS, 4R, 56 6a -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 9g (193 mg, 0.43 1^^1) and (1 2-2- (3, 4- difluorophenyls) cyclopropylamine L- (+)-tartrate lg (0.19 g, 0.60 mmol) it is dissolved in 10 mL acetonitriles, triethylamine (0.15 g is added dropwise, 1.50 mmol), reaction 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain the title product 2- { [(6＆-6- of 3＆ 456 [7- [(1 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl] fluoro- 2, the 2- dimethyl-4 of-5-, 5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide）Ethanol 9hC0.17 g, colorless oil), yield： 68.0%.

MS m/z (ESI): 581.2 [M+l] 9th step

(1S, 2 3^4S, 5R)-3- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4, 5-d] pyrimidin-3-yl } the fluoro- 5- of -4- (2- hydroxyl-oxethyls) cyclopenta -1, 2- glycol is by 2- { [(3aS, 4R, 56 6a -6- [7- [(lR, 2S) -2- (3, 4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazol [4, 5- pyrimidin-3-yls } -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide] ethanol 9h (0.17 g, 0.29 mmol) it is dissolved in l lmL first alcohol and waters (V/V=10:1) in the mixed solvent, adds D_OweThe resin cations of x 50 (0.2 g), react 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (S, 2S, 3S, 4S, 5R)-3- { 7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5 pyrimidin-3-yls } the fluoro- 5- of-4- (2- hydroxyl-oxethyls) cyclopenta-1,2- glycol 9 (0.13 g, white solid yield： 81.2%.

MS m/z (ESI): 541.46 [M+l]

1H NMR (400 MHz, CD₃OD) δ 7.23-7.00 (m, 3H), 5.35-5.32 (m, 0.5H), 5.30 (t, 1H), 5.22-5.18 (0.5H, m), 5.16-5.05 (m, 1H), 4.37-4.33 (m, 1H), 4.12-4.01 (m, 1H), 3.77-3.70 (m, 4H), 3.13 (br, 1H), 3.07-3.00 (m, 1H), 3.00-2.90 (m, 1H), 2.15-2.10 (m, 1H), 1.70-1.33 (m, 4H), 0.9 l (t, 3H) embodiments 10

({ 7- [(lR, 2R/lS, 2-2- (4- methylthiazol-5- bases) the cyclopropyl ammonia of-3- of 1^2 35 (2- hydroxyl-oxethyls)-5

- 5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } cyclopenta -1,2- glycol

The first step

(1R, 2R/1S, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acid ethyl esters are by 4- methyl-5- vinyl-thiazole 10a (5 g, 40 mmol) it is heated to 135 °C, ethyl diazoacetate (2.28 g are added dropwise, 20 mmol), drop finishes in 2 hours.Be cooled to room temperature, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (lR, 2R, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acid ethyl ester 10b (2.01 g, light yellow oil), yield： 47.6%.

MS m/z (ESI): 212.1 [M+l]

1H NMR (400 MHz, CDC1₃) δ 8.40 (s, 1H), 4.19-4.14 (q, /=7.16 Hz, 2H), 2.55-2.51 (m, 1H), 2.50 (s, 3H), 1.87-1.82 (m, 1H), 1.67-1.63 (m, 1H), 1.27 (t, /=7.12 Hz, 3H), 1.23-1.17 (m, 1H)

Second step

(1R, 2R/1S, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acids are by (1R, 2R/1S, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acid second tenth of the twelve Earthly Branches purport 10b (2.01 g, 9.50 mmol) it is dissolved in 30 mL methanol, the sodium hydroxide solutions of 2.5 mL 30% are added dropwise, react 12 hours.Jian Ya Nong Shrink, add 40 mL ethyl acetate and 30 mL water, and 37% hydrochloric acid is added dropwise to reaction solution pH=4.Divide liquid, aqueous phase is extracted with ethyl acetate (60 mLx2), is merged organic phase, is washed with saturated nacl aqueous solution (50 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink obtain title product (lR, 2R, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acid 10c (1.54 g, light yellow solid), yield： 88.5%.

3rd step

N- [(1R,-the 2- of 2R/1 2 (4- methylthiazol-5- bases) cyclopropane base] t-butyl carbamate is by (1R, 2R/1S, 2-2- (4- methylthiazol-5- bases) cyclopropane-carboxylic acid 10c (732 mg, 4 mmol) it is dissolved in the 20 mL tert-butyl alcohols, sequentially add diphenyl phosphate azide (1.10 g, 4 mmol) and triethylamine (485.70 mg, 4.80 83 °C of mmol reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add 40 mL dichloromethane, washed successively with sodium bicarbonate solution (20 mL) and saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- [(1R,-the 2- of 2R/1 2 (4- methylthiazol -5- bases) cyclopropane base] t-butyl carbamate 10d (390 mg, white solid), yield： 38.6%.

MS m/z (ESI): 255.1 [M+1]

4th step

(1R,-the 2- of 2R/1 2 (4- methylthiazol -5- bases) cyclopropylamine hydrochlorides are by N- [(1R,-the 2- of 2R 12 (4- methylthiazol -5- bases) cyclopropane base] t-butyl carbamate 10d (254 mg, l mmol) it is dissolved in 5 mL ethyl acetate, the M Hydrochloride/ethyl acetates of 3 mL 6.8 are added, are reacted 3.5 hours.Subtract the dense Shrink of pressure, obtaining crude title product, (- the 2- of lR, 2R l 2 (4- methylthiazol -5- bases) cyclopropylamine hydrochloride 10e (180 mg, white solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 155.1 [M+l]

5th step

2- { [(3aS, 4R, 6 6aR)-2,2- dimethyl-4- [7- [(lR, 2R/lS, 2-2- (4- methylthiazol-5- bases) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl]-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-6- bases] epoxide）Ethanol

By 2- { [(3aR, 4S, 6R, 6a-6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yl] epoxide } ethanol 5g (254 mg, 1 mmol) is dissolved in 5 mL acetonitriles, add 5 mL ClR, 2R 1^2-2-C4- methylthiazol-5- bases) cyclopropylamine hydrochloric acid Salt 10e (100 mg, 0.65 mmol) acetonitrile solution, is added dropwise triethylamine (51.70 mg, 0.51 mmol), reacts 12 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product 2- { [(3aS, 4R, 6 6aR)-2,2- dimethyl-4- [7- [(lR, 2R/lS, 2-2- (4- methylthiazol-5- bases) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl]-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-6- bases] epoxide } ethanol 10f (140 mg, light yellow solid), yield： 100%.

MS m/z (ESI): 548.56 [M+l]

6th step

(1 2S, 3 5R) -3- (2- hydroxyl-oxethyls) -5- { 7- [(lR, 2R 1^2-2- (4- methylthiazol-5- bases) cyclopropylamino]-5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl } cyclopenta -1, 2- glycol is by 2- { [(3aS, 4R, 6 6aR) -2, 2- dimethyl -4- [7- [(lR, 2R lS, 2-2- (4- methylthiazol-5- bases) cyclopropylamino]-5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl] -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- bases] epoxide } ethanol 10fC140 mg, 0.26 mmol) it is dissolved in 8 mL methanol, add the M hydrochloric acid of 3 mL 2.5, reaction 12 hours.4 M sodium hydroxide solutions are added dropwise to reaction solution ρ Η=8, extracted with ethyl acetate (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (50 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system F purify gained residue, obtain title product（1^2S, 3^5R) -3- (2- hydroxyl-oxethyls) -5- { 7- [(lR, 2R/lS, 2^-2- (4- methylthiazol -5- bases) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5 pyrimidin-3-yls } cyclopenta -1,2- glycol 10 (100 mg, white solid), yield： 76.9%.

MS m/z (ESI): 508.2 [M+l]

1H NMR (400 MHz, DMSO-J₆) 9.40 (d of δ, the Hz of J=3.96, 1H), 8.78 (s, 1H), 5.25-4.90 (br, 1H), 5.02-4.95 (m, 1H), 4.60-4.55 (m, 1H), 3.95-3.94 (m, 1H), 3.78-3.75 (m, 1H), 3.52-3.48 (m, 3H), 3.34 (br, 2H), 3.14-3.02 (m, 3H), 2.68-2.61 (m, 1H), 2.41 (s, 3H), 2.32-2.25 (m, 1H), 2.08-2.01 (m, 1H), 1.69-1.51 (m, 2H), 1.25-1.15 (m, 2H), 1.02-0.95 (m, 1H), 0.69 (t, the Hz of /=7.36, 3H) embodiments 11

(15,25,3R, 55)-3- 7- [(1 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-pyrimidin-3-yl }-5- (2,3- dihydroxy propoxyl group) cyclopenta-1,2- glycol

The first step

N- [(3aR, 4S, 6R, 6a -4- allyloxy -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases] benzyq carbamate

By N- [(3aR, 4S, 6R, 6a-6- hydroxyl-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] benzyq carbamate 5b (l g, 3.20 mmol) it is dissolved in 20 mL tetrahydrofurans, add potassium tert-butoxide (0.73 g, 6.50 mmol), stirring 20 minutes, 3- bromopropenes (1.1 mL, 13 mmol) are added dropwise, react 16 hours.Add 10 mL water, extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- [(3aR, ^, 6R, 6a -4- allyloxys -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas W] [l, 3] dioxole -6- bases] benzyq carbamate lla (0.40 g, colorless oil), yield： 35.0%.

Second step

N- [(3aR, 4S, 6R, 6a -4- (2,3- dihydroxy propoxyl group) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas

W] [l, 3] dioxole -6- bases] benzyq carbamate is by N- [C3aR, 4S, 6R, 6a -4- allyloxys -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- bases] benzyq carbamate lla (0.40 g, 1.15 mmol) it is dissolved in 10 mL tetrahydrofurans, add N-methylmorpholine-N- oxides (0.54 g, 2.30 mmol) and osmium tetroxide (59 mg, 0.23 mmol), react 5 hours.Add 10 mL saturated sodium thiosulfate solution, extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink obtain title product N- [(3aR, 4^6R, 6a -4- (2,3- dihydroxy propoxyl group) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases] benzyq carbamate lib (0.45 g, light yellow oil), yield： 99.0%. 3rd step

N- { (3aR, 4S, 6R, 6a -4- [(2, 2- dimethyl -1, 3- dioxolane -4- bases) methoxyl group] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases } benzyq carbamate is by N- [(3aR, 4S, 6R, 6a -4- (2, 3- dihydroxy propoxyl group) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -6- bases] benzyq carbamate llbC0.45 g, 1.20 mmol) it is dissolved in 10 mL 2, in 2- dimethoxy propanes, add one and be hydrated p-methyl benzenesulfonic acid (13 mg, 0.068 mmol), reaction 30 minutes.Add 10 mL saturated sodium bicarbonate solutions, extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- [(3aR, 6R, 6a -4- [(2, 2- dimethyl -1, 3- dioxolane -4- bases) methoxyl group] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- bases] benzyq carbamate l lc (0.41 g, light yellow oil), yield： 82.0%.

MS m/z (ESI): 422.2 [M+l]

4th step

(3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl

- 4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -6- amine is by the ^ { (6＆ -4- of 3＆ 46 [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- bases } benzyq carbamate l lc (0.41 g, 1 mmol) it is dissolved in 10 mL ethanol, adding palladium/carbon, (10%, 0.10 g), hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression Nong Shrink, obtain title product OR, 4S, 6R, 6a -4- [(;2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -6- amine l ld (0.22 g, light yellow oil), yield： 81.0%.

5th step

N- { (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl -4,5,6, the chloro- 5- nitros -2- propyl group sulfydryls of 6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases 6--pyrimidine -4- amine

By (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases）Methoxyl group] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- amine l ld (0.11 g, 0.38 mmol) are dissolved in 8 mL tetrahydrofurans, add 4,6- chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b CO.11 g, 0.42 mmol), triethylamine (0.2 mL is added dropwise, 1.15 mmol), react 1 hour.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- 3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases } the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- amine l leG34 mg of -6-, yellow oil), yield： 38.0%.

MS m/z (ESI): 519.1 [M+l]

6th step

^- { (6＆-the 4- of 3＆ 46 [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl - 4,5,6, the 6a- chloro- 2- propyl group mercapto-pyrimidines of tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases 6-

- 4,5- diamines

By N- { (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases）Methoxyl group] -2,2- dimethyl -4,5,6,6a- chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- amine l le (134 mg of tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases 6-, 0.26 mmol) it is dissolved in 5 mL acetic acid, iron powder (116 mg, 2.10 mmol) is added, is reacted 2.5 hours.10 mL water are added, are extracted with ethyl acetate (30 mLx3), merges organic phase, is washed, anhydrous sodium sulfate drying with saturated nacl aqueous solution (10 mL), are filtered, the dense Shrink of filtrate decompression obtains crude title product N⁴- { (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases）Methoxyl group] -2,2- dimethyl -4,5,6, the 6a- chloro- 2- propyl group sulfydryl-pyrimidines -4 of tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases 6-, 5- diamines l lf (134 mg, brown oil), product is not purified directly to carry out next step reaction. MS m/z (ESI): 490.52 [M+l]

7th step

3- { (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases) methoxyl group] -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases } the chloro- 5- propyl group sulfydryl-triazols of -7-

[4,5-d] pyrimidine

By N⁴- { (3aR, 4S, 6R, 6a -4- [(2,2- dimethyl -1,3- dioxolane -4- bases）Methoxyl group] -2,2- dimethyl -4,5,6, the 6a- chloro- 2- propyl group mercapto-pyrimidines -4 of tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -6- bases 6-, 5- diamines l lf (0.25 g, 0.50 mmol) are dissolved in 2 mL acetic acid.The aqueous solution of 0.4 mL natrium nitrosums (36 mg, 0.53 mnol) is added in 0 °C, is reacted 10 minutes.15 mL ethyl acetate and 10 mL unsaturated carbonate potassium solutions are added, point liquid, aqueous phase is extracted with ethyl acetate (10 mLx3), merge organic phase, washed, anhydrous sodium sulfate drying with saturated nacl aqueous solution (10 mL), filtering, filtrate decompression Nong Shrink, obtain crude title product 3- { (3aR, 45,6R, 6a5) -4- [(2,2- dimethyl -1,3- dioxolane -4- bases）Methoxyl group] -2,2- dimethyl -4,5,6, the chloro- 5- propyl group sulfydryls of 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -6- bases 7--triazol [4,5-d] pyrimidine l lg (0.25 g, brown oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 500.1 [M+l]

8th step

N- [(lR, 2-2- (3,4- difluorophenyls) cyclopropyl] t-butyl carbamate is by (lR, 2R)-2- (3,4- difluorophenyls) ethylene-acetic acid ld (12 g, 60.55 mmol) is dissolved in the 600 mL tert-butyl alcohols, sequentially adds diphenyl phosphate azide (16.70 g, 60.55 mmol) and triethylamine (6.20 g, 60.55 80 °C of mmol reaction 16 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product N- [(lR, 2-2- (3,4- difluorophenyls) cyclopropyl] t-butyl carbamate l lh (1.90 g, white solid), yield： 11.7%.

MS m/z (ESI): 214.35[M-55]

9th step

(lR, 2^-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride

By N- [(lR, 2-2- (;3,4- difluorophenyls) cyclopropyl] t-butyl carbamate l lh (1.90 g, 7.05 mmol) It is dissolved in 38 mL ethyl acetate, the M Hydrochloride/ethyl acetates of 38 mL 5 is added dropwise, reacts 16 hours.Reaction solution subtracts the dense Shrink of pressure, and obtaining crude title product, (lR, 2-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride l li (1.40 g, yellow solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 170.1 [M+1]

Tenth step

3- { (3aR, 4S, 6R, 6a)-6- [(2,2- dimethyl-1,3- dioxolane-4- bases) methoxyl group]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl }-[(1 2-2- (3,4- difluorophenyls) cyclopropyl]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidine-7- amine is by 3- { (3aR, 4S, 6R, 6a-4- [(2,2- dimethyl-1,3- dioxolane-4- bases）Methoxyl group]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] the chloro- 5- propyl group sulfydryl-triazols [4 of dioxole-6- bases 7-, 5-d] pyrimidine l lg (126 mg, 0.25 mmol) and (1R, 2-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride l li (67 mg, 0.33 mmol) it is dissolved in 5 mL acetonitriles, triethylamine (0.2 mL, 0.88 mmol) is added dropwise, reacts 12 hours.Reaction solution Jian Ya Nong Shrink, add 10 m water, and 2.5 M hydrochloric acid are added dropwise to reaction solution ρ Η<4, aqueous phase is extracted with ethyl acetate (15 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product 3- { (6＆ of 3＆ 4 6) -6- [(2, 2- dimethyl -1, 3- dioxolane -4- bases) methoxyl group] -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl } ^- [(1 2^-2- (3, 4- difluorophenyls) cyclopropyl] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidine -7- amine l lj (75 mg, yellow oil), yield： 47.0%.

MS m/z (ESI): 633.63 [M+l]

11st step

(S, 2S, 3R, 5S)-3- { 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryls-triazol [4,5-d] pyrimidin-3-yl }-5- (2,3- dihydroxy propoxyl group) cyclopenta-1,2- glycol is by 3- { (3aR, 4S, 6R, 6a)-6- [(2,2- dimethyl-1,3- dioxolane-4- bases）Methoxyl group]-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopenta M [l, 3] Dioxol-4 -yl } ^- [(1 2^-2- (3,4- difluorophenyls) cyclopropyl]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidine-7- amine l lj (0.15 g, 0.24 mmol) are dissolved in 8 mL methanol, the M hydrochloric acid of 2 mL 2.5 is added dropwise, reacts 16 hours.Reaction solution Jian Ya Nong Shrink, add 10 mL water.Power mouthful enters saturated sodium carbonate solution to reaction solution ρ Η=7, extracted with ethyl acetate (30 mLx3), organic phase is washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product<^, 2 3R, 5-3- 7- [(;IR, 2-2- (;3,4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl } -5- (2,3- dihydroxy propoxyl group) cyclopenta -1,2- glycol 11 (134 mg, yellow solid), yield： 99.0%.

MS m/z (ESI): 553.55 [M+l]

1H NMR (400 MHz, CDC1₃) δ 7.68 (s, 1H), 7.05-6.93 (m, 2H), 6.84 (s, 1H), 5.06 (br s, 1H), 4.78 (br s, 1H), 4.36 (br s, 1H), 4.06-3.90 (m, 3H), 3.73-3.65 (m, 5H), 3.28-3.08 (m, 2H), 3.06-2.94 (m, 1H), 2.85-2.70 (m, 2H), 2.22-2.11 (m, 1H), 2.01-1.95 (m, 1H), 1.45-1.21 (m, 4H), 0.79 (t, 3H) Embodiment 12

(1S, 23 4R, 5-3- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

- d] pyrimidin-3-yl } -5- (2- hydroxyl-oxethyls) cyclopenta -1,2,4- triols

The first step

2 :-{[(3& 4 6&5>2,2- dimethyl-4,6a- dihydro-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide）Ethyl acetate

Will（3a＆4R, 6aR) [[1,3] dioxole -4- alcohol ln (1.22 g, 7.82 mmol) is dissolved in 50 mL tetrahydrofurans -2,2- dimethyl -4,6a- dihydro -3aH- cyclopentas.20% potassium tert-butoxide tetrahydrofuran solution (7.2 mL, 11.73 mmol) is added dropwise in 0 °C, reacts 30 minutes.Bromoacetate (1.3 mL, 11.73 mmol) is added dropwise, after reacting 30 minutes, reaction 12 hours is warmed to room temperature.10 mL water are added, point liquid, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- { [(3aR,, 6a^) and -2,2- dimethyl -4,6a- dihydro -3aH- cyclopenta [[1,3] dioxole - 4- bases] epoxide } ethyl acetate 12a (1.90 g, brown oil), product is not purified directly to carry out next step reaction.

Second step

2- [(3aR, 4S, 6a-2,2- dimethyl-4,6a- dihydro-3aH- cyclopentas [l, 3] Dioxol-4 -yl] epoxide } ethanol

By 2- { [OR, 4S, 6a-2,2- dimethyl-4,6a- dihydro-3aH- cyclopentas M [l, 3] Dioxol-4 -yl] epoxide } ethyl acetate 12a (1.90 g, 7.82 mmol) it is dissolved in 40 mL tetrahydrofurans, lithium borohydride (341 mg, 15.64 mmol) is added, is reacted 2 hours.10 mL water are added, point liquid, aqueous phase is extracted with ethyl acetate (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain crude title product 2- { [(3aR, 4S, 6a-2,2- dimethyl-4,6a- dihydro-3aH- cyclopentas M [l, 3] Dioxol-4 -yl] epoxide）Ethanol 12b (1.56 g, yellow oil), product is not purified directly to carry out next step reaction.

3rd step

(3aR, 4S, 6a -4- (2- Benzyloxyethoxies) -2,2- dihydro -4,6a- dihydro -3aH- cyclopentas M [l, 3] dioxole

By 2- { [(3 aR, 45,6a5)-aH- cyclopentas [d] [1 of 2,2- dimethyl-4,6a- dihydro-3,3] Dioxol-4 -yl] epoxide } ethanol 12b (1.56 g, 7.82 mmol) it is dissolved in 30 mL DMFs, 60% sodium hydride (626 mg are added in 0 °C, 15.64 mmol), react at room temperature 30 minutes.Benzyl bromine (1.4 mL, 11.73 mmol) is added in 0 °C, is reacted at room temperature 16 hours.10 mL methanol are added, Jian Ya Nong Shrink add 50 mL ethyl acetate and 15 mL water, divide liquid, aqueous phase is extracted with ethyl acetate (20 mLx2), merges organic phase, washed with water (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product OR, 4S, 6a -4- (;2- Benzyloxyethoxies) -2,2- dihydro -4,6a- dihydro -3aH- cyclopentas M [l, 3] dioxole 12cC1.60 g, colorless oil), yield： 70.0%.

1H NMR (400 MHz, CDC1₃) δ 7.35-7.28 (m, 5H), 6.05-6.02 (m, 1H), 5.95-5.92 (m, 1H), 5.26-5.24 (m, 1H), 4.60-4.58 (m, 1H), 4.58 (2H, s), 4.51-4.48 (m, 1H), 3.84-3.78 (m, 1H), 3.74-3.68 (m, 1H), 3.65 (2H, t), 1.41 (s, 3H), 1.26 (s, 3H)

4th step

(the amyl- 3- alkene-1 of 12 5-5- (2- Benzyloxyethoxies) ring, 2- glycol is by (3aR, 4S, 6a-4- (2- Benzyloxyethoxies)-2,2- dihydros-4,6a- dihydro-3aH- cyclopentas M [l, 3] dioxole 12cG.60 g, 5.50 mmol) be dissolved in 22 mL first alcohol and waters (； V/V = 1 :1) in the mixed solvent, adds the resin cations of Dowex 50 (3.50 g), reacts 72 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (, the amyl- 3- alkene -1 of 2W -5- (2- Benzyloxyethoxies) ring, 2- glycol 12d (1.37 g, colorless oil), yield： 100%.

5th step

(1 2 3^^, 5^-4- (2- Benzyloxyethoxies)-6- oxabicyclos [3 Shang 0] hexane-2,3- glycol is by (1S, the amyl- 3- alkene-1 of 2 5-5- (2- Benzyloxyethoxies) ring, 2- glycol 12d (1.35 g, 5.40 mmol) is dissolved in 40 mL dichloromethane, adds 70% metachloroperbenzoic acid (2.40 g, 9.72 mmol), react 24 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain Title product（1R, 2R, 3 4R, 5R) -4- (2- Benzyloxyethoxies) -6- oxabicyclos [3.1.0] hexane -2,3- glycol 12e (630 mg, yellow oil), yield： 44%.

1H NMR (400 MHz, CDC1₃) δ 7.40-7.30 (m, 5H), 4.60 (2H, s), 4.42-4.40 (d, 1H), 4.02 (br, 1H), 3.89-3.77 (m, 3H), 3.73-3.68 (m, 2H), 3.65 (t, 2H)

6th step

(1 23 4R, 5-3- azidos-5- (2- Benzyloxyethoxies) pentamethylene-1,2,4- triols will（1R, 2R, 3 4R, 5R) -4- (2- Benzyloxyethoxies）- 6- oxabicyclos [3.1.0] hexane -2,3- glycol 12e (630 mg, 2.36 mmol) is dissolved in 12 mL DMFs and water (V/V=5:1) in the mixed solvent, adds sodium azide (230 mg, 3.54 mmol).Reacted 16 hours in 80 °C.Jian Ya Nong Shrink, add 30 mL ethyl acetate, washed with water (10 mLx2), merge aqueous phase, extracted with ethyl acetate (10 mLx2), merge organic phase, dried with anhydrous magnesium sulfate, filtered, filtrate decompression Nong Shrink, obtain crude title the product (- 3- azidos of 1S, 23 4R, 5-5- (2- Benzyloxyethoxies) pentamethylene-1,2,4- triols 12f (730 mg, yellow oil), product is not purified directly to carry out next step reaction.

7th step

(3aS, 4R, 5R, 6 6a -4- azidos -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [^] [1,3] dioxole -5- alcohol

By (1 23 4R, 5-3- azidos-5- (2- Benzyloxyethoxies) pentamethylene-1,2,4- triols 12f (730 mg, 2.36 mmol) is dissolved in 10 mL acetone, sequentially adds 2,2- dimethoxy propanes (0.6 mL, 4.72 mmol) and a hydration p-methyl benzenesulfonic acid (180 mg, 0.94 mmol), react 3 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (3a^, 4R, 5R, 6 6a -4- azidos -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12g (470 mg, colorless oil), yield： 57.0%.

1H NMR (400 MHz, CDC1₃) δ 7.37-7.31 (m, 5H), 4.61-4.58 (m, 2H), 4.38-4.33 (m, 1H) 4.32-4.27 (m, 1H), 3.96-3.90 (m, 2H), 3.77-3.60 (m, 5H), 1.51 (s, 3H), (1.28 s, 3H)

8th step

(3aS, 4R, 5R, 6 6a -4- amino -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol

By (3aS, 4R, 5R, 6 6a -4- azidos -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12gC460 mg, 1.32 mmol) it is dissolved in 15mL tetrahydrofurans, add triphenylphosphine (450 mg, 1.71 mmol), 3 mL water are added dropwise, react 16 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aS, 4R, 5R, 6 6a -4- amino -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12h (427 mg, yellow oil yield： 100%.

MS m/z (ESI): 324.50 [M+l]

9th step

(3aS, 4R, 5R, 6 6a -4- amino -6- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas [d] [l, 3] dioxole -5- alcohol Will（3aS, 4R, 5R, 6 6aS) -4- amino -6- (2- Benzyloxyethoxies) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12h (427 mg, 1.32 mmol) are dissolved in 20 mL methanol, add palladium dydroxide/carbon (0.80 g, 5.69 mmol), hydrogen is replaced three times, is reacted 16 hours.Filtering, filtrate decompression Nong Shrink, obtain title product C3a^, 4R, 5R, 6 6a -4- amino -6-P- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12i (250 mg, colorless oil yield： 81.2%.

MS m/z (ESI): 234.44 [M+l]

Tenth step

(3aS, 4R, 5R, 6 6a -4- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol is by (3aS, 4R, 5R, 6 6aS) -4- amino -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [l, 3] dioxole -5- alcohol 12iC250 mg, 1.07 mmol) and 4, chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (430 mg of 6-, 1.60 mmol) it is dissolved in 20 mL ethanol, add triethylamine (0.3 mL, 2.14 mmol), reaction 16 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product OS, 4R, 5R, 6S, 6a -4- [(;The chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -6-0 hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12j (320 mg, yellow oil), yield： 64.3%.

MS m/z (ESI): 465.1 [M+l]

11st step

(3aS, 4R, 5R, 6 6a -4- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol is by (3a^, 4R, 5R, 6 6a -4- [(the chloro- 5- nitros -2- propyl group mercapto-pyrimidine -4- bases of 6-) amino] -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol 12j (320 mg, 0.69 mmol) it is dissolved in 10 mL acetic acid, add iron powder (200 mg, 3.50 mmol), reaction 4 hours.Add 20 mL ethyl acetate, filtering, filtrate water (20 mLx2) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aS, 4R, 5R, 6 6a -4- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-）Amino] -6- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12k (200 mg, yellow oil), yield： 66.6%.

MS m/z (ESI): 435.45 [M+l]

12nd step

(3aS, 4R, 5R, 6 6a -4- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5-d] pyrimidin-3-yl) -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol is by (3a^, 4R, 5R, 6 6a -4- [(the chloro- 2- propyl group mercapto-pyrimidine -4- bases of 5- amino -6-) amino] -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol 12k (200 mg, 0.46 mmol) it is dissolved in 3 mL acetic acid and 1.5 mL water, natrium nitrosum (35 mg are added in 0 °C, 0.51 ), mnol react 10 minutes.20 mL ethyl acetate are added, 10 mL saturated sodium carbonate solutions are then added to reaction solution pH=7, point liquid, organic phase is washed with saturated sodium carbonate solution (10 mL), aqueous phase ethyl acetate (10 mL><2) extract, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain crude title product (3a^, 4R, 5R, 6 6a -4- (the chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidin-3-yl) -6- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopentas M [l, 3] dioxole -5- alcohol 12m (205 mg, yellow solid), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 446.43 [M+l]

13rd step

(3aS, 4R, 5R, 6S, 6a-4- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl }-6- (2- hydroxyl-oxethyls)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-5- alcohol

By (3a^, 4R, 5R, 6 6a -4- (the chloro- 5- propyl group sulfydryls of 7--triazol [4,5-d] pyrimidin-3-yl) -6- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol 12m (205 mg, 0.46 mmol) standing grain mouthful（LR, 2^-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride l li (132 mg, 0.64 mmol) are dissolved in 10 mL acetonitriles, and triethylamine (0.2 mL, 1.60 mmol) is added dropwise, and are reacted 16 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3aS, 4R, 5R, 6S, 6a-4- { 7- [(lR, 2-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5-d] pyrimidin-3-yl }-6- (2- hydroxyl-oxethyls)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3aH- cyclopentas M [l, 3] dioxole-5- alcohol 12nC230 mg, yellow oil), yield： 86.5%.

MS m/z (ESI): 577.2 [M-l]

14th step

(1 23 4R, 5-3- 7- [(lR, 2-2- (3,4- difluorophenyl) cyclopropylamino]-5- propyl group sulfydryl-triazol

[4, 5-d] pyrimidin-3-yl } -5- (2- hydroxyl-oxethyls) cyclopenta -1, 2, 4- triols are by (3a^, 4R, 5R, 6S, 6a -4- { 7- [(lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino] -5- propyl group sulfydryl-triazol [4, 5-d] pyrimidin-3-yl } -6- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] dioxole -5- alcohol 12n (230 mg, 0.40 mmol) it is dissolved in 10 mL methanol and 1 mL water, add the resin cations of Dowex 50 (500 mg), reaction 16 hours.Filtering, filtrate decompression Nong Shrink, with HPLC preparative chromatographies purify gained residue, obtain title product (1 234 5-3- { 7- [(lR, 25)-2- (3,4- difluorophenyls) cyclopropylamino]-5- propyl group sulfydryl-triazol [4,5- pyrimidin-3-yls }-5- (2- hydroxyl-oxethyls) cyclopenta-1,2, (130 mg of 4- triols 12, white solid), yield： 60.0%.

MS m/z (ESI): 539.1 [M+l]

1H NMR (400 MHz, CD₃OD) δ 7.22-7.07 (m, 3H), 5.02-4.95 (m, 1H), 4.65-4.55 (m, 2H), 4.15-4.11 (m, 1H), 3.80-3.71 (m, 5H), 3.15-2.90 (m, 3H), 2.20-2.07 (m, 1H), 1.66-1.60 (m, 2H), 1.50-1.35 (m, 2H), 0.94 (t, 3H) embodiments 13

(1S, 23 5R) -3- (2- hydroxyl-oxethyls) -5- { 5- propyl group sulfydryls -7- [(lR, 2S/l 2R) -2- (3- pyridine radicals) rings third

Diastereoisomer diastereoisomer

The first step

(E) -3- (3- pyridine radicals) propyl- 2- olefin(e) acid ethyl esters

60% sodium hydride (2.40 g, 60 mmol) is suspended in 30 mL tetrahydrofurans, (diethoxy-phosphate)-ethyl acetate (11.9 mL, 60 mmol) is added dropwise in 0 °C, is reacted at room temperature 1 hour.10 mL pyridine -3- formaldehyde 13a (3.8 mL, 50 mmol) tetrahydrofuran solution is added dropwise in 0 °C, reacts 3 hours.Room temperature continues to react 12 hours.Add 100 mL water, extracted with ethyl acetate (50 mLx4), merge organic phase, washed, anhydrous sodium sulfate drying with saturated nacl aqueous solution (50 mL), filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product (E) -3- (3- pyridine radicals) propyl- 2- olefin(e) acid ethyl ester 13b (6.90 g, colorless oil), yield： 80.0%.

MS m/z (ESI): 178.1 [M+l]

Second step

(E) -3 3- pyridine radicals) propyl- 2- olefin(e) acids

By (E) -3-0 pyridine radicals) propyl- 2- olefin(e) acid ethyl esters 13b (6.90 g, 38.90 mmol) is dissolved in 50 mL methanol, adds 10 mL sodium hydroxide C3.40 g, 85 mmol) solution, react 1.5 hours.Jian Ya Nong Shrink, add 30 mL water, and 2 M hydrochloric acid are added dropwise to reaction solution pH=6, extracted with ethyl acetate (200 mLx4), merge organic phase, subtract the dense Shrink of pressure and obtain white solid, aqueous phase adjusts pH=4, filtering, filter cake is dried in vacuo, and is merged with above-mentioned solid, is obtained title product CEHH3-pyridine radicals) propyl- 2- olefin(e) acid 13cC5.80 g, white solid), yield： 100%. MS m/z (ESI): 150.1 [M+1]

3rd step

[(1R, 2 ＆ 5R) -2- isopropyl -5- methyl-cyclohexyls base] (E) -3- (3- pyridine radicals) propyl- 2- olefin(e) acid esters By (E) -3- (3- pyridine radicals) propyl- 2- olefin(e) acids 13c (5.80 g, 38.90 mmol) it is dissolved in 100 mL dichloromethane, sequentially add MENTHOL (6.68 g, 42.80 mmol), Ν, Ν '-dicyclohexylcarbodiimide (12.03 g, 58.30 mmol) and DMAP (5.22 g, 42.80 mmol), react 12 hours.With silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product [(1R, 2 ＆ 5R)-2- isopropyl-5- methyl-cyclohexyls base] EHH3-pyridine radicals) 13 5 g of propyl- 2- olefin(e) acids ester, colorless oil yield： 50.0%.

MS m/z (ESI): 288.2 [M+l]

4th step

[GR, 2 ＆ 5R) -2- isopropyl -5- methyl-cyclohexyl bases：LR, 2R/l^, 2-2- (3- pyridine radicals) cyclopropane formic ethers are by Trimethylsulfoxonium Iodide (9.57 g, 43.5 mmol) and potassium tert-butoxide (4.88 g, 43.50 mmol) it is dissolved in 40 mL dimethyl sulfoxide (DMSO)s, add 20 mL [(2 ＆ 5R)-2- isopropyl-5- methyl-cyclohexyls base] (￡)-3- (3- pyridine radicals) propyl- 2- olefin(e) acid esters 13d (5 g, 17.40 mmol) dimethyl sulphoxide solution.50 °C are reacted 30 minutes.2 M hydrochloric acid are added dropwise to reaction solution pH=7, add 500 mL ethyl acetate, washed with saturated nacl aqueous solution (100 mLx2), aqueous phase is extracted with ethyl acetate (150 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product [(1R, 2S, 5R)-2- isopropyls-5- methyl-cyclohexyls base] (lR, 2R/, 2-2- (3- pyridine radicals）Cyclopropane formic ether 13e (3.58 g, colorless oil), yield： 68.0%.

MS m/z (ESI): 302.2[M+1]

5th step

(1R, 2R/1 2S) -2- (3- pyridine radicals) cyclopropane-carboxylic acid

By [(1R, 2 ＆ 5R) -2- isopropyl -5- methyl-cyclohexyls base] (1R,-the 2- of 2R/1 2 (3- pyridine radicals) cyclopropane-carboxylic acid tenth of the twelve Earthly Branches purport 13e (3.58 g, 11.90 mmol) it is dissolved in 100 mL methanol, add 10 mL sodium hydroxides (3.80 g, 95 mmol) solution, reacts 20 minutes.40 °C are reacted 1.5 hours.Jian Ya Nong Shrink, add 40 mL water, and 2 M hydrochloric acid of power mouthful are dripped in 0 °C to reaction solution pH=5, filtering, aqueous phase is extracted with ethyl acetate (150 mLx7), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain the title product (- 2- of lR, 2R l 2 (3- pyridine radicals) cyclopropane-carboxylic acid 13fC1.80 g, light yellow oil), yield： 92.0%.

MS m/z (ESI): 164.1 [M+1]

6th step

N- [(lR, 2S/1^2R)-2- (3- pyridine radicals) cyclopropyl] t-butyl carbamate is by (1R, 2R/1S, 2-2- (3- pyridine radicals) cyclopropane-carboxylic acid 13f (407 mg, 2.50 mmol) it is dissolved in the 15 mL tert-butyl alcohols, sequentially add diphenyl phosphate azide (0.8 mL, 3.75 mmol), (0.5 mL, 3.75 mmol react 16 hours triethylamine in 80 °C.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [(lR, 2S/1^2R) -2- (3- pyridine radicals) cyclopropyl] t-butyl carbamate 13gC335 mg, light yellow oil), yield： 57.0%.

MS m/z (ESI): 235.1 [M+1]

7th step

(lR, 2S/1^2R) -2- (3- pyridine radicals) cyclopropylamine

By N- [(lR, 2S/1^2R) -2- (3- pyridine radicals）Cyclopropyl] t-butyl carbamate 13g (300 mg, 1.28 Mmol) it is dissolved in 2 mL ethyl acetate, the M Hydrochloride/ethyl acetates of 6 mL 5 is added dropwise, reacts 2 hours.Saturated sodium carbonate solution is added dropwise to reaction solution pH=9,50 mL ethyl acetate are added, point liquid, aqueous phase is extracted with ethyl acetate (50 mLx4), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system A purify gained residue, obtain title product (1R, 2S/1 2R) -2- (3- pyridine radicals) cyclopropylamine 13h (60 mg, colorless oil), yield： 35%.

MS m/z (ESI): 135.1 [M+1]

8th step

2- [(6＆-2, the 2- dimethyl-6- of 3＆ 46 [5- propyl group sulfydryls-7- [[(1 2-2- (3- pyridine radicals) cyclopropyl] amino：Triazol [4,5-d] pyrimidin-3-yl }-4,5,6,6＆- tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yls] epoxide] ethanol

By 2- { [(3aS, 4R, 6 6aR) -6- (the chloro- 5- propyl group sulfydryl-triazols [4 of 7-, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopentas [[1, 3] Dioxol-4 -yl] epoxide } ethanol 5g (80 mg, 0.19 mmol) it is dissolved in 4 mL tetrahydrofurans, sequentially add triethylamine (0.3 mL, 0.67 mmol) and 2 mL (lR, 2S/1^2R) -2- (3- pyridine radicals) cyclopropylamine 13h (30 mg, 0.22 mmol) tetrahydrofuran solution, reaction 12 hours.Jian Ya Nong Shrink, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 2- { [(3aR, 4S, 6R, 6a -2,2- dimethyl -6- [5- propyl group sulfydryls -7- [[(lR, 25/l 2R) -2- (3- pyridine radicals）Cyclopropyl] amino] triazol [4,5-d] pyrimidin-3-yl }-4,5,6-tetrahydrochysene-3aH- cyclopentas M [l, 3] Dioxol-4 -yl] epoxide] ethanol 13i (45 mg, colorless oil), yield： 45.8%.

MS m/z (ESI): 528.54 [M+l]

9th step

(1S, 23 5R)-3- (2- hydroxyl-oxethyls)-5- 5- propyl group sulfydryls-7- [[(1 2/1 2-2- (3- pyridine radicals) cyclopropyl] amino] triazol [4, 5-d] pyrimidin-3-yl } pentamethylene -1, 2- glycol is by 2- { [(3aR, 4S, 6R, 6a -2, 2- dimethyl -6- [5- propyl group sulfydryl -7- [(lR, 25/l 2R) -2- (3- pyridine radicals) cyclopropylamino] triazol [4, 5-d] pyrimidin-3-yl] -4, 5, 6, 6a- tetrahydrochysene -3aH- cyclopenta M [l, 3] Dioxol-4 -yl] epoxide } ethanol 13i (45 mg, 0.085 mmol) it is dissolved in 4 mL methanol, add the M hydrochloric acid of l mL 2, reaction 4 hours.Saturated sodium carbonate solution is added dropwise to reaction solution ρ Η=8, Jian Ya Nong Shrink, extracted with ethyl acetate (50 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (1S, 23 5R) -3- (2- hydroxyl-oxethyls) -5- { 5- propyl group sulfydryls -7- [(lR, 2S/l 2R) -2- (3- pyridine radicals) cyclopropylamino] triazols [4,5-d] pyrimidin-3-yl } pentamethylene -1,2- glycol 13 (27 mg, white solid), yield： 65.0%. MS m/z (ESI): 488.2 [M+l]

1H NMR (400 MHz, CD₃OD the) (br of δ 8.56, 1H), 8.38 (br, 1H), 7.70 (d, 1H), 7.39 (m, 1H), 5.05-5.20 (m, 1H), 4.74-4.80 (m, 1H), 4.15-4.19 (m, 1H), 3.89-3.95 (m, 1H), 3.67-3.72 (m, 2H), 3.60-3.67 (m, 2H), 3.19 (br, 1H), 2.88-3.10 (m, 1H), 2.70-2.85 (m, 1H), 2.15-2.30 (m, 2H), 1.50-1.65 (m, 2H), 1.40-1.50 (m, 1H), 1.26-1.35 (m, 2H), 0.89 (t, 3H) embodiments 14 (1S, 23 4R, 5R)-3- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] three-d] pyrimidin-3-yl) the fluoro- 5- of-4- (2- hydroxyl-oxethyls) pentamethylene-1,2- glycol

The first step

4- nitrobenzoic acids ((3^, 456 6) -4- azidos -6- (benzyloxy) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene

- 3oH- cyclopentanos W] [l, 3] dioxole -5- bases) ester general (3, 4R, 5R, 6 6^) -4- azido -6- benzyloxies -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -5- alcohol 7e (1.20 g, 4 mmol), paranitrobenzoic acid (1.34 g, 8 mmol) and triphenylphosphine (2.15 g, 8 mmol) it is dissolved in 60 mL tetrahydrofurans, add diisopropyl azodiformate (1.6 mL, 8 mmol), 55 °C of stirring reactions 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- nitrobenzoic acids ((3^, 4566 α -4- azidos -6- (benzyloxy) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -5- bases) ester 14a (1.32 g, yellow oil), yield： 73.0%.

Second step

(3,4R, 56 6^) -4- azido -6- benzyloxy -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3aH- cyclopentanos

M [l, 3] dioxole -5- alcohol

By 4- nitrobenzoic acids ((3i^, 4S, 56 6^) -4- azidos -6- (benzyloxy) -2,2- dimethyl -4,5,6,6 β-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -5- bases) ester 14a (1.32 g, 3 mmol) is dissolved in 24 mL First alcohol and water (V/V=5:L) in mixed solution, potassium hydroxide (337 mg, 6 mmol), stirring reaction 1 hour are added.Jian Ya Nong Shrink, add 10 mL water, extracted with dichloromethane (20 mL X 4), merge organic phase, washed, anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution (10 mL), filtrate decompression Nong Shrink, obtain title product (3,4R, 56 6^) -4- azido -6- benzyloxies -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3aH- cyclopentano M [l, 3] dioxole -5- alcohol 14bC870 mg, pale yellow oil yield： 95.0%.

MS m/z (ESI): 323.3[M+18]

3rd step

Fluoro- 2, the 2- dimethyl -4,5 of (3i^, 4S, 5R, 6R, 6i^) -4- azidos -6- (benzyloxy) -5-, 6,6 beta-tetrahydro -3flH- cyclopentanos

[d] [l, 3] dioxole

By (3,4R, 56 6^) -4- azido -6- benzyloxies -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -5- alcohol 14b (750 mg, 2.50 mmol) it is dissolved in 40 mL dichloromethane, diethylin sulfur trifluoride (0.5 mL, 3.70 mmol), stirring reaction 3 hours is added dropwise.Reaction solution is washed with saturated sodium bicarbonate solution (10 mL X 2), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (3,4WR, 6R, 6) -4- azidos -6- (benzyloxy) -5- fluoro- 2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole 14c (380 mg, colorless oil), yield： 50%.

4th step

Fluoro- 2, the 2- dimethyl -4,5 of (3i^, 4S, 5R, 6R, 6i^) -6- (benzyloxy) -5-, 6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- amine

By (3i^, 4S, 5R, 6R, 6i^) -4- azidos -6- (benzyloxy) -5- fluoro- 2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos W] [l, 3] dioxole 14c (480 mg, 1.56 mmol) is dissolved in 30 mL methanol, adds 5% Pd/CaCO₃(900 mg), stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3i^, 4S, 5R, 6R, 6i^) -6- (benzyloxy) -5- fluoro- 2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- amine 14d (430 mg, colorless oil), product is not purified directly to carry out next step reaction. MS m/z (ESI): 282.2[M+1]

5th step

(3oR, 4R, 5R, 6 6) -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol

By (3^, 4 5R, 6R, 6) -6- (benzyloxy) -5- fluoro- 2,2- dimethyl -4,5,6,6a- tetrahydrochysene -3oH- cyclopentanos [l, 3] dioxole -4- amine 14d (430 mg, 1.56 mmol) is dissolved in 15 mL methanol, adds 20%Pd/C (900 mg), hydrogen is replaced three times, stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3oR, 4R, 5R, 6 6^) -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos [d] [l, 3] dioxole -4- alcohol 14e (300 mg, colorless oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 192.1 [M+1]

6th step Fluoro- 6- hydroxyls-2, the 2- dimethyl-4,5 of (3i^, 4S, 5R, 6R, 6flR)-5-, 6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl benzyq carbamates

By (3oR, 4R, 5R, 6 6^) -6- amino-5-fluorine -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol 14e (200 mg, 1.05 mmol) are dissolved in 13 mL tetrahydrofurans and water (V/V=3.33:L) in mixed solution, potassium carbonate C290 mg, 2.10 mmol are added), benzyl chloroformate (215 mg, 1.26 mmol), stirring reaction 12 hours is added dropwise.Ethyl acetate (10 mL) and water (10 mL) are sequentially added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (10 mL), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (3i^, 4S, 5R, 6R, 6flR) the fluoro- 6- hydroxyls -2 of -5-, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] Dioxol-4 -yl benzyq carbamate 14f (260 mg, white solid), yield： 76.2%.

MS m/z (ESI): 326.3[M+1]

7th step

2- ((3,4R, 5R, 6 6) fluoro- 2, the 2- dimethyl -4,5 of -6- (benzyloxy amide groups) -5-, 6,6 α-tetrahydrochysene -3flH- cyclopentanos

M [l, 3] dioxole -4- epoxides) ethyl acetate

Will（3i^, 4S, 5R, 6R, 6flR) fluoro- 6- hydroxyls -2, the 2- dimethyl -4,5 of -5-, 6,6 beta-tetrahydros ->AH- cyclopentano M [l, 3] mg of Dioxol-4 -yl benzyq carbamate 14 260,0.80 mmol) it is dissolved in 10 mL tetrahydrofurans, the potassium tert-butoxide solution C0.7 mL of 0 °C of dropwise addition 20%, 1.20 mmol), bromoacetate (0.1 mL is added dropwise in 0 °C of stirring reaction 30 minutes, 1.20 mmol), reaction 12 hours is stirred at room temperature.Saturated ammonium chloride solution (10 mL) is added into reaction solution, point liquid, aqueous phase is extracted with ethyl acetate (20 mLx2), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 2- ((3,4R, 5R, 6S, 6) -6- (benzyloxy amide groups) -5- fluoro- 2,2- dimethyl -4,5,6 add-tetrahydrochysene -3aH- cyclopentanos M [l, 3] dioxole -4- epoxides）Ethyl acetate 14g (328 mg, colorless oil), product is not purified directly to carry out next step reaction.

8th step

The fluoro- 6- of (3i^, 4S, 5R, 6R, 6i^) -5- (2- hydroxyl-oxethyls) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos

^] [1,3] Dioxol-4 -yl benzyq carbamate

By 2- ((3,4R, 5R, 6 6^) -6- (benzyloxy amide groups) -5- fluoro- 2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- epoxides) ethyl acetate 14g (328 mg, 0.80 mmol) is dissolved in 10 mL tetrahydrofurans, adds lithium borohydride C35 mg, 1.60 mmol), stirring reaction 2 hours.Water (10 mL) is added into reaction solution, extracted with ethyl acetate (10 mL X 3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3i^, 4S, 5R, 6R, 6i^) the fluoro- 6- of -5- (2- hydroxyl-oxethyls) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentanos [^] [1, 3] Dioxol-4 -yl benzyq carbamate 14h (170 mg, colorless oil), yield： 57.6%.

MS m/z (ESI): 370.3[M+1]

9th step

2- ((3,4R, 5R, 6 6) -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] two Oxole -4- epoxides) ethanol

By (3i^, 4S, 5R, 6R, 6i^) the fluoro- 6- of-5- (2- hydroxyl-oxethyls)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos [d] [l, 3] Dioxol-4 -yl benzyq carbamate 14hC170 mg, 0.46 mmol) it is dissolved in 8 mL methanol, the Pd/C (170 mg) of addition 10%, hydrogen is replaced three times, stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink obtain title product 2- ((3,4R, 5R, 6 6^) -6- amino-5-fluorines -2,2- dimethyl -4,5,6,6 β-tetrahydrochysene -3oH- cyclopentanos [d] [l, 3] dioxole -4- epoxides) 14 108 mg of ethanol, colorless oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 236.1 [M+l]

Tenth step

2- ((3, 4R, 5R, 6^6i^) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentanos W] [l, 3] dioxole -4- epoxides) ethanol is by 2- ((3, 4R, 5R, 6 6^) -6- amino-5-fluorines -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3oH- cyclopentanos W] [l, 3] dioxole -4- epoxides) ethanol 14i (108 mg, 0.46 mmol), 4, the chloro- 2- propyl group sulfydryls of 6- bis--pyrimidine -5- amine ls (220 mg, 0.92 mmol) and N, N- diisopropylethylamine (0.24 mL, 1.38 mmol) it is dissolved in 5 mL N, in dinethylformamide, 100 °C of stirring reactions 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system A purify gained residue, obtain title product 2- ((>AS, AR, 5R, 6S, 6aS)-e- (5- amino -6- chloro- 2- (rosickyite bases）Pyrimidine -4- amino) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos [d] [l, 3] dioxole -4- epoxides) ethanol 14j (65 mg, brown oil), yield： 36.0%.

MS m/z (ESI): 437.3 [M+l]

11st step

2- ((3i^, 4R, 5R, 6^6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- epoxides) ethanol is by 2- ((3, 4R, 5R, 6^6i^) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3flH- cyclopentano M [l, 3] dioxole -4- epoxides）Ethanol 14j (65 mg, 0.15 mmol) is dissolved in 3 mL acetic acid and water (V/V=2:L) in mixed solution, 0 °C adds natrium nitrosum (12 mg, 0.17 mmol), 0 °C of stirring reaction 10 minutes.Ethyl acetate (15 mL) is added into reaction solution, be added dropwise saturated sodium carbonate solution to reaction solution ρ Η be 7, divide liquid, organic phase is washed with saturated sodium carbonate solution (15 mL), divide liquid, aqueous phase is extracted with ethyl acetate (15 mL X 3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 2- ((3, 4R, 5R, 6 6^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- epoxides) ethanol 14k (67 mg, rufous grease), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 448.2 [M+l]

12nd step

2- ((3i^, 4R, 5R, 6^6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 beta-tetrahydro -3flH- cyclopentanos [d] [l, 3] dioxole -4- epoxides) ethanol

By 2- ((3,4R, 5R, 6 6^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidine -3- bases) fluoro- 2, the 2- dimethyl -4 of -5-, 5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- epoxides）Ethanol 14k (67 mg, 0.15 11^101) standing grain mouthful（1 2-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride l li (40.10 mg, 0.20 mmol) are dissolved in 5 mL acetonitriles, add triethylamine (53.13 mg, 0.53 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 2- ((3i^, 4R, 5R, 6S, 6i^) -6- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5- pyrimidin-3-yls) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- epoxides) ethanol 141C43 mg, pale yellow oil yield： 50%.

MS m/z (ESI): 581.4[M+1]

13rd step

(1 23 4R, 5R)-3- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) the fluoro- 5- of-4- (2- hydroxyl-oxethyls) pentamethylene-1,2- glycol is by 2- ((3,4R, 5R, 6 6i^)-6- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5- pyrimidin-3-yls) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos W] [l, 3] dioxole -4- epoxides) ethanol 141 (43 mg, 0.07 mmol) is dissolved in 5.5 mL first alcohol and waters (V/V=10:L) in mixed solution, the ion exchange resin of dowex 50 (50 mg), stirring reaction 60 hours are added.Filtering, filtrate decompression Nong Shrink, obtain title product (1 23 4R, 5R)-3- (7- (lW, 2-2- (;3,4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) the fluoro- 5- of -4- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol 14 (35 mg, faint yellow solid), yield： 87.5%.

MS m/z (ESI): 581.4[M+1]

1H NMR (400 MHz, CD₃OD) δ 7.23-7.09 (m, 3H), 5.50-5.47 (m, 0.5H), 5.36-5.3 l (m, 1.5H), 4.71-4.65 (m, 1H), 4.20-4.18 (m, 1H), 4.05-4.00 (m, 1H), 3.77-3.74 (m, 4H), 3.13-2.90 (m 3H), 2.20-2.12 (m, 1H), 1.70-1.30 (m, 4H), 0.93 (t, 3H) embodiment 15

(1R, 23 4S, 5R)-4- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-5- fluorine pentamethylene-1,2,3- triols

The first step

OR, 4R, 5R, 6S, 6i^) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) fluoro- 2,2- dimethyl of -5-

- 4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol is by (3oR, 4R, 5R, 6 6^) -6- amino-5-fluorines -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 14e (100 mg, 0.52 mmol) it is dissolved in 3 mL N, in dinethylformamide, sequentially add 4, chloro- 2- propyl group sulfanyl-pyrimidine -5- amine Is (250 mg of 6- bis-, 1.05 mmol) and N, N- diisopropylethylamine (0.3 mL, 1.57 mmol), 100 °C of stirring reactions 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3flR, 4R, 5R, 6S, 6) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -5- fluoro- 2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 15aC100 mg, brownish red grease), yield： 50%.

MS m/z (ESI): 393.1 [M+l]

Second step

(3flR, 4R, 5R, 6^6i^)-6- (the chloro- 5- of 7- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) fluoro- 2, the 2- dimethyl-4 of-5-, 5,6,6 α-tetrahydrochysene-3oH- cyclopentanos M [l, 3] dioxole-4- alcohol by 045 6^60-6- (the chloro- 2- of 5- amino-6- (；Rosickyite base) pyrimidine -4- amino) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- alcohol 15a (200 mg, 0.51 mmol) is dissolved in 4.5 mL acetic acid and water (V/V=2:L) in mixed solution, 0 °C adds natrium nitrosum (43 mg, 0.62 mmol), 0 °C of stirring reaction 10 minutes.Ethyl acetate (10 mL) is added into reaction solution, saturated sodium carbonate solution (15 mL), divide liquid, organic phase is washed with saturated sodium carbonate solution (10 mL), divide liquid, aqueous phase is extracted with ethyl acetate (15 mL X 3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (3flR, 4R, 5R, 6^6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 15b (180 mg, rufous grease), yield： 87.5%.

MS m/z (ESI): 404.2 [M+l] 3rd step

(3flR, 4R, 5R, 6^6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) fluoro- 2, the 2- dimethyl -4 of -5-, 5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol

By (3flR, 4R, 5R, 6^6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 15b (180 mg, 0.45 mmol) and (lR, 2-2- (3, 4- difluorophenyls) cyclopropylamine hydrochloride l li (120 mg, 0.58 mmol) it is dissolved in 8 mL acetonitriles, add triethylamine (159 mg, 1.58 mmol), stirring reaction 48 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3oR, 4R, 5R, 6 6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -5- fluoro- 2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 15c (160 mg, pale yellow oil), yield： 66.3%.

MS m/z (ESI): 537.1 [M+1]

4th step

(1R, 23 4S, 5R)-4- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-5- fluorine pentamethylene-1,2,3- triols are by Pfl ^R^R^S^i^^--GR J-P^ difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5- pyrimidin-3-yls) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- alcohol 15c (160 mg, 0.30 mmol) is dissolved in 5.5 mL first alcohol and waters (V/V=10:L) in mixed solution, the ion exchange resin of dowex 50 (200 mg), stirring reaction 12 hours are added.Filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system A purify obtained by residue, obtain title product（1R, 2 3^^, 5R) -4- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -5- fluorine pentamethylene -1,2,3- triols 15 (100 mg, white solid), yield： 67%.

MS m/z (ESI): 497.3[M+1]

1H NMR (400 MHz, CD₃OD) δ 7.26-7.09 (m, 3H), 5.35-5.15 (m, 2H), 4.75-4.65 (m, 1H), 4.25-4.16 (m, 1H), 4.10-4.05 (m, 1H), 3.13-3.05 (m, 2H), 2.96-2.85 (m, 1H), 2.20-2.09 (m, 1H), 1.70-1.61 (m, 1H), 1.39-1.24 (m, 3H), 0.95-0.90 (t, 3H) embodiment 16

(1 2S, 3R, 5-3- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazols

[4,5-d] pyrimidin-3-yl) -5- (the fluoro- 3- hydroxy propyloxy groups of 2-) pentamethylene -1,2- glycol

The first step

(3,4R, 6 6flR)-6- (allyloxy)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl benzyq carbamates

By N- [(3,4R, 6 6flR)-6- hydroxyls-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl] benzyq carbamate 5b (4 g, 13 mmol) is dissolved in 20 mL tetrahydrofurans, sequentially adds potassium tert-butoxide (2.20 g, 19.50 mmol), bromopropene (2.2 mL, 26 mmol), stirring reaction 12 hours.Water (20 mL) is added into reaction solution, extracted with ethyl acetate (20 mL X 3), merge organic phase, saturated nacl aqueous solution (10 mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 03^, 46 6^) -6- (allyloxy) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] Dioxol-4 -yl benzyq carbamate 16a (2.10 g, colorless oil), yield： 48.0%.

MS m/z (ESI): 348.1 [M+1]

Second step

(3,4R, 6 6flR) -2,2- dimethyl -6- (epoxy second protective embankment -2- methoxyl groups) -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos

^] [1,3] Dioxol-4 -yl benzyq carbamate

By (3,4R, 6 6flR)-6- (allyloxy)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl benzyq carbamate 16a (2.10 g, 6 mmol) it is dissolved in 15 mL dichloromethane, 0 °C adds metachloroperbenzoic acid (2.10 g, 12.17 mmol), stirring reaction 12 hours.Filtering, filtrate is washed, anhydrous sodium sulfate drying with saturated sodium bicarbonate solution (20 mL) and saturated nacl aqueous solution (10 mL) successively, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title Product (3,4R, 6 6flR)-2,2- dimethyl-6- (oxirane-2- methoxyl groups)-4,5,6,6 beta-tetrahydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl benzyq carbamate 16b (2.16 g, pale yellow oil), yield： 98.0%. MS m/z (ESI): 364.1 [M+1]

3rd step

(3,4R, 6 6flR) -6- (3- (benzyloxy) -2- hydroxy propyloxy groups) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos

^] [1,3] Dioxol-4 -yl benzyq carbamate

Phenmethylol (0.7 mL, 6.90 mmol) is dissolved in 5 mL tetrahydrofurans, 0 °C sequentially add 60% sodium hydrogen (60 mg, 1.50 mmol), (3,4R, 6 6aR)-2,2- dimethyl-6- (oxirane-2- methoxyl groups)-4,5,6,6 α-tetrahydrochysene-3oH- cyclopentano M [l, 3] Dioxol-4 -yl benzyq carbamate 16b (0.50 g, 1.40 mmol), stirring reaction 12 hours.Ethyl acetate (10 mL) is added into reaction solution, add 5% hydrochloric acid (10 mL), be added dropwise 5% sodium bicarbonate solution to reaction solution ρ Η be 7, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system Β purify gained residue, obtain title product (3, 4R, 6 6flR) -6- (3- (benzyloxy) -2- hydroxy propyloxy groups) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentanos [d] [l, 3] Dioxol-4 -yl benzyq carbamate 16^0.35 g, colorless oil), yield： 57.0%.

MS m/z (ESI): 472.2[M+1]

4th step

(3,4R, 6 6flR) -6- (3- (benzyloxy) -2- fluorine propoxyl group) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos

^] [1,3] Dioxol-4 -yl benzyq carbamate

By (3,4R, 6 6flR)-6- (3- (benzyloxy)-2- hydroxy propyloxy groups)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos W] [l, 3] Dioxol-4 -yl benzyq carbamate 16cC330 mg, 0.70 mmol) it is dissolved in 10 mL dichloromethane,-78 °C are added dropwise diethylin sulfur trifluoride (0.2 mL, 1.67 mmol), and reaction 6 hours is stirred at room temperature in liter.Water (15 mL) is added into reaction solution, extracted with dichloromethane (15 mL X 3), merge organic phase, saturated nacl aqueous solution (10 mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3, 4R, 6S, 6flR) -6- (3- (benzyloxy) -2- fluorine propoxyl group) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] Dioxol-4 -yl benzyq carbamate 16d (260 mg, brownish red grease), yield： 79.0%.

MS m/z (ESI): 474.2[M+1]

5th step

3- ((3flR, 4S, 6R, 6i^) -6- amino -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol

By (3,4R, 6 6flR)-6- (3- (benzyloxy)-2- fluorine propoxyl group)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos W] [l, 3] Dioxol-4 -yl benzyq carbamate 16dC260 mg, 0.55 mmol) it is dissolved in 10 mL methanol, the Pd/C (100 mg) of addition 10%, hydrogen is replaced three times, stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink, obtain title product 3- (；046 6^) -6- amino -2,2- dimethyl -4,5,6,60- tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16eG00 mg, brown oil Thing), yield： 74.0%.

MS m/z (ESI): 250.3[M+1]

6th step

3- ((3flR, ^, 6R, 6) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) fluoro- 2,2- dimethyl of -5-

- 4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol is by 3- ((3flR, 4S, 6R, 6i^) -6- amino -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16e (100 mg, 0.40 mmol), 4, chloro- 2- propyl group sulfanyl-pyrimidine -5- amine Is (143 mg of 6- bis-, 0.60 mmol) and N, N- diisopropylethylamine (0.2 mL, 1.20 mmol) it is dissolved in 5 mL N, in dinethylformamide, 100 °C of stirring reactions 12 hours.Into reaction solution add water (；10 mL), extracted with ethyl acetate (10 mL X 3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 3- (；The 046 60 chloro- 2- of -6-0 amino -6- (；Rosickyite base) pyrimidine -4- amino) fluoro- 2, the 2- dimethyl -4,5 of -5-, 6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16f (45 mg, brown oil), yield： 25.1%.

MS m/z (ESI): 451.1 [M+l]

7th step

3- ((3flR, 4^6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol is by 3- ((3flR, ^, 6R, 6) -6- (5- amino -6- chlorine 2- (rosickyite base) pyrimidine -4- amino) -5- fluoro- 2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- epoxides) small alcohol 16f (45 mg of -2- fluoro-propanes, 0.10 mmol) it is dissolved in 2 mL acetic acid, 0 °C of 0.1 mL natrium nitrosums (7.2 mg of addition, 0.10 mmol), 0 ° of 〇 stirring reaction 20 minutes.Ethyl acetate (15 mL) is added into reaction solution, unsaturated carbonate potassium solution (10 mL) is added dropwise, divide liquid, aqueous phase is extracted with ethyl acetate (15 mL X 3), merge organic phase, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product 3- ((3flR, ^, 6R, 6) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentanos [d] [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16g (50 mg, rufous grease), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 462.3[M+1]

8th step

3- ((3oR, 45,6R, 6o5) -6- (7- ((lR, 25) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol

By 3- ((3flR, 4^6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16g (50 mg, 0.11 mmol) and (lR, 2-2- (3, 4- difluorophenyls) cyclopropylamine hydrochloride l li (29 mg, 0.14 mmol) it is dissolved in 5 mL acetonitriles, add triethylamine (38 mg, 0.38 mmol), stirring reaction 12 hours. Reaction solution Jian Ya Nong Shrink, add water (10 mL), be added dropwise 2.5 M hydrochloric acid to reaction solution pH be 4, extracted with ethyl acetate (10 mL), divide liquid, organic phase is washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 3- ((3flR, 4^6R, 6)-6- (7- ((lR, 2-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16hC24 mg, orange red grease), yield： 38.0%. MS m/z (ESI): 595.2[M+1]

9th step

(1 2S, 3R, 5-3- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazols

[4,5-d] pyrimidin-3-yl) -5- (the fluoro- 3- hydroxy propyloxy groups of 2-) pentamethylene -1,2- glycol is by 3- ((3oR, 45,6R, 6o5) -6- (7- ((lR, 25) -2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- epoxides) -2- fluoro-propane -1- alcohol 16hC24 mg, 0.04 mmol) it is dissolved in 8 mL methanol, the M hydrochloric acid of 2 mL 2.5, stirring reaction 12 hours is added dropwise.Reaction solution Jian Ya Nong Shrink, add water (10 mL) be added dropwise saturated sodium carbonate solution to reaction solution ρ Η be 7, extracted with ethyl acetate (10 mL X 3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product (1 2S, 3R, 5-3- (7- ((lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5 pyrimidin-3-yls) -5- (the fluoro- 3- hydroxy propyloxy groups of 2-) pentamethylene -1, (10 mg of 2- glycol 16, faint yellow solid yield： 45.0%.

MS m/z (ESI):555.2 [M+1] embodiments 17

(1^2R, 5R)-5- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazols

[4,5-d] pyrimidin-3-yl) amyl- 3- alkene -1, the 2- glycol of ring

17

The first step

(3flR, 4S, 6R, 6i^) -6- amino -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole

- 4- alcohol

By ((3,4R, 6 6flR) -6- hydroxyls -2,2- dimethyl-tetrahydro -3flH- cyclopenta M [l, 3] dioxole -4- aminocarbamic acid benzyl ester 5bC3 g, 9.80 mmol) it is dissolved in 100 mL methanol, add 10% Pd/C (600 mg), hydrogen is replaced three times, stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3flR, 4S, 6R, 6i^) -6- amino -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol 17aC1.60 g, pale yellow oil), yield： 94.0%.

Second step

(3flR, ^, 6R, 6) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene

- 3oH- cyclopentanos [d] [l, 3] dioxole -4- alcohol

By (3flR, 4S, 6R, 6i^-6- amino -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 17a (1.60 g, 9.20 mmol), 4, chloro- 2- propyl group sulfanyl-pyrimidine -5- amine Is (2.60 g of 6- bis-, 11 mmol) and DIPEA (3.60 g, 27.60 mmol) be dissolved in 20 mL N, in dinethylformamide, 100 °C of stirring reactions 5 hours.Water (100 mL) and ethyl acetate (100 mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (100 mL X 3), merge organic phase, washed successively with water (50 mL) and saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3flR, 4S, 6R, 6) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 17b (1.85 g, orange solids), yield： 55.0%.

MS m/z (ESI): 375.1 [M+l]

3rd step

(3flR, 4^6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1,2,3] triazol [4,5- pyrimidin-3-yls) -2,2- dimethyl - 4,5,6,6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol is by (3flR, 4^6R, 6i^) -6- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -2,2- dimethyl -4,5,6,6 β-tetrahydrochysene -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 17b (1.85 g, 4.90 mmol) is dissolved in 30 mL acetic acid and water (V/V=l:L) in mixed solution, the ice water solution of 1 mL natrium nitrosums (0.38 g, 5.40 mmol), 0 °C of stirring reaction 30 minutes is added dropwise.Ethyl acetate (50 mL) is added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (50 mL X 3), merge organic phase, washed successively with saturated sodium bicarbonate solution (50 mL X 2) and saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (3flR, 4^6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 17c (1.90 g, brown oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 386.1 [M+1]

4th step

(3flR, 4^6R, 6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole

- 4- alcohol

By (3flR, 4^6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 17c (1.90 g, 4.90 mmol) it is dissolved in 50 mL acetonitriles, sequentially add (1R, 2-2- (3, 4- difluorophenyls) cyclopropylamine hydrochloride l li (1.30 g, 6.40 mmol) and triethylamine (1.70 g, 17 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add ethyl acetate (80 mL) and water (80 mL), divide liquid, aqueous phase is extracted with ethyl acetate (50 mL X 2), merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3flR, 4^6R, 6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyls）Cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5- pyrimidin-3-yls) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- alcohol 17d (2 g, orange solids), yield： 80%.

MS m/z (ESI): 519.2[M+1]

5th step

N- ((lR, 2^-2- (3,4- difluorophenyls) cyclopropyl)-3- ((3i^, 4R, 6flR)-2,2- dimethyl-4,6 β-dihydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine will（3flR, 4^6R, 6)-6- (7- ((lR, 2-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol 17d (130 mg, 0.25 mmol) and triphenylphosphine (263 mg, 1 mmol) it is dissolved in 2 mL toluene, diisopropyl azodiformate C200 mg, 1 mmol is added dropwise), 80 °C of stirring reactions 2.5 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product ^- ((1 2^-2- (3,4- difluorophenyl) cyclopropyl)-3- ((3^, 4 6^)-2,2- dimethyl-4,60- dihydros-30 cyclopentano M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine 17e (125 mg, colorless oil), yield： 99%.

MS m/z (ESI): 501.2[M+1]

6th step

(1^2R, 5R)-5- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazols

[4,5-d] pyrimidin-3-yl) amyl- 3- alkene -1, the 2- glycol of ring

By N- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropyl)-3- ((3i^, 4R, 6flR)-2,2- dimethyl-4,6a- dihydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine 17e (120 mg, 0.24 mmol) is dissolved in 14 mL methanol and tetrahydrofuran (V/V=l:1.33) in mixed solution, the M hydrochloric acid of 4 mL of drop power B 2.5, stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add water (15 mL), be added dropwise saturation sodium hydroxide solution to reaction solution ρ Η be 6, extracted with ethyl acetate (15 mL X 3), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product (1^2R, 5R) -5- (7- ((lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) the amyl- 3- alkene -1 of ring, (30 mg of 2- glycol 17, white solid), yield： 27.3%.

MS m/z (ESI): 461.3[M+1]

1H NMR (400 MHz, DMSO-J₆) δ 9.26 (d, 1H), 7.17-7.26 (m, 2H), 6.95-6.97 (m, 1H), 6.06-6.08 (m, 1H), 5.87-5.89 (m, 1H), 5.53-5.54 (m, 1H), 5.06 (d, 1H), 4.90 (d, 1H), 4.45-4.47 (_m, 1H), 4.32-4.36 (m, 1H), 3.03-3.06 (m, 1H), 2.70-2.85 (m, 2H), 2.00-2.04 (m, 1H), 1.35-1.50 (m, 3H), 1.20-1.30 (m, 1H), 0.7 l (t, 3H) embodiment 18

(1S, 23 5R)-3- (2,2- difluoroethoxies)-5- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene-1,2- glycol

18

The first step

(3,4R, 6 6flR)-2,2- dimethyl-6- (2- oxoethoxies)-4,5,6,6 beta-tetrahydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl-benzyq carbamate

By (3,4R, 6 6flR)-6- (2- hydroxyl-oxethyls)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3oH- cyclopenta M [l, 3] Dioxol-4 -yl-benzyq carbamate 5d (2 g, 5.69 mmol) be dissolved in 20 mL dichloromethane, 0 °C of addition Dai Si-Martin oxidant C2.90 g, 6.83 mmol), reaction 12 hours is stirred at room temperature in 0 °C of stirring reaction 5 minutes, liter.Dichloromethane (50 mL) is sequentially added into reaction solution, saturated sodium bicarbonate (20 mL), saturated sodium thiosulfate solution (20 mL), divide liquid, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (3, 4R, 6 6flR) -2, 2- dimethyl -6- (2- oxoethoxies) -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentanos [l, 3] Dioxol-4 -yl-benzyq carbamate 18a (1.46 g, yellow oil), product is not purified directly to carry out next step reaction.

Second step

(3,4R, 6 6flR)-6- (2,2- difluoroethoxy)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls-benzyq carbamate

Will（3,4R, 6 6flR)-2,2- dimethyl-6- (2- oxoethoxies)-4,5,6,6a- tetrahydrochysene-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl-benzyq carbamate 18aC1.46 g, 4.18 mmol) it is dissolved in 15 mL dichloromethane, diethylin sulfur trifluoride (1.01 g, 6.27 mmol) is added, reaction 1.5 hours is stirred at room temperature.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3,4R, 6 6flR)-6- (2,2- difluoroethoxy)-2,2- dimethyl-4,5, the mg of 6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl-benzyq carbamate 18 925, pale yellow oil), yield： 59.7%. MS m/z (ESI): 372.45 [M+l]

3rd step

(3,4R, 6 6flR) -6- (2,2- difluoroethoxy) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- amine

By (3,4R, 6 6flR)-6- (2,2- difluoroethoxies)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3oH- cyclopentano M [l, 3] Dioxol-4 -yl-benzyq carbamate 18bC925 mg, 2.50 mmol) it is dissolved in 20 mL methanol, add 10% Pd/C (100 mg), hydrogen is replaced three times, stirring reaction 3 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3,4R, 6 6flR) -6- (2,2- difluoroethoxy) -2,2- dimethyl -4,5,6,6 β-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- amine 18cC565 mg, colorless oil), yield： 95.3%.

MS m/z (ESI): 238.2[M+1]

4th step

The chloro- A^- Pfl^lR^ 6flR of 6-) -6- (2,2- difluoroethoxy) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos

M [l, 3] Dioxol-4 -yl)-2- (rosickyite base) pyrimidine-4, 5- diamines incites somebody to action (3, 4R, 6 6flR) -6- (2, 2- difluoroethoxies) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3oH- cyclopentanos [l, 3] dioxole -4- amine 18c (365 mg, 1.54 mmol) it is dissolved in ethylene glycol, sequentially add 4, chloro- 2- propyl group sulfanyl-pyrimidine -5- amine Is (550 mg of 6- bis-, 2.31 mmol) and triethylamine (778 mg, 7.69 mmol), 100 °C of stirring reactions 12 hours.Water (50 mL) and ethyl acetate (50 mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (25 mL X 2), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain the chloro- ^- of title product 6- { aSARfiS R H^- difluoroethoxies）- 2,2- dimethyl-4,5,6,6 beta-tetrahydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yls)-2- (；Rosickyite base) pyrimidine -4,5- diamines 18d (250 mg, dark red oil yield： 37.6%.

MS m/z (ESI): 439.1 [M+l]

5th step

The chloro- 3- of 7- ((3,4R, 6 6flR) -6- (2,2- difluoroethoxy) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos

M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidines are by the chloro- N of 6-⁴- ((3,4R, 6 6flR)-6- (2,2- difluoroethoxy)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls)-2- (；Rosickyite base) pyrimidine -4,5- diamines 18d (250 mg, 0.57 mmol) is dissolved in I mL acetic acid, sequentially adds 0.4 mL water, natrium nitrosum (42 mg, 0.60 mmol), stirring reaction 20 minutes.Ethyl acetate (10 mL) is added into reaction solution, unsaturated carbonate potassium solution (45 mL) is added dropwise, divide liquid, aqueous phase is extracted with ethyl acetate (45 mL X 2), merge organic phase, unsaturated carbonate potassium solution (45 mL) is used successively, saturated nacl aqueous solution (45 mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain chloro- the 3- ((3o5 of title product 7-, 4R, 65, 6oR) -6- (2, 2- difluoroethoxies) -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3oH- cyclopentano M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1, 2, 3] triazol [4, 5-d] pyrimidine 18e (128 mg, it is light Yellow oil), yield： 50.0%.

MS m/z (ESI): 450.1 [M+1]

6th step

3- ((3,4R, 6 6flR)-6- (2,2- difluoroethoxies)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls)-N- ((lR, 2^-2- (3,4- difluorophenyls) cyclopropane base)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine

By the chloro- 3- of 7- ((3,4R, 6 6flR)-6- (2,2- difluoroethoxies)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine 18e (128 mg, 0.29 mmol) is dissolved in 15 mL tetrahydrofurans, adds（LR, 2-2- (3,4- difluorophenyl) cyclopropylamine hydrochloride l li (79 mg, 0.38 mmol), are added dropwise triethylamine (101 mg, 1 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 3- ((3,4R, 6 6flR)-6- (2,2- difluoroethoxies)-2,2- dimethyl-4,5,6,6a- tetrahydrochysene-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl）- N- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropane base）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidine -7- amine 18f (108 mg, colorless oil), yield： 65.0%. MS m/z (ESI): 583.2[M+1]

7th step

(1S, 23 5R)-3- (2,2- difluoroethoxies)-5- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene-1,2- glycol is by 3- ((3,4R, 6 6flR)-6- (2,2- difluoroethoxy)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] dioxolane-4- bases)-N- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropane base) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidine -7- amine 18f (108 mg, 0.19 mmol) it is dissolved in 3.2 mL methanol, the M hydrochloric acid of 2.2 mL 2.5, stirring reaction 12 hours is added dropwise.To reaction solution be added dropwise 4 M sodium hydroxide solutions to reaction solution ρ Η be 8, extracted with ethyl acetate (25 mL X 3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product (1S, 23 5R) -3- (2, 2- difluoroethoxies) -5- (7- ((lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5 pyrimidin-3-yls) pentamethylene -1, (99 mg of 2- glycol 18, pale white solid), yield： 99.0%

MS m/z (ESI): 543.51 [M+1]

1H NMR (400Hz, CDC1₃) δ 7.06-7.17 (m, 1H), 6.96-7.04 (m, 1H), 6.57-6.67 (m, 1H), 5.85 (ddt, 1H), 4.83-4.95 (m, 1H), 4.60-4.65 (m, 1H), 4.26 (d, 1H), 4.02-4.06 (m, 1H), 3.78 (td, 2H), 3.00-3.19 (m, 3H), 2.88-3.00 (m, 1H), 2.50-2.67 (m, lH), 2.10-2.22 (m, 1H), 1.20-1.70 (m, 6H), 0.97 (t, 3H) embodiment 19

(1R, 2R, 3 4R, 5-4- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl 1- (；Methylol) two rings simultaneously [3 Shang 0] hexane -2,3- glycol The first step

(3flR, 3M, 4,5R, 5fl -5- (l, 3- istain -2- bases) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano

[l, 2-d] [l, 3] dioxole -3b- Ethyl formates

By (3flR, 3M, 4, 5 5^) -5- hydroxyls -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19a (370 mg, 1.53 mmol, using known method " Nucleosides, Nucleotides ＆ Nucleic Acids (2008), 27 (3), 279-291 " is prepared) it is dissolved in 20 mL tetrahydrofurans, sequentially add triphenylphosphine (400 mg, 1.53 mmol) and phthalimide (225 mg, 1.53 mmol), 10 mL diisopropyl azodiformate C309 mg are added dropwise, 1.53 mmol) tetrahydrofuran solution, stirring reaction 12 hours.With silica gel column chromatography with solvent system B purification reaction liquid, title product (3aR, 3bS are obtained, 4 S, 5R, 5aS) -5- (, 3- istain -2- bases) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19b (420 mg, micro- pink solid), yield： 74.0%.

Second step

(3^, 3^, 4^, 5 5^) -5- amino -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [1,2- (1] [1,3] dioxole -3b- Ethyl formates

By (3flR, 3M, 4,5R, 5i^) -5- (l, 3- istain -2- bases) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19b (420 mg, 1.11 mmol) it is dissolved in 8 mL ethanol, add 85% a water hydrazine hydrate (653 mg, 11.10 mmol), 70 °C of stirring reactions 2 hours.Reaction solution is cooled to room temperature, filtered, filtrate decompression Nong Shrink, obtain title product (3flR, 3M, 4,5R, 5) -5- amino -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19c (220 mg, white oil thing), yield： 82.0%. 3rd step

(3flR, 3M, 4, 5R, 5i^) -5- (6- chloro- 5- nitros -2- (rosickyite base) pyrimidine -4- amino) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates are by (3flR, 3M, 4i^, 5R, 5i^) -5- amino -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19c (140 mg, 0.58 mmol) it is dissolved in 15 mL ethanol, sequentially add 4, chloro- 5- nitros -2- propyl group mercapto-pyrimidine 6b (170 mg of 6-, 0.64 mmol) and triethylamine (117 mg, 1.16 mmol), it is stirred at room temperature 12 hours.Reaction solution Jian Ya Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product 3oR, 3M 5R, 5fl -5- (the chloro- rosickyite bases of 5- nitros -2 of 6-) pyrimidine -4- amino) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19d (160 mg, brown oil), yield： 58.6%.

4th step

(3flR, 3M, 4, 5R, 5i^) -5- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates are by (3flR, 3M, 4, 5R, 5i^) -5- (6- chloro- 5- nitros -2- (rosickyite base) pyrimidine -4- amino) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19d (200 mg, 0.42 mmol) it is dissolved in 3 mL acetic acid, add iron powder (190 mg, 3.40 mmol), stirring reaction 2 hours.Diatomite is filtered, and saturated sodium bicarbonate (30 mL) is added into filtrate, point liquid, aqueous phase is washed with ethyl acetate (20 mLx2), is merged organic phase, is washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink obtain title product (3flR, 3M, 4,5R, 5) -5- (5- amino -6- chloro- 2- (rosickyite bases）Pyrimidine -4- amino) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19e (300 mg, brown oil), product is not purified directly to carry out next step reaction.

MS m/z (ESI): 441.1 [M+l]

5th step

(3flR, 3M, 4i^, 5R, 5i^) -5- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates are by (3flR, 3M, 4, 5R, 5i^) -5- (the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine -4- amino) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19e (300 mg, 0.42 mmol) it is dissolved in 2 mL acetic acid, add 0.5 mL water, 0 °C of 1 mL natrium nitrosums (30 mg of dropwise addition, 0.44 mmol) the aqueous solution, it is warmed to room temperature stirring reaction 5 minutes.Ethyl acetate (6 mL) is added into reaction solution, saturated sodium carbonate solution (25 mL) is added dropwise, divide liquid, aqueous phase is extracted with ethyl acetate (20 mL X 2), merge organic phase, saturated sodium carbonate solution (25 mL) is used successively, saturated nacl aqueous solution (25 mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (3flR, 3M, 4, 5R, 5i^) -5- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19f (190 mg, dark brown oil), product is not purified directly to carry out next step reaction. MS m/z (ESI): 454.1 [M+1]

6th step (3aR, 3bS, 4 S, 5R, 5aS) -5- (7- ((lR, 2S) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano

[l, 2-d] [l, 3] dioxole -3b- Ethyl formates

Will（3flR, 3M, 4i^, 5R, 5i^) -5- (7- chloro- 5- (rosickyite bases）- 3H- [1,2,3] triazol [4,5-d] pyrimidine -3- bases) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19f (190 mg, 0.42 mmol) is dissolved in 20 mL acetonitriles, is added（1R, 2-2- (3,4- difluorophenyl) cyclopropylamine L- (+)-tartrate lg (181 mg, 0.57 mmol), is added dropwise triethylamine (148 mg, 1.47 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add ethyl acetate (20 mL) and water（20 mL), divide liquid, aqueous phase is extracted with ethyl acetate (20 mL X 2), merge organic phase, Jian Ya Nong Shrink, obtain title product (3flR, 3M, 4i^, 5R, 5i^) -5- (7- ((lR, 2S) -2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19g (215 mg, pale solid), yield： 87.3 %.

MS m/z (ESI): 587.2[M+1]

7th step

((3flR, 3bR, 4i^, 5R, 5i^) -5- (7- ((lR, 2S) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano

[1,2-d] [1,3] dioxole -3b- bases) methanol

Will（3flR, 3M, 4i^, 5R, 5i^) -5- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite bases）- 3H- [l, 2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- Ethyl formates 19g (215 mg, 0.37 mmol) is dissolved in 10 mL tetrahydrofurans, add the tetrahydrofuran solution of the M lithium aluminium hydrides of 1.5 mL 1, stirring reaction 12 hours.Saturation sodium potassium tartrate solution (3 mL), stirring reaction 1 hour are added into reaction solution.Filtering, the dense Shrink of filtrate decompression adds ethyl acetate (25 mL) and water (20 mL), and point liquid, aqueous phase is extracted with ethyl acetate (15 mL X 2), merges organic phase, uses saturated nacl aqueous solution（15 mL) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product ((3flR, 3bR, 4, 5R, 5i^) -5- (7- ((lR, 2^-2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [l, 2, 3] triazol [4, 5 pyrimidin-3-yls) -2, 2- dimethyl-hexahydro ring third simultaneously [3, 4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- bases) methanol 19hC260 mg, light yellow solid), product is not purified directly to carry out next step reaction.

8th step

(1R, 2R, 3 4R, 5-4- (7- ((lR, 2-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl 1- (；Methylol) simultaneously [3 Shang 0] hexane -2,3- glycol will for two rings（(3flR, 3bR, 4i^, 5R, 5i^) -5- (7- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite bases）- 3H- [l, 2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl-hexahydro ring third simultaneously [3,4] cyclopentano [l, 2-d] [l, 3] dioxole -3b- bases）Methanol 19h (260 mg, 0.37 mmol) is dissolved in 15 mL methanol, and 4 mL2.5 M hydrochloric acid, stirring reaction 12 hours are added dropwise.It is 7 that 1 M sodium hydroxide solutions, which are added dropwise, to reaction solution ρ Η to reaction solution, adds ethyl acetate (20 mL) and water (10 mL), point liquid, aqueous phase ethyl acetate (15 mL X 3) extract, merge organic phase, use saturated nacl aqueous solution（15 mL) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, through the isolated title product (1R of HPLC preparative chromatographies, 2R, 3 4R, 5-4- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) two ring simultaneously [3.1.0] hexanes-2 of-1- (methylol), 3- glycol 19 (40 mg, white solid), yield： 22.0%.

MS m/z (ESI): 505.2[M+1]

1H NMR (400 MHz, CDC1₃) 7.39 (br of δ, 1H), 7.15-7.02 (m, 2H), 6.94 (d, 1H), 5.24 (s, 1H), 5.14 (d, 1H), 4.16 (d, 2H), 3.79-3.74 (m, 1H), 3.54-3.51 (d, 1H), 3.14-3.13 (m, 1H) 3.10-3.00 (m, 1H), 2.91-2.80 (m, 1H), 2.20-2.12 (m, 1H), 1.70-1.65 (m, 1H), 1.60-1.55 (m, 2H), 1.50-1.45 (m, 1H), 1.40-1.30 (m, 1H), 1.30-1.26 (t, 1H), 0.88 (m, 3H), 0.85-0.80 (m, 1H) embodiments 20

(1 2 3R, 5-3- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d]-3- bases)-5- fluorine pentamethylene-1,2- glycol

20g

The first step

((3,4R, 6i^) -2,2- dimethyl -6- oxos -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos Μ [1,3] dioxole

- 4- bases) benzyl formate By ((3,4R, 6 6flR)-6- hydroxyls-2,2- dimethyl-4,5,6,6 α-tetrahydrochysene-3oH- cyclopentas Μ [1,3] Dioxol-4 -yl) benzyq carbamate 5b (5 g, 16.3 mmol) it is dissolved in 150 mL dichloromethane, 4A molecular sieves (5 g) are added, pyridinium chloro-chromate (10.50 g are slowly added to, 48.80 mmol), stirring reaction 60 hours.Filtering, filtrate decompression Nong Shrink, obtain title product CO 4R, 6)-2,2- dimethyl-6- oxos-4,5,6,6 α-tetrahydrochysene-3oH- cyclopentanos [d] [l, 3] Dioxol-4 -yl) benzyl formate 20a (3.10 g, grey grease), yield： 62.0%

Second step

((3i^, 4R, 6R, 6flR)-6- hydroxyl-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentas M [l, 3] Dioxol-4 -yls) benzyq carbamate

By ((3i^, 4R, 6)-2,2- dimethyl-6- oxos-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls) benzyl formate 20a (l g, 3.30 mmol) it is dissolved in 30 mL tetrahydrofurans,-78 °C add sodium borohydride C495 mg, 13.10 mmol) ,-78 °C of stirring reactions 1 hour.With silica gel column chromatography with solvent system B purification reaction liquid, obtain title product ((3,4R, 6R, 6flR)-6- hydroxyls-2,2- dimethyl-4,5,6,6 α-tetrahydrochysene-3oH- cyclopenta M [l, 3] Dioxol-4 -yl) benzyq carbamate 20b (510 mg, white solid), yield： 51.0%.

3rd step

(3aR, 4R, 6R, 6i^-6- amino -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole

- 4- alcohol

By ((3i^, 4R, 6R, 6flR)-6- hydroxyls-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopenta M [l, 3] Dioxol-4 -yl) benzyq carbamate 20b (800 mg, 2.60 mmol) is dissolved in 50 mL methanol, adds 10% Pd/C (80 mg), hydrogen is replaced three times, stirring reaction 12 hours.Filtering, filtrate decompression Nong Shrink obtain title product (3aR, 4R, 6R, 6fl^-6- amino -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- alcohol 20cC410 mg, orange solids), yield： 91.0%.

4th step

(3flR, 4R, 6R, 6) -6- ((the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine-4-yl) amino) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentanos [l, 3] dioxole -4- alcohol is by (3flR, 4R, 6R, 6i^) -6- amino -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 20c (410 mg, 2.36 mmol) it is dissolved in 30 mL N, in dinethylformamide, sequentially add 4, chloro- 2- propyl group sulfanyl-pyrimidine -5- amine Is (676 mg of 6- bis-, 2.84 mmol) and N, N- diisopropylethylamine (915 mg, 7.08 mmol), 100 °C of stirring reactions 12 hours.It is cooled to room temperature, water (60 mL) and ethyl acetate (60 mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (60 mL X 3), merge organic phase, washed successively with water (50 mL) and saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product (3flR, 4R, 6R, 6) -6- ((the chloro- 2- of 5- amino -6- (rosickyite base) pyrimidine-4-yl) amino) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 20d (390 mg, orange solids yield： 44.0%. MS m/z (ESI): 375.1 [M+l] 5th step

(3oR, 4R, 6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl

- 4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole -4- alcohol are by (3flR, 4R, 6R, 6) -6- ((5- amino -6- chloro- 2- (rosickyite bases）Pyrimidine-4-yl）Amino) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos [] [1,3] dioxole -4- alcohol 20 390 mg, 1.04 mmol) it is dissolved in 10 mL acetic acid and water (V/V=l:L) in mixed solution, it is added dropwise 1 mL natrium nitrosums (79 mg, 1.15 mmol) ice water solution under ice-water bath, 0 °C of stirring reaction 30 minutes.Ethyl acetate (20 mL) and water (20 mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (30 mL X 3), merge organic phase, washed successively with saturated sodium bicarbonate solution (30 mL X 2) and saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product (3flR, 4R, 6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6 beta-tetrahydro -3flH- cyclopentano M [l, 3] dioxole -4- alcohol 20e (340 mg, orange solids), yield： 86.0%.

MS m/z (ESI): 386.2[M+1]

6th step

(3flR, 4R, 6R, 6i^) -6- (7- ((lR, 2S) -2- (3,4- difluorophenyl) cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 α-tetrahydrochysene -3oH- cyclopentanos M [l, 3] dioxole

- 4- alcohol

By (3flR, 4R, 6R, 6i^) -6- (the chloro- 5- of 7- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5- pyrimidin-3-yls) -2, 2- dimethyl -4, 5, 6, 6 α-tetrahydrochysene -3oH- cyclopentano M [l, 3] dioxole -4- alcohol 20e (340 mg, 0.88 mmol) it is dissolved in 30 mL acetonitriles, sequentially add (lR, 2-2- (3, 4- difluorophenyls) cyclopropylamine hydrochloride l li (235 mg, 1.15 mmol) and triethylamine (311 mg, 3.10 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, add ethyl acetate (60 mL) and water (60 mL), point liquid, aqueous phase is extracted with ethyl acetate (20 mL X 2), is merged organic phase, is washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, obtain title product OR, 4R, 6R, 6fl-6- (7- (1 W, 2-2- (3,4- difluorophenyls）Cyclopropylamino) -5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol 20f (480 mg, brown solid), product is not purified directly to carry out next step reaction. MS m/z (ESI): 519.4[M+1]

7th step

Trifluoromethanesulfonic acid ((3i^, 4R, 6R, 6)-6- (7- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yls) ester

Will（3flR, 4R, 6R, 6)-6- (7- ((lR, 2-2- (3,4- difluorophenyls）Cyclopropylamino）- 5- (rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl -4,5,6,6 beta-tetrahydro -3flH- cyclopentanos M [l, 3] dioxole -4- alcohol 20f (320 mg, 0.62 mmol) it is dissolved in 20 mL dichloromethane, -78 °C of addition pyridines（198 mg, 2.48 mmol), trifluoromethanesulfanhydride anhydride (350 mg, 1.24 mmol) is added dropwise, stirring reaction is warmed to room temperature 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, Obtain title product trifluoromethanesulfonic acid ((3 o5,4R, 6R, 6o5)-6- (7- ((lR, 25)-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5- pyrimidin-3-yls)-2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl) ester 20gC320 mg, colorless oil yield： 79.0%.

8th step

N- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropyl)-3- ((3,4R, 6 6^) fluoro- 2, the 2- dimethyl-4,5 of-6-, 6,6 beta-tetrahydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yls)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine

- 7- amine

By trifluoromethanesulfonic acid ((3i^, 4R, 6R, 6) -6- (7- ((lR, 2-2- (3, 4- difluorophenyls) cyclopropylamino) -5- (rosickyite base) -3H- [l, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl -4, 5, 6, 6 α-the α of tetrahydrochysene -3 Η-cyclopentano M [l, 3] Dioxol-4 -yl) ester 20gC320 mg, 0.49 mmol) it is dissolved in 20 mL tetrahydrofurans,-40 °C of three (dimethylamino) sulfonium difluoro (trimethyl) silicate (165 mg of addition, 0.60 mmol, ),-40 °C of stirring reactions 1.5 hours, rise and reaction 12 hours is stirred at room temperature.Reaction solution Jian Ya Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product N- ((1R, 2-2- (3,4- difluorophenyls）Cyclopropyl)-3- ((3,4R, 6 6^)-6- fluoro- 2,2- dimethyl-4,5,6,6 beta-tetrahydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine 20h (190 mg, white solid), yield： 44.7%.

MS m/z (ESI): 521.3[M+1]

9th step

(1 2 3R, 5-3- (7- ((lR, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-5- fluorine pentamethylene-1,2- glycol

By N- ((lR, 2^-2- (3,4- difluorophenyls）Cyclopropyl）- 3- ((3,4R, 6 6^)-6- fluoro- 2,2- dimethyl-4,5,6,6 α-tetrahydrochysene-3oH- cyclopentano M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine 20h (190 mg, 0.37 mmol) it is dissolved in 5 mL methanol, add the M hydrochloric acid of 10 mL 2,40 °C of stirring reactions 30 minutes.Reaction solution Jian Ya Nong Shrink, through the separating obtained residue of HPLC preparative chromatographies, title product (1 2 3R, 5-3- (7- ((lR are obtained, 2-2- (3,4- difluorophenyls) cyclopropylamino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5 pyrimidin-3-yls)-5- fluorine pentamethylene-1,2- glycol 20 (70 mg, white solid), yield： 40.0%.

MS m/z (ESI): 481.2[M+1]

1H NMR(400 MHz, CDC1₃) δ 7.05-7.15 (m, 2H), 6.92-7.02 (m, 1H), 5.12-5.18 (m, 0.5H), 5.08-4.95 (m, 1.5H), 4.72-4.82 (m, 1H), 4.38- 4.45 (m, 1H), 3.14-3.20 (m, 2H), 3.04-3.01 (m, 1H), 2.94-2.9 l (m, 1H), 2.10-2.20 (m, 1H), 1.60-1.70 (m, 3H), 1.30-1.47 (m, 2H), 1.20-1.30 (m, 1H), 0.95 (t, 3H) embodiments 21

(1^2R, 5R)-5- (7- (((lR, 2-2- (3,4- difluorophenyls) cyclopropyl) amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-3- (2- hydroxyethyls)-3- cyclopentene-1,2- glycol

The first step

2- ((3aS, 4R, 6aR)-6- (2- ((tertiary butyl dimethyl Si base) ethyl)-2,2- dimethyl-4,6 β-dihydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl) iso-indoles-1,3- diketone is by (3aS, 4S, 6aR)-6- (2- ((tertiary butyl dimethyl Si bases）Ethyl) -2, 2- dimethyl -4, 6a- dihydro -3flH- cyclopentanos W] [l, 3] dioxole -4- alcohol 21a (240 mg, 0.76 mmol, " the Journal of Medicinal Chemistry using known method, 2005 (48), 5043-5046 " is prepared) it is dissolved in 10 mL tetrahydrofurans, sequentially add BIDA (168 mg, 1.14 mmol) triphenylphosphine (300 mg, 1.14 mmol) and diisopropyl azodiformate (231 mg, 1.14 mmol), stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 2- ((3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6 α-dihydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl) iso-indoles-1,3- diketone 21M210 mg, pale yellow oil), yield： 61.9%.

MS m/z (ESI):444.4[M+1]

Second step

(3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si base) ethyl) -2,2- dimethyl -4,6 α-dihydro -3flH- cyclopentanos

M [l, 3] dioxole -4- amine

By 2- ((3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3oH- cyclopentano M [l, 3] Dioxol-4 -yl) iso-indoles-1,3- diketone 21b (210 mg, 0.47 mmol) is dissolved in 5 mL ethanol, adds hydrazine hydrate (118 mg, 2.37 mmol), 70 °C of stirring reactions 3 hours.Instead Liquid is answered to filter, filtrate decompression Nong Shrink, obtain title product (3a^, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si base) ethyl) -2,2- dimethyl -4,6a- dihydro -3flH- cyclopentano M [l, 3] dioxole -4- amine 21c (142 mg, yellow oil), yield： 95.9%.

MS m/z (ESI):314.1 [M+l]

3rd step

A^- Pa^lR^aR-P- ((tertiary butyl dimethyl Si base) ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl) the chloro- 2- of-6- (rosickyite base) pyrimidine-4,5- diamines is by (3aS, 4R, 6aR)-6- (2- ((tertiary butyl dimethyl Si bases）Ethyl) -2,2- dimethyl -4,6a- dihydro -3flH- cyclopentanos W] [l, 3] dioxole -4- amine 21c (140 mg, 0.45 mmol) it is dissolved in 5 mL N, in dinethylformamide, 4,6- bis- chloro- 2- (rosickyite base) pyrimidine -5- amine lv (159 mg are sequentially added, 0.67 mmol) and N, N- diisopropylethylamine (173 mg, 1.34 mmol), 100 °C of stirring reactions 12 hours.It is cooled to room temperature, saturated ammonium chloride solution (40 mL) is added into reaction solution, extracted with ethyl acetate (20 mL X 3), merge organic phase, washed with saturated nacl aqueous solution (40 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product A^- Pa^lR^aR-P- ((tertiary butyl dimethyl Si base) ethyl) -2, 2- dimethyl -4, 6a- dihydro -3oH- cyclopentano M [l, 3] Dioxol-4 -yl) the chloro- 2- of-6- (；Rosickyite base) pyrimidine -4,5- diamines 21d (93 mg, red brown solid), yield： 40.4%.

MS m/z (ESI): 513.4[M+1]

4th step

3- ((3aS, 4R, 6aR)-6- (2- ((tertiary butyl dimethyl Si base) ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine is by A^- Pa^lR^aR-P- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl) the chloro- 2- of-6- (；Rosickyite base) pyrimidine -4,5- diamines 21d (85 mg, 0.17 mmol) is dissolved in 3.3 mL acetic acid and water (V/V=10:L) in mixed solution, natrium nitrosum (12 mg, 0.17 mmol), ice-water bath stirring reaction 30 minutes are added under ice-water bath.Water (40 mL) is added into reaction solution, extracted with ethyl acetate (15 mLx3), merge organic phase, washed, anhydrous sodium sulfate drying, filtered with saturated sodium bicarbonate solution (40 mL) and saturated nacl aqueous solution (40 mL) successively, filtrate decompression Nong Shrink, obtain title product 3- ((3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidine-7- amine 21e (70 mg, colorless oil), yield： 80.5%.

5th step

3- ((3aS, 4R, 6aR)-6- (2- ((tertiary butyl dimethyl Si base) ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl)-N- ((lR, 2-2- (3,4- difluorophenyl) cyclopropyl)-5- (rosickyite

Base) -3 Η-[1,2,3] triazol [4,5-d] pyrimidine -7- amine

By 3- ((3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl)-5- (rosickyite base)-3 Η-[1,2,3] triazol [4,5-d] pyrimidine - 7- amine 21e (65 mg, 0.12 mmol) it is dissolved in 5 mL acetonitriles, sequentially add (lR, 2-2- (3,4- difluorophenyls) cyclopropylamine hydrochloride l li (33 mg, 0.16 mmol) and triethylamine (37 mg, 0.37 mmol), stirring reaction 6 hours.Reaction solution Jian Ya Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product 3- ((3aS, 4R, 6aR) -6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentano M [l, 3] Dioxol-4 -yl)-N- ((lR, 2^-2- (3,4- difluorophenyl) cyclopropyl)-5- (rosickyite base)-3 Η-[1,2,3] triazol [4,5-d] pyrimidine-7- amine 21f (60 mg, colorless oil).

6th step

(1^2R, 5R)-5- (7- (((lR, 2-2- (3,4- difluorophenyls) cyclopropyl) amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-3- (2- hydroxyethyls)-3- cyclopentene-1,2- glycol is by 3- ((3aS, 4R, 6aR)-6- (2- ((tertiary butyl dimethyl Si bases）Ethyl)-2,2- dimethyl-4,6a- dihydro-3flH- cyclopentanos M [l, 3] Dioxol-4 -yl)-N- ((lR, 2^-2- (3,4- difluorophenyls) cyclopropyl)-5- (rosickyite base)-3 Η-[1,2,3] triazol [4,5-d] pyrimidine-7- amine 21f (55 mg, 0.08 mmol) it is dissolved in 5 mL methanol, add the M hydrochloric acid of 0.5 mL 3, stirring reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with thin-layered chromatography with solvent system B purify gained residue, obtain title product (1 2R, 5R)-5- (7- GW, 2-2- 3,4- difluorophenyls) cyclopropyl) amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-3- (2- hydroxyethyls)-3- cyclopentene-1,2- glycol 21 (25 mg, colorless oil), yield： 40.0%.

MS m/z (ESI): 505.2[M+1]

1H NMR (400 MHz, CDC1₃) 6.91-7.13 (m of δ, 3H), 6.08 (s, 1H), 5.69 (s, 1H), 4.74 (d, 1H), 4.57 (t, 1H), 4.02-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.18-3.08 (m, 1H), 3.08-2.98 (m, 1H), 2.98-2.87 (m, 1H), 2.71-2.61 (m, 1H), 2.57-2.44 (m, 1H), 2.19-2.09 (m, 1H), 1.71-1.56 (m, 2H), 1.46-1.25 (m, 2H), 0.93 (t, 3H) embodiments 22

(1 2 3R, 5-3- (7- (((lR, 2-2- (3,4- difluorophenyls) cyclopropyl) amino)-5- ((rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-5- (2- (2- hydroxyl-oxethyls) ethyoxyl) pentamethylene-1,2- glycol

Step

The first step

2- (2- (((3aR, 4S, 6R, 6a-6- (7- (((lR, 2-2- (3,4- difluorophenyls) cyclopropyl) amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-2,2- dimethyl tetrahydro-3oH- cyclopentanos M [l, 3] dioxole-4- yls) epoxide) ethyoxyl) ethyl acetate

By 2- (((3aR, 4 6R, 6a-6- (7- (((lR, 2-2- (3,4- difluorophenyls）Cyclopropyl）Amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-2,2- dimethyl tetrahydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl）Epoxide）Ethanol 22a (562 mg, 1 mmol are prepared using known process patent " WO2011017108 ") is dissolved in 10 mL tetrahydrofurans, is cooled to 0 °C, adds potassium tert-butoxide（180 mg, 1.60 mmol), the tetrahydrofuran solution of 2 mL bromoacetates (200 mg, 1.20 mmol), stirring reaction 2 hours is added dropwise in stirring reaction 15 minutes.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system B purify gained residue, obtain title product 2- (2- (;(3aR, ^6R, 6a -6- (;7-( (;IW, 2-2- (;3,4- difluorophenyls) cyclopropyl) amino)-5- (rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-2,2- dimethyl tetrahydro-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl) epoxide) ethyoxyl) ethyl acetate 22b (60 mg, pale yellow oil), yield： 9.2%.

MS m/z (ESI):649.3[M+1]

Second step

2- (2- (((3aR, 4S, 6R, 6a-6- (7- (((lR, 2-2- (3,4- difluorophenyls) cyclopropyl) amino)-5- ((rosickyite base)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl)-2,2- dimethyl tetrahydro-3oH- cyclopentanos M [l, 3] dioxole-4- yls) epoxide) ethyoxyl) ethanol

By 2- (2- (((3aR, 4S, 6R, 6a -6- (7- (((lR, 2-2- (3, 4- difluorophenyls) cyclopropyl) amino) -5- (rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl tetrahydro -3oH- cyclopentano M [l, 3] dioxole -4- yls) epoxide) ethyoxyl) ethyl acetate 22b (60 mg, 0.09 mmol) it is dissolved in 2 mL tetrahydrofurans, add lithium borohydride (11 mg, 0.50 mmol), stirring reaction 0.5 hour.To reaction solution add 1 mL water, filtering, filtrate decompression Nong Shrink, obtain title product 2- (2- (;(3aR, ^6R, 6a -6- (;7-( (;IW, 2-2- (;3,4- difluorophenyls) cyclopropyl) amino) -5- ((rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -2,2- dimethyl Tetrahydrochysene-3oH- cyclopentanos M [l, 3] Dioxol-4 -yl) epoxide) ethyoxyl) ethanol 22c (54 mg, colorless oil), yield： 99%.

MS m/z (ESI): 607.3[M+1]

3rd step

(1 2 3R, 5-3- (7- (((lR, 2-2- (3, 4- difluorophenyls) cyclopropyl) amino) -5- ((rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -5- (2- (2- hydroxyl-oxethyls) ethyoxyl) pentamethylene -1, 2- glycol is by 2- (2- (((3aR, 4S, 6R, 6a -6- (7- (((lR, 2-2- (3, 4- difluorophenyls) cyclopropyl) amino) -5- ((rosickyite base) -3H- [1, 2, 3] triazol [4, 5-d] pyrimidin-3-yl) -2, 2- dimethyl tetrahydro -3oH- cyclopentano M [l, 3] dioxole -4- yls) epoxide) ethyoxyl) ethanol 22c (50 mg, 0.08 mmol) it is dissolved in 1.5 mL tetrahydrofurans, the M hydrochloric acid of 1 mL 2.5 is added dropwise, stirring reaction 12 hours.To reaction solution be added dropwise 4 M saturated sodium carbonate solutions to reaction solution ρ Η be 7, extracted with ethyl acetate (30 mL X 3), merge organic phase, saturated nacl aqueous solution (20 mL X 2) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, gained residue is prepared with HPLC, title product is obtained（1 S, 2S, 3R, 5S) -3- (7- (((lR, 2S) -2- (3,4- difluorophenyls）Cyclopropyl）Amino) -5- ((rosickyite base) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) -5- (2- (2- hydroxyl-oxethyls) ethyoxyl) pentamethylene -1, (20 mg of 2- glycol 22, white solid), yield： 13.5%.

MS m/z (ESI): 567.5[M+1]

1H NMR (400 MHz, CD₃OD) δ 7.17-7.22 (m, 2H), 7.10 (s, 1H), 5.13-5.20 (m, 1H), 4.82-4.85 (m, 1H), 4.30-4.34 (m, 1H), 4.14-4.16 (m, 1H), 4.03-4.05 (m, 1H), 3.81-3.83 (m, 2H), 3.58-3.60 (m, 2H), 3.51-3.54 (m, 2H), 3.09-3.20 (m, 2H), 2.76-2.84 (m, 1H), 2.23-2.28 (m, 1H), 2.10-2.2 l (m, 1H), 1.80-1.25 (m, 6H), 1.01 (m, 3H) embodiment 23

(1S, 2R, 3 4R) -4- (5- ((Cvclopropvlmethvls）Sulfenyl)-7- (((lR, 2-2- (3,4- difluorophenyl) cyclopropyl) amino)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene-1,2,3- triols

3rd step

The first step

(1 2R, 3 4R) -4- Aminocyclopentanes -1, 2, the alcohol hydrochlorides of 3- tri- are by (3aR, 4S, 6R, 6a -6- amino -2, 2- dimethyl -4, 5, 6, 6a- tetrahydrochysene -3flH- cyclopenta M [l, 3] dioxole -4- alcohol L- (-)-dibenzoyl tartaric acid salt 5a (6.10 g, 11.50 mmol) add in 10 mL methanol, add the M hydrochloric acid of 20 mL 12, 40 °C of stirring reactions 12 hours, filtering, filtrate decompression Nong Shrink, obtain title product (1S, 2R, 3 4R) -4- Aminocyclopentanes -1, 2, alcohol hydrochloride 23a (1.53 g of 3- tri-, yellow oil), yield： 100%.

MS m/z (ESI): 134.2 [M+l]

Second step

(1 2R, 3^4R) -4- ((the chloro- 2- of 5- amino -6- ((Cvclopropvlmethvl) sulfenyl) pyrimidine-4-yl) amino) pentamethylene -1,2,3- triols

By (1 2R, 3 4R) -4- amino-cyclopropanes -1,2,3- triols 23a (1.53 g, 11.50 mmol) it is dissolved in 15 mL N, in dinethylformamide, 4,6- bis- chloro- 2- (Cvclopropvlmethvl sulfenyl) pyrimidine -5- amine 2p (3.45 g are sequentially added, 13.80 mmol) and N, N- diisopropylethylamine (10.40 g, 80.50 mmol), 100 °C of stirring reactions 12 hours.It is cooled to room temperature, reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system A purify gained residue, obtain title product (1 2R, 3 4R) -4- ((the chloro- 2- of 5- amino -6- ((Cvclopropvlmethvl) sulfenyl) pyrimidine-4-yls）Amino) pentamethylene -1,2,3- triols 23b (3.01 g, yellow oil), yield： 77.2%.

MS m/z (ESI): 345.1 [M-l]

3rd step

(1^2R, 3S, 4R) -4- (the chloro- 5- of 7- ((Cvclopropvlmethvl) sulfenyl) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene -1,2,3- triols

By (1 2R, 3 4R) -4- ((the chloro- 2- of 5- amino -6- ((Cvclopropvlmethvl) sulfenyl) pyrimidine-4-yl) amino) pentamethylene -1,2,3- triols 23b (3.01 g, 8.68 mmol) is dissolved in 30 mL acetic acid and water (V/V=2:L) in mixed solution, natrium nitrosum (898 mg, 13.02 mmol), 0 °C of stirring reaction 35 minutes are added under ice-water bath.80 mL unsaturated carbonates potassium solutions are added dropwise to reaction solution ρ Η 8, is extracted with ethyl acetate (30 mL X 4), merges organic phase, washed, anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution (40 mL X 2), filtrate decompression Nong Shrink, obtain title Product (1^2R, 3S, 4R) -4- (the chloro- 5- of 7- ((Cvclopropvlmethvl) sulfenyl) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene -1,2,3- triols 23c (2.20 g, yellow solid), yield： 70.8%.

MS m/z (ESI): 356.1 [M-1]

4th step

(1 2R, 3 4R) -4- (5- ((Cvclopropvlmethvl) sulfenyl) -7- (((lR, 2^-2- (3,4- difluorophenyls) cyclopropyl) amino) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene -1,2,3- triols will（1^2R, 3^4R) -4- (chloro- the 5- ((Cvclopropvlmethvls of 7-）Sulfenyl)-3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene-1,2,3- triols 23c (2.20 g, 6.15 mmol) it is dissolved in 25 mL acetonitriles, GR, 2-2-C3,4- difluorophenyls are sequentially added under ice-water bath) cyclopropylamine hydrochloride l li (2.23 g, 9.22 mmol) and N, N- diisopropylethylamine (3.18 g, 24.60 mmol), is stirred at room temperature reaction 12 hours.Reaction solution Jian Ya Nong Shrink, with silica gel column chromatography with solvent system A purify gained residue, obtain title product (1 23 4-4- (5- ((Cvclopropvlmethvls）Sulfenyl) -7- (((lR, 2^-2- (3,4- difluorophenyls) cyclopropyl) amino) -3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl) pentamethylene -1,2,3- triols 23 (1.24 g, white solid), yield 41.3%.

MS m/z (ESI): 491.2[M+1]

1H NMR (400 MHz, CD₃OD) δ 7.13-7.20 (m, 2H), 7.04 (s, 1H), 5.13 (m, 1H), 4.79 (m, 1H), 4.15 (m, 1H), 4.03 (m, 1H), 3.31 (m, 1H), 3.13 (m, 1H), 2.80 (m, 2H), 2.13 (m, 2H)_:(d, 2H) the test cases of 1.49 (m, 1H), 1.35 (m, 3H), 1.03 (m, 1H), 0.46 (d, 2H), 0.12：

Biological assessment

Test case 1

Following methods are used for determining inhibitory action of the compounds of this invention to ADP induced rats and human platelet aggregation.

Experimental method is summarized as follows：

Through abdominal aortic blood after rat anesthesia, after whole blood is centrifuged 10 minutes with 200 g rotating speeds（22 °C) take out upper strata platelet rich plasma (PRP).PRP buffered liquid (Tai Shi cushioning liquid again）（NaCl 129 mM、 KCl 2.8 mM、 KH₂P0₄ 0.8 mM、 MgCl₂ 0.8 mM、 NaHC0₃8.9 10 mM of mM, HEPEs, the mM of glucose 5.5) suspend again after washing, obtain rich platelet buffer solution.Hematoblastic PAR is detected with 96 well plate method ELIASAs：188 rich platelet buffer solution, the 4 μ L CaCl prepared are added per hole₂, 2 be dissolved in DMSO compound or 2 DMSO (；Blank control), 37 degree are incubated 2 minutes, after 0 minute absorbance of detection, add 10 μ LA P (the μ Μ of final concentration 20), and concussion detects Τ after 23 minutes₅OD during minute₄₅₀" numerical value.

The platelet aggregation rate of ADP inductions is represented with Aggregation% (aggegation rate %)：

Aggregation %=(A_To-A_T5)/A_TO* 100 %。

T0, Α are designated as to add ADP time point_τ.Represent OD during TO₄₅。_nmReading, A_T5Represent OD when addition ADP is induced 5 minutes_{45Q nm}Reading.

The inhibitory action of compounds on platelet aggegation is expressed as：Inhibiting rate (%)=100 %- aggegation rates % The ic of compound_5QValue can be calculated by the inhibiting rate under each concentration.

ADP induction human platelet aggregation inhibitory action experimental method with it is upper identical, human blood platelets is derived from the venous blood of healthy volunteer.

The IC of test-compound_5QValue is as shown in table 1 below：

Inhibitory action of the compounds of this invention of table 1 to ADP induced rats and human platelet aggregation.

Conclusion：Test compound of the present invention is obvious to having for ADP induced rats and human platelet aggregation:Auxiliary acts on test case 2

Following methods are used for determining the compounds of this invention and P2Y12 acceptor combinations.

Experimental method is summarized as follows：

The Retroviral Transfer method construction expression P2Y12 commonly used with those skilled in the art CHO-K1 cell lines（CH0-K1/P2Y12).CHO-Kl is purchased from the American Type Culture Collection committee of Chinese Academy of Sciences cell bank, Cat. GNHa 7.P2Y12 is purchased from origene, Cat. SC319680.

The CHO-K1/P2Y12 cell cell scrapers of structure are collected and are resuspended in homogenate buffer (10 mM Hepes, lO mM NaCK ImM EDTApH 7.4), and are incubated 15 minutes on ice.Cell is placed in and is homogenized on ice 3 times, 10 seconds every time, is spaced 10 seconds.By homogenate in 4 °C, 2000 g are centrifuged 15 minutes；Supernatant is collected, and is centrifuged 1 hour in 30000 rpm.Supernatant is discarded, precipitation is resuspended in reaction buffer (10mM Hepes, 138mM NaCl, H 7.4), membrane protein concentration is determined with Bradford methods, packing is stored in -80 °C.

P2Y12 memebrane proteins are diluted to 1 μ with reaction buffer_§/ μ Ι ^, and prepare reaction system according to following table： The g/ holes of LMP-1 00

[³H] 0.2 μ α of the 2-Mes-ADP/holes of 2 μ Ι 7

The hole of compound 10

The μ of reaction buffer 88/lonely L

By reaction system in incubation at room temperature 2 hours, and memebrane protein is collected on Perkin Elmer GF/B films with 96 hole cell harvestors.GF/B films are washed after 5 times with ice-cold reaction buffer, GF/B films are dried one hour in 70 °C of environment.Film is encapsulated in Nylon Bag, power B lO mL scintillation solutions, the reading in Perkin Elmer counters.Data streams read carries out IC with Graphpad softwares_5QAnalysis.

The IC of test-compound_5QValue is as shown in table 2 below:

Inhibitory action of the compounds of this invention of table 2 to P2Y12 acceptors

Conclusion：The compounds of this invention has obvious inhibitory action to P2Y12 acceptors.Pharmacokinetic Evaluation

The pharmacokinetics test of test case 3, the compounds of this invention

1st, make a summary

Using rat as animal subject, determine rat oral gavage using LC/MS/MS methods and give after the compound of embodiment 2, the compound of embodiment 8, the compound of embodiment 9, the compound of embodiment 12, the compound of embodiment 17, the compound of embodiment 20 and the compound of embodiment 23 not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compound of the present invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.

2nd, testing program

2.1 test drug

The compound of embodiment 2, the compound of embodiment 8, the compound of embodiment 9, the compound of embodiment 12, the compound of embodiment 17, the compound of embodiment 20 and the compound of embodiment 23.

2.2 experimental animal Healthy adult SD rat 28, male and female half and half are divided into 7 groups, every group 4, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2008-0016.

2.3 medicines are prepared

Appropriate amount of sample is weighed, 0.5% CMC-Na is added, 0.5 mg/ml suspensions are made in ultrasound.

2.4 administration

SD rats 28, male and female half and half are divided into after 7 groups, the night of fasting one and distinguish gastric infusion, and dosage is 10.0 mg/kg, the ml/kg of administered volume 10.

3rd, operate

Rat oral gavage administration embodiment 2 compound, the compound of embodiment 8, the compound of embodiment 9, the compound of embodiment 12, the compound of embodiment 17, the compound of embodiment 20 and the compound of embodiment 23, in before administration and 0.5,1.0 after administration, 2.0,3.0,4.0,6.0,8.0,11.0,24.0 hours 0.1 ml of blood sampling, are placed in heparinised tubes, 3500 rpm centrifuge 5 min separated plasmas, 20 °C of preservations.Feed within 2 hours after administration.

The testing compound content after different compound gastric infusions in rat plasma is determined with LC/MS/MS methods.The range of linearity of method is 1.00 2000 ng/ml;Plasma sample is analyzed after being handled through methanol extraction albumen.

4th, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention is as follows：

Conclusion：In the medicine generation of the compounds of this invention, absorbs good, with obvious pharmacokinetic advantage_t

Claims (16)

1. Claims:

   1st, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I),

   Its towel_:

   ^ is singly-bound or double bond；

   R¹Selected from cycloalkyl or heteroaryl；

   Work as R¹During selected from cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced, or R¹Selected from aryl or heteroaryl-condensed cycloalkyl, wherein described with aryl or heteroaryl-condensed cycloalkyl is optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

   Work as R¹During selected from heteroaryl, the heteroaryl is optionally further selected from alkyl, halogen, hydroxyl, alkoxy, nitro, cyano group ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

   R²Selected from alkyl, the alkyl is optionally further replaced by one or more cycloalkyl；

   When=be singly-bound when, R³Selected from halogen, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced；Or R³And R⁴- play formation=0 or alkenyl；When=be double bond when, R³It is not present, and meets valence bond theory；

   When=be singly-bound when, R⁴Selected from hydrogen atom or alkyl, or R³And R⁴- formation=0 or alkenyl are played, wherein the alkenyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, alkoxy, nitro or cyano group；Or R⁴With R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory；When¹When ^ is double bond, R⁴Selected from hydrogen atom；

   R⁵Selected from hydrogen atom, alkyl, hydroxyl or halogen；When¹When ^ is singly-bound, R⁵With R⁴Optionally into cycloalkyl, and cyclization meets valence bond theory；

   Condition is to work as R²Selected from unsubstituted alkyl, R³Selected from alkoxy or hydroxyl, wherein alkoxy is replaced by a hydroxyl, R⁴Selected from hydrogen atom, R⁵During selected from hydrogen atom, R¹It is not the C being substituted by phenyl₃〜C₈Cycloalkanes Base；

   R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more independently of one another⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

   R R⁸And R⁹It is each independently selected from hydrogen atom, alkyl, cycloalkyl, hydroxyalkyl, heterocyclic radical, aryl or heteroaryl；

   M is 0,1 or 2.

   2nd, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1, its be a kind of logical formula (II) shown in compound or its

   ( II

   Wherein： 1^〜1⁵Definition as described in the appended claim 1.

   3rd, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1 or 2, it is the compound shown in a kind of logical formula (III)

   ( III

   Wherein： 1^〜1⁵Definition as described in the appended claim 1.

   4th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in the logical formula (I) according to any one of claim 13, wherein R¹For cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced； R⁶Definition as described in the appended claim 1.

   5th, shown in logical formula (I) according to claim 4 compound or its dynamic isomer, mesomer, Racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt, wherein

   R¹Be selected from,, ' " ' A, R⁶, R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl or halogen independently of one another.

   6th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in the logical formula (I) according to claim 1 ~ 3 any one, wherein R³Selected from ^ elements, hydroxyl, alkyl or alkoxy, the alkyl, alkoxy are optionally further selected from hydroxyl, OR by one or more independently of one another⁷Or the substituent of halogen is replaced.

   7th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1 or 2, its towel：

   R¹Selected from cycloalkyl or heteroaryl；

   Work as R¹During selected from cycloalkyl, the cycloalkyl is optionally further by one or more respective independent R⁶Replaced, or R¹Selected from aryl or heteroaryl-condensed cycloalkyl, wherein described with aryl or heteroaryl-condensed cycloalkyl is optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

   Work as R¹During selected from heteroaryl, the heteroaryl is optionally further selected from alkyl, halogen, hydroxyl, alkoxy, nitro, cyano group ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_mR⁹Or-S (0)_mNR⁸R⁹Substituent replaced；

   R²Selected from alkyl, the alkyl is optionally further replaced by one or more cycloalkyl；

   When=it is singly-bound, R⁵Selected from alkyl, hydroxyl or halogen, or and R⁴Optionally into cycloalkyl, and cyclization is when meeting valence bond theory：

   R³Selected from halogen, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are further selected from hydroxyl, halogen, cycloalkyl, OR by least two independently of one another⁷Or the substituent of heterocyclic radical is replaced；

   R⁴Selected from hydrogen atom, or and R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory；

   When=it is singly-bound, R⁵During for hydrogen atom：

   R³For alkoxy, wherein the alkoxy is further replaced by least two substituents for being each independently selected from hydroxyl, halogen, cycloalkyl, hydroxyalkyl or heterocyclic radical；

   R⁴For hydrogen atom；

   When=be double bond when： R³It is not present, and meets valence bond theory； R⁴ 、 R⁵Selected from hydrogen atom； R⁶Selected from aryl or heteroaryl, wherein described aryl or heteroaryl are optionally further selected from alkyl, halogen, alkoxy, nitro, cyano group, cycloalkyl, heterocyclic radical ,-C (0) R by one or more⁷、 -C(0)OR⁷、 -S(0)_mR⁷、 -NR⁸R⁹、 -C(0)NR⁸R⁹、 -NR⁸C(0)R⁹、 -NR⁸S(0)_MR⁹Or-S (0)_MNR⁸R⁹Substituent replaced；

   R⁷、 R⁸And R⁹It is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;M is 0,1 or 2.

   8th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1, its be a kind of logical formula (IV) shown in compound or

   Its towel：

   R³Selected from ^ elements, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced； R⁴Selected from alkyl, hydrogen atom, or and R⁵Optionally into cycloalkyl, and cyclization meets valence bond theory； R⁵Selected from alkyl, hydroxyl or halogen, or and R⁴Optionally into cycloalkyl, and cyclization meets valence bond theory； R⁷Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；

   R R²Definition as described in the appended claim 1.

   9th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1, its be a kind of logical formula (V) shown in compound or its

   ( V

   Its towel：

   R³Selected from ^ elements, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy improve independently of one another is selected from hydroxyl, halogen, cycloalkyl, OR by least two⁷Or the substituent of heterocyclic radical is replaced；

   R⁷Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；

   R R²Definition as described in the appended claim 1.

   10th, shown in logical formula (I) according to claim 1 compound or its dynamic isomer, mesomer, Racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt, its be a kind of logical formula (VI) shown in compound or its

   (VI)

   Wherein： R R²Definition as described in the appended claim 1.

   11st, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1, its be a kind of formula (VD) shown in compound or

   ( VH

   Its towel：

   R²Selected from alkyl, the alkyl is further replaced by one or more cycloalkyl；

   R³Selected from ^ elements, alkyl, alkoxy or hydroxyl, wherein the alkyl, alkoxy are optionally further selected from hydroxyl, halogen, cycloalkyl, OR by one or more independently of one another⁷Or the substituent of heterocyclic radical is replaced； R⁷Selected from hydrogen atom, alkyl, cycloalkyl, hydroxyalkyl, heterocyclic radical, aryl or heteroaryl；

   R¹Definition is as described in the appended claim 1.

   12nd, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in logical formula (I) according to claim 1 or 2,

   HO OH or HO OH

   13rd, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its preparation method of officinal salt shown in a kind of logical formula (I) as claimed in claim 1, it comprises the following steps：

   ( IA )

   Formula (IA) compound and Ι ^ Ν Η₂Reaction, optionally further sloughs the protection group P and P' of hydroxyl, obtains logical formula (I) compound；

   Wherein：L is leaving group, preferably halogen；

   P and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or P and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy;

   R R²〜R⁵Definition as described in the appended claim 1.

   14th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its preparation method of officinal salt shown in a kind of logical formula (I) as claimed in claim 2, it comprises the following steps：

   ( II A)

   Formula (Π Α) compound and Ι ^ Ν Η₂Reaction, optionally further sloughs the protection group Ρ and Ρ ' of hydroxyl, obtains logical formula (II) compound；

   Wherein：L is leaving group, preferably halogen；

   Ρ and P' is the protection group or hydrogen atom of hydroxyl; the protection group of hydroxyl is selected from alkyl, benzyl, silylation or acetyl group; or Ρ and P' forms 56 circle heterocycles bases together with the atom that they are connected, 56 described circle heterocycles bases are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl or alkoxy;

   R R²-R⁵Definition as described in the appended claim 1.

   15th, a kind of pharmaceutical composition, described pharmaceutical composition contains the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in the logical formula (I) according to claim 1 of therapeutically effective amount, or pharmaceutically acceptable carrier, diluent and excipient. 16th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I) according to claim 1, or purposes of the pharmaceutical composition according to claim 15 in the medicine for preparing P2Y12 receptor antagonists.

   17th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I) according to claim 1, or pharmaceutical composition according to claim 15 are preparing the purposes in treating or preventing miocardial infarction, embolic breaking-out, Transient ischemic attacks, peripheral vascular disease or anginal medicine.

   18th, the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer and its form of mixtures and its officinal salt shown in a kind of logical formula (I) according to claim 1, or purposes of the pharmaceutical composition according to claim 15 in the medicine for treating or preventing the disorderly disease of platelet aggregation is prepared.