WO2013023511A1

WO2013023511A1 - Triazolopyrimidine derivative and preparation method and use thereof

Info

Publication number: WO2013023511A1
Application number: PCT/CN2012/078798
Authority: WO
Inventors: 屠汪洋; 范江; 张海棠; 徐国际; 刘志伟; 瞿健; 杨方龙; 董庆; 孙飘扬
Original assignee: 上海恒瑞医药有限公司; 江苏恒瑞医药股份有限公司
Priority date: 2011-08-12
Filing date: 2012-07-18
Publication date: 2013-02-21
Also published as: TW201311692A; CN103221413B; CN103221413A; CN102924457A

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

Triazolopyrimidine derivatives, preparation methods thereof and uses thereof

The present invention relates to a novel triazolopyrimidine derivative, a pharmaceutical composition containing the same, a process for the preparation thereof and use thereof as a therapeutic agent, particularly as a P2Y12 receptor antagonist. Background technique

Signal transduction is the process of transmitting extracellular information into cells, participating in various biological regulation processes of cells, enhancing, differentiating, integrating and transmitting the acquired information to downstream sensors to achieve various biological effects processes. Signal transduction is transmitted through membrane surface receptors, which are currently the largest family of membrane surface receptors and are involved in numerous signal transduction processes.

G protein-coupled receptors (GPCRs) are classified into three classes according to the downstream G-protein types: Gs protein, Gi protein, Gq protein, and G12/13 protein, four G protein subtypes to mediate signaling. Currently, G-protein coupled receptors are found only in eukaryotic organisms. Ligands capable of binding to G protein-coupled receptors include information hormones, neurotransmitters, polypeptides, small molecule compounds, and the like. G protein-coupled receptors are involved in the formation of many diseases and are therefore important drug targets. About 30% of the drugs on the market today use G-protein coupled receptors as targets.

There are numerous subfamilies of Gq/Gi-coupled receptors, including: (1) Purinergic receptors, members including PI, P2; (2) Adenosine receptors, Members include Al, A2A, A2B, A3, which are one of the PI subfamilies of the purine receptor family. The purine receptor family plays a key role in regulating cardiac muscle oxygen consumption, coronary blood flow, anti-inflammatory, vascular reactivity, apoptosis, and cytokine secretion.

The P2 subfamily can be further divided into five phenotypes according to pharmacological characteristics and tissue distribution: P2X, P2Y, Ρ2Ζ, P2U and Β2Τ. Among them, Ρ2Χ and Ρ2Ζ belong to ion channel type receptors, and P2Y, P2U and Ρ2Τ belong to G protein coupled receptors.

The Ρ2Υ receptor family that has been found to couple G proteins includes nine (Ρ2Υ1, 2, 4, 6, 11-14) subtypes, which are widely distributed in many cells and tissues, and the subtypes have low homology. Therefore, different subtypes have high selectivity for ligands. Ρ2Υ1, 2, 6, and 14 bind Gq and activate the PLC pathway; P2Y12, 13 binds Gi to inhibit adenylate cyclase activity; P2Y4 couples Gq/Gi two G proteins; P2Y11 couples Gq/Gs two G proteins . The P2Y receptor mediates a range of biological effects including platelet aggregation, immune regulation, and smooth muscle cell proliferation.

Thrombosis is formed by platelet aggregation during coagulation. Thrombosis formed in non-injury can reduce blood flow velocity or even block terminal blood vessels, causing tissue necrosis, atherosclerosis, myocardial infarction and other diseases. Platelet activation has multiple pathways and mechanisms such as collagen exposed in blood vessels, tissue factor, endogenous stimulatory factor ADP, and the like.

Co-activation of the P2Y1 and P2Y12 receptors is integral to platelet aggregation. The P2Y1 receptor releases Ca ²⁺ by activating the PBK pathway to cause aggregation of platelet deformation. P2Y1 gene knockout type small Rats do not respond to ADP-induced platelet aggregation and deformation [Fabre JE et al, Nat Med 5: 1199-1202 (1999)].

The P2Y12 receptor was first cloned in 2001 [Hollopeter G et al., Nature 409: 202-207 (2001)]. Studies have shown that the P2Y12 receptor is involved in fibrinogen receptor activation, thrombosis, thromboxane A2 production, and platelet aggregation induced by trauma. The human P2Y12 receptor consists of 342 amino acids, mainly distributed in platelets and brain tissue, and is a target for antithrombotic thiophene pyridines. Endogenous stimulating factors such as ADP and other binding to the P2Y12 receptor activate pathways such as PBK and activate Raplb, Akt, and ER pathways to cause activation of fibrinogen receptors in combination with fibrinogen to induce thrombosis or platelet aggregation. This process must be achieved with simultaneous activation of the P2Y1 receptor. It is noteworthy that the PAR-1 receptor belongs to the G protein-coupled receptor family, and the structural extracellular N-terminal portion is cleaved by serine proteases such as thrombin to activate itself, thereby exerting coagulation. Activation of the Akt pathway activation must also rely on activation of the P2Y12 receptor and amplify the signal through the G12/13 pathway. Blocking the P2Y12 receptor significantly inhibits platelet aggregation and thrombosis induced by ADP and other stimulating factors such as the PAR-1 activating peptide SFLLR, collagen, and the like.

A series of patent applications for P2Y12 receptor antagonists are disclosed, including WO1999005143, WO2000034283, and WO200103642.

Although a series of P2Y12 receptor antagonists for diseases such as platelet aggregation and thrombosis have been disclosed, there is still a need to develop new compounds having better pharmacological effects. With continuous efforts, the present invention has a formula (I). The compound of the structure shown, and the compound having such a structure was found to exhibit excellent effects and effects. Summary of the invention

The object of the present invention is to provide a novel triazolopyrimidine derivative represented by the formula ω or a tautomer, a mesogen, a racemate, an enantiomer thereof, a diastereomer a construct, a mixture thereof, and a pharmaceutically acceptable salt thereof,

Its towel:

― is a single key or double key;

R ^{1 is} selected from cycloalkyl or heteroaryl;

When R ^{1 is} selected from a cycloalkyl group, the cycloalkyl group is optionally further substituted with one or more of each independently R ⁶ , or R ^{1 is} selected from a cycloalkyl group fused to an aryl or heteroaryl group, Wherein the fused to an aryl or heteroaryl group The cycloalkyl group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, -C(0)R ⁷ , -C(0) 0R ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) _m R ⁹ or - Substituted by a substituent of S(0) _m NR ⁸ R ⁹ ;

When R ^{1 is} selected from heteroaryl, the heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(0)R ⁷ - C(0)OR ⁷ -S(0) _m R ⁷ -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ -NR ⁸ C(0)R ⁹ -NR ⁸ S( ) _m R ⁹ or -S Substituted by a substituent of ( ) _m NR ⁸ R ⁹ ;

R ^{2 is} selected from an alkyl group, which is optionally further substituted by one or more substituents selected from cycloalkyl; when = is a single bond, R ^{3 is} selected from halogen, alkyl, alkoxy or a hydroxy group, wherein the alkyl group and the alkoxy group are each independently optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ group or a heterocyclic group; or R ³ and R ⁴ - Forming = 0 or alkenyl; when = is a double bond, R ³ does not exist, and conforms to the valence bond theory;

When = is a single bond, R ^{4 is} selected from a hydrogen atom or an alkyl group, or R ³ and R ^{4 together} form a = 0 or an alkenyl group, wherein the alkenyl group is optionally further further selected from one or more selected from the group consisting of halogen and hydroxyl groups. Substituting a substituent of an alkoxy group, a nitro group or a cyano group; or R ⁴ and R ^{5 are} optionally a cycloalkyl group, and ring-forming is in accordance with a valence bond theory; when ¹ ^ is a double bond, R ^{4 is} selected from a hydrogen atom;

R ^{5 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group or a halogen; when ¹ ^ is a single bond, R ⁵ and R ^{4 are} optionally a cycloalkyl group, and the ring formation is in accordance with a valence bond theory;

The condition is, when R ^{2 is} selected from unsubstituted alkyl, R ^{3 is} selected from alkoxy or hydroxy, wherein alkoxy is substituted by one hydroxy group, R ^{4 is} selected from a hydrogen atom, and R ^{5 is} selected from a hydrogen atom, R ¹ is not a C ₃ -C ₈ cycloalkyl group substituted by a phenyl group;

R ^{6 is} selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkane Base, heterocyclic group, -C(0)R -C(0)0R ⁷ -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0 Substituting a substituent of R ⁹ , —NR ⁸ S(0) _m R ⁹ or —S(0) _m NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

m is 0, 1 or 2. In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (Π) or a pharmaceutically acceptable salt thereof:

Wherein: ^~11 ^{5 is} as defined above for the definition of formula (I). In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a salt of the formula:

Wherein: ^~11 ^{5 is} as defined above for the definition of formula (I). In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer isomers thereof, and mixtures thereof, and pharmaceutically acceptable salts thereof, in which R ¹ is selected from cycloalkyl, said cycloalkyl optionally further substituted with one or more R ⁶ each independently substituted; R ⁶ is defined As described above for the definition of formula (I). In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein

And R ^{6 is} selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently, optionally, further substituted with one or more substituents selected from alkyl or halogen. In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ^{3 is} selected from halogen, hydroxy, alkyl or alkoxy, said alkyl, alkoxy, each independently optionally further one or more Substituted by a hydroxyl group, OR ⁷ or halogen. In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and A pharmaceutically acceptable salt, wherein:

R ^{1 is} selected from cycloalkyl or heteroaryl;

When R ^{1 is} selected from a cycloalkyl group, the cycloalkyl group is optionally further substituted with one or more of each independently R ⁶ , or R ^{1 is} selected from a cycloalkyl group fused to an aryl or heteroaryl group, The cycloalkyl group described herein fused to an aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, a halogen, an alkoxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ Substituted by a substituent of -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ ;

R ^{2 is} selected from an alkyl group, which is optionally further substituted with one or more cycloalkyl groups;

When = is a single bond, R ^{5 is} selected from alkyl, hydroxy or halogen, or R ^{4 is} optionally cycloalkyl, and the ring is in accordance with the valence bond theory:

R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl and alkoxy are each independently further substituted by at least two selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ group or a heterocyclic group. Substituted by

R ^{4 is} selected from a hydrogen atom, or R ^{5 is} optionally a cycloalkyl group, and the ring formation is in accordance with a valence bond theory;

When = is a single bond and R ⁵ is a hydrogen atom:

R ³ is an alkoxy group, wherein the alkoxy group is further substituted with at least two substituents each independently selected from a hydroxyl group, a halogen, a cycloalkyl group, a hydroxyalkyl group or a heterocyclic group;

R ⁴ is a hydrogen atom;

When = is a double bond: R ³ is absent and conforms to the valence bond theory; R ⁴ and R ^{5 are} selected from hydrogen atoms;

R ^{6 is} selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, Heterocyclic group, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ -NR ⁸ C(0 Substituting a substituent of R ⁹ -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is 0, 1 or 2. In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof, which are a salt of the formula (IV):

( IV ) Its towel:

R ^{3 is} selected from the group consisting of an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ or a hetero group. Substituted by a substituent of a cyclic group; R ^{4 is} selected from an alkyl group, a hydrogen atom, or R ^{5 is} optionally a cycloalkyl group, and the ring-forming is in accordance with a valence bond theory; R ^{5 is} selected from an alkyl group, a hydroxyl group or a halogen, or R ⁴ Optionally forming a cycloalkyl group, and ring-forming conforms to the valence bond theory; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

The definition of RR ² is as described above for the definition of the general formula ω. In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof, which are a salt of the formula (V):

(V)

Its towel:

R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

The definition of RR ² is as described above for the definition of the general formula ω. In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof, which are a salt of the formula (VI):

( VI )

Wherein: ^~11 ^{2 is} as defined above for the definition of formula (I). In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and a pharmaceutically acceptable salt which is a general formula (νπ) salt:

( VH

Its towel:

R ^{2 is} selected from an alkyl group, and the alkyl group is further substituted with one or more cycloalkyl groups;

R ^{3 is} selected from the group consisting of an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ or a hetero group. Substituted by a substituent of the ring group; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

R ¹ is as defined above for the definition of the formula ω. In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein further, preferably:

R ¹ is a cycloalkyl group, which is optionally further substituted by one or more of each independently R ⁶ ; R ^{2 is} selected from an alkyl group which is further substituted by one or more cycloalkyl groups The cycloalkyl group is preferably a cyclopropyl group;

R ^{3 is} selected from alkoxy or hydroxy, wherein said alkoxy is optionally further substituted with one or more substituents selected from hydroxy or halo;

R ^{6 is} selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, and ring. Alkyl, heterocyclic, -C(0)R ⁷ , -C(0)0R ⁷ , -S(0) _M R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR Substituting for a substituent of ⁸ C(0)R ⁹ , -NR ⁸ S(0) _M R ⁹ or -S(0) _M NR ⁸ R ⁹ ; Typical compounds of the invention include, but are not limited to:

^HN , ^YY ^F

ΗΟ^ Ν, J 丄

Eight people ^s ,

HO OH

(1S,2 3R,5 -3- {5-(cyclopropylmethylhydrazino)-7-[[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]amino] Zoxa[4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

HO N 丄 1 1

HO Ώ OH

(lR, 2R, 35, 5R)-3- {5-(cyclopropylmethylhydrazino)-7-[[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]amino) Triazolo[4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

(1S,2 3R,5 -3-{7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

^ΗΟ飞^Ν ' Eight

(1S,2 3WR)-3-(2-hydroxyethoxy)-5-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-d] Pyrimidin-3-yl]cyclopentyl-1,2-diol

HO OH (1S,2 3S,4 -5- {7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

HON. Jl

Η ⁰ Γ N ^S ~

HO OH

(1S,2 3 4R)-5- {7-[[(lR,2^-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylindolyl-triazolo[ 4,5-d]-3-yl}cyclopentyl-1,2,3,4-tetraol

(lR, 2S, 3S, 4S, 5S)-4- {7-[[(lR,25)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylindolyl- Triazolo-d]pyrimidin-3-yl 5-fluoro-cyclopentyl-1,2,3-triol

(1S,2 3^^,5R)-3-{7-[[(lR,2^-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylindolyl-three Zoxa[4,5-d]pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

(15,25,35,5R)-3-(2-hydroxyethoxy)-5-{7-[[(lR,2R)-2-(4-methylthiazol-5-yl)cyclopropyl Amino]-5-propyldecyl-triazolo[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2-diol

HO OH (1S,2 3R,5^-3-{7-[[(lR,2^-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propyldecyl-triazole [4,5-d]pyrimidin-3-yl}-5-(2,3-dihydroxypropoxy)cyclopentyl-1,2-diol

(\S,2S,3S,4R,5S)-3-{7-[[(\R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propyl Mercapto-triazolo[4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol

(lS,2S,3S,5R)-3-(2-hydroxyethoxy)-5- {5-propylindolyl-7-[(lR,2S/lS,2R)-2-(3-pyridyl) Cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl}cyclopentane-1,2-diol

(1S,2 3 4R,5R)-3-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluoro-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

(1R,2 3 4S,5R)-4-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluorocyclopentane-1,2,3-triol

(\S,2S,3R,5S)-3-(7-((\R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl sulfide -3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-fluoro-3-hydroxypropoxy)cyclopentane-1,2 -diol

s~

ΗΟ ΟΗ

(15,2R,5R)-5-(7-((lR,25)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1, 2,3]triazole-d]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol

(15,25,35,5R)-3-(2,2-difluoroethoxy)-5-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropane) Amino) -5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol

(lR, 2R, 3^4R, 5 -4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3^[ 1,2,3]triazolo[4,5-^]pyrimidin-3-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol

N- J 丄 ΗΟ ΟΗ

(1S,2 3R,5^-3-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluorocyclopentane-1,2-diol

ΗΟ, ' ΟΗ

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

Form, and its pharmaceutically acceptable salt. The present invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and a mixture thereof, And a preparation method thereof and a pharmaceutically acceptable salt thereof, comprising the steps of:

( IA )

The compound of the formula (IA) is reacted with 1 ΝΗ ₂ , optionally further deprotecting the protecting group Ρ and Ρ ' of the hydroxy group to give a compound of the formula (I);

Wherein: L is a leaving group, preferably a halogen;

Ruthenium and P' are a protecting group or a hydrogen atom of a hydroxyl group, and a protecting group of a hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or an anthracene and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring. Further, the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from alkyl, halogen, hydroxy or alkoxy;

The definitions of RR ^{2 to} R ⁵ are as described above for the definition of the general formula (I). The invention further relates to a compound of the formula (A) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof And a preparation method of the pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (ΠΑ) is reacted with 1 ΝΗ ₂ , optionally further deprotecting the protecting group Ρ and Ρ ' of the hydroxy group to obtain a compound of the formula (Π);

Wherein: L is a leaving group, preferably a halogen;

The definition of RR ² -R ⁵ is as described above for the definition of formula (I). Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer , diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for a P2Y12 receptor antagonist.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment or prevention of myocardial infarction, embolic episodes, transient ischemic attack, peripheral vascular disease or angina pectoris.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing a disorder of platelet aggregation disorder. Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Alkyl" means a saturated aliphatic hydrocarbon group which is a straight chain and a branched chain group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, and non-limiting examples include methyl group, B Base, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropane Base, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3- Methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3- Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl -2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl And various branched isomers thereof and the like; more preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl Propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- Methyl amyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably by one or more groups independently selected from the group consisting of: alkyl, alkenyl, Block group, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Cycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 5 to 10 cycloalkyl rings. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

"Spirocycloalkyl" means a polycyclic group of 5 to 20 members, which shares a carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings are fully conjugated π electronic system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

"Fused cycloalkyl" means 5 to 20 members, each ring of the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Double keys, but no One ring has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of fused cycloalkyl groups include:

"Bridge cycloalkyl" means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π electronic system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Bridged cycloalkyl

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of: alkyl, alkenyl, block, alkoxy, alkane Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ -NR ⁸ C(0)R ⁹ -NR ⁸ S(0) _m R ⁹ , -S(0 _m NR ⁸ R ⁹ , -C(O)R ¹⁰ -C(0)OR ¹⁽⁾ or -S(O) _m R ¹⁰ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C( 0) R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Block group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, an ethyl group, a 1-propyl block group, a 2-propyl block group, a 1-, 2- or 3-butyl group, and the like. The block group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of: alkyl, alkenyl, block, alkoxy, alkylthio, alkane Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, -C(0)R', -C(0)OR\ -S(0) _m R\ -NR ^y , -C(0)NR ^y , -NRT(0)R ^y -NR ⁸ S(0) _m R ^y or -S(0) _m NR ⁸ R ⁹ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) _m ( Wherein m is an integer from 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Non-limiting examples of polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

"spiroheterocyclyl" means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting

"Fused heterocyclic group" means 5 to 20 members, each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more The bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5. Non-limiting examples of fused heterocyclic groups include:

"Bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a complete conjugation a π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) _m (where m is an integer from 0 to 2), and the remaining ring atoms are Carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The heterocyclic group may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridge depending on the number of constituent rings, and is preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic ring. Non-limiting examples include:

with

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted by one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(0)R ⁷ , -C(0)OR ⁷ -S(0) _m R ⁷ -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having adjacent pairs) The ring group of a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, and the ring together is an aryl ring, non-limiting examples include:

The aryl group may be substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C( 0) R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. It is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. . The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio. Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Alkoxy" means -o-(indenyl) and -o-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio. Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(0)R ⁷ , -C(0)OR ⁷ -S(0) _m R ⁷ -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C (0) R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ .

"Haloalkyl" means that the alkyl group is substituted by one or more halogens.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -N0 ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Oxo group" means =0.

"Carboxylic acid group" means -C(0)OH.

The "carboxylate group" means -C(0)0(alkyl) or -C(0)0(cycloalkyl), wherein the alkyl group and the cycloalkyl group are as defined above.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their The possible chemical positions, those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby the biological activity.

"Pharmaceutically-acceptable salt" means a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.

R ^{7 to} R ⁹ are as defined in the compound of the formula, and m is 0, 1 or 2. Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following synthetic technical scheme:

A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

( IE ) ( I )

The aromatic compound (IB) of the formula (IB) and the compound of the formula (IC) are subjected to aromatic nucleophilic substitution reaction in a solvent to obtain a compound of the formula (ID); the compound of the formula (ID) is dissolved in a solvent, and sodium nitrite is added in an ice bath. The reaction is carried out under the conditions to obtain the compound of the formula (IA); the compound of the formula (IA) is reacted with R^NH^ under basic conditions to obtain the compound of the formula (IE); the compound of the formula (IE) is further dehydroxylated. Protecting groups P and P' to give compound of formula (I) o Reaction solvents include, but are not limited to, ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, N, N-di Methylformamide or a mixed solvent thereof;

Reducing agents include, but are not limited to, iron powder;

Reagents that provide basic conditions include, but are not limited to, organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butanol, and inorganic bases. Potassium, the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate;

The reaction temperature is controlled at -80 ° C to 200 ° C, preferably 0 ° C to 100 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably 15 minutes to 24 hours; Its towel:

Ri~R ^{5 is} as defined in the general formula (; I);

L and L' are leaving groups, preferably halogen;

P and P' are a protecting group or a hydrogen atom of a hydroxyl group, and the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring. Further, the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group. The 5- to 6-membered heterocyclic group described above is optionally reacted under acidic conditions, and the protecting group is removed to obtain a compound of the formula (1). a general formula (VI)

H ₂ N

(IB)

The aromatic compound (IB) and the compound of the formula (VIA) are subjected to aromatic nucleophilic substitution reaction in a solvent to obtain a compound of the formula (VIB); the compound of the formula (VIB) is dissolved in a solvent, and sodium nitrite is added in an ice bath. The reaction is carried out under the conditions to obtain the compound of the formula (VIC); the compound of the formula (VIC) is reacted with R^NH^ under basic conditions to obtain the compound of the formula (VID); the compound of the formula (VID) in triphenylphosphine And reacting with an azodicarboxylate diester (preferably diisopropyl azodicarboxylate) to obtain a compound of the formula (VIE); the compound of the formula (VIE) further deprotects the protecting groups P and P' of the hydroxyl group, Compound (VI) of the formula.

The reaction solvent includes, but is not limited to, ethylene glycol, ethanol, methanol, acetic acid, water, acetonitrile, methanol, tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide or a mixed solvent thereof;

Reducing reagents include, but are not limited to, hydrogen, iron powder or zinc powder;

The reaction temperature is controlled from -80 ° C to 200 ° C, preferably from 0 ° C to 100 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably from 15 minutes to 24 hours;

Its towel:

Ri~R ^{2 is} as defined in the general formula (; I);

L and L' are leaving groups, preferably halogen; P and P' are a protecting group or a hydrogen atom of a hydroxyl group, and the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring. Further, the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group.

(IVA) (IV) (IV) The aromatic nucleophilic substitution reaction of the compound of the formula (IVB) with the compound of the formula (IVC) in a solvent gives the compound of the formula (IVD); the compound of the formula (IVD) is dissolved in a solvent. Reducing the nitro group under acidic conditions to obtain the compound of the formula (IVF); the compound of the formula (IVF) is dissolved in a solvent, and sodium nitrite is added and reacted in an ice bath to obtain a compound of the formula (IVA); The compound (IVA) is reacted with R^NH^ under basic conditions to obtain the compound of the formula (IVE); the compound of the formula (IVE) is further deprotected from the protecting group P and P' of the hydroxyl group to obtain the compound of the formula (IV). .

Reducing agents include, but are not limited to, iron powder;

Its towel:

Ri~R ^{5 is} as defined in the general formula (; I);

L and L' are leaving groups, preferably halogen;

P and P' are a protecting group or a hydrogen atom of a hydroxyl group, and the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring. Further, the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group or an alkoxy group. Detailed ways The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions recommended by the original material or the manufacturer of the article. Reagents without specific source are routinely purchased from the market.

The structure of the compound is determined by nuclear magnetic resonance (1H NMR) and/or mass spectrometry (MS). The iHNMR shift (δ) is given in parts per million (ppm). The 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDC1 ₃ ), hexamethyl dimethyl sulfoxide (OMSO-d ₆ ), internal standard. It is tetramethylsilane (TMS).

The MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C 18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The IC ₅ o value was determined using a NovoStar plate reader (BMG, Germany).

Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography

(TLC) The silica gel plate used has a specification of 0.15 mm to 0.2 mm, and the silica gel plate used for thin layer chromatography separation and purification is 0.4 mm to 0.5 mm.

The silica gel column generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

The alkaline alumina column is generally used as a carrier for FCP200~300 mesh basic alumina using the national medicine chromatography.

Known starting materials of the invention may be synthesized or synthesized according to methods known in the art, or may be

ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company purchased from companies such as Accela ChemBio Inc and Dary Chemical.

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen or argon atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction uses a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

There is no particular description in the examples, and the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature, preferably 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system of the eluent for column chromatography and the system of the developer for thin layer chromatography using the purified compound 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, volume of solvent It is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid.

Example 1

(1S,2 & 3 & S')-5-{7-[[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propyldecyl-triazole and

[4,5-d]-3-yl}cyclopentyl-1,2,3,4-tetraol

first step

2-chloro-l-(3,4-difluorophenyl)ethanone

Add aluminum trichloride (26.3 g, 197 mmol) to 1,2-difluorobenzene (25 g, 219 mmol), heat to 50 ° C, slowly add chloroacetyl chloride C17.5 mL, 219 mmol) , Stir at 50 ° C for 1 hour. The reaction solution was slowly added to a mixed solution of 100 g of ice, 25 mL of water and 38 mL of concentrated hydrochloric acid, keeping the temperature below 60 ° C. After the addition was completed, the mixture was heated to 60 ° C, layered, and used for organic phase. The residue was washed with EtOAc (EtOAc m. Yellow solid), Yield: 88.7%.

GC-MS m/z: 190.0 [M ⁺ ]

Second step

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

(^-Diphenyl-pyrrolidin-2-yl-methanol (1.8 g, 6.8 mmol) was dissolved in 45 mL of toluene, trimethyl borate (1 g, 9.6 mmol) was added, and the reaction was carried out at 40 ° C. Hours, keep the temperature at 35 °C ~ 45 °C, add dimethyl sulfide borane, react at 40 °C for 1 hour, keep the temperature at 35 °C ~ 45 °C and add 75 mL 2-chloro-1-(3, 4-Difluorophenyl)ethanone la (26 g, 136 mmol) in toluene, continue to react at 40 ° C for 1 hour. Cool the reaction to 10 ° C, keep the temperature below 35 ° C, add 25 mL Methanol, the reaction solution was cooled to 20 ° C, and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was washed with 10% acetic acid (100 mL×4), extracted with toluene (50 mL). Washed, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The solution is directly subjected to the next reaction.

GC-MS m/z: 192.0 [M ⁺ ]

third step

(lR,2R)ethyl 2-(3,4-difluorophenyl)cyclopropylcarboxylate 60% sodium hydride (10.9 g, 273 mmol) was suspended in 100 mL of toluene and heated to 40 ° C. 60 mL (diethoxy-phosphate)-ethyl acetate (33.7 g, 150 mmol) in toluene was added dropwise, reacted at 40 ° C for 1 hour, and 60 mL (lS)-2-chloro was added below 60 ° C. A solution of 1-(3,4-difluorophenyl)ethanol lb (26.3 g, 137 mmol) in toluene was stirred at 60 ° C for 12 hours. To the reaction mixture, 150 ml of water was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Ethyl 2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylate lc (13.8 g, pale yellow solid), yield: 44.7%.

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

the fourth step

(lR,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid

Ethyl (lR,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylate lc (13.8 g, 61 mmol) was dissolved in 90 mL of methanol, then 30% sodium hydroxide C. 109 mmol) solution, reacted at 65 °C for 2 hours. Concentrated under reduced pressure, adding 100 mL of toluene and 100 mL of water, layering, adjusting pH ≤7 with 35% hydrochloric acid, layering, using toluene (500 After extraction with EtOAc (3 mL), EtOAc (EtOAc m. 12.1 g, yellow liquid), the product was directly subjected to the next reaction without purification.

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

the fifth step

(lR,2R)-2-(3,4-difluorophenyl)cyclopropylformamide

(lR,2R)-2-(3,4-Difluorophenyl)cyclopropylcarboxylic acid Id (12.1 g, 61 mmol) was dissolved in 100 mL of toluene and then added to dichloromethane (5.4 mL, 73.9 mmol) The mixture was reacted at 35 ° C for 6 hours, concentrated under reduced pressure, and less than 10 ° C. To the residue, 28% aqueous ammonia (14.9 g, 244 mmol), 35 mL of water and 100 mL of ethyl acetate were added and reacted for 1 hour. The pH was adjusted to ≤7 with 35% hydrochloric acid, EtOAc (EtOAc) (EtOAc)EtOAc. The title compound (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxamide le (9.8 g, white solid), yield: 81.7%. .

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

Step 6

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

Add (lR,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxamide le (9 g, 45.64 mmol) to a solution of 30% sodium hydroxide (16.43 g, 411 mmol). To a solution of 13% sodium hypochlorite (8.49 g, 114 mmol) was added dropwise at 20 to 25 ° C, and stirred at about 60 ° C for 1 hour. The reaction solution was cooled to 5 ° C, the pH was adjusted to 8.5 to 9.5 with 37% hydrochloric acid, 55 mL of isopropyl acetate and 30 mL of methanol were added, stirred, layered, extracted with isopropyl acetate (30 mL×2), and the organic phase was combined. Concentration under reduced pressure gave the crude title product (l,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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

Seventh step

(lR, 2^-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine If ( 7.29 g, 43.1 mmol) was dissolved in 100 mL of a mixed solvent of ethyl acetate and methanol (V/V = 7:3). L-(+)-tartaric acid (3.88 g, 25.9 mmol) was added with stirring, and stirred for 12 hours. The solid was precipitated. The solid was purified by silica gel column chromatography eluting with eluent system D to give the title product (1R, 2 -2-03, 4-difluorophenyl) 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-d ₆ ) 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).

Eighth step

[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-ί ][1,3]dioxa Cyclopentene-4-yl]methanol

Dissolve 1 M hydrochloric acid in methanol (90 mL, 90 mmol) and trimethyl orthoformate (90 mL, 0.82 mol) In 70 mL of acetone, add 30 mL of (3R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol 1h (22.5g, 150 mmol) in acetone, 70 ° C reaction 5 hours. The reaction was quenched by the addition of 6 mL of pyridine, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL), EtOAc EtOAc (EtOAc) The title product [(3aR,4R,6R,6aR)- was obtained by the purification of EtOAc (EtOAc). 6-Methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-4-yl]methanol li ( 15.5 g, light brown oil), Yield: 50.6%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Step 9

(3aS,4^6R,6aR)-4-(iodomethyl)-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [ 1,3]dioxole

[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxo Heterocyclopentene-4-yl]methanol li (15.5 g, 76 mmol) was dissolved in 300 mL of a mixed solvent of toluene and acetonitrile (V/V = 1:1), followed by the addition of triphenylphosphine (24 g, 91). Methyl) and imidazole (7.75 g, 1 14 mmol), iodine (23 g, 91 mmol) was added portionwise with stirring and refluxed for 5 min. Cool to room temperature, concentrate under reduced pressure, add 400 mL of diethyl ether and wash with saturated sodium thiosulfate solution (60 mL X 2), water (60 mL) and saturated sodium chloride solution (60 mL X 2). The residue was dried over sodium sulfate, filtered, and then evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,U][1,3]dioxol lj (22.2 g, yellow oily yield: 93.3% .

Step 10

(4R,5R)-2,2-methyl-5-vinyl-1,3-dioxolane-4-carboxaldehyde (3aS,4 6R,6aR)-4-(iodomethyl)- 6-Methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,U][1,3]dioxole lj (83 g, 264 mmol) was dissolved in Zinc powder (25.7 g, 396 mmol) was added to 500 mL of isopropanol, and acetic acid (26.4 g, 462 mmol) was added thereto under ice bath, and reacted at 30 ° C for 4 hours. Add saturated sodium bicarbonate solution, adjust pH ≤7, concentrate under reduced pressure, add 400 mL of ethyl acetate, filter, filter cake washed with ethyl acetate (100 mL X 2), and the organic phase is combined with water (60 mL) Washed with saturated sodium bicarbonate solution (60 mL) and saturated sodium chloride solution (60 mL EtOAc), dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained gave the title product (4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxacyclopentane-4-carbaldehyde lk (31 g, colorless oil yield : 75.3%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

The eleventh step

L-[(4WR)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]prop-2-enyl alcohol (4R,5R)-2 ,2-Dimethyl-5-vinyl-1,3-dioxolane-4-carbaldehyde lk (30 g, 192 mmol) dissolved in 50 mL of tetrahydrofuran, quickly added to 1 M ethylene at -78 °C Magnesium bromide in tetrahydrofuran solution (550 mL, 384 mmol), react at -78 ° C for 1 hour, warm to room temperature and continue the reaction for 30 minutes. Add 120 mL of saturated ammonium chloride solution, add silica gel, filter, filter cake with ethyl acetate (200 mL X 4), and combine the organic phase with water (60 mL) and saturated sodium chloride solution (60 mL X 2) Washed, dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated.

1- [(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]prop-2-en-1-ol lm (20 g , colorless oil), Yield: 56.7%.

Step 12

O 4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-ol bis(tricyclohexylphosphine) Benzylpyridinium dichloride (444 mg, 0.54 mmol) was added to the reaction flask, and 100 mL of l-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3 was added to the syringe. - Dioxalan-4-yl]prop-2-enol lm (10 g, 54 mmol) in chloroform, mp. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 3aH-cyclopenteno[l,3]dioxol-4-ol In (4.5 g, light brown oil), yield: 53.2%.

Step 13

2-(0 4 6& -2,2-Dimethyl-4,6&-dihydro-3&^cyclopenta[[1,3]dioxol-4-yl)isoindoline- 1,3-diketone

(3aS,4R,6aR)-2,2-Dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-ol In (936 mg , 6 mmol), phthalimide (1.32 g, 9 mmol) and triphenylphosphine (2.36 g, 9 mmol) were dissolved in tetrahydrofuran, and 10 mL of diisopropyl azodicarboxylate (1.9 mL) was added. , 9 mmol) in tetrahydrofuran solution, reacted at 20 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 3aH-cyclopentenyl M[l,3]dioxol-4-yl)isoindoline-1,3-dione lo (1.4 g, white solid), Yield: 82.3%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Fourteenth step

2-( 3aR,4S,5 6 6a -4,5-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl Isoporphyrin-1,3-dione

2-( 3aR,4R,6a -2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-yl)isoindole Porphyrin-1,3-dione lo (500 mg, 1.75 mmol) was dissolved in 10 mL of tetrahydrofuran, and a catalytic amount of ruthenium tetroxide was added thereto, and the reaction was carried out at room temperature for 24 hours. The reaction mixture was combined with EtOAc (EtOAc) (EtOAc m. -( 3aR,4S,5 6 6a -4,5-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-6- (iso) porphyrin-1,3-dione lp (558 mg, colorless oil).

Step fifteenth

2-((3aS,3M,6aS,7a^-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene[l,2 3,4-if|linked ([1,3] Dioxa Cyclopentene)-7-yl)isoindoline-1,3-dione

2-( 3aR,4S,5 6 6a -4,5-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene M[l,3]dioxol-6- Isomerin-1,3-dione lp (558 mg, 1.75 mmol) dissolved in 10 mL of acetone, added with p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol), heated to 50 ° C Reaction for 24 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hydrogen-3aH-cyclopentene[l,2 3,4-if|linked ([1,3]dioxole)-7-yl)isoindoline-1,3-dione lq ( 230 mg, white solid), Yield: 36.6%.

Step 16

(3aS, 3M, 6aS, 7a -2, 2,5,5-tetramethyltetrahydro-3aH-cyclopentene[1,2-ί :3,4-ί '] ([1,3] Dioxol)-7-amine

2-((3aS,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene[1,2-ί:3,4-ί ']) ([ 1,3] Dioxol)-7-yl)isoindoline-1,3-dione lq (220 mg, 0.61 mmol) dissolved in 10 mL of ethanol, added hydrazine hydrate (0.36 mL, 6.12) The reaction mixture is heated to 70 ° C for 2.5 hours. The reaction mixture is cooled to room temperature, filtered, and the filtrate is evaporated. (3a^,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene[l,2 3,4-^((1,3)dioxole Pentene)-7-amine lr (130 mg, pale yellow liquid), Yield: 93.1%. 1H NMR (400 MHz, CDC1 ₃ ) 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).

Step 17

6-Chloro-2-(propylindenyl)-N ⁴ -[(3aS,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene

[1,2-(1:3,4-(1'](([1,3]dioxole)-7-yl]pyrimidine-4,5-diamine will be 4,6-di Chloro-2-propylmercapto-pyrimidin-5-amine Is (162 mg, 0.68 mmol, prepared by the well-known method "Specialty lj WO2001092263") and (3aS, 3bS, 6aS, 7a-2, 2, 5 ,5-tetramethyltetrahydro-3aH-cyclopenta[l,2 3,4-if|linked ([1,3]dioxole)-7-amine lr (130 mg, 0.57 mmol Dissolve in 5 mL of ethylene glycol and heat to 100 ° C for 24 hours. Add 30 mL of ethyl acetate to the reaction solution, and wash with water (10 mL X 3) and saturated sodium chloride solution (10 mL). over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product, 6-chloro-2- (mercapto-propyl) -N ⁴ - ((3aS ,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopenta[1,2- 3,4-^((1,3)dioxole -7-ylpyrimidine-4,5-diamine It (80 mg, yellow solid), Yield: 32.6%.

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

Eighteenth step

7-Chloro-5-(propylmercapto)-3-[(3aS,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene

[l,2 3,4 ]((1,3]dioxole)-7-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine ice bath Next, 6-chloro-2-(propylindenyl)-N ⁴ -((3aS,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene[l , 2 3,4-^((1,3)dioxole-7-yl)pyrimidine-4,5-diamine It (80 mg, 0.19 mmol) dissolved in 1.5 mL of acetic acid and water ( Sodium nitrite (12 mg, 0.20) in a mixed solvent of V/V = 2: 1) Methyl), reacted at 0 ° C for 5 minutes. 15 mL of ethyl acetate and 10 mL of saturated sodium carbonate solution were added to the reaction mixture, stirred for 10 minutes, separated, and extracted with ethyl acetate (10 mL X 2), and the organic phases were combined with saturated sodium carbonate (10 mL) The mixture was washed with aq. EtOAc (EtOAc) (EtOAcjjjjjjjjjj 6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopenta[l,2-i:3,4]([1,3]dioxole)- 7-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (82 mg, brown oil).

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

Step 19

N-{[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]-5-(propylindolyl)-3-[(3aS,3M,6aS,7a-2,2, 5,5-Tetramethyltetrahydro-3aH-cyclopenta[l,2 3,4 ]([1,3]dioxole-7-yl)-3H-[1,2 , 3] triazole

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

7-Chloro-5-(propylindenyl)-3-((3a^,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro-3aH-cyclopentene[l,2 3,4-^((1,3)dioxole-7-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinelu (82 mg, 0.19 mmol) and (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (83 mg, 0.26 mmol) dissolved in 10 mL of acetonitrile, added three Ethylamine (0.09 mL, 0.67 mmol) was reacted for 24 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjj 2-(3,4-Difluorophenyl)cyclopropyl]-5-(propylindolyl)-3-[(3aS,3M,6aS,7a-2,2,5,5-tetramethyltetrahydro) -3aH-cyclopentene[l,2 3,4 ]-([1,3]dioxol-7-yl}-3^[1,2,3]triazolo[4, 5-d]pyrimidin-7-amine lv (80 mg, yellow oily yield: 73.4%.

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

Step 20

(1 2^^, 3⁄4-5-{7-[[(lR,2^-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylindolyl-triazole

[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

N-{[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]-5-(propylindolyl)-3-[(3aS,3M,6aS,7a^-2, 2,5,5-tetramethyltetrahydro-3aH-cyclopenta[1,2- 3,4-^((1,3]dioxole]-7-yl} -3H- [1,2,3] Triazolo[4,5-d]pyrimidin-7-amine lv (80 mg, 0.14 mmol) was dissolved in 3 mL of methanol, then 5 M hydrochloric acid (0.3 mL, 1.5 mmol) The mixture was stirred for 5 min. The residue was purified by high-purity preparative chromatography to give the title product (1 2^3 4 -5-{7-[[(1 2 -2-(;3,4-difluorophenyl)) Propyl]amino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol l (18 mg, white solid) , Yield: 25.7%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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-(cyclopropylmethylhydrazino)-7-[[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]amino] Triazolo[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (1 2 3R,5 -3-{5- (cyclopropylmethylhydrazino)-7-[[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]amino]tri

-d]pyrimidin-3-yl}-5-(2-hydroxy-1,2-diol 3

〇 0 '

(lake

First step

Benzyl N-hydroxycarbamate

Hydroxylamine (7.65 g, 0.11 mol) and sodium bicarbonate C58.8 g, 0.70 mol) were dissolved in a mixed solvent of 630 mL of tetrahydrofuran and water (V/V = 1:1), and benzyl chloroformate was slowly added dropwise ( 33.8 mL, 0.10 mol), reacted at room temperature for 12 hours. The THF was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was dissolved in a mixed solvent of 270 mL of dichloromethane and n-hexane (V/V = 5.5:8) at 45 ° C, and then cooled to crystallize to give the title product N-hydroxycarbamate 2a (15.48) g, white solid), Yield: 92.6%.

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

Second step

(1R,4 1 4R)-2-oxo-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester N-hydroxycarbamic acid benzyl ester 2aC20.4 g, 0.12 mol) Dissolved in a mixed solvent of 800 mL of methanol and water (V/V = 3:1), and added cyclopentadiene (22.98 g, 0.35 mol) and sodium periodate (25.3 g, 0.12 mol) in an ice bath. The reaction was carried out for 10 minutes at 0 ° C to 5 ° C, and allowed to react at room temperature for 2 hours. After cooling to 0 ° C to 5 ° C, cyclopentadiene (16.5 g, 0.25 mol) and sodium periodate (14.9 g, 0.07 mol) were added and reacted at room temperature for 12 hours. The organic solvent was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) , vacuum drying, got To the crude title product (1R,4S/1 4R)-2-oxo-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester 2b (32.39 g, m. The next reaction was carried out without purification.

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

third step

(1 4R,6S/1R, 6R)-5,6-Dihydroxy-2-oxo-3-azabicyclo[2.2.1]heptane-3-carboxylic acid benzyl ester crude product (1R, 4 1 4R)- 2-oxo-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester 2b (32.39 g, 0.12 mol) was dissolved in 600 mL of tetrahydrofuran, and N-methyloxymorpholine was added (57.2 g, 0.24 mol) and osmium tetroxide (100 mg, 0.39 mmol) were reacted for 1.5 hours, and sodium dithionite (63.7 g, 0.37 mol) was added and reacted for 30 minutes. The THF was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. Drying to give the crude title product C, 4R, 6S/1R, 6R)-5,6-dihydroxy-2-oxo-3-azabicyclo[2.2.1]heptane-3-carboxylic acid benzyl ester 2c (31.73 g, yellow oil), the product was taken directly to the next reaction without purification.

1HNMR (400 MHz, CDC1 ₃ ) 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).

the fourth step

(3& 4 7 7&5/3& 4 7 7& -2,2-Dimethyldihydro-3&^4,7-methylene[1,3]dioxol[4,5-d][ l,2] Oxazine-6 (4H benzyl formate)

The crude product (1S, 4R, 6S/1R, 6R)-5,6-dihydroxy-2-oxo-3-azabicyclo[2.2.1]heptane-3-carboxylic acid benzyl ester 2c (31.73 g, 0.12 mol) Dissolved in 150 mL of acetone, and added p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol), and reacted at 30 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjj ,7-methylene[1,3]dioxol[4,5-d][l,2]oxazin-6 (4H benzyl formate 2d (27.8 g, white solid), yield : 76.1%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fifth step

(3& 4 6 6&5>3&^^,6 6& -6-Amino-2,2-dimethyltetrahydro-3&cyclopentene[^][1,3]dioxol-4-ol

Will (3& 4 7 7&5/3& 4 7 7& -2,2-dimethyldihydro-3&^4,7-methylene[1,3]dioxole[4,5-^] [1,2] Oxazine-6 (4H benzyl formate 2d (27.8 g, 91.06 mmol) was dissolved in 400 mL of methanol, added palladium/carbon (10%, 1.4 g), replaced with hydrogen three times, reacted at 50 °C After 40 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude title product: 4 4 6 & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & Dioxol-4-ol 2e (16.8 g, yellow solid), product was taken to the next step without purification.

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

Step 6 N-[(3a5,4R,65,6aR /3aR,45,6R,6a5 )-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene [d][l,3]dioxol-6-yl]carbamic acid benzyl ester crude product (3aR,4^6R,6a5>3a^4R,6 6aR)-6-amino-2,2- Dimethyl 4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-ol 2e (16.8 g, 91.06 mmol) was dissolved in 195 mL 4 To a mixed solvent of methyl-2-pentanone and water (V/V = 3:1), add potassium carbonate (22.65 g, 163.9 mmol) and add benzyl chloride (27 mL, 0,87 mol) , react at room temperature for 12 hours. The mixture was separated and the aqueous phase was extracted with 4-methyl-2-pentanone (50 mL×2). The organic phase was combined, washed with saturated sodium chloride (100 mL×2), dried over anhydrous magnesium sulfate 200 mL of a mixed solvent of n-hexane and dichloromethane (V/V = 20:1) was added, and the mixture was filtered, filtered and dried in vacuo to give the title product N-[(3aS,4R,6 6aR /3aR,45,6R ,6a5)-6-hydroxy-2,2-dimethyl 4,5,6,6a-tetrahydro-3aH-cyclopenta[^][1,3]dioxol-4-yl Benzyl carbamate 2f (18.82 g, off-white solid), Yield: 77.3%.

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

Seventh step

2-((3&^^,6 6&^3& 4 6 6& -6-(benzyloxycarbonylamino-2,2-dimethyltetrahydro-3&11-cyclopentene-W][l,3]dioxa Ethyl cyclopenten-4-yl)oxyacetate will be N-[(3aS,4R,6 6aR/3aR,4S,6R,6aS )-6-hydroxy-2,2-dimethyl-4,5, 6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]carbamic acid benzyl ester 2f (2 g, 6.51 mmol) was dissolved in 100 mL of tetrahydrofuran. Cool to -22 ° C (internal temperature) in a dry ice bath, keep warm for 30 minutes, add 10 mL of potassium t-butoxide (3.65 g, 9.76 mmol) in tetrahydrofuran, and keep at -22 ° C for 30 minutes (internal temperature). Stirring at -10 ° C for 30 minutes, adding ethyl bromoacetate (1.09 mL, 9.76 mmol) in tetrahydrofuran (10 mL), incubated at -22 ° C for 1 hour, then raised to room temperature. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjj - (Benzyloxycarbonylamino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)oxyacetic acid Ester 2g (2.16 g, pale yellow oil). Yield: 84.4% MS m / z (ESI):. 394.3 [M + l]

Eighth step

(3aS,4R,6 6aR/3aR,4^6R,6aS)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-ring Benzene [d][l,3]dioxol-4-yl]carbamic acid benzyl ester 2-((3aS,4R,6 6aR/3aR,4S,6R,6aS )-6- ( Benzyloxycarbonylamino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)oxyacetate 2 g (8 g, 20.34 mmol) dissolved in 60 mL of tetrahydrofuran, added lithium tetrahydroborate (887 mg, 40.7 mmol), and stirred at room temperature overnight. The reaction solution was poured into 150 mL of water and extracted with ethyl acetate (60 mIX3). The residue was washed with EtOAc (EtOAc) (EtOAc) 3aR,45,6R,6a5)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3 Benzyl dioxol-4-yl]carbamate 2h (6.82 g, colorless thick), yield 49.7%. MS m/z (ESI): 352.1 [M+l]

Step 9

2-{[(3aR,4^6R,6aS/3a^4R,6 6aR)-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene

M[l,3]dioxol- ⁴ -yl]oxy}ethanol

N-[(3aS,4R,6 6aR/3aR,4S,6R,6a -6-(2-hydroxyethoxy)-2,2-dimethyl 4,5,6,6a-tetrahydro-3aH - Cyclopenteno[l,3]dioxol-4-yl]carbamate 2hC6.8 g, 19.35 mmol) dissolved in 150 mL of methanol, palladium on carbon (10%, 600 mg) The hydrogen was replaced three times and stirred at room temperature for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the crude title product 2-{[(3aR,4S,6R,6aS/3aS,4R,6 6aR)-6-amino-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 2i (4.43 g, pale yellow liquid), product was directly purified without purification One step reaction.

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

1H NMR (400 MHz, CDC1 ₃ ) 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).

Step 10

2-(cyclopropylmethylmercapto)pyrimidine -4,6-diol

2-Mercaptopyrimidine-4,6-diol 2j (10.0 g, 69.3 mmol) was dissolved in 30 mL of water, sodium hydroxide (6.4 g, 160 mmol) was added, stirred for 40 min, 20 mL water was added, and then added 1 -methylpyrrol-2-one (20.6 g, 207.9 mmol) bromomethylcyclopropane (9.6 g, 71.4 mmol), stirred at 20 ° C for 12 h, then added 30 mL 1 M hydrochloric acid then 15 mL 6 M hydrochloric acid. After stirring for 12 h, it was filtered, washed sequentially with water (10 mL×4)-ethanol (10 mL)-water (10 mL×2) and dried to give the title product 2- (cyclopropylmethylmethyl)pyrimidine-4,6-diol 2k (12.0 g, white solid), Yield: 87.6%.

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

The eleventh step

2-(cyclopropylmethylhydrazino)-5-toluene azide pyrimidine-4,6-diol dissolves 4-methylaniline (6.7 g, 62 mmol) and 36% hydrochloric acid (18.7 mL, 224 mmol) In 20 mL of water, 20 mL of sodium nitrite solution (4.5 g, 65 mmol) was added dropwise in an ice bath. After the addition was completed, the solution was kept in an ice bath and the solution was reserved.

Dissolve 2-(cyclopropylmethylmercapto)pyrimidine-4,6-diol 2k (10 g, 50 mmol) in 100 mL of a mixed solvent of water and ethanol (V/V = 1:1), and add sequentially Sodium hydroxide (1.92 g, 48 mmol) and sodium acetate (20.83 g, 254 mmol) were added dropwise to the reaction solution under ice-cooling, and allowed to react at room temperature for 24 hours. 15 mL of concentrated hydrochloric acid was added to adjust pH = 1 and a solid precipitated, which was filtered, washed with water (100 mL) and dried in vacuo to give the title product 2- (cyclopropylmethyl decyl) -5-(toluene azide) Pyrimidine-4,6-diol 2 m (14.1 g, yellow solid), Yield: 78.4%.

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

Step 12

(E)-[4,6-Dichloro-2-(cyclopropylmethylmethyl)pyrimidin-5-yl]-toluene) 2-(cyclopropylmethylmercapto)-5-toluene azide pyrimidine-4,6-diol 2m (12.2 g, 39 mmol) was suspended in 40 mL of toluene, and pyridine C6 mL was added at 70 ° C, 77 Methyl), phosphorus oxychloride (44 mL, 482 mmol) was added dropwise below 94 ° C for 4.5 hours. The reaction solution was cooled to room temperature, and poured slowly into 400 mL of ice water, stirred at room temperature for 1 hour, extracted with ethyl acetate (100 mIX3), and the organic phases were combined and washed sequentially with saturated sodium chloride solution (200 mL) The residue was purified by EtOAcjjjjjjjjjjjjjj巯 )) pyrimidin-5-yl] toluene) 肼 2n (9.5 g, red solid), Yield: 69.9%.

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

Step 13

4,6-dichloro-2-(cyclopropylmethylmercapto)pyrimidine-5-amine

(E)-[4,6-Dichloro-2-(;cyclopropylmethylhydrazino)pyrimidin-5-yl]-(toluene) 2N (9.5 g, 27 mmol) was dissolved in 190 mL ethyl acetate Palladium on carbon (10%, 2.56 g) was added, and the hydrogen was replaced three times, and reacted at room temperature for 9 hours under a pressure of 3 atm. The reaction solution was filtered, concentrated to 40 mL at 40 ° C, washed with 3 M hydrochloric acid (30 mL X 2), and adjusted to pH = 1.5~2 with 3 M hydrochloric acid, and the filtrate was concentrated under reduced pressure to give crude title product 4, 6 -Dichloro-2-(cyclopropylmethylmercapto)pyrimidine-5-amine 2p (6.5 g, dark red oil).

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

Fourteenth step

2-{[(3aR,4^6R,6aS/3aS,4R,6 6aR)-6-[[5-amino-6-chloro-2-(cyclopropylmethylmercapto)pyrimidin-4-yl]amino -2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol

4,6-Dichloro-2-(cyclopropylmethylmercapto)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-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl] Oxygen}ethanol 2i (500 mg, 2.3 mmol) was dissolved in 15 mL of ethylene glycol and reacted at 100 ° C for 7 hours. 50 ml of ethyl acetate and 50 ml of water were added to the reaction mixture, and the mixture was washed with water (10 mL EtOAc) The residue obtained was purified by column chromatography using eluent system B to give the title product 2- {[3 & 4 6 6 & ^ 3 & 4 6 6 & -6-[[5-amino-6-chloro-2-(cyclopropyl) (1,3)dioxole- 4-yl]oxy}ethanol 2q (250 mg, dark red oil), Yield: 25.2%.

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

Step fifteenth

2-{[(3aR,4^6R,6aS/3a^4R,6 6aR)-6-[7-chloro-5-(cyclopropylmethylhydrazino)triazolo[4,5-d]pyrimidine- 3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy} Ethanol

2-{[(3aR,4S,6R,6aS/3aS,4R,6 6aR)-6-[[5-Amino-6-chloro-2-(cyclopropylmethylhydrazine) under ice bath Pyrimidin-4-yl]amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxole-4 -Acetyloxy}ethanol 2q (250 mg, 0.58 mmol) was dissolved in 1 mL of acetic acid, sodium nitrite (42 mg, 0.61 mmol) was added and reacted at 0 ° C for 20 min. 10 mL of ethyl acetate and 50 mL of saturated sodium carbonate solution were added to the reaction mixture, and the mixture was separated, and extracted with ethyl acetate (50 mL X 2), and the organic phase was combined with saturated sodium carbonate (50 mL) and saturated sodium chloride The solution (50 mL) was washed with EtOAc EtOAc (mjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ,6aS/3aS,4R,6 6aR)-6-[7-chloro-5-(cyclopropylmethylhydrazino)triazolo[4,5-d]pyrimidin-3-yl]-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 2r (212 mg, pale yellow oil ), Yield: 82.8%.

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

Step 16

2-{[((3aR,4 6R,6aS/3aS,4R,6 6aR)-6-[5-(cyclopropylmethylhydrazino)-7-[[(lR,2^-2-(3, 4-Difluorophenyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- Cyclopentene[d][l,3]dioxol-4-yl]oxy}ethanol 2-{[(3aS,4^6R/3aR,4^6R)-6-[7 -chloro-5-(cyclopropylmethylhydrazino)triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH -cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 2r (212 mg, 0.48 mmol) and (lR,2 -2-(3,4-difluorobenzene) Cyclopropylamine L-(+)-tartrate lg (207 mg, 0.65 mmol) was dissolved in 15 mL of acetonitrile, and triethylamine (170 mg, 1.68 mmol) was added for 24 hours. Reduce, add 50 mL of ethyl acetate and 50 mL of water, add 2.5 M hydrochloric acid to adjust ρΗ<4, separate the liquid, extract the aqueous phase with ethyl acetate (300 mL X 2), combine the organic phase, and use saturated brine (50 mL) X 2) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 2-{[(3& 4 6 6& /3& 4 6 6& -6-[5-(cyclopropylmethylmercapto)-7-[[(lR,2 -2-(3,4-difluoro)) Phenyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 2s (225 mg, pale yellow solid), yield: 81.5%.

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

Step 17

(1R,2R,3 5R/ lS,2^3R,5^-3-{5-(cyclopropylmethylhydrazino)-7-[ (lR,2S)-2-(3,4-difluorobenzene Cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2-diol will be 2-{[(3aR, 4S,6R,6aS/3aS,4R,6 6aR)-6-[5-(cyclopropylmethylhydrazino)-7-[[(lR,2 -2-(3,4-difluorophenyl)) ring Propylamino]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[l,3 Dioxol-4-yl]oxy}ethanol 2s (225 mg, 0.39 mmol) was dissolved in 15 mL of methanol, and then added with 2.5 M hydrochloric acid (4.5 mL, 1 1.25 mmol) for 24 hours. Sodium hydroxide solution, adjust ρ Η ≥ 7, add 60 mL of ethyl acetate and 20 mL of water, stir for 15 minutes, separate the liquid, extract the aqueous phase with ethyl acetate (300 mL X 2), combine the organic phase, with saturated brine (50 mL X 2) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, recrystallized from 4.7 The obtained solid was purified by column chromatography using eluent system B to give the racemic product (1R, 2R, 3 5R / 1 2^3R, 5S)-3-{5-(cyclopropylmethylhydrazino)- 7-[ (lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethyl Oxy)cyclopentyl-1,2-diol 2s (149 mg, colorless oil), yield: 71.5%.

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

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (d, 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).

Eighteenth step

(1 2 3 5 -3-{5-(cyclopropylmethylhydrazino)-7-[(1 2 -2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4, 5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (1 2^3 5 -3-{5-(cyclopropylmethyl) Sulfhydryl)-7-[(1 2 -2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyl Ethoxy)cyclopentyl-1,2-diol 3 a mixture of diastereomers (1R, 2R, 3 5R 1 2 3R, 5 -3- {5-(cyclopropylmethyldecyl) - 7-[ (lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxyl The title product (lR, 2R, 3WR) is obtained by separation of the chiral isomers using a chiral column by HPLC method using hexanes-1,2-diol 2s (149 mg, EtOAc). 3-{5-(cyclopropylmethylhydrazino)-7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5-d]pyrimidine 3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (61.8 mg, colorless oil), yield: 41.5%; (1 2 3R,5 - 3-{5-(cyclopropylmethylhydrazino)-7-[ (lR,25)-2-(3,4-difluorophenyl)cyclopropylamide Triazolo[4,5-pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 3 (61.5 mg, colorless oil), yield: 41.3 %: MS m/z (ESI): 535.3 [M+l]

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

(1 2^3R,5 -3-{7-[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

the fourth step

first step

2-chloro-l-Ochloro-2-thienyl)ethanone

Dissolve 2-chloroacetyl chloride (22.5 g, 0.2 mol) in 100 mL of dichloromethane, add aluminum trichloride (24 g, 0.18 mol), stir at room temperature, and add 150 mL of 2-chlorothiophene (23.72 g, 0.2 mol) of a dichloromethane solution was reacted for 3.5 hours. To the reaction mixture, a mixture of 125 mL of ice water and 35 mL of concentrated hydrochloric acid was added, and the mixture was stirred for 30 minutes. The organic phase was washed with saturated sodium chloride (150 mL EtOAc) The crude title product 2-chloro-1-(5-chloro-2-thienyl)ethanone 4a (32 g, yellow oil) was obtained.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, / = 4.12 Hz, 1H), 7.00 (d, / = 4.12 Hz, 1H), 4.52 (s, 2H).

Second step

(1 -2-chloro-l-(5-chloro-2-thienyl)ethanol

Dissolve S)-diphenyl-pyrrolidin-2-yl-methanol (2.08 g, 8.2 mmol) in 45 mL of toluene, add trimethyl borate (1.1 g, 11.5 mmol), and react at 40 ° C for 1.5 hours. , keep 35 ° C ~ 45 ° C drop plus two Methyl sulfide borane (65.5 mL, 131 mmol), reacted at 40 ° C for 1 hour, maintained at 35 ° C ~ 45 ° C, 150 2-chloro-1-(5-chloro-2) was added dropwise over 1.5 hours. -Thienyl)ethanone 4 & (32 _§ , 0.16 mol) in toluene solution, reaction for 12 hours. The reaction solution was kept below 35 ° C, 30 mL of methanol was added dropwise, cooled to 20 ° C, stirred for 30 minutes, and the reaction liquid was concentrated under reduced pressure to remove methanol and trimethyl borate, and washed with 10% acetic acid (100 mL X 4 ). The combined aqueous phases were extracted with EtOAc (EtOAc) (EtOAc) Ethanol 4b (32.3 g, yellow oil).

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

third step

(lR,2R)-2-(5-Chloro-2-thienyl)cyclopropylcarboxylic acid ethyl ester 60% sodium hydride (13.12 g, 0.33 mol) was suspended in 50 mL of toluene and heated to 40 ° C. A solution of ethyl 2-diethoxyphosphorylacetate (40.5 g, 0.18 mol) in toluene was added dropwise, and the mixture was reacted at 40 ° C for 1 hour, dropwise (1 -2-chloro-1-(5-chloro-2-) a solution of thienyl)ethanol 4b (32.3 g, 0.16 mol), stirred at 60 ° C for 12 hours, added with 150 mL of water, separated, and then dried over anhydrous sodium sulfate and purified by silica gel column chromatography with eluent system B The residue was obtained to give the title compound (l,,,,,,,,,,,,,,,,,

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fourth step

(lR, 2R)-2-(5-chloro-2-thienyl)cyclopropylcarboxylic acid

Ethyl (lR,2R)-2-(5-chloro-2-thienyl)cyclopropylcarboxylate 4c (10.9 g, 0.047 mol) was dissolved in 80 mL of ethanol, and 30% sodium hydroxide solution (3.4 g) , 0.085 mol), stirring for 4.5 hours, concentrating most of the ethanol under reduced pressure, adding 100 mL of water and 100 mL of toluene, adding concentrated hydrochloric acid dropwise, adjusting pH ≤ 7, layering, and extracting the aqueous phase with toluene (100 mL X 2 ) The organic phase was combined, washed with EtOAc EtOAc (EtOAcjjjjjjj Cyclopropyl formic acid 4d (7.8 g, yellow liquid), Yield: 81.6%.

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

the fifth step

(lR, 2R)-2-(5-chloro-2-thienyl)cyclopropylcarbonyl chloride

(lR,2R)-2-0chloro-2-thienyl)cyclopropylcarboxylic acid 4d (3.24 g, 16 mmol) was dissolved in 10 mL of toluene, and dichloromethane (3.04 g, 25.6 mmol) was added dropwise. After stirring at 25 ° C for 24 hours, the reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated to give the crude title product 5 <RTIgt; (lR,2R)-2-(5-chloro-2-thienyl) cyclopropyl. A solution of the acid chloride 4e (3.53 g) in toluene was taken directly to the next reaction without purification.

Step 6

(lR,2R)-2-(5-chloro-2-thienyl)cyclopropanoyl azide

Dissolve sodium azide (1.0 g, 16.8 mmol), sodium carbonate (0.76 g, 7.2 mmol) and n-butylammonium bromide (0.16 g, 0.48 mmol) in 10 mL of water, cool to 0 ° C, and add the crude 15 mL (lR, 2R)-2-(chloro-2- a solution of thienyl)cyclopropylcarbonyl chloride 4e (3.53 g, 16 mmol) in toluene, stirring at 0 ° C for 3 hours, adding 10 mL of ice water to the reaction mixture, layering, and the aqueous phase with toluene (20 mL) The organic phase was combined and washed with EtOAc (EtOAc) (EtOAc) Toluene solution of chloro-2-thienyl)cyclopropanoyl azide 4f, the product was directly subjected to the next reaction without purification.

Seventh step

(lR, 2R)-2-(5-chloro-2-thienyl)cyclopropylamine

20 mL of toluene was placed in a 250 mL three-necked flask, heated to 100 ° C, and 35 mL of the crude (lR, 2R)-2-(5-chloro-2-thienyl)cyclopropanoyl complex of the above procedure was added dropwise. A toluene solution of nitrogen 4f was reacted at 100 ° C for 1 hour, cooled to room temperature, and the solution was used.

2.5 M hydrochloric acid (19.2 mL, 48 mmol) was heated to 80 ° C, and 80 ° C was added dropwise to the above-mentioned standby solution. The mixed solution was reacted at 80 ° C for 1.5 hours, added to 45 mL, cooled to room temperature, and separated. The toluene layer was discarded, the aqueous phase was adjusted to pH-12 with saturated aqueous sodium hydroxide, and ethyl acetate (35 mL EtOAc) was evaporated. The title product (lR,2R)-2-(5-chloro-2-thiazyl)cyclopropylamine 4 g (715 mg, yellow oil) was obtained.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Eighth step

2-{[(3& 4 6 6& /3&^^,6 6& -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl 4-(5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 2-{[(3aR,4S,6R ,6aS/3aS,4R,6 6aR)-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxa Cyclopenten-4-yl]oxy}ethanol 2i (1.95 g, 9 mmol) was dissolved in 30 mL of ethylene glycol and 4,6-dichloro-2-propylindenyl-pyrimidine-5-amine ls ( 2.6 g, 10.8 mmol) and triethylamine (4.5 g, 45 mmol), react at 100 ° C for 12 hours, cool to room temperature, add 150 mL of ethyl acetate and 150 mL of saturated sodium chloride solution, stir for 20 minutes, The mixture was extracted with EtOAc (EtOAc)EtOAc. The resulting residue was purified to give the title product 2-{[(3aR,4S,6R,6aS /3aS,4R,6 6aR)-6-[(5-amino-6-chloro-2-propyl) Mercapto-pyrimidin-4-yl)amino]-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 4h (1.8 g, brownish yellow oil) , Yield: 47.6%.

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

Step 9

2-{[(3& 4 6 6& /3& 4 6 6& -6-(7-chloro-5-propylindolyl-3^[1,2,3]-triazolo[4,5-^]pyrimidine- 3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy) Ethanol

Under the ice bath, 2-{[(3aR,4S,6R,6aS /3aS,4R,6 6aR)-6-[(5-amino-6-chloro-2-propylindolyl-pyrimidine) Pyridin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl Oxygen}ethanol 4h (1.8 g, 4.3 mmol) was dissolved in 7.2 mL of acetic acid, sodium nitrite (310 mg, 4.5 mmol) was dissolved in 3 mL of water, added dropwise to the above solution in portions, stirred for 30 minutes and then added. 60 mL of ethyl acetate, then 30 mL of saturated potassium carbonate solution, quenched and partitioned. The aqueous phase was extracted with ethyl acetate (50 mL X 2) and the organic phase was combined with saturated potassium carbonate solution (80 mL) It was washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate. 6R,6aS /3aS,4R,6 6aR)-6-(7-chloro-5-propylindolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl) -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 4j (1.27 g, light yellow solid), Yield: 69.0%

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

1H NMR (400 MHz, CDC1 ₃ ) δ 5.54-5.52 (m, 1H), 5.22-5.19 (m, 1H), 4.89-4.87 (d, J = 6.36 Hz, 1H), 4.06-4.03 (m, 1H) , 3.64-3.54 (m, 3H), 3.52-3.48 (m, 1H), 3.21 (t, / = 7.08 Hz, 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, / = 7.36 Hz, 3H).

Step 10

2-{[(3& 4^6 6& /3&^^,6 6& -6-[7-[[(1 2 -2-(5-chloro-2-thienyl)cyclopropyl]amino] -5- Propylmercapto-triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene

[d][l,3]dioxol-4-yl]oxy}ethanol

2-{[(3& 4^6 6& /3& 4 6 6& -6-(7-chloro-5-propyldecyl-triazolo[4,5-pyrimidin-3-yl)-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 4j (215 mg, 0.5 mmol) dissolved Add (1R,2R)-2-(5-chloro-2-thienyl)cyclopropylamine 4g (117 g, 0.68 mmol) to 15 mL of acetonitrile, stir at 25 ° C or below, add triethylamine (177.1) Mg, 1.75 mmol), stirred at 25 °C for 12 hours, concentrated most of the acetonitrile under reduced pressure, then added 30 mL of water and 30 mL of ethyl acetate, adjusted ρΗ-4 with 2.5 M hydrochloric acid, and separated. The ester was extracted with EtOAc (EtOAc) (EtOAc (EtOAc. 2-{[OR,4S,6R,6aS /3aS,4R,6S,6aR)-6-[7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl] Amino]-5-propyldecyl-triazolo[4,5-pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[ l,3]dioxol-4-yl]oxy}ethanol 4k (245 Mg, light yellow solid), Yield: 86.6%

1H NMR (400 MHz, CDC1 ₃ ) 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).

The eleventh step

(1 2^3R,5S/lR,2R,3^5R)-3-{7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino] -5 -propylmercapto-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentane-1,2-di Alcohol 2-{[(3aR, ^,6R,6aS /3aS,4R,6 6aR)-6-[7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl) Amino]-5-propyldecyl-triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentyl Alkene W][l,3]dioxol-4-yl]oxy}ethanol 4k (245 mg, 0.43 mmol) was dissolved in 15 mL of methanol, and 5 mL of 2.5 M hydrochloric acid was added dropwise at 20 ° C. After stirring for 12 hours at ° C, the reaction mixture was adjusted to pH Η-7 with a saturated sodium hydroxide solution, and extracted with ethyl acetate (35 mL X 3 ). The organic phase was combined and washed with saturated sodium chloride solution (40 mL X 2 ), anhydrous sulfuric acid The sodium was dried, and the filtrate was concentrated under reduced pressure. 1.5 mL ethyl acetate was added to the crude mixture, and the mixture was stirred at 57 ° C for 10 minutes, then 2 mL of n-hexane was added, and the mixture was stirred at 57 ° C for 1 hour, cooled to room temperature, and filtered to give the title. Product (1^2S,3R,5S/lR,2R,3^5R)-3-{7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino] -5-propyldecyl-triazolo[4,5-d]pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentane-1,2-diol 4m (190 mg, pale yellow solid ), Yield: 83.7%.

1H NMR (400 MHz, DMSO-J ₆ ) δ 9.33 (d, J = 6.36 Hz, 1H), 6.95 (d, J = 3.76 Hz, 1H), 6.78 (d, J = 3.72 Hz, 1H), 5.11 ( d, / = 6.40 Hz, 1H), 5.05 (d, J = 4.08 Hz, 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, / = 7.32 Hz, 3H).

Step 12

(1 2^3R,5 -3- {7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol (1S,2 3R,5S/lR,2R,3^5R) -3- {7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[4,5-d]pyrimidine -3-yl 5-(2-hydroxyethoxy)cyclopentane-1,2-diol 4m (190 mg, 0.36 mol), isolated by chiral column of chiral isomers by HPLC The title product was obtained (1 2^3R,5 -3-{7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl- Zizo[4,5-pyrimidin-3-yl 5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 4 (52 mg, yellow solid yield: 27.3%.

MS m/z (ESI): 527.1 [M ⁺ ]

1H NMR (400 MHz, DMSO-J ₆ ) δ 9.33 (d, J = 6.36 Hz, 1H), 6.95 (d, J = 3.76 Hz, 1H), 6.78 (d, J = 3.72 Hz, 1H), 5.11 ( d, / = 6.40 Hz, 1H), 5.05 (d, J = 4.08 Hz, 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, / = 7.32 Hz, 3H). Example 5

(1 2 3 5R)-3-(2-hydroxyethoxy)-5-{7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-pyrimidine- 3-yl}cyclopentyl-1,2-diol

(3aR4S6R6a^-6-Amino-2,2-dimethyl-4566a-tetrahydro-3aH-cyclopentene M[l 3]dioxol-4-ol L-(-)-diphenyl Formyl tartrate

Will (3& 4 7 7&5>3& 4 7 7& -22-dimethyldihydro-3& 47-methylene [13]dioxole[45-^][12]oxazin-6 (4H Benzyl formate 2d (20 g 65.5 mmol) was added to 400 mL of methanol, palladium on carbon (lg 5%) was added, three times of hydrogen was replaced, and reacted at 50 ° C for 24 hours, filtered, and L-(-)-diphenyl was added. Formyl tartaric acid (23.4 g, 65.5 mmol), concentrated under reduced pressure, 262 mL of acetonitrile and 43.7 mL of water were added to the mixture. The mixture was stirred at 60 ° C for 1 hour, and then allowed to cool to room temperature. The solid was slowly precipitated and stirred at room temperature for 12 hours. Product (3aR4S6R6a^-6-Amino-2,2-dimethyl-4566a-tetrahydro-3aH-cyclopentene M[l 3]dioxol-4-ol L+)-dibenzoyl Tartrate 5a (11.8 g, off-white solid), Yield: 33.9% MS m/z (ESI): 174.1 [M+l]

Second step

N-[(3aS4R6 6aR)-6-Hydroxy-2,2-dimethyl-4566a-tetrahydro-3aH-cyclopentene M[l 3]dioxol-4-yl]carbamic acid benzyl Ester

(3aR^6R6a -6-Amino-2,2-dimethyl-4566a-tetrahydro-3aH-cyclopentene M[l 3]dioxol-4-ol L-)-diphenyl Formyl tartrate 5aC11.8 g 22.2 mmol) was dissolved in a mixed solvent of 195 mL of tetrahydrofuran and water (V/V = 10:3), potassium carbonate was added dropwise, and benzyl chloroformate (7.57 g 22.2 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssss The residue was slurried with a mixed solvent of 63 mL of n-hexane and dichloromethane (V/V = 20:1), filtered, and the filter cake was dried in vacuo to give the title product N-[(3aS4R6 6aR 6-hydroxy-2,2- Dimethyl-4566a- Benzyl tetrahydro-3aH-cyclopenteno[d][l,3]dioxol-4-yl]carbamate 5b (6.51 g, white solid), yield: 95.4%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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).

third step

2-[[(3aR,4S,6R,6a -6-benzyloxycarbonylamino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene

M[l,3]dioxol-4-yl]oxy]acetate

N-[(3aS,4R,6 6aR)-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxo Benzene heterocyclopenten-4-yl]carbamate 5b (2 g, 6.51 mmol) was dissolved in 20 mL of tetrahydrofuran, and potassium t-butoxide (3.65 g, 9.76 mmol) was added dropwise in a dry ice bath. The reaction was carried out at ° C for 1 hour, and ethyl bromoacetate (1.63 g, 9.76 mmol) was added dropwise at -20 ° C or less, and the reaction was carried out at -20 ° C for 1 hour, and the mixture was naturally warmed to room temperature, stirred for 12 hr. The residue obtained was purified by silica gel column chromatography eluting elut elut elut elut ,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy]acetate 5c (2.16 g, pale yellow oil), Rate: 84.2%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fourth step

N-[(3aS,4R,6 6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene

W][l,3]dioxol-4-yl]carbamic acid benzyl ester

2-{[(3aR,4^6R,6a -6-benzyloxyamide-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene-W][l , 3]dioxol-4-yl]oxy}acetate 5c (8 g, 20.34 mmol) was dissolved in 60 mL of THF, EtOAc (EtOAc, EtOAc, The reaction mixture was poured into water (150 mL), EtOAc (EtOAc) OS,4R,6 6aR)-6-(hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxo Benzene heterocyclopenten-4-yl]carbamate 5d (7.04 g, light yellow mp.).

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

the fifth step

2-{[(3aR,4S,6R,6a^-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Olelenyl-4-yl]oxy}ethanol

N-[(3aS,4R,6 6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M Benzyl [l,3]dioxol-4-yl]carbamate 5d ( .04 g, 20.03 mmol) dissolved in 100 mL To the methanol, palladium on carbon 350 mg, 5%) was added, and the mixture was stirred three times with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-yl]oxy)ethanol 5e (4.54 g , light yellow oil), the product was directly subjected to the next reaction without purification.

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

Step 6

2-{[OR,4S,6R,6a -6-[0amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6 ,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethanol will be crude 2- { [(3aR,45,6R,6a5)- 6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 5e (1.5 g, 6.9 mmol) was dissolved in 25 mL of ethylene glycol and added triethylamine (3.49 g, 34.5 mmol) and 4,6-dichloro-2-propylindolyl-pyrimidine-5-amine ls (l .98 g, 8.28 mmol), react at 100 ° C for 12 hours, cool to room temperature, add 100 mL of ethyl acetate and 100 mL of saturated sodium chloride solution, stir for 20 minutes, dispense, and the aqueous phase with ethyl acetate (50 mL) X 3) extraction, the organic phase was combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The title product 2-{[(3aR,4S,6R,6a -6-[(5-amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentyl And M [l, 3] dioxol-4-yl] oxy) ethanol 5f (1.6 g, yellow oil). Yield: 55.4%.

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

Seventh step

2-{[(3aR,4S,6R,6a^-6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl 4-[5,6,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethanol in an ice bath, 2-{[ (3aR,4 6R,6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a -tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 5f (1.6 g, 3.8 mmol) dissolved in 6.5 mL of acetic acid, stirred, added dropwise 3 mL of sodium nitrite (277 mg, 4 mmol) solution, stirring for 30 minutes in an ice bath, adding 50 mL of ethyl acetate and 30 mL of saturated potassium carbonate solution, quenching, liquid separation, and ethyl acetate (50) The mixture was extracted with EtOAc (3 mL), EtOAc (EtOAc)EtOAc. The resulting residue was purified by eluent B to give the title product 2-{[(3aR,45,6R,6a5)-6-(7-chloro-5-propylindolyl-triazolo[4,5-J] Pyrimidin-3-yl)-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 5g CU8 g, pale yellow viscous), Yield: 72.4%.

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

Eighth step

2-{[(3aR,4S,6R,6a -6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl -2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 2 - {[(3aR,4S,6R,6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl -4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-yl]oxy}ethanol 5g (100 mg, 0.23 mmol) dissolved in 8 mL Add 2-aminoindan (418 mg, 0.31 mmol) to acetonitrile, stir, add triethylamine (82.2 mg, 0.81 mmol) dropwise, stir at room temperature for 24 hours, add 15 mL of water to the reaction solution, adjust with 2.5 M hydrochloric acid The organic phase was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) - {[(3aR,45,6R,6a5)-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-pyrimidin-3-yl]- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 5h (100 mg , light yellow solid), the product was directly subjected to the next reaction without purification.

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

Step 9

(1S,2 3 5R)-3-(2-hydroxyethoxy)-5-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-d Pyrimidin-3-yl]cyclopentyl-1,2-diol

The crude product is 2-{[(3aS,4R,6 6aR)-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5-d]pyrimidine-3 -yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 5h (100 mg, 0.19 mmol) dissolved in 5 mL of methanol, added with hydrochloric acid (4 mL, 2.5 M), stirred for 12 hours, and then added saturated sodium hydroxide solution to adjust ρΗ-9, ethyl acetate (30 mL) X 2), the organic phase is combined, washed with a saturated sodium chloride solution (25 mL of EtOAc), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The title product (lS, 2S, 3S, 5R)-3-(2-hydroxyethoxy)-5-[7-(indanyl-2-ylamino)-5-propyldecyl-triazole was obtained. [4,5-d]pyrimidin-3-yl]cyclopentyl-1,2-diol 5 (75 mg, white solid), yield: 81.2%.

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

1H NMR (400 MHz, DMSO-J ₆ ) δ 7.25 (m, 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, / = 7.18 Hz, 3H). Example 6

(1^2S,3 4 -5-{7-[[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propyldecyl-triazole

[4,5--3-yl}cyclopentyl-1,2,3,4-tetraol

first step

5-nitro-2-propylmercapto-pyrimidine-4,6-diol

2-propylmercapto-pyrimidine-4,6-diol 6a (prepared by the well-known method "patent WO2001092263" to obtain X8.0 g, 43 mmol) was dissolved in 35 mL of fuming nitric acid under ice-water bath, 0 The reaction was carried out at ° C for 1.5 hours. The reaction solution was poured into ice cubes, stirred at room temperature for 1 hour, a small amount of solid was precipitated, potassium carbonate was added to the reaction solution, pH=1~2, a large amount of solid was precipitated, filtered, and the filter cake was washed with water (50 mL×2), and dried. The crude title product 5-nitro-2-propylindolyl-pyrimidine-4,6-diol 6b (11.1 g, yellow powdery solid) was obtained. Yield: 100%. 1H NMR (400 MHz, CDC1 ₃ ) 53.27-3.17 (t, 2H), 1.90-1.74 (m, 2H), 1.1 1 (t, 3H).

Second step

4,6-chloro-5-nitro-2-propylindolyl-pyrimidine

The crude 5-nitro-2-propylindolyl-pyrimidine-4,6-diol 6b (1.0 g, 4.3 mmol) was dissolved in phosphorus oxychloride (8.4 g, 85.64 mmol) and N,N-di Ethylaniline (1.12 g, 7.5 mmol). The reaction was refluxed for 1.5 hours. The reaction mixture was poured into ice, and stirred for 20 min, EtOAc (EtOAc) The title product was 4,6-chloro-5-nitro-2-propylindolyl-acridine _6c (0.45 g, m.

third step

0 6 -2,2-dimethyl-6,6&-dihydro-3&^cyclopentene[^][1,3]dioxol-6-ol will be bis(tricyclohexylphosphine) Benzylphosphonium chloride 6d (177 mg, 0.216 mmol) was added to the reaction flask, and 40 mL of l-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3 was added to the syringe. - Dioxalan-4-yl]prop-2-enol lm (2 g, 10.8 mmol) in chloroform solution, which was reacted for 2 hr. The reaction solution was concentrated under reduced pressure and applied to silica gel column chromatography The obtained residue was purified with eluent B to give the title product (3aR, 6-2,2-dimethyl-6,6a-dihydro-3aH-cyclopentene and W][l,3]dioxa Cyclopentene-6-ol 6e C450 mg, brownish black oil, yield: 26.7%. 1H NMR (400 MHz, DMSO-J ₆ ) 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).

the fourth step

(4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-amine triphenylphosphine (3.26 g, 12.43 mmol) was dissolved in 30 mL of tetrahydrofuran, and diisopropyl azodicarboxylate (2.5 mL, 12.43 mmol) was added dropwise at -20 °C, and reacted at -20 ° C for 10 minutes, and 20 mL (3aR, 6) was added dropwise. a solution of -2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[[1,3]dioxol-6-ol 6e (1.77 g, 11.3 mmol) in tetrahydrofuran, After reacting at -20 ° C for 30 minutes, the temperature was raised to 0 ° C, diphenyl azide phosphate (3.73 g, 13.56 mmol) was added dropwise, and reacted at 0 ° C for 7 hours, and triphenylphosphine (3.26 g, 12.43 mmol) was added. The reaction was carried out at 0 ° C for 12 hours, 5 mL of water was added, the reaction was carried out for 8 hours, and the reaction was carried out for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give crude title product (4,,,,,,,,, , 6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-amine 6f (1.7 g, colorless oil).

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fifth step

N-[(3aR,6R)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-6-yl]carbamic acid benzyl Ester

C4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M [1,3]dioxol-4-amine 6f (1.7 g, 11 mmol Dissolve in 20 mL of tetrahydrofuran, add 10 mL of water and potassium carbonate (3.04 g, 22 mmol), add benzyl chloroformate (4.5 mL, 13.2 mmol), and react for 12 hours, and extract with ethyl acetate (20 mL×2). The organic phase was combined, dried and evaporated tolulujjjjjjjjjjjjjj Hydrogen-3aH-cyclopentenyl M[l,3]dioxol-6-yl]carbamic acid benzyl ester 6g (570 mg, white solid), yield: 17.9%.

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

Step 6

((3aS,4R,5 6 6aR)-5,6-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl Benzyl carbamate

N-[(3aR,6R)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[l,3]dioxol-6-yl]carbamic acid benzyl Ester 6g (570 mg, 1.97 mmol) was dissolved in 10 mL of tetrahydrofuran, and N-methyl oxidized morpholine (0.94 mL, 4 mmol) and osmium tetroxide (102 mg, 0.4 mmol) were added for 12 hours. Water, ethyl acetate (60 mL×3), EtOAc (EtOAc) (EtOAc) The obtained residue was purified to give the title product (3aS, 4R, 5 6 6 aR)-5,6-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene and M[l,3]dioxa Benzyl cyclopenten-4-yl)carbamate 6h (500 mg, colorless oil), yield: 78.0%.

MS m/z (ESI): 324.3 [M+1] 1H NMR (400 MHz, CDC1 ₃ ) 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).

Seventh step

OR,4S,5 6R,6a -6-amino-2,2-dimethyltetrahydro-3aH-cyclopentene M[l,3]dioxole

-4,5-diol

(3aS,4R,5 6 6aR)-5,6-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl Benzyl carbamate 6h (500 mg, 1.54 mmol) dissolved in 15 mL of methanol, added palladium / carbon (150 mg, 10%), three times with hydrogen, stirred for 12 hours, added to diatomaceous earth, filtered, filtrate reduced Concentration gave the crude title product OR,4S,5 6R,6a -6-amino-2,2-dimethyltetrahydro-3aH-cyclopenteno[d][l,3]dioxole -4,5-diol 6j (270 mg, colorless oil).

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

1H NMR (400 MHz, CDC1 ₃ ) 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).

Eighth step

(3aR,4S,5 6R)-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6 ,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4,5-diol will be OR,4S,5 6R,6a^-6-amino-2,2-di Methyltetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol 6j (270 mg, 1.42 mmol) was dissolved in 15 mL of ethanol and triethylamine was added ( 0.4 mL, 2.84 mmol), 4,6-chloro-5-nitro-2-propylindolyl-pyrimidine 6b (419 mg, 1.57 mmol), mp. The residue obtained was purified by eluent system A to give the title product (3aR, 4S, 5^6R)-6-[(6-chloro-5-nitro-2-propylindenyl-pyrimidin-4-yl) Amino] -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4,5-diol 6kC390 mg, Yellow solid), Yield: 65.4%.

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

Step 9

OR,4S,5 6R,6a -6-[0 amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl

-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol will be OR,4S,5 6R)-6-[( 6-Chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M [l,3]dioxol-4,5-diol 6k (390 mg, 0.93 mmol) dissolved in 10 mL of acetic acid, iron powder (260 mg, 4.64 mmol), reacted for 12 hours, added 50 Ethyl acetate, stirred, filtered, EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjjjj The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut Pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole-4,5 -diol 6 m (200 mg, brown solid), Yield: 55%. MS m/z (ESI): 391.1 [M+1]

1H NMR (400 MHz, DMSO-J ₆ ) 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).

Step 10

(3aR,4S,5 6R)-6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4,5-diol will be OR, ^, 5S, 6R, 6a -6-[0 amino-6 -Chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Oxycyclopentene-4,5-diol 6m (200 mg, 0.51 mmol) was dissolved in 4 mL of acetic acid, 0.5 mL water was added, and 0.5 mL of sodium nitrite (38.9 mL, 0.56 mmol) in ice water was added dropwise. After stirring for 5 minutes, 60 mL of ethyl acetate was added, EtOAc (EtOAc) (EtOAc) , the crude title product (3aR, 4S, 5^6R)-6-(7-chloro-5-propylindolyl-triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl -4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol 6n (220 mg), brown oil, product The next reaction was carried out directly by purification.

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

The eleventh step

(3aR,4S,5^6R)-6-{7-[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole

-4,5-diol

(3aR,4S,5^6R)-6-(7-chloro-5-propylindolyl-triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol 6n (80 mg, 0.2 mmol) was dissolved in 10 mL of acetonitrile and added ( lR, 2^-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (58.8 mg, 0.28 mmol), stirred, triethylamine (0.1 mL, 0.7 mmol) After reacting for 12 hours, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2R)-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl 2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4,5-diol 6p (107 mg, pale yellow oil), yield 100 %.

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

Step 12

(1 2 3 4 -5- {7-[ (1 2 -2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

(3aR,4S,5^6R)-6- {7-[(lR,2R)-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyldecyl-triazole [4,5-d]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole Ethylene-4,5-diol 6p (107 mg, 0.2 mmol) was dissolved in 8 mL of methanol, added to 2 mL of 2 M hydrochloric acid and stirred for 12 hr. The mixture was extracted with ethyl acetate (60 mL×3). To the title product (; 1 2^3 4 -5- -[(;1 2 -2-(;5-chloro-2-thienyl)cyclopropylamino]-5-propylindolyl-triazolo[4 , 5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol 6 (45 mg, white solid), Yield: 45.2% MS m/z (ESI): 499.1 [M +1]

1H NMR (400 MHz, CD ₃ OD) 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). Example 7

(lS, 2S, 3S, 4R)-5-{7-[ (lR,2 ] -5-propyldecyl-triazolo[4,5-d]

First step

0 6 6& -6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4^][1,3]dioxol-4-ol Dissolve (3R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol lh (20 g, 133 mmol) in 250 mL of acetone, add 0.6 mL of concentrated sulfuric acid, and react at room temperature. 4 hours. The solid sodium hydrogencarbonate solid was added to the reaction mixture until pH=7, filtered, and the filtrate was evaporated to dryness. -(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,U][1,3]dioxol-4-ol 7a (17.8 g, colorless oil), yield 70.4 %.

Second step

(R)- 1 -((4R,5 -2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethane-1,2-diol will be methyl Triphenylphosphonium bromide (94.6 g, 265 mmol) was suspended in 600 mL of tetrahydrofuran, the solution was cooled to 0 ° C, potassium tert-butoxide (32.9 g, 293 mmol) was added, and reacted at 0 ° C for 20 minutes, liter After reacting for 1 hour at room temperature, 200 mL of 0 6 6 & -6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4^][1,3]dioxole-4 was added dropwise. - a solution of the alcohol 7a (18 g, 95 mmol) in THF, EtOAc EtOAc (EtOAc)EtOAc. The phase was washed with a saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Base-5-vinyl-1,3-dioxolan-4-yl)ethane-1,2-diol 7b (17.8 g, brown-brown oil).

third step

(4 5 -2,2-dimethyl-5-vinyl-1,3-dioxolan-4-carbaldehyde (R)-l-((4R,5 -2,2-dimethyl-) 5-vinyl-1,3-dioxolan-4-yl)ethane-1,2-diol 7b (17 g, 90 mmol) was dissolved in 300 mL of tetrahydrofuran, and 200 mL of sodium periodate was added dropwise. (29 g, 135 mmol) solution, complete the addition for 30 minutes, continue the reaction for 30 minutes. Add 200 mL of water to the reaction solution, separate the liquid, extract the aqueous phase with dichloromethane (200 mL X 2), combined organic phase The residue was dried over anhydrous sodium sulfate, filtered and evaporated. -1,3-dioxolan-4-carbaldehyde 7c (7.5 g, colorless oil), yield 53.4%.

the fourth step

1-((4R,5 -2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-enyl alcohol (4 5 -2,2- Dimethyl-5-vinyl-1,3-dioxolan-4-carbaldehyde 7c (25 g, 160 mmol) was dissolved in 300 mL of tetrahydrofuran, the solution was cooled to -78 ° C, and 1 M vinyl was added dropwise. Magnesium bromide (320 mL, 320 mmol), after the addition was completed, reacted at -78 °C for 1 hour, and raised to 0 ° C for 30 minutes. Add 200 mL of saturated ammonium chloride solution to the reaction solution, and stir for 10 minutes. The liquid phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue gave the title product l-((4R,5 -2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-en-1-ol 7d C18 g, colorless oil), yield 61%.

the fifth step

0 4 6&^-2,2-dimethyl-4,6&-dihydro-3&^cyclopentene[^][1,3]dioxol-4-ol will be di(tricyclohexyl) Phosphine)benzylidene ruthenium dichloride (0.5 g, 0.63 mmol) was added to a 1000 mL single-mouth bottle. Add 450 mL of 1-((4R,5 -2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-enyl alcohol 7d (11.5 g) to the syringe. , 62.5 mmol), chloroform solution, mp mp mp mp. Methyl-4,6a-dihydro-3aH-cyclopenta[^][1,3]dioxol-4-ol 7e (3.2 g, light brownish black oil), yield 50% .

Step 6

0 4 6&^-4-benzyloxy-2,2-dimethyl-4,6--dihydro-3&^cyclopentene-[],1,3]dioxole (3aR,4R ,6a-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-ol 7e (2.5 g, 16 mmol) was dissolved in In 30 mL of DMF, 60% sodium hydride (1.28 g, 32 mmol) was added in portions at 0 ° C, and reacted at room temperature for 30 minutes. Benzyl bromide (2.85 mL, 24 mmol) was added for 12 hours, and methanol was quenched. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj Product 0 4 6 & -4-benzyloxy-2,2-dimethyl-4,6&-dihydro-3&^cyclopentene[],[1,3]dioxole 7fC3.9g, none Color oil), Yield: 100%.

Seventh step

(1 2 5 -5-benzyloxycyclopentene-3-ene-1,2-diol

(3aR, ^,6a -4-benzyloxy-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxole 7f (3.9 g, 16 mmol) was dissolved in 20 mL of methanol, added Dowex 50 cation resin (3 g), stirred for 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B. The title product, benzyloxycyclopentene-3-ene-1,2-diol 7 g (2.2 g, pale yellow oil), yield: 66.6%.

Eighth step

(lR, 2R, 3^4R, 5R)-4-benzyloxy-6-oxabicyclo[3丄0]hexane-2,3-diol (1^2 5 -5-benzyloxy) 7-cyclopentene-3-ene-1,2-diol 7g (2.2 g, 10.67 mmol) was dissolved in 50 mL of dichloromethane, and m-chloroperoxybenzoic acid (4.74 g, 19.2 mmol) was added for 24 hours. The solution was concentrated under reduced pressure. EtOAcjjjjjjjjjj丄0] Hexane-2,3-diol 7h (2.14 g, pale yellow oil), Yield: 90.3%.

Step 9

(1 2 3 4R,5 -3-azido-5-benzyloxy-cyclopentyl-1,2,4-triol (1 2 3^4 5 -4-benzyloxy-6-oxyl) Heterobicyclo[3丄0]hexane-2,3-diol 7h (2.14 g, 9.63 mmol) was dissolved in 30 mL of N,N-dimethylformamide and water (V/V = 5:1) In a mixed solvent, sodium azide (940 mg, 14.5 mmol) was added, and the mixture was reacted at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced vacuo. Extraction (10 mL x 2), dried over anhydrous sodium sulfate, EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2,4-triol 7j (2.55 g, light yellow oil). The product was taken to the next step without purification. Step 10

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

M[l,3]dioxol-5-ol

Dissolve (1 2 3 4R,5S)-3-azido-5-benzyloxy-cyclopentyl-1,2,4-triol 7j (2.55 g, 9.63 mmol) in 20 mL of acetone, add 2,2-Dimethoxypropane C2.36 mL, 19.3 mmol) and p-toluenesulfonic acid (750 mg, 4.4 mmol) were reacted for 4 hours, and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified to give the titled product: 4 4 R, 5 R, 6 6 a -4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro- 3aH-cyclopentene M[l,3]dioxol-5-ol 7k (1.78 g, white solid yield: 60.5%

The eleventh step

(3aS, 4R, 5R, 6 6aS)-4-amino-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l, 3] Dioxol-5-ol

(3aS,4R,5R,6 6a -4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l , 3] Dioxol-5-ol 7k (400 mg, 1.31 mmol) and triphenylphosphine (490 mg, 1.86 mmol) were dissolved in 6 mL of tetrahydrofuran, added to 1.2 mL of water, and reacted at 30 ° C. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj ,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-5-ol 7m (340 mg, white solid), yield : 93%.

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

1H NMR (400 MHz, DMSO-J ₆ ) 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).

Step 12

(3aR, 4S, 5R, 6R, 6a -6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole Pentene-4,5-diol

(3aS,4R,5R,6 6a -4-amino-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l , 3]dioxol-5-ol 7m (340 mg, 1.22 mmol) was dissolved in 8 mL of methanol, palladium hydroxide (600 mg, 4.27 mmol) was added, and reacted at l atm for 12 hours. Concentration by pressure gave the crude title product (3aR,4S,5R,6R,6a-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and M[ l,3]dioxol-4,5-diol 7 _n (230 mg, white viscous solid), the product was taken to the next step without purification.

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

Step 13

OR,4S,5R,6R,6a -6-[(;6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol (3aR,4S,5R,6R,6a -6-amino-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol 7η (230 mg, 1.22 mmol And 4,6-chloro-5-nitro-2-propylindolyl-pyrimidine 6b (423.5 mg, 1.6 mmol) was dissolved in 15 mL of ethanol, and triethylamine (0.34 mL, 2.44 mmol) was added dropwise. After reacting for 4 hours, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjj 2-propyldecyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole Pentene-4,5-diol 7p (310 mg, pale yellow solid), Yield: 60.5%.

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

Fourteenth step

C3aR,4S,5R,6R,6a -6-[0amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a -tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol will (3aR,4S,5R,6R,6a -6-[(6-chloro-5) -nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Dioxetane-4,5-diol 7p (310 mg, 0.74 mmol) was dissolved in 10 mL of acetic acid, iron powder (207 mg, 3.7 mmol) was added, and reacted for 3 hours, and 20 mL of ethyl acetate was added. Stir for 5 minutes, filter, and wash the filter cake with a large amount of ethyl acetate. The filtrate was washed sequentially with water (20 mL EtOAc) and saturated sodium hydrogen carbonate (20 mL EtOAc). X 2) extraction, combined organic phase and concentrated under reduced pressure to give the title product C3aR, 4 WR, 6R, 6a -6-[(5-amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino -2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol 7q (210 mg , yellow solid), yield 93%.

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

Step fifteenth

(3aR, 4S, 5R, 6R, 6a^-6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4,5-diol will be OR,4S,5R,6R,6a -6-[ 0 amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l ,3]dioxol-4,5-diol 7q (270 mg, 0.7 mmol) was dissolved in a mixed solvent of 4.5 mL of acetic acid and water (V/V = 2:1), and added to the ice bath. Sodium nitrite (53.2 mg, 0.77 mL), reacted at 0 ° C for 5 minutes, added 20 mL of ethyl acetate and 20 mL of saturated sodium carbonate solution, stirred for 5 minutes, separated, and the organic phase was sequentially saturated with sodium carbonate (10) The residue was washed with EtOAc (EtOAc) (EtOAc m. 5R,6R,6a -6-(;7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6 ,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole-4,5- Glycol 7r (281 mg, brown oil).

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

Step 16

(3aR, 4S, 5R, 6R, 6a -6- {7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole Alkene

-4,5-diol

(3aR, 4S, 5R, 6R, 6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4,5-diol 7r (281.3 mg, 0.7 mmol), (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (312.9 mg, 0.98 mmol) was dissolved in 10 mL of acetonitrile and triethylamine was added dropwise. 0.34 mL, 2.45 mmol), the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj - {7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazole[4,5-d]pyrimidin-3-yl 2, 2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxole-4,5-diol 7s (310 mg, white solid) , Yield: 83%.

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

Step 17

(1S,2 3S,4R)-5-[7-[[(lR,2^-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl]cyclopentyl-1,2,3,4-tetraol

(3aR,4S,5R,6R,6a -6- {7-[(lR,2^-2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole) [4,5-d]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole The ene-4,5-diol 7s (310 mg, 0.58 mmol) was dissolved in 10 mL of a mixed solvent of methanol and water (V/V = 9:1), and Dowex 50 (300 mg) was added for 16 hours. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol 7 (260 Mg, white solid), Yield: 91%.

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

1H NMR (400 MHz, CD ₃ OD) 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). Example 8

(lR, 2S, 3^4S, 5 -4- {7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole)

[4,5-d]pyrimidin-3-yl}-5-fluoro-cyclopentyl-1,2,3-triol

first step

(3a^4S,5R,6R,6a-4-azido-6-(benzyloxy)-2,2-dimethyltetrahydro-3aH-cyclopentene M[ 1,3]dioxa Cyclopentene-5-yl trifluoromethanesulfonate

(3aS,4R,5R,6 6a -4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l , 3]dioxol-5-ol 7k (0.10 g, 0.33 mmol) was dissolved in 5 mL of dichloromethane, then pyridine (39 mg, 0.50 mmol) and trifluoromethanesulfonic anhydride (113 mg, 0.40 mmol), 1 hour of reaction. Add 5 mL of saturated sodium bicarbonate solution and 10 mL of dichloromethane, and separate the organic phase, washed with saturated sodium bicarbonate solution (10 mL) and saturated copper sulfate solution (10 mL×2). Drying over anhydrous magnesium sulfate, filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-5-yl trifluoromethanesulfonate 8a (145 mg, light yellow oil), product One step reaction.

Second step

(3aS,4R,5 6 6a -6-azido-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene

M[l,3]dioxole

(3aS,4 5R,6R,6a -4-azido-6-(benzyloxy)-2,2-dimethyltetrahydro-3aH-cyclopentene-W][l,3]diox The heterocyclopentene-5-yl trifluoromethanesulfonate 8a (136 mg, 0.33 mmol) was dissolved in 5 mL of tetrahydrofuran, and 0.5 mL of a solution of 1 M tetrabutylammonium fluoride trihydrate in tetrahydrofuran was added and reacted for 3 hours. The mixture was washed with EtOAc (10 mL EtOAc) (EtOAc) Filtration and concentrating the filtrate under reduced pressure. EtOAc mjjjjjjjjjj -Fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole 8b (0.10 g, colorless oil) , Yield: 99.0%. MS m/z (ESI): 308.1 [M+l]

third step

(3aS,4R,5 6 6a -4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Dioxol-6-amine

(3aS,4R,5 6 6a -6-azido-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene [1,3]dioxole 8b (0.60 g, 1.96 mmol) was dissolved in 10 mL of tetrahydrofuran, and triphenylphosphine (0.66 g, 2.54 mmol) and 2 mL of water were successively added and reacted for 48 hours. The solution was concentrated under reduced pressure. EtOAcjjjjjjjjjjj Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-amine 8c (0.60 g, colorless oil), product Purification proceeds directly to the next reaction. MS m/z (ESI): 282.2 [M+l]

the fourth step

N-[(3aS,4R,5 6 6a -4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l ,3] Benzedione-6-yl]carbamate

The crude product (3aS, 4R, 5S, 6 6a -4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[d] [l,3]dioxole-6-amine 8cC550 mg, 1.90 mmol) dissolved in 10 mL of tetrahydrofuran and 3 mL of water, added potassium carbonate (525 mg, 3.80 mmol), and added benzyl chloroformate (0.5 mL, 3 mmol), reaction for 1 hour. The mixture was separated, and the aqueous layer was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product N-[(3aS,4R,5 6 6a -4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene) was obtained. Benzyl M[l,3]dioxol-6-ylcarbamate 8d (590 mg, colorless oil), yield: 75.0% MS m/z (ESI): 416.1 [M+ l]

the fifth step

(3aR, 4R, 5 6 & 6a -6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Oxe-4-ol

N-[(3aS,4R,5 6 6a -4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M [ l,3]Dioxol-6-yl]carbamic acid benzyl ester 8d (88 mg, 1.90 mmol) was dissolved in 20 mL of methanol, then palladium hydroxide/carbon (1.20 g, 7.83 mmol) was added and replaced with hydrogen. Three times, the reaction was carried out for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to give the title product (3aR, 4R, 5 6 & 6a -6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a -tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-ol 8e C270 mg, colorless oily yield: 72.0%. MS m/z (ESI): 192.35 [M +l]

Step 6

OR,4R,5 6 6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl

-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-ol (3aR,4R,5 6 & 6a -6-amino-5- Fluorin-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-ol 8e (0.08 g, 0.42 mmol) And 4,6-chloro-5-nitro-2-propylindenyl-pyrimidine 6b (0.20 g, 0.75 mmol) was dissolved in 10 mL of ethanol, and triethylamine (88 mg, 0.84 mmol) was added. 16 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjj Propylmercapto-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxo Heterocyclopenten-4-ol 8f (0.10 g, yellow solid), Yield: 56.5%.

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

Seventh step

OR,4R,5 6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl

-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-ol will be OR,4R,5^6 6a -6-[(6-chloro -5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene [^][1,3]dioxol-4-ol 8f (0.10 g, 0.24 mmol) was dissolved in 5 mL of acetic acid, and iron powder (66 mg, 1.20 mmol) was added and reacted for 1.5 hours. 20 mL of ethyl acetate was added, and the filtrate was filtered. -Chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l , 3] Dioxol-4-ol 8 g (93 mg, colorless oil), product was taken to the next step without purification.

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

Eighth step

(3aR,4R,5^6^6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-di Methyl

-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-4-ol will be OR,4R,5^6 6a -6-[(5-amino) -6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[ l,3]dioxol-4-ol 8g (93 mg, 0.43 mmol) was dissolved in 4 mL of a mixed solvent of acetic acid and water (V/V = 1:1), and nitrous acid was added at 0 °C. Sodium (18 mg, 0.47 mnol) was reacted for 10 minutes. Add 15 mL of ethyl acetate, then add 10 mL of saturated sodium carbonate solution to the reaction solution ρΗ=7, and separate the organic phase. Wash the organic phase with saturated sodium carbonate solution (10 mL) and saturated sodium chloride solution (10 mL). The aqueous phase was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjj Chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- Cyclopentene M[l,3]dioxol-4-ol 8h (96 mg, colorless oil).

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

Step 9

(3& 4 5^6 6& -6-{7-[ (1 2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazolo[4,5- d]pyrimidin-3-yl 5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole-4 - alcohol

The crude product (3aR, 4R, 5S, 6 6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2- Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-ol 8h (96 mg, 0.24 mmol) and (lR,2 -2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (106 mg, 0.33 mmol) It was dissolved in 5 mL of acetonitrile, and triethylamine (86 mg, 0.85 mmol) was added dropwise for 48 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl 5-fluoro-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-anol 8i (0.10 g, white solid), yield: 78.7%.

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

Step 10

[4,5-d]pyrimidin-3-yl}-5-fluoro-cyclopentyl-1,2,3-triol

(3aR,4R,5 6^6a -6-{7-[ (lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl}-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxo Heterocyclopenten-4-ol 8 0.10 g, 0.19 mmol) was dissolved in 6 mL of a mixed solvent of methanol and water (V/V = 5:1), and Dowex 50 cationic resin (0.15 g) was added for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 4-difluorophenyl)cyclopropyl]amino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl]-5-fluoro-cyclopentyl-1,2,3 - Triol 8 (0.07 g, white solid), Yield: 76.0%.

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

1H NMR (400 MHz, CD ₃ OD) 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). Example 9

(1S,2 3^4S,5R)-3- {7-[ (lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

first step

N-[(3aS,4S,5 6R,6aR)-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l ,3] Benzodioxet-4-yl]carbamate

(3aR, 4R, 5 6 & 6a -6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Dioxol-4-ol 8eC 0.19 g, 1 mmol) was dissolved in 10 mL of methanol and 3 mL of water, potassium carbonate (276 mg, 2 mmol) was added, and benzyl chloroformate was added dropwise at 0 °C. 0.24 g, 1.40 mmol), reacted at room temperature for 1 hour. The mixture was separated, and the aqueous layer was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product N-[(3aS,4S,5 6R,6aR)-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene was obtained. Benzyl M[l,3]dioxol-4-yl]carbamate 9a (0.28 g, colorless oil), yield: 86.0%. MS m/z (ESI): 282.2 [M-43]

Second step

2-{[(3aS,4R,5 6 6a -6-benzyloxycarbonylamino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[ d][l,3]dioxol-4-yl]oxy}ethyl acetate N-[(3aS,4S,5 6R,6aR)-5-fluoro-6-hydroxy-2,2 - Benzyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]carbamate 9a (0.28 g, 0.86 mmol It was dissolved in 10 mL of tetrahydrofuran, and a solution of 20% potassium t-butoxide in tetrahydrofuran (0.7 mL, 1.30 mmol) was added dropwise at 0 ° C for 30 minutes. Ethyl 2-bromoacetate (217 mg, 1.30 mmol) was added dropwise and allowed to react for 30 min. Raise to room temperature and react for 16 hours. 10 ml of water was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj (3aS,4R,5 6 6a -6-benzyloxycarbonylamino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[d][l , 3]dioxol-4-yl]oxy}acetate 9b (0.36 g, mp.). third step

N-[(3aS,4R,5 6 6a -5-fluoro-4-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentyl Benzene [d][l,3]dioxol-6-yl]carbamate 2-{[(3aS,4R,5 6 6a -6-benzyloxycarbonylamino-5-fluoro- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethyl acetate 9b (354 mg, 0.86 mmol) was dissolved in 10 mL of tetrahydrofuran, lithium borohydride (C38 mg, 1.72 mmol) was added, and the reaction was carried out for 3 hours. 5 mL of water was added to the reaction mixture, and the mixture was separated with ethyl acetate (10 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 6a^-5-fluoro-4-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[d][l, 3] Benzyl dioxol-6-yl]carbamate 9c (0.29 g, colorless oil), yield: 91.3%.

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

the fourth step

2-{[(3aS,4R,5 6 6a -6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l, 3] Dioxol-4-yl]oxy)ethanol

N-[(3aS,4R,5^6 6a -5-fluoro-4-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- Cyclopenteno[d][l,3]dioxol-6-yl]carbamic acid benzyl ester 9c (0.29 g, 0.79 mmol) was dissolved in 10 mL of methanol, then palladium/carbon (10%, 0.30 g), the hydrogen was replaced three times, and the reaction was carried out for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated. Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy]ethanol 9d (185 mg, white solid) The product was directly subjected to the next reaction without purification.

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

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fifth step

2-{[(3aS,4R,5^6 6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2- Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethanol 2-{[(3aS) , 4R,5 6 6a -6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxole Penten-4-yl]oxy}ethanol 9d (185 mg, 0.79 mmol) and M,6-chloro-5-nitro-2-propylindolyl-pyrimidine 6b (315 mg, 1.18 mmol) dissolved in 10 mL To the ethanol, triethylamine (0.16 g, 1.58 mmol) was added, and the mixture was reacted for 16 hours. The reaction mixture was concentrated under reduced pressure. ,4R,5S,6S,6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4 ,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 9e (0.20 g, yellow oil), yield: 54.3%

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

Step 6 2-{[(3aS,4R,5^6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethanol 2-{[0 4R, 5S,6 6a -6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 9e (0.20 g, 0.43 mmol) dissolved in 6 mL of acetic acid, iron Powder (123 mg, 2.20 mmol), EtOAc (2 mL). 3aS,4R,5 6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy)ethanol 9f (188 mg, yellow oil), product Carry out the next reaction. MS m/z (ESI): 437.1 [M+l]

Seventh step

2-{[(3aS,4R,5 6 6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and W][l,3]dioxol-4-yl]oxy}ethanol 2-{[0 4R,5S,6 6a -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5, 6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 9f (188 mg, 0.43 1^^1) dissolved in 4.5 1^ In a mixed solvent of acetic acid and water (^/¥ = 2: 1), add sodium nitrite (33 mg, 0.47 mmol) at 0 ° C for 10 minutes. Add 20 mL of ethyl acetate to the reaction solution and add saturated carbonic acid. The sodium solution was poured into a reaction solution of ρ Η = 7. The organic phase was washed successively with a saturated sodium carbonate solution (10 mL) and a saturated sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered, The crude title product 2-{[(3aS,4R,5 6 6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4- ] Oxy} ethanol 9g (0.20 g, yellow oil), was used without purification in the next step.

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

Eighth step

2-{[(3&^^,5 6 6& -6-[7-[ (1 2^-2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole) And [4,5-d]pyrimidin-3-yl]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Dioxol-4-yl]oxy}ethanol

2-{[(3aS,4R,5 6 6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 9g (193 mg, 0.43 1^^1) and (1 2 -2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (0.19 g, 0.60 mmol) dissolved in 10 mL of acetonitrile Triethylamine (0.15 g, 1.50 mmol) was added for 16 hours. The reaction mixture was evaporated. mjjjjjjjjjjjjjj 6 6& -6-[7-[(1 2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazolo[4,5-d]pyrimidine-3 -yl]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl] Oxy)ethanol 9hC 0.17 g, colorless oil), Yield: 68.0%.

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

[4,5-d]pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2-{[(3aS,4R,5 6 6a -6-[7-[ (lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-pyrimidine-3- -5-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy Ethyl alcohol 9h (0.17 g, 0.29 mmol) was dissolved in a mixed solvent of 1 lmL of methanol and water (V/V = 10:1), and D _Owe x 50 cationic resin (0.2 g) was added and reacted for 16 hours. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut eluting (3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5 pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy) Cyclopentyl-1,2-diol 9 (0.13 g, white solid yield: 81.2%).

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

1H NMR (400 MHz, CD ₃ OD) 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). Example 10

(1^2 3 5 -3-(2-hydroxyethoxy) -5 {7-[ (lR,2R/lS,2 -2-(4-methylthiazole-5-yl)cyclopropylamide

-5-propyldecyl-triazolo[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2-diol

First step

(1R, 2R/1S, 2 -2-(4-methylthiazol-5-yl)cyclopropanecarboxylic acid ethyl ester 4-methyl-5-vinyl-thiazole 10a (5 g, 40 mmol) was heated to 135 Ethyl diazoacetate (2.28 g, 20 mmol) was added dropwise, EtOAc (EtOAc m. , 2 -2-(4-methylthiazol-5-yl)cyclopropanecarboxylic acid ethyl ester 10b (2.01 g, pale yellow oil), Yield: 47.6%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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-yl)cyclopropanecarboxylic acid (1R,2R/1S,2 -2-(4-methylthiazol-5-yl)cyclopropane Ethyl formate 10b (2.01 g, 9.50 mmol) was dissolved in 30 mL of methanol, and 2.5 mL of 30% sodium hydroxide solution was added dropwise for 12 hours. Concentrated under reduced pressure, 40 mL of ethyl acetate and 30 mL of water were added. Add 37% hydrochloric acid to the reaction solution pH=4. Dissolve, the aqueous phase is extracted with ethyl acetate (60 mL×2), the organic phase is combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

third step

N-[(1R,2R/1 2 -2-(4-methylthiazol-5-yl)cyclopropane]carbamic acid tert-butyl ester (1R, 2R/1S, 2 -2-(4-methyl) Thiazol-5-yl)cyclopropanecarboxylic acid 10c (732 mg, 4 mmol) was dissolved in 20 mL of tert-butanol, followed by the addition of diphenyl azide (1.10 g, 4 mmol) and triethylamine (485.70 mg, 4.80). The reaction was carried out at a temperature of 83 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) Filtration, the filtrate was concentrated under reduced pressure, and then purified tolulululululululululululululululululululululululululululululululululu tert-Butylpropyl]carbamic acid tert-butyl ester 10d (390 mg, white solid), yield: 38.6%.

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

the fourth step

(1R,2R/1 2 -2-(4-methylthiazol-5-yl)cyclopropylamine hydrochloride N-[(1R,2R 1 2 -2-(4-methylthiazol-5-yl)) The tert-butyl cyclopropyl]carbamic acid tert-butyl ester 10d (254 mg, 1 mmol) was dissolved in ethyl acetate (5 mL). (lR, 2R l 2 -2-(4-methylthiazol-5-yl)cyclopropylamine hydrochloride 10e (180 mg, white solid).

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

the fifth step

2-{[(3aS,4R,6 6aR)-2,2-dimethyl-4-[7-[(lR,2R/lS,2 -2-(4-methylthiazol-5-yl)) ring Propylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl]-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3 Dioxol-6-yl]oxy)ethanol

2-{[(3aR,4S,6R,6a -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl 4-,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl]oxy}ethanol 5g (254 mg, 1 mmol) dissolved in 5 mL of acetonitrile, 5 mL of ClR, 2R 1^2 -2-C4-methylthiazole-5-yl)cyclopropylamine hydrochloride A solution of 10e (100 mg, 0.65 mmol) in EtOAc (EtOAc m. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting [(lR, 2R/lS, 2 -2-(4-methylthiazol-5-yl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl -4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl]oxy}ethanol 10f (140 mg, pale yellow solid), Yield: 100%.

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

Step 6

(1 2S,3 5R)-3-(2-hydroxyethoxy) -5- {7-[ (lR,2R 1^2 -2-(4-methylthiazol-5-yl)cyclopropylamino -5-propyldecyl-triazolo[4,5-d]pyrimidin-3-yl}cyclopentyl-1,2-diol will be 2-{[(3aS,4R,6 6aR)-2, 2-Dimethyl-4-[7-[(lR,2R lS,2 -2-(4-methylthiazol-5-yl)cyclopropylamino]-5-propyldecyl-triazolo[4 ,5-d]pyrimidin-3-yl]-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl]oxy}ethanol 10fC140 mg, 0.26 mmol) was dissolved in 8 mL of methanol, and 3 mL of 2.5 M hydrochloric acid was added for 12 hours. Add 4 M sodium hydroxide solution to the reaction solution ρΗ=8, extract with ethyl acetate (30 mL×3), and combine The organic phase was washed with a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. ^2S,3^5R)-3-(2-hydroxyethoxy)-5-{7-[(lR,2R/lS,2^-2-(4-methylthiazol-5-yl)cyclopropane Aminoamino-5-propylindolyl-triazolo[4,5pyrimidin-3-yl}cyclopentyl-1,2-diol 10 (100 mg White solid), yield: 76.9%.

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

1H NMR (400 MHz, DMSO-J ₆ ) δ 9.40 (d, J = 3.96 Hz, 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, / = 7.36 Hz, 3H). Example 11

(15,25,3R,55)-3-{7-[ (1 2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-pyrimidin-3-yl} -5-(2,3-dihydroxypropoxy)cyclopentyl-1,2-diol

First step

N-[(3aR,4S,6R,6a-4-allyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Benzyl dioxol-6-yl]carbamate

N-[(3aR,4S,6R,6a -6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxo Benzene heterocyclopenten-4-yl]carbamate 5b (lg, 3.20 mmol) was dissolved in 20 mL of tetrahydrofuran, potassium tert-butoxide (0.73 g, 6.50 mmol) was added, stirred for 20 min, 3-bromopropene was added dropwise (1.1 mL, 13 mmol), EtOAc (3 mL), EtOAc (EtOAc) The residue obtained was purified by eluent from EtOAc (EtOAc) toield of the title product N-[(3aR,^,6R,6a -4- allyloxy-2,2-dimethyl-4-,5,6,6a- Tetrahydro-3aH-cyclopentene and W][l,3]dioxol-6-yl]carbamic acid benzyl ester lla (0.40 g, colorless oil), yield: 35.0%.

Second step

N-[(3aR,4S,6R,6a -4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene and

W][l,3]dioxol-6-yl]carbamic acid benzyl ester N-[C3aR,4S,6R,6a-4-allyloxy-2,2-dimethyl-4 , 5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl]carbamic acid benzyl ester lla (0.40 g, 1.15 mmol) dissolved in 10 mL of tetrahydrofuran N-methylmorpholine-N-oxide (0.54 g, 2.30 mmol) and osmium tetroxide (59 mg, 0.23 mmol) were added and reacted for 5 hours. After adding 10 mL of a saturated sodium thiosulfate solution, the mixture was extracted with ethyl acetate (30 mL, EtOAc) (EtOAc) 6R,6a -4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Benzyl epoxide-6-yl]carbamate lib (0.45 g, pale yellow oil), yield: 99.0%. third step

N-{(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl Benzyl-4,5,6,6a-tetrahydro-3aH-cyclopenteno[d][l,3]dioxol-6-yl}carbamic acid benzyl ester N-[(3aR,4S ,6R,6a -4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene[d][l, 3] Benzyl dioxol-6-yl]carbamate llbC0.45 g, 1.20 mmol) dissolved in 10 mL of 2,2-dimethoxypropane, added p-toluenesulfonic acid monohydrate (13 mg , 0.068 mmol), reaction for 30 minutes. Add 10 mL of saturated sodium bicarbonate solution, and ethyl acetate (30 mL×3). Chromatography of the residue obtained from eluent E to give the title product N-[(3aR, 6R, 6a -4-[(2,2- dimethyl-1,3-dioxolane-4) -yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-6-yl] Benzyl carbamate l lc (0.41 g, pale yellow oil), Yield: 82.0% .

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

the fourth step

(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl

-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-6-amine will be ^{(3& 4 6 6& -4-[(2,2- Dimethyl-1,3-dioxol-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M Benzyl [l,3]dioxol-6-yl}carbamate l lc (0.41 g, 1 mmol) was dissolved in 10 mL of ethanol, palladium/carbon (10%, 0.10 g), hydrogen replacement Three times, the reaction was carried out for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure to give the title product s,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-amine Ld (0.22 g, pale yellow oil), yield: 81.0%.

the fifth step

N-{(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl 4-,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl 6-chloro-5-nitro-2-propylindolyl- Pyrimidine-4-amine

(3aR, 4S, 6R, 6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-amine l ld (0.11 g, 0.38 mmol) was dissolved in 8 mL of tetrahydrofuran, added 4,6-Chloro-5-nitro-2-propylindolyl-pyrimidine 6b CO.11 g, 0.42 mmol), triethylamine (0.2 mL, 1.15 mmol) The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjj ,3-dioxol-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3] Dioxol-6-yl}-6-chloro-5-nitro-2-propylindolyl-pyrimidine-4-amine 1 leG 34 mg, yellow oil), Yield: 38.0%.

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

Step 6

^-{(3& 4 6 6& -4-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl -4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl 6-chloro-2-propylindolyl-pyrimidine

-4,5-diamine

N- {(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl 6-chloro-5-nitro-2-propylindolyl -pyrimidine-4-amine l le (134 mg, 0.26 mmol) was dissolved in 5 mL of acetic acid, iron powder (116 mg, 2.10 mmol) was added and reacted for 2.5 hours. Add 10 mL of water and ethyl acetate (30 mL x 3) The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product ^{N 4 - {(3aR, 4S} , 6R, 6a -4 -[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro- 3aH-cyclopentene M[l,3]dioxol-6-yl 6-chloro-2-propylindolyl-pyrimidine-4,5-diamine l lf (134 mg, brown oil) The product was directly subjected to the next reaction without purification. MS m/z (ESI): 490.52 [M+l]

Seventh step

3-{(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl 4-,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-6-yl}-7-chloro-5-propylindolyl-triazole

[4,5-d]pyrimidine

N ⁴ -{(3aR,4S,6R,6a -4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2- Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-6-yl 6-chloro-2-propylindolyl-pyrimidine-4 , 5-diamine l lf (0.25 g, 0.50 mmol) was dissolved in 2 mL of acetic acid. Add 0.4 mL of an aqueous solution of sodium nitrite (36 mg, 0.53 mnol) at 0 ° C for 10 minutes. Add 15 mL of acetic acid The ester and 10 mL of saturated potassium carbonate solution were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. Concentration by pressure gave the crude title product 3-{(3aR,45,6R,6a5)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxol-6-yl 7-chloro-5-propenyl The hydrazino-triazolo[4,5-d]pyrimidine l lg (0.25 g, brown oil) was taken to the next step without purification.

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

Eighth step

tert-Butyl N-[(lR,2 -2-(3,4-difluorophenyl)cyclopropyl]carbamate (lR,2R)-2-(3,4-difluorophenyl)cyclopropane The carboxylic acid ld (12 g, 60.55 mmol) was dissolved in 600 mL of tert-butanol, and then diphenylphosphoryl azide (16.70 g, 60.55 mmol) and triethylamine (6.20 g, 60.55 mmol 80 ° C for 16 hours) were added. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj Tert-butyl carbamate l lh (1.90 g, white solid), Yield: 11.7%.

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

Step 9

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

tert-Butyl N-[(lR,2 -2-(;3,4-difluorophenyl)cyclopropyl]carbamate l lh (1.90 g, 7.05 mmol) The solution was dissolved in 38 mL of ethyl acetate, and 38 mL of a 5 M aqueous solution of hydrogen chloride was added dropwise thereto for 16 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssss One step reaction.

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

Step 10

3- {(3aR,4S,6R,6a)-6-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-di Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl}- [(1 2 -2-(3,4- Difluorophenyl)cyclopropyl]-5-propylindolyl-triazolo[4,5-d]pyrimidin-7-amine will be 3-{(3aR,4S,6R,6a -4-[(2, 2-Dimethyl-1,3-dioxol-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene And M[l,3]dioxol-6-yl 7-chloro-5-propylindolyl-triazolo[4,5-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) was dissolved in 5 mL of acetonitrile and triethylamine (0.2 mL, 0.88 mmol) , the reaction was carried out for 12 hours. The reaction solution was concentrated under reduced pressure, water (10 m) was added, 2.5 M hydrochloric acid was added dropwise to the reaction mixture ρ Η < 4, and the aqueous phase was extracted with ethyl acetate (15 mL×3), and the organic phase was combined with saturated sodium chloride. The solution (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 3-{(3& 4 6 6&)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl}^-[(1 2^-2-( 3,4-difluorophenyl)cyclopropyl]-5-propylindolyl-triazolo[4,5-d]pyrimidin-7-amine l lj (75 mg, yellow oil), yield: 47.0 %.

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

The eleventh step

(\S,2S,3R,5S)-3- {7-[ (lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazolo[ 4,5-d]pyrimidin-3-yl}-5-(2,3-dihydroxypropoxy)cyclopentyl-1,2-diol will be 3-{(3aR,4S,6R,6a)- 6-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro -3aH-cyclopentene M[l,3]dioxol-4-yl}^-[(1 2^-2-(3,4-difluorophenyl)cyclopropyl]-5 -propylmercapto-triazolo[4,5-d]pyrimidin-7-amine l lj (0.15 g, 0.24 mmol) was dissolved in 8 mL of methanol, and 2 mL of 2.5 M hydrochloric acid was added dropwise for 16 hours. Concentrate under reduced pressure, add 10 mL of water. Add saturated sodium carbonate solution to the reaction solution ρΗ=7, extract with ethyl acetate (30 mL×3), and wash the organic phase with saturated sodium chloride solution (10 mL). The residue was dried over sodium sulfate, filtered, and then evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -2-(;3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl }-5-(2,3-Dihydroxypropoxy)cyclopentyl-1,2-diol 11 (134 mg, yellow solid), Yield: 99.0%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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). Example 12

(1S,2 3 4R,5 -3-{7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole

-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol

First step

2 :-{[(3& 4 6&5>2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy Ethyl acetate

(3a&4R,6aR)-2,2-Dimethyl-4,6a-dihydro-3aH-cyclopenta[[1,3]dioxol-4-ol ln (1.22 g, 7.82 Methyl) was dissolved in 50 mL of tetrahydrofuran. A 20% solution of potassium t-butoxide in tetrahydrofuran (7.2 mL, 11.73 mmol) was added dropwise at 0 ° C for 30 min. Ethyl bromoacetate (1.3 mL, 11.73 mmol) was added dropwise, and the mixture was reacted for 30 min. After adding 10 mL of water, the mixture was separated, EtOAcjjjjjjjjjjjjjjjjj ,6a^)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[[1,3]dioxole Ethyl acetate 12a (1.90 g, brown oil).

Second step

2-{[(3aR,4S,6a-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[l,3]dioxol-4-yl]oxy }ethanol

2-{[OR,4S,6a-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy Ethyl acetate 12a (1.90 g, 7.82 mmol) was dissolved in 40 mL of tetrahydrofuran, and lithium borohydride (341 mg, 15.64 mmol) was added and reacted for 2 hours. After adding 10 mL of water, the mixture was separated, EtOAcjjjjjjjjjjjjjjjjjj 4S,6a-2,2-dimethyl-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy)ethanol 12b (1.56 g , yellow oil), the product was directly subjected to the next reaction without purification.

third step

(3aR,4S,6a -4-(2-Benzyloxyethoxy)-2,2-dihydro-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxole Pentene

2-{[(3 aR,45,6a5)-2,2-dimethyl-4,6a-dihydro-3 aH-cyclopenteno[d][ 1,3 ]dioxole -4-yl]oxy}ethanol 12b (1.56 g, 7.82 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and 60% sodium hydride (626 mg, 15.64 mmol) was added at 0 °C. The reaction was carried out for 30 minutes at room temperature. Benzyl bromide (1.4 mL, 11.73 mmol) was added at 0 ° C and allowed to react at room temperature for 16 hours. Add 10 mL of methanol, concentrate under reduced pressure, add 50 mL of ethyl acetate and 15 mL of water, and separate the mixture. The aqueous phase is extracted with ethyl acetate (20 mL×2). The organic phase is combined and washed with water (20 mL×2) The sodium was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjj 2,2-Dihydro-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxole 12cC1.60 g, colorless oil), Yield: 70.0%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

the fourth step

(1 2 5 -5-(2-Benzyloxyethoxy)cyclopent-3-ene-1,2-diol (3aR,4S,6a -4-(2-benzyloxyethoxy) -2,2-dihydro-4,6a-dihydro-3aH-cyclopentene M[l,3]dioxole 12cG.60 g, 5.50 mmol) dissolved in 22 mL of methanol and water (; To the mixed solvent of V/V = 1 : 1), Dowex 50 cationic resin (3.50 g) was added and the reaction was carried out for 72 hours. The residue was concentrated under reduced pressure. Product (2W-5-(2-Benzyloxyethoxy)cyclopent-3-ene-1,2-diol 12d (1.37 g, colourless oil), yield: 100%.

the fifth step

(1 2 3^^,5^-4-(2-Benzyloxyethoxy)-6-oxabicyclo[3丄0]hexane-2,3-diol will (1S,2 5 - 5-(2-Benzyloxyethoxy)cyclopent-3-ene-1,2-diol 12d (1.35 g, 5.40 mmol) dissolved in 40 mL of dichloromethane, 70% m-chloroperoxybenzene The formic acid (2.40 g, 9.72 mmol) was reacted for 24 hours. The reaction mixture was concentrated under reduced pressure. Product (1R,2R,3 4R,5R)-4-(2-Benzyloxyethoxy)-6-oxabicyclo[3.1.0]hexane-2,3-diol 12e (630 mg , yellow oil), Yield: 44%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Step 6

(1 2 3 4R,5 -3-azido-5-(2-benzyloxyethoxy)cyclopentane-1,2,4-triol (1R, 2R, 3 4R, 5R)- 4-(2-Benzyloxyethoxy)-6-oxabicyclo[3.1.0]hexane-2,3-diol 12e (630 mg, 2.36 mmol) dissolved in 12 mL of N,N- Sodium azide (230 mg, 3.54 mmol) was added to a mixed solvent of methylformamide and water (V/V = 5:1). The reaction was carried out at 80 ° C for 16 hours. Concentrated under reduced pressure, 30 mL of acetic acid was added. The ethyl ester was washed with EtOAc (EtOAc) (EtOAc (EtOAc) 2 3 4R,5 -3-azido-5-(2-benzyloxyethoxy)cyclopentane-1,2,4-triol 12f (730 mg, yellow oil), product Go directly to the next step.

Seventh step

(3aS,4R,5R,6 6a -4-azido-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- Cyclopenta[^][1,3]dioxol-5-ol

(1 2 3 4R,5-3-azido-5-(2-benzyloxyethoxy)cyclopentane-1,2,4-triol 12f (730 mg, 2.36 mmol) was dissolved in 10 In mL acetone, 2,2-dimethoxypropane (0.6 mL, 4.72 mmol) and p-toluenesulfonic acid monohydrate (180 mg, 0.94 mmol) were added in sequence for 3 hours. The residue obtained was purified by eluent system E to give the title product (3a^, 4R, 5R, 6 6a -4-azido-6-(2-benzyloxyethoxy)-2,2- Methyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-5-ol 12g (470 mg, colorless oil), yield: 57.0%.

1H NMR (400 MHz, CDC1 ₃ ) 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).

Eighth step

(3aS,4R,5R,6 6a -4-amino-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentyl Oxo M[l,3]dioxol-5-ol

(3aS,4R,5R,6 6a -4-azido-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH -cyclopentene M[l,3]dioxol-5-ol 12gC460 mg, 1.32 mmol) was dissolved in 15 mL of tetrahydrofuran, triphenylphosphine (450 mg, 1.71 mmol) was added, 3 mL was added dropwise Water, reaction for 16 hours. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut -2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12h (427 mg, yellow oily product Rate: 100%.

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

Step 9

(3aS,4R,5R,6 6a -4-amino-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene [d][l,3]dioxol-5-ol (3aS,4R,5R,6 6aS)-4-amino-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- Cyclopentene M[l,3]dioxol-5-ol 12h (427 mg, 1.32 mmol) was dissolved in 20 mL of methanol, palladium hydroxide/carbon (0.80 g, 5.69 mmol), hydrogen Replace three times and react for 16 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product C3a^,4R,5R,6 6a -4-amino-6-P-hydroxyethoxy) -2,2-dimethyl-4,5,6,6a -tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-5-ol 12i (250 mg, colorless oily yield: 81.2%.

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

Step 10

(3aS,4R,5R,6 6a -4-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2-hydroxyethoxy)-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol (3aS,4R,5R,6 6aS )-4-amino-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[l,3]dioxa Cyclopentene-5-ol 12iC 250 mg, 1.07 mmol) and 4,6-chloro-5-nitro-2-propylindolyl-pyrimidine 6b (430 mg, 1.60 mmol) dissolved in 20 mL of ethanol, added to triethyl The amine (0.3 mL, 2.14 mmol) was reacted for 16 h. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut elut eluting Propylmercapto-pyrimidin-4-yl)amino]-6-0 hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l , 3]dioxol-5-ol 12j (320 mg, yellow oil), Yield: 64.3%.

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

The eleventh step

(3aS, 4R, 5R, 6 6a -4-[(5-amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2-hydroxyethoxy)-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol (3a^,4R,5R,6 6a 4-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2-hydroxyethoxy)-2,2-dimethyl-4, 5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12j (320 mg, 0.69 mmol) was dissolved in 10 mL of acetic acid and iron powder was added ( 200 mg, 3.50 mmol), 4 hours. Add 20 mL of ethyl acetate. EtOAc (EtOAc)EtOAc. The resulting residue was purified to give the title product (3aS,4R,5R,6 6a -4-[(5-amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6- (2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12k (200 mg, yellow oil), Yield: 66.6%.

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

Step 12

(3aS, 4R, 5R, 6 6a -4-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-6-(2-hydroxyethoxy) -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol (3a^,4R,5R ,6 6a -4-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2-hydroxyethoxy)-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12k (200 mg, 0.46 mmol) dissolved in 3 mL of acetic acid and 1.5 mL water , adding sodium nitrite (35 mg, 0.51) at 0 °C Mnol), react for 10 minutes. Add 20 mL of ethyl acetate, then add 10 mL of saturated sodium carbonate solution to the reaction solution pH=7, and separate the organic phase with saturated sodium carbonate solution (10 mL). The aqueous phase is ethyl acetate (10 mL><2 The organic phase is combined, dried over anhydrous sodium sulfate, filtered, and filtered, evaporated Triazolo[4,5-d]pyrimidin-3-yl)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-ring Pentacene M[l,3]dioxol-5-ol 12 m (205 mg, yellow solid).

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

Step 13

(3aS,4R,5R,6S,6a -4-{7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[ 4,5-d]pyrimidin-3-yl}-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M [l,3] Dioxol-5-ol

(3a^,4R,5R,6 6a -4-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-6-(2-hydroxyethoxyl -2,2-Dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12m (205 mg, 0.46 Methyl) and (lR, 2^-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (132 mg, 0.64 mmol) dissolved in 10 mL of acetonitrile, triethylamine (0.2) The residue was purified by silica gel column chromatography eluting tolululululululululululululululululululululululululululululululululululululu [(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl}-6-( 2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-5-ol 12nC230 Mg, yellow oil), Yield: 86.5%.

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

Fourteenth step

(1 2 3 4R,5 -3-{7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazole

[4,5-d]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol (3a^,4R,5R,6S,6a -4 - {7-[(lR,2 -2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl} -6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopentenyl M[l,3]dioxole- 5-Alcohol 12n (230 mg, 0.40 mmol) was dissolved in 10 mL of methanol and 1 mL of water, and Dowex 50 cation resin (500 mg) was added to react for 16 hours. The filtrate was concentrated under reduced pressure and purified by HPLC. The residue obtained the title product (1 2 3 4 5 -3- {7-[(lR,25)-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl- Zoxa[4,5-pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol 12 (130 mg, white solid), Yield: 60.0% .

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

1H NMR (400 MHz, CD ₃ OD) 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). Example 13

(1S,2 3 5R)-3-(2-hydroxyethoxy)-5-{5-propylindolyl-7-[(lR,2S/l 2R)-2-(3-pyridyl)cyclopropane

Diastereomer diastereomer

First step

(E)-3-(3-pyridyl)prop-2-enoate

60% sodium hydride (2.40 g, 60 mmol) was suspended in 30 mL of tetrahydrofuran, and (diethoxy-phosphate)-ethyl acetate (11.9 mL, 60 mmol) was added dropwise at 0 ° C. hour. 10 mL of a solution of pyridine-3-carbaldehyde 13a (3.8 mL, 50 mmol) in tetrahydrofuran was added dropwise at 0 ° C for 3 hours. The reaction was continued at room temperature for 12 hours. After adding 100 mL of water, and extracting with ethyl acetate (50 mL×4), the organic phase was combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, The obtained residue was purified tolulululululululululululululululululululululululululululululululululululululu .

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

Second step

(E)-3 3-pyridyl)prop-2-enoic acid

Ethyl (E)-3-0 pyridyl)prop-2-enoate 13b (6.90 g, 38.90 mmol) was dissolved in 50 mL of methanol and then 10 mL sodium hydroxide C 3.40 g, 85 mmol Reaction for 1.5 hours. The organic layer was extracted with ethyl acetate (200 mL×4). After filtration, the cake was dried in vacuo to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS m/z (ESI): 150.1 [M+1]

third step

[(1R,2 & 5R)-2-isopropyl-5-methyl-cyclohexyl](E)-3-(3-pyridyl)prop-2-enoate (E)-3-(3-Pyridyl)prop-2-enoic acid 13c (5.80 g, 38.90 mmol) was dissolved in 100 mL of dichloromethane, then EtOAc <RTIgt; Ν, Ν'-Dicyclohexylcarbodiimide (12.03 g, 58.30 mmol) and 4-dimethylaminopyridine (5.22 g, 42.80 mmol) were reacted for 12 hours. The obtained residue was purified to silica gel column chromatography elut elut elut elut elut elut elut elut elut elut elut - enoate 13 5 g, colorless oil Yield: 50.0%.

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

the fourth step

[GR, 2 & 5R)-2-isopropyl-5-methyl-cyclohexyl: lR, 2R/l^, 2 -2-(3-pyridyl)cyclopropanecarboxylate iodide Sulfoxide (9.57 g, 43.5 mmol) and potassium t-butoxide (4.88 g, 43.50 mmol) were dissolved in 40 mL of dimethyl sulfoxide and 20 mL [(2 & 5R)-2-isopropyl-5- A solution of methyl-cyclohexyl](£)-3-(3-pyridyl)prop-2-enoate 13d (5 g, 17.40 mmol) in dimethyl sulfoxide. The reaction was carried out at 50 ° C for 30 minutes. Add 2 M hydrochloric acid to the reaction solution pH=7, add 500 mL of ethyl acetate, wash with saturated sodium chloride solution (100 mL×2), extract the aqueous phase with ethyl acetate (150 mL×3), combine the organic phase, anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjj Cyclohexyl](lR,2R/,2-2-(3-pyridyl)cyclopropanecarboxylate 13e (3.58 g, mp.

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

the fifth step

(1R,2R/1 2S)-2-(3-pyridyl)cyclopropanecarboxylic acid

[(1R,2 & 5R)-2-isopropyl-5-methyl-cyclohexyl](1R,2R/1 2 -2-(3-pyridyl)cyclopropanecarboxylic acid hydrazine 13e (3.58 g, 11.90 mmol) dissolved in 100 mL of methanol, added with 10 mL of sodium hydroxide (3.80 g, 95 mmol) solution for 20 minutes. Reaction at 40 ° C for 1.5 hours. Concentrate under reduced pressure, add 40 mL of water at 0 ° C The residue was diluted with 2 M hydrochloric acid to pH </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; lR, 2R l 2 -2-(3-pyridyl)cyclopropanecarboxylic acid 13fC 1.80 g, pale yellow oil, yield: 92.0%.

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

Step 6

tert-Butyl N-[(lR,2S/1^2R)-2-(3-pyridyl)cyclopropyl]carbamate (1R,2R/1S,2 -2-(3-pyridyl)cyclopropane Formic acid 13f (407 mg, 2.50 mmol) was dissolved in 15 mL of tert-butanol, followed by the addition of diphenyl azide (0.8 mL, 3.75 mmol) and triethylamine (0.5 mL, 3.75 mmol at 80 ° C for 16 hours). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj Tert-butyl carbamate 13 g C335 mg, pale yellow oil, yield: 57.0%.

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

Seventh step

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

tert-Butyl N-[(lR,2S/1^2R)-2-(3-pyridyl)cyclopropyl]carbamate 13g (300 mg, 1.28 Methyl) was dissolved in 2 mL of ethyl acetate, and 6 mL of a 5 M aqueous solution of hydrogen chloride was added dropwise for 2 hours. Add saturated sodium carbonate solution to the reaction solution pH=9, add 50 mL of ethyl acetate, and separate the mixture. The aqueous phase is extracted with ethyl acetate (50 mL×4), and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, The residue was purified by EtOAc (EtOAc) elute , Yield: 35%.

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

Eighth step

2- {[(3& 4 6 6& -2,2-Dimethyl-6-[5-propylindolyl-7-[[(1 2 -2-(3-pyridyl))cyclopropyl]amino) Zoxao[4,5-d]pyrimidin-3-yl}-4,5,6,6&-tetrahydro-3aH-cyclopentenyl M[l,3]dioxol-4-yl] Oxyl]ethanol

2-{[(3aS,4R,6 6aR)-6-(7-chloro-5-propylindolyl-triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[[1,3]dioxol-4-yl]oxy}ethanol 5g (80 mg, 0.19 mmol) dissolved in 4 mL In tetrahydrofuran, a solution of triethylamine (0.3 mL, 0.67 mmol) and 2 mL of (lR,2S/1^2R)-2-(3-pyridyl)cyclopropylamine 13h (30 mg, 0.22 mmol) in tetrahydrofuran was added. Reaction for 12 hours. The organic layer was concentrated under reduced pressure. Benido-7-[[(lR,25/l 2R)-2-(3-pyridyl)cyclopropyl]amino]triazolo[4,5-d]pyrimidin-3-yl}-4,5 , 6-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy]ethanol 13i (45 mg, colorless oil), yield: 45.8%.

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

Step 9

(1S,2 3 5R)-3-(2-hydroxyethoxy)-5-{5-propylindolyl-7-[[(1 2 /1 2 -2-(3-pyridyl))cyclopropyl Amino]triazolo[4,5-d]pyrimidin-3-yl}cyclopentane-1,2-diol 2-{[(3aR,4S,6R,6a-2,2-dimethyl -6-[5-propyldecyl-7-[(lR,25/l 2R)-2-(3-pyridyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl -4,5,6,6a-tetrahydro-3aH-cyclopentene M[l,3]dioxol-4-yl]oxy}ethanol 13i (45 mg, 0.085 mmol) was dissolved in 4 mL of methanol, add 1 mL of 2 M hydrochloric acid, and react for 4 hours. Add saturated sodium carbonate solution to the reaction solution ρΗ=8, concentrate under reduced pressure, extract with ethyl acetate (50 mL×3), combine organic phase, anhydrous Drying over sodium sulfate, filtration, and EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH /l 2R)-2-(3-pyridyl)cyclopropylamino]triazolo[4,5-d]pyrimidin-3-yl}cyclopentane-1,2-diol 13 (27 mg, white Solid), Yield: 65.0% MS m/z (ESI): 488.2 [M+l]

1H NMR (400 MHz, CD ₃ OD) δ 8.56 (br, 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). Example 14 (1S,2 3 4R,5R)-3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1 ,2,3]tri-d]pyrimidin-3-yl)-4-fluoro-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

First step

4-nitrobenzoic acid ((3^,4 5 6 6 )-4-azido-6-(benzyloxy)-2,2-dimethyl-4,5,6,6α-tetrahydro

-3oH-cyclopenta W][l,3]dioxol-5-yl) ester (3,4R,5R,6 6^)-4-azido-6-benzyloxy- 2,2-Dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-5-ol 7e (1.20 g, 4 mmol), Nitrobenzoic acid (1.34 g, 8 mmol) and triphenylphosphine (2.15 g, 8 mmol) were dissolved in 60 mL of tetrahydrofuran, diisopropyl azodicarboxylate (1.6 mL, 8 mmol) was added and stirred at 55 °C Reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjj (benzyloxy)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-5-yl)ester 14a ( 1.32 g, yellow oil), Yield: 73.0%.

Second step

(3,4R,5 6 6^)-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3aH-cyclopenta

M[l,3]dioxol-5-ol

4-Nitrobenzoic acid ((3i^,4S,5 6 6^)-4-azido-6-(benzyloxy)-2,2-dimethyl-4,5,6,6β- Tetrahydro-3oH-cyclopenta M[l,3]dioxol-5-yl)ester 14a (1.32 g, 3 mmol) was dissolved in 24 mL To a mixed solution of methanol and water (V/V = 5:1), potassium hydroxide (337 mg, 6 mmol) was added, and the mixture was stirred for 1 hour. Concentrate under reduced pressure, add 10 mL of water, EtOAc (EtOAc)EtOAc. The title product (3,4R,5 6 6^)-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3aH-cyclod was obtained. Pentylene M[l,3]dioxol-5-ol 14bC870 mg, pale yellow oil Yield: 95.0%.

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

third step

(3i^,4S,5R,6R,6i^)-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro -3flH-cyclopenta

[d][l,3]dioxole

(3,4R,5 6 6^)-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[ l,3]dioxol-5-ol 14b (750 mg, 2.50 mmol) was dissolved in 40 mL of dichloromethane, and diethylamine trifluorosulfide (0.5 mL, 3.70 mmol) was added dropwise and stirred. Reaction for 3 hours. The reaction mixture was washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3,4WR,6R,6)-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopentyl And M[l,3]dioxole 14c (380 mg, colorless oil), yield: 50%.

the fourth step

(3i^,4S,5R,6R,6i^)-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3] dioxol-4-amine

(3i^, 4S, 5R, 6R, 6i^)-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetra Hydrogen-3flH-cyclopenta W][l,3]dioxole 14c (480 mg, 1.56 mmol) was dissolved in 30 mL of methanol, 5% Pd/CaCO ₃ (900 mg) was added, and the reaction was stirred. 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3i^,4S,5R,6R,6i^)-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6 , 6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-amine 14d (430 mg, colorless oil). MS m/z (ESI): 282.2 [M+1]

the fifth step

(3oR,4R,5R,6 6 )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3flH-cyclopenta M[l,3] Oxe-4-ol

(3^,4 5R,6R,6 )-6-(Benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3oH-cyclopenta[ 1,3]dioxol-4-amine 14d (430 mg, 1.56 mmol) was dissolved in 15 mL of methanol, 20% Pd/C (900 mg) was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3oR, 4R, 5R, 6 6 ) 6-amino-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro- 3flH-cyclopenta[d][l,3]dioxol-4-ol 14e (300 mg, colorless oil).

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

Step 6 (3i^,4S,5R,6R,6flR)-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3 Benzyl dioxol-4-ylcarbamate

(3oR, 4R, 5R, 6 6^)-6-amino-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3 Dioxet-4-ol 14e (200 mg, 1.05 mmol) was dissolved in a mixture of 13 mL of tetrahydrofuran and water (V/V = 3.33:1). Benzyl chloroformate (215 mg, 1.26 mmol) was added dropwise, and the reaction was stirred for 12 hr. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture, and the mixture was evaporated. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut elut -4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-ylcarbamate 14f (260 mg, white solid), Yield: 76.2 %.

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

Seventh step

2-((3,4R,5R,6 6 )-6-(benzyloxyamido)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3flH-cyclopentyl and

M[l,3]dioxol-4-ethoxy)acetate

(3i^, 4S, 5R, 6R, 6flR)-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6β-tetrahydro->aH-cyclopenta M[l , 3] Benzyl dioxol-4-ylcarbamate 14 260 mg, 0.80 mmol) dissolved in 10 mL of tetrahydrofuran, and added dropwise 20% potassium t-butoxide solution C 0.7 mL at 0 ° C, 1.20 (mmol), the reaction was stirred at 0 ° C for 30 min, ethyl bromoacetate (0.1 mL, 1.20 mmol). A saturated ammonium chloride solution (10 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Product 2-((3,4R,5R,6S,6)-6-(Benzyloxyamido)-5-fluoro-2,2-dimethyl-4,5,6-tetrahydro-3aH-cyclo Ethyl pentyl M[l,3]dioxol-4-yloxy)acetate 14 g (328 mg, mp.

Eighth step

(3i^, 4S, 5R, 6R, 6i^)-5-fluoro-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH- Cyclopenta

^][1,3]Benzyl dioxol-4-ylcarbamate

2-((3,4R,5R,6 6^)-6-(benzyloxyamido)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH- Ethyl bromide M[l,3]dioxol-4-yloxyacetate 14 g (328 mg, 0.80 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium borohydride (C35 mg, 1.60 mmol) was added. The reaction was stirred for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained was purified to give the title product (3i, 4S, 5R, 6R, 6i^)-5-fluoro-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5, Benzyl 6,6β-tetrahydro-3flH-cyclopenta[^][1,3]dioxol-4-ylcarbamate 14h (170 mg, colorless oil), yield: 57.6% .

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

Step 9

2-((3,4R,5R,6 6 )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l, 3] two Olecyclopentene-4-oxy)ethanol

(3i^, 4S, 5R, 6R, 6i^)-5-fluoro-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH - Cyclopenta[d][l,3] benzyl dioxol-4-ylcarbamate 14hC170 mg, 0.46 mmol) dissolved in 8 mL of methanol, 10% Pd/C (170 mg) The hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product 2-((3,4R,5R,6 6^)-6-amino-5-fluoro-2,2-dimethyl-4,5,6,6β- Tetrahydro-3oH-cyclopenta[d][l,3]dioxol-4-yloxy)ethanol 14 108 mg, colorless oil).

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

Step 10

2-((3,4R,5R,6^6i^)-6-(5-Amino-6-chloro-2-(propylthio)pyrimidine-4-amino)-5-fluoro-2,2-di Methyl-4,5,6,6α-tetrahydro-3oH-cyclopenta W][l,3]dioxol-4-oxy)ethanol 2-((3,4R,5R, 6 6^)-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3oH-cyclopenta W][l,3]dioxole -4-oxy)ethanol 14i (108 mg, 0.46 mmol), 4,6-dichloro-2-propylindolyl-pyrimidine-5-amine ls (220 mg, 0.92 mmol) and N,N-diisopropyl Ethylethylamine (0.24 mL, 1.38 mmol) was dissolved in 5 mL of N,N-dimethylformamide and stirred at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Chloro-2-(propylthio)pyrimidine-4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta[d][l, 3] Dioxol-4-oxy)ethanol 14j (65 mg, brown oil), Yield: 36.0%.

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

The eleventh step

2-((3i^,4R,5R,6^6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d Pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxole-4 -oxy)ethanol 2-((3,4R,5R,6^6i^)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro -2,2-dimethyl-4,5,6,6α-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-yloxy)ethanol 14j (65 mg, 0.15 Methyl) was dissolved in a mixed solution of 3 mL of acetic acid and water (V/V = 2:1), sodium nitrite (12 mg, 0.17 mmol) was added at 0 ° C, and the reaction was stirred at 0 ° C for 10 minutes. Ethyl acetate (15 mL) was added to the reaction mixture, and a saturated sodium carbonate solution was added dropwise until the reaction mixture was pH 7. The organic phase was washed with saturated sodium carbonate solution (15 mL), and the mixture was separated. The ester (15 mL X3) was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjj Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4, 5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-oxy)ethanol 14k (67 mg, red brown oil), product The next step is to react.

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

Step 12

2-((3i^,4R,5R,6^6i^)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(- Thio)]3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6β- Tetrahydro-3flH-cyclopenta [d][l,3]dioxol-4-oxy)ethanol

2-((3,4R,5R,6 6^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] Pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4- Ethyloxyl 14k (67 mg, 0.15 11^101) and 1 2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (40.10 mg, 0.20 mmol) dissolved in 5 mL To the acetonitrile, triethylamine (53.13 mg, 0.53 mmol) was added, and the reaction was stirred for 12 hr. The reaction mixture was concentrated under reduced vacuo. ^,4R,5R,6S,6i^)-6-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H -[1,2,3]triazolo[4,5-pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopentyl And M[l,3]dioxol-4-oxy)ethanol 141C43 mg, pale yellow oily yield: 50%.

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

Step 13

(1 2 3 4R,5R)-3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1, 2,3] Triazolo[4,5-d]pyrimidin-3-yl)-4-fluoro-5-(2-hydroxyethoxy)cyclopentane-1,2-diol will 2-(( 3,4R,5R,6 6i^)-6-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H- [1,2,3]triazolo[4,5-pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta W][l,3]dioxol-4-oxy)ethanol 141 (43 mg, 0.07 mmol) was dissolved in a mixed solution of 5.5 mL of methanol and water (V/V=10:1), and added The dowex 50 ion exchange resin (50 mg) was stirred for 60 hours. The filtrate was concentrated under reduced pressure to give the title product (1 2 3 4 R, 5R) -3- (7-( lW, 2 -2- (3) ,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluoro 5-(2-Hydroxyethoxy)cyclopentane-1,2-diol 14 (35 mg, pale yellow solid), yield: 87.5%.

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

1H NMR (400 MHz, CD ₃ OD) 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) Example 15

(1R,2 3 4S,5R)-4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1 , 2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluorocyclopentane-1,2,3-triol

First step

OR,4R,5R,6S,6i^)-6-(5-Amino-6-chloro-2-(propylthio)pyrimidine-4-amino)-5-fluoro-2,2-dimethyl

-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol (3oR,4R,5R,6 6^)-6-amino- 5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-ol 14e (100 mg, 0.52 Ment) dissolved in 3 mL of N,N-dimethylformamide, followed by 4,6-dichloro-2-propylthio-pyrimidin-5-amine Is (250 mg, 1.05 mmol) and N,N Diisopropylethylamine (0.3 mL, 1.57 mmol) was stirred at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjj (propylthio)pyrimidin-4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxole Penten-4-ol 15aC 100 mg, brownish red oil), Yield: 50%.

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

Second step

(3flR, 4R, 5R, 6^6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3 -yl)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol will be 0 4 5 6^60 -6-(5-Amino-6-chloro-2-(;propylthio)pyrimidine-4-amino)-5-fluoro-2,2-dimethyl-4,5,6, 6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 15a (200 mg, 0.51 mmol) dissolved in 4.5 mL of acetic acid and water (V/V = 2:1) In the mixed solution, sodium nitrite (43 mg, 0.62 mmol) was added at 0 ° C, and the reaction was stirred at 0 ° C for 10 minutes. Ethyl acetate (10 mL), saturated sodium carbonate solution (15 mL) was added to the mixture, and the organic phase was washed with saturated sodium carbonate (10 mL). X 3) Extraction, combined organic phase, dried over anhydrous sodium sulfate, filtered, filtered, and evaporated to give the title product (3F, 4R, 5R, 6^6i^)-6-(7-chloro-5- ( Thio)]3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6α- Tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 15b (180 mg, reddish brown oil), Yield: 87.5%.

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

(3flR, 4R, 5R, 6^6i^)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)- 3H-[1,2,3] Triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH -cyclopenta M[l,3]dioxol-4-ol

(3flR, 4R, 5R, 6^6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine- 3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 15b (180 mg, 0.45 mmol) and (lR,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (120 mg, 0.58 mmol) dissolved in 8 mL of acetonitrile, triethylamine (159 mg, 1.58 mmol), the reaction was stirred for 48 hr. The reaction mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[ 4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxa Cyclopenten-4-ol 15c (160 mg, pale yellow oil), Yield: 66.3%.

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

the fourth step

(1R,2 3 4S,5R)-4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluorocyclopentane-1,2,3-triol will be Pfl ^R^R^S^i^^- - GR JP^difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-pyrimidin-3-yl)-5-fluoro- 2,2-Dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 15c (160 mg, 0.30 mmol) was dissolved in In a mixed solution of 5.5 mL of methanol and water (V/V = 10:1), dowex 50 ion exchange resin (200 mg) was added, and the reaction was stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to afford to afford the title product (1R,2 3^^,5R)-4-(7-((lR,2^-2) -(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl) - 5-Fluorocyclopentane-1,2,3-triol 15 (100 mg, white solid), Yield: 67%.

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

1H NMR (400 MHz, CD ₃ OD) 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) Example 16

(1 2S,3R,5 -3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2 , 3] triazole

[4,5-d]pyrimidin-3-yl)-5-(2-fluoro-3-hydroxypropoxy)cyclopentane-1,2-diol

First step

(3,4R,6 6flR)-6-(allyloxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxo Benzene heterocyclopenten-4-ylcarbamate

N-[(3 ,4R,6 6flR)-6-hydroxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxa Cyclopentene-4-yl]carbamic acid benzyl ester 5b (4 g, 13 mmol) was dissolved in 20 mL of tetrahydrofuran, followed by potassium t-butoxide (2.20 g, 19.50 mmol), bromopropene (2.2 mL, 26 mmol) The reaction was stirred for 12 hours. Water (20 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained was purified by silica gel column chromatography eluting with EtOAc 6,6α-Tetrahydro-3oH-cyclopenta M[l,3] benzyl dioxol-4-ylcarbamate 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-(epoxyacetam-2-yloxy)-4,5,6,6α-tetrahydro-3oH-cyclopenta

^][1 ,3]Benzyl dioxol-4-ylcarbamate

(3,4R,6 6flR)-6-(allyloxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3] Benzyl oxol-4-ylcarbamate 16a (2.10 g, 6 mmol) was dissolved in 15 mL of dichloromethane, and m-chloroperoxybenzoic acid (2.10 g, 12.17 mmol) was added at 0 ° C. 12 hours. Filtration, the filtrate was washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and filtered. Purify the resulting residue to give the title Product (3,4R,6 6flR)-2,2-dimethyl-6-(oxirane-2-methoxy)-4,5,6,6β-tetrahydro-3flH-cyclopenta M [l,3] Benzyl dioxol-4-ylcarbamate 16b (2.16 g, pale yellow oil), yield: 98.0%. MS m/z (ESI): 364.1 [M+1]

third step

(3,4R,6 6flR)-6-(3-(Benzyloxy)-2-hydroxypropoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-ring Penta

^][1,3]Benzyl dioxol-4-ylcarbamate

Dissolve benzyl alcohol (0.7 mL, 6.90 mmol) in 5 mL of tetrahydrofuran, add 60% sodium hydrogen (60 mg, 1.50 mmol), (3,4R,6 6aR)-2,2-dimethyl at 0 °C. -6-(oxirane-2-methoxy)-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ylamino Benzyl formate 16b (0.50 g, 1.40 mmol) was stirred for 12 hours. Ethyl acetate (10 mL) was added to the reaction mixture, 5% hydrochloric acid (10 mL) was added, and a 5% sodium hydrogencarbonate solution was added dropwise to the reaction mixture, and the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting to afford to afford the title product (3,4R,6 6flR)-6-(3-(benzyloxy)-2-hydroxypropyl Oxy) -2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta[d][l,3]dioxol-4-ylcarbamate 16^0.35 g, colorless oil), Yield: 57.0%.

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

the fourth step

(3,4R,6 6flR)-6-(3-(Benzyloxy)-2-fluoropropoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-ring Penta

^][1,3]Benzyl dioxol-4-ylcarbamate

(3 ,4R,6 6flR)-6-(3-(Benzyloxy)-2-hydroxypropoxy) -2,2-dimethyl-4,5,6,6β-tetrahydro-3flH- Cyclopenta W][l,3] benzyl dioxol-4-ylcarbamate 16cC330 mg, 0.70 mmol) was dissolved in 10 mL of dichloromethane, and diethylamine was added dropwise at -78 °C. Sulfur fluoride (0.2 mL, 1.67 mmol) was stirred at room temperature for 6 hours. Water (15 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated The residue obtained was purified by silica gel column chromatography eluting elut elut elut ,2-Dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ylcarbamate 16d (260 mg, brown red Oil), Yield: 79.0%.

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

the fifth step

3-((3flR,4S,6R,6i^)-6-amino-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxo Heterocyclic pentene-4-oxy)-2-fluoropropan-1-ol

(3,4R,6 6flR)-6-(3-(Benzyloxy)-2-fluoropropoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH- Cyclopenta W][l,3] benzyl dioxol-4-ylcarbamate 16dC260 mg, 0.55 mmol) dissolved in 10 mL of methanol, 10% Pd/C (100 mg), hydrogen After three replacements, the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product: 3-(; 4 6 6 6)-6-amino-2,2-dimethyl-4,5,6,60-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-2-fluoropropan-1-ol 16eG00 mg, brown oil ()), Yield: 74.0%.

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

Step 6

3-((3flR, ^,6R,6)-6-(5-amino-6-chloro-2-(propylthio)pyrimidine-4-amino)-5-fluoro-2,2-dimethyl

-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-oxy)-2-fluoropropan-1-ol 3-((3flR) ,4S,6R,6i^)-6-Amino-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxolane- 4-oxy)-2-fluoropropan-1-ol 16e (100 mg, 0.40 mmol), 4,6-dichloro-2-propylthio-pyrimidine-5-amine Is (143 mg, 0.60 mmol) And N,N-diisopropylethylamine (0.2 mL, 1.20 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and the reaction was stirred at 100 ° C for 12 hours. Water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate (10 mL EtOAc). The mixture was concentrated under reduced pressure. 4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-oxy -2-fluoropropan-1-ol 16f (45 mg, brown oil), Yield: 25.1%.

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

Seventh step

3-((3flR,4^6R,6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine- 3-yl)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-2- Fluoropropan-1-ol will be 3-((3flR, ^,6R,6 )-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2, 2-Dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-yloxy)-2-fluoropropane small alcohol 16f (45 Mg, 0.10 mmol) was dissolved in 2 mL of acetic acid, 0.1 mL of sodium nitrite (7.2 mg, 0.10 mmol) was added at 0 ° C, and the reaction was stirred for 20 min at 0 °. Ethyl acetate (15 mL) was added to the reaction mixture, and a saturated aqueous solution of potassium carbonate (10 mL) was added dropwise, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (15 mL X 3 ). The organic layer was dried (MgSO4) 1,2,3]triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta[d][l , 3]dioxol-4-oxy)-2-fluoropropan-1-ol 16 g (50 mg, red brown oil).

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

Eighth step

3-((3oR,45,6R,6o5)-6-(7-((lR,25)-2- 2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)- 3H-[1,2,3] Triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxole-4-oxy)-2-fluoropropan-1-ol

3-((3flR,4^6R,6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-pyrimidine-3 -yl) - 2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yloxy)-2-fluoro Propane-1-ol 16g (50 mg, 0.11 mmol) and (lR,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (29 mg, 0.14 mmol) dissolved in 5 mL acetonitrile Triethylamine (38 mg, 0.38 mmol) was added and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and then, then, then, then, then, and then, and then, and, and The mixture was washed with anhydrous sodium sulfate and filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5 -d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-oxo Base) -2-fluoropropan-1-ol 16hC24 mg, orange-red oil), Yield: 38.0%. MS m/z (ESI): 595.2 [M+1]

Step 9

[4,5-d]pyrimidin-3-yl)-5-(2-fluoro-3-hydroxypropoxy)cyclopentane-1,2-diol 3-((3oR,45,6R,6o5) -6-(7-((lR,25)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazole And [4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3] dioxane Ethyl-4-oxy)-2-fluoropropan-1-ol 16hC24 mg, 0.04 mmol) was dissolved in 8 mL of methanol, 2 mL of 2.5 M hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. Water (10 mL) was added dropwise to a saturated sodium carbonate aqueous solution, and the mixture was taken to pH 7 and extracted with ethyl acetate (10 mL X 3 ), and the organic phase was combined with saturated sodium chloride solution (10) The title product (1 2S,3R,5 -3-(7-() was obtained by washing with EtOAc. (lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5 pyrimidine-3- -5-(2-Fluoro-3-hydroxypropoxy)cyclopentane-1,2-diol 16 (10 mg, pale yellow solid yield: 45.0%.

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

(1^2R,5R)-5-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2 , 3] triazole

[4,5-d]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol

17

First step

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

-4-ol

((3,4R,6 6flR)-6-Hydroxy-2,2-dimethyl-tetrahydro-3flH-cyclopentene M[l,3]dioxol-4-ylcarbamic acid Benzyl ester 5bC3 g, 9.80 mmol) was dissolved in 100 mL of methanol, 10% Pd/C (600 mg) was added, and hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, M[l,3]dioxol-4-ol 17aC1.60 g, pale yellow oil), yield: 94.0%.

Second step

(3flR, ^,6R,6 )-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl-4,5,6,6α -tetrahydrogen

-3oH-cyclopenta[d][l,3]dioxol-4-ol

(3flR, 4S, 6R, 6i^-6-amino-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxole En-4-ol 17a (1.60 g, 9.20 mmol), 4,6-dichloro-2-propylthio-pyrimidine-5-amine Is (2.60 g, 11 mmol) and N,N-diisopropyl Ethylamine (3.60 g, 27.60 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and stirred at 100 ° C for 5 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The liquid phase was extracted with ethyl acetate (100 mL×3). The organic phase was combined, washed sequentially with water (50 mL) and saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut Pyrimidine-4-amino)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 17b ( 1.85 g, orange solid), Yield: 55.0%.

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

third step

(3flR, 4^6R, 6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-pyrimidin-3-yl)- 2,2-dimethyl -4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol (3flR,4^6R,6i^)-6-(5- Amino-6-chloro-2-(propylthio)pyrimidine-4-amino)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3] Dioxol-4-ol 17b (1.85 g, 4.90 mmol) was dissolved in 30 mL of a mixed solution of acetic acid and water (V/V = 1:1), and 1 mL of sodium nitrite (0.38 g, 5.40) was added dropwise. Aqueous ice water was stirred at 0 ° C for 30 minutes. Ethyl acetate (50 mL) was added to the mixture and the mixture was evaporated. mjjjjjjjjjjjjjj The sodium chloride solution (50 mL) was washed with EtOAc (EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -3H-[1,2,3]triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-ol 17c (1.90 g, brown oil).

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

the fourth step

(3flR, 4^6R, 6i^)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[ l,3]dioxole

-4-ol

(3flR, 4^6R, 6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3- -2,2-Dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 17c (1.90 g, 4.90 mmol Dissolved in 50 mL of acetonitrile, and sequentially added (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (1.30 g, 6.40 mmol) and triethylamine (1.70 g, 17) (mmol), the reaction was stirred for 12 hours. The reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The residue was washed with a saturated aqueous solution of sodium chloride (50 mL). 6R,6i^)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2, 3] Triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxa Cyclopenten-4-ol 17d (2 g, orange solid), Yield: 80%.

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

the fifth step

N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-3-((3i^,4R,6flR)-2,2-dimethyl-4,6β- Dihydro-3flH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5 -d]pyrimidine-7-amine will be (3flR,4^6R,6)-6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-( Propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro- 3flH-cyclopenta M[l,3]dioxol-4-ol 17d (130 mg, 0.25 mmol) and triphenylphosphine (263 mg, 1 mmol) dissolved in 2 mL of toluene, added dropwise The reaction mixture was stirred under reduced pressure for 2.5 hours. ((1 2^-2-(3,4-difluorophenyl)cyclopropyl)-3-((3^,4 6^)-2,2-dimethyl-4,60-dihydro- 30 cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine -7-amine 17e (125 mg, colorless oil), Yield: 99%.

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

Step 6

[4,5-d]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol

N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-3-((3i^,4R,6flR)-2,2-dimethyl-4,6a -dihydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4, 5-d]pyrimidin-7-amine 17e (120 mg, 0.24 mmol) was dissolved in 14 mL of a mixture of methanol and tetrahydrofuran (V/V=l: 1.33), dropping B 4 mL 2.5 M hydrochloric acid, stirring reaction 12 The reaction solution was concentrated under reduced pressure. Water (15 mL) was added, and a saturated aqueous sodium hydroxide solution was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL X 3 ). The sodium solution (10 mL) was washed with EtOAc (mjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5 -d]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol 17 (30 mg, white solid), yield: 27.3%.

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

1H NMR (400 MHz, DMSO-J ₆ ) 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) 18

(1S,2 3 5R)-3-(2,2-difluoroethoxy)-5-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)) 5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol

18

First step

(3,4R,6 6flR)-2,2-dimethyl-6-(2-oxoethoxy)- 4,5,6,6β-tetrahydro-3oH-cyclopenta M[l,3 Dioxol-4-yl-carbamic acid benzyl ester

(3,4R,6 6flR)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3oH-cyclopentene M[l, 3] Dioxol-4-yl-carbamic acid benzyl ester 5d (2 g, 5.69 mmol) was dissolved in 20 mL of dichloromethane, and then added to Dess-Martin oxidant C 2.90 g, 6.83 mmol at 0 °C. The reaction was stirred at 0 ° C for 5 minutes, and the reaction was stirred at room temperature for 12 hours. Dichloromethane (50 mL), saturated sodium bicarbonate (20 mL), saturated sodium thiosulfate solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. Concentration by pressure gave the title product (3,4R,6 6 flR)-2,2-dimethyl-6-(2-oxoethoxy)-4,5,6,6?-tetrahydro-3oH-ring Pheno[l,3]dioxol-4-yl-carbamic acid benzyl ester 18a (1.46 g, yellow oil).

Second step

(3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l ,3] Dioxol-4-yl-carbamic acid benzyl ester

(3,4R,6 6flR)-2,2-dimethyl-6-(2-oxoethoxy)-4,5,6,6a-tetrahydro-3oH-cyclopenta M[l, 3] Dioxol-4-yl-carbamic acid benzyl ester 18aC1.46 g, 4.18 mmol) was dissolved in 15 mL of dichloromethane, and diethylamine trifluorosulfide (1.01 g, 6.27 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-Dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-yl-carbamic acid benzyl ester 18 925 mg, light yellow oil ()), Yield: 59.7%. MS m/z (ESI): 372.45 [M+l]

third step

(3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l , 3]dioxol-4-amine

(3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3oH-cyclopenta M[ l,3]Dioxol-4-yl-carbamic acid benzyl ester 18bC925 mg, 2.50 mmol) dissolved in 20 mL of methanol, added with 10% Pd/C (100 mg), replaced with hydrogen three times, stirred reaction 3 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3,4,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-amine 18cC565 mg, colorless oil, yield: 95.3%.

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

the fourth step

6-chloro-A^- Pfl^lR^ 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-ring Penta

M[l,3]dioxol-4-yl)-2-(propylthio)pyrimidine-4,5-diamine (3,4R,6 6flR)-6-(2,2- Difluoroethoxy) -2,2-dimethyl-4,5,6,6β-tetrahydro-3oH-cyclopenta[l,3]dioxol-4-amine 18c (365 mg , 1.54 mmol) dissolved in ethylene glycol, followed by 4,6-dichloro-2-propylthio-pyrimidin-5-amine Is (550 mg, 2.31 mmol) and triethylamine (778 mg, 7.69 mmol) The reaction was stirred at 100 ° C for 12 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture and the mixture was evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting eluting 5,6,6β-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-2-(;propylthio)pyrimidine-4,5-diamine 18d ( 250 mg, dark red oil Yield: 37.6%.

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

the fifth step

7-Chloro-3-((3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH - cyclopenta

M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine 6-chloro -N ⁴ -((3 ,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-ring Pentacene M[l,3]dioxol-4-yl)-2-(;propylthio)pyrimidine-4,5-diamine 18d (250 mg, 0.57 mmol) dissolved in 1 mL of acetic acid Then, 0.4 mL of water, sodium nitrite (42 mg, 0.60 mmol) was added in order, and the reaction was stirred for 20 minutes. Ethyl acetate (10 mL) was added to the reaction mixture, and a saturated aqueous solution of potassium carbonate (45 mL) was added dropwise, and the aqueous phase was extracted with ethyl acetate (45 mL X 2). The solution was washed with a saturated aqueous solution of sodium chloride (45 mL), dried over anhydrous sodium sulfate, filtered and evaporated. -Chloro-3-((3o5,4R,65,6oR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3oH -cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine 18e (128 mg, light Yellow oil), Yield: 50.0%.

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

Step 6

3-((3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-yl)-N-((lR,2^-2-(3,4-difluorophenyl)cyclopropanyl)-5-(propylthio) -3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine

7-Chloro-3-((3,4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro- 3flH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] Pyrimidine 18e (128 mg, 0.29 mmol) was dissolved in 15 mL of tetrahydrofuran, and (lR,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (79 mg, 0.38 mmol), Triethylamine (101 mg, 1 mmol) was added, and the reaction was stirred for 12 hr. The reaction mixture was evaporated evaporated. 6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3oH-cyclopenta M[l,3]dioxo Heterocyclopenten-4-yl)-N-((lR,2^-2-(3,4-difluorophenyl)cyclopropanyl)-5-(propylthio)-3H-[1,2 , 3] Triazolo[4,5-d]pyrimidin-7-amine 18f (108 mg, colorless oil), yield: 65.0% MS m/z (ESI): 583.2[M+1]

Seventh step

(1S,2 3 5R)-3-(2,2-difluoroethoxy)-5-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)) 5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol 3-((3, 4R,6 6flR)-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3] Dioxol-4-yl)-N-((lR,2^-2-(3,4-difluorophenyl)cyclopropenyl)-5-(propylthio)-3H-[1 , 2,3] Triazolo[4,5-d]pyrimidin-7-amine 18f (108 mg, 0.19 mmol) was dissolved in 3.2 mL of methanol, and 2.2 mL of 2.5 M hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. Add 4 M sodium hydroxide solution to the reaction solution to pH 8, and extract with ethyl acetate (25 mL X 3 ). The organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified to give titled product (1S, 2 3 5 R) -3-(2,2-difluoroethoxy) -5-(7-((lR,2 -2-) 3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5 pyrimidin-3-yl)cyclopentane-1, 2-diol 18 (99 mg, light Colored solid), yield: 99.0%

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

1H NMR (400Hz, CDC1 ₃ ) 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) Example 19

(1R,2R,3 4R,5 -4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio) -3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl 1-(;hydroxymethyl)bicyclo[3丄0]hexane-2,3-diol

first step

(3flR, 3M, 4, 5R, 5fl -5-(l,3-indol-2-yl)-2,2-dimethyl-hexahydrocyclopropan [3,4]cyclopenta

[l,2-d][l,3]dioxole-3b-carboxylic acid ethyl ester

(3flR, 3M, 4, 5 5^)-5-hydroxy-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[l,2-d][l,3] Dioxetane-3b-formic acid ethyl ester 19a (370 mg, 1.53 mmol, prepared by a known method) Nucleosides, Nucleotides & Nucleic Acids (2008), 27(3), 279-291 "Prepared" In 20 mL of tetrahydrofuran, triphenylphosphine (400 mg, 1.53 mmol) and phthalimide (225 mg, 1.53 mmol) were added in sequence, and 10 mL of diisopropyl azodicarboxylate C309 mg, 1.53 was added dropwise. A solution of mmol) in tetrahydrofuran was stirred for 12 hours. The reaction mixture was purified by silica gel column chromatography eluting elut elut eluting Dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylic acid ethyl ester 19b (420 mg, slightly pink solid) , Yield: 74.0%.

Second step

(3^,3^,4^,5 5^)- 5-Amino-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-(1][1 , 3] dioxol-3b-carboxylic acid ethyl ester

(3flR, 3M, 4, 5R, 5i^)-5-(l,3-indol-2-yl)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopentyl And [l,2-d][l,3]dioxole-3b-formic acid ethyl ester 19b (420 mg, 1.11 mmol) was dissolved in 8 mL of ethanol, and 85% hydrazine monohydrate (653) was added. Mg, 11.10 mmol), and the reaction was stirred at 70 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated tolululululululululululululululululululululululululululululululululululululululululululululululululululu 4] Cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate 19c (220 mg, white oil), yield: 82.0%. third step

(3flR, 3M, 4, 5R, 5i^)-5-(6-chloro-5-nitro-2-(propylthio)pyrimidine-4-amino)-2,2-dimethyl-hexahydrocyclohexane Methyl [3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate (3flR,3M,4i^,5R,5i^)-5 -amino-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate 19c ( 140 mg, 0.58 mmol) dissolved in 15 mL of ethanol, followed by 4,6-chloro-5-nitro-2-propylindolyl-pyrimidine 6b (170 mg, 0.64 mmol) and triethylamine (117 mg, 1.16) Methyl), stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Pyrimidin-4-amino)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxol-3b-formic acid Ethyl ester 19d (160 mg, brown oil), yield: 58.6%.

the fourth step

(3flR, 3M, 4, 5R, 5i^)-5-(5-amino-6-chloro-2-(propylthio)pyrimidine-4-amino)-2,2-dimethyl-hexahydrocyclopropane And [3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylic acid ethyl ester (3flR,3M,4,5R,5i^)-5-( 6-chloro-5-nitro-2-(propylthio)pyrimidine-4-amino)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[l,2-d ][l,3]Ethyl dioxetane-3b-carboxylate 19d (200 mg, 0.42 mmol) was dissolved in 3 mL of acetic acid, iron powder (190 mg, 3.40 mmol) was added, and the reaction was stirred for 2 hours. The mixture was filtered over Celite. EtOAc (EtOAc) (EtOAc)EtOAc. The aqueous solution was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated,462462462462462462462462462462462462462462462462462462462462462462462462462462462462462 Amino) -2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate 19e ( 300 mg, brown oil), the product was taken to the next step without purification.

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

the fifth step

(3flR, 3M, 4i^, 5R, 5i^)-5-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine- 3-yl)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxol-3b-carboxylate (3flR, 3M, 4, 5R, 5i^)-5-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl-hexahydrocyclo Propiono[3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate 19e (300 mg, 0.42 mmol) was dissolved in 2 mL of acetic acid and added 0.5 mL of water, 1 mL of an aqueous solution of sodium nitrite (30 mg, 0.44 mmol) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate (6 mL) was added to the reaction mixture, and a saturated sodium carbonate solution (25 mL) was added dropwise, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL X 2 ). The solution (25 mL), EtOAc (EtOAc) (EtOAc m. 7-Chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropane And [3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylate 19f (190 mg, dark brown oil). The next step is to react. MS m/z (ESI): 454.1 [M+1]

Step 6 (3aR,3bS,4 S,5R,5aS)- 5-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta

[l,2-d][l,3]dioxole-3b-carboxylic acid ethyl ester

(3flR, 3M, 4i^, 5R, 5i^)-5-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine -3-yl)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxol-3b-formate B Ester 19f (190 mg, 0.42 mmol) was dissolved in 20 mL of acetonitrile and (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate lg (181 mg) , 0.57 mmol), triethylamine (148 mg, 1.47 mmol) was added dropwise, and the mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure. ethyl acetate (20 mL) and water (20 mL) The mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAcjjjjjj 2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl) -2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[l,2-d][l,3]dioxole-3b-carboxylic acid ethyl ester 19g (215 mg , off-white solid), Yield: 87.3 %.

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

Seventh step

((3flR, 3bR, 4i^, 5R, 5i^)-5-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio) -3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta

[ 1,2-d] [1,3]dioxol -3b-yl)methanol

(3flR, 3M, 4i^, 5R, 5i^)-5-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio) -3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[ l,2-d][l,3]dioxol-3b-carboxylic acid ethyl ester 19g (215 mg, 0.37 mmol) was dissolved in 10 mL of tetrahydrofuran, and 1.5 mL of 1 M lithium aluminum hydride in tetrahydrofuran was added. The reaction was stirred for 12 hours. A saturated solution of sodium potassium tartrate (3 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. The filtrate was concentrated under reduced pressure and ethyl acetate (25 mL) and water (20 mL) The aqueous phase was extracted with ethyl acetate (15 mL EtOAc)EtOAc. 3flR,3bR,4,5R,5i^)-5-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H -[l,2,3]triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[l,2-d] [l,3]dioxole-3b-yl)methanol 19hC260 mg, Light yellow solid), the product was directly subjected to the next reaction without purification.

Eighth step

(1R,2R,3 4R,5 -4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio) -3H-[1 , 2,3]triazolo[4,5-d]pyrimidin-3-yl 1-(;hydroxymethyl)bicyclo[3丄0]hexane-2,3-diol ((3flR, 3bR,4i^,5R,5i^)-5-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[l,2- d][l,3]dioxole-3b-yl)methanol 19h (260 mg, 0.37 mmol) was dissolved in 15 mL of methanol, 4 mL of 2.5 M hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. Add 1 M sodium hydroxide solution to the reaction solution to pH 7, add ethyl acetate (20 mL) and water (10 mL), and separate the mixture. 3) Extraction, the organic phase is combined, washed with a saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title product (1R, 2R, 3 4R ,5 -4-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazole And [4,5-d]pyrimidin-3-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol 19 (40 mg, white solid), yield : 22.0%.

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

1H NMR (400 MHz, CDC1 ₃ ) δ 7.39 (br, 1H), 7.15-7.02 (m, 2H), 6.94 (d, 1H), 5.24 (s, 1H), 5.14 (d, 1H), 4.16 (d , 2,,,,, 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). Example 20

(1 2 3R,5 -3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2 ,3]triazolo[4,5-d]-3-yl)-5-fluorocyclopentane-1,2-diol

20g

First step

((3,4R,6i^)-2,2-dimethyl-6-oxo-4,5,6,6β-tetrahydro-3flH-cyclopentazepine [1,3]dioxole Alkene

-4-yl) benzyl formate ((3,4R,6 6flR)-6-hydroxy-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopentenoindole [ 1,3] diox heterocycle Benzene-4-yl)carbamate 5b (5 g, 16.3 mmol) was dissolved in 150 mL of dichloromethane, 4A molecular sieve (5 g) was added, and pyridinium chlorochromate (10.50 g, 48.80 mmol) was slowly added. The reaction was stirred for 60 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product: CO 4 R, 6)-2,2-dimethyl-6-oxo-4,5,6,6α-tetrahydro-3oH-cyclopenta[d][ Benzyl l,3]dioxol-4-yl)carboxylate 20a (3.10 g, gray oil), yield: 62.0%

Second step

((3i^, 4R, 6R, 6flR)-6-hydroxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopentene M[l,3]dioxa Cyclopentene-4-yl)carbamate

((3i^,4R,6)-2,2-Dimethyl-6-oxo-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxole Benzene-4-yl)carboxylate 20a (lg, 3.30 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium borohydride (C495 mg, 13.10 mmol) was added at -78 °C, and the reaction was stirred at -78 °C for 1 hour. The reaction solution was purified by silica gel column chromatography eluting to afford to afford the title product ((3,4R,6R,6flR)-6-hydroxy-2,2-dimethyl-4,5,6,6?-tetrahydrogen -3oH-cyclopentene M[l,3]dioxol-4-yl)carbamate 20b (510 mg, white solid), yield: 51.0%.

third step

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

-4-ol

((3i^,4R,6R,6flR)-6-hydroxy-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopentene M[l,3]dioxo Benzene heterocyclopent-4-yl)carbamate 20b (800 mg, 2.60 mmol) was dissolved in 50 mL of methanol, 10% Pd/C (80 mg) was added, and the mixture was stirred three times with hydrogen, and the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3a,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, [l,3] Dioxol-4-ol 20cC410 mg, orange solid), Yield: 91.0%.

the fourth step

(3flR,4R,6R,6)-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyl-4,5, 6,6α-tetrahydro-3oH-cyclopenta[l,3]dioxol-4-ol (3flR,4R,6R,6i^)-6-amino-2,2-dimethyl -4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 20c (410 mg, 2.36 mmol) dissolved in 30 mL of N,N- In methylformamide, 4,6-dichloro-2-propylthio-pyrimidine-5-amine Is (676 mg, 2.84 mmol) and N,N-diisopropylethylamine (915 mg, 7.08 mmol), the reaction was stirred at 100 ° C for 12 hours. After cooling to room temperature, water (60 mL) and ethyl acetate (60 mL) were added to the mixture and the mixture was evaporated. It was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate. ,6)-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyl-4,5,6,6α-tetrahydro -3oH-cyclopenta M[l,3]dioxol-4-ol 20d (390 mg, orange solid yield: 44.0%. MS m/z (ESI): 375.1 [M+l] the fifth step

(3oR,4R,6R,6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl ) -2,2-dimethyl

-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol (3flR,4R,6R,6 )-6-((5- Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta[ί ][ 1,3]dioxol-4-ol 20 390 mg, 1.04 mmol) was dissolved in 10 mL of a mixed solution of acetic acid and water (V/V=l:1), and 1 mL of nitrous acid was added dropwise in an ice water bath. Sodium (79 mg, 1.15 mmol) in ice water was stirred at 0 ° C for 30 min. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the mixture was evaporated. X 2) Washed with a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, filtered, and evaporated to give the title product (3FR,4R,6R,6i^)-6-(7-chloro- 5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β- Tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-ol 20e (340 mg, orange solid), Yield: 86.0%.

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

Step 6

(3flR, 4R, 6R, 6i^)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[ l,3]dioxole

-4-ol

(3flR, 4R, 6R, 6i^)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-pyrimidin-3-yl) -2,2-Dimethyl-4,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-ol 20e (340 mg, 0.88 mmol) dissolved (1R,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (235 mg, 1.15 mmol) and triethylamine (311 mg, 3.10 mmol) were added sequentially in 30 mL of acetonitrile. The reaction was stirred for 12 hours. The reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The residue was washed with EtOAc (3 mL, dry 3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2, 2-Dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxol-4-ol 20f (480 mg, brown solid), product Purification proceeds directly to the next reaction. MS m/z (ESI): 519.4 [M+1]

Seventh step

Trifluoromethanesulfonic acid ((3i^,4R,6R,6)-6-(7-((lR,2^-2-(3,4-difluorophenyl)cyclopropylamino)-5-(- Thio)]3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH -cyclopenta M[l,3]dioxol-4-yl)ester

(3flR,4R,6R,6 )-6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l , 3] Dioxol-4-ol 20f (320 mg, 0.62 mmol) was dissolved in 20 mL of dichloromethane, pyridine (198 mg, 2.48 mmol) was added at -78 ° C, and trifluoromethanesulfonic anhydride was added dropwise. (350 mg, 1.24 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The title product trifluoromethanesulfonic acid ((3 o5,4R,6R,6o5)-6-(7-((lR,25)-2-(3,4-difluorophenyl)cyclopropylamino))-5 was obtained. - (propylthio)-3H-[1,2,3]triazolo[4,5-pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6β-tetrahydro- 3flH-cyclopenta M[l,3]dioxol-4-yl) ester 20 g C 320 mg, colorless oily yield: 79.0%.

Eighth step

N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-3-((3,4R,6 6^)-6-fluoro-2,2-dimethyl -4,5,6,6β-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2, 3] Triazolo[4,5-d]pyrimidine

-7-amine

Trifluoromethanesulfonic acid ((3i^,4R,6R,6)-6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(- Thio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6α-tetrahydro-3αΗ - cyclopenta M[l,3]dioxol-4-yl) ester 20g C320 mg, 0.49 mmol) dissolved in 20 mL of tetrahydrofuran, added tris(dimethylamino)phosphonium difluoride at -40 °C Trimethyl) silicate (165 mg, 0.60 mmol,) was stirred at -40 ° C for 1.5 hours, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 3-((3,4R,6 6^)-6-fluoro-2,2-dimethyl-4,5,6,6β-tetrahydro-3flH-cyclopenta M[l,3]dioxa Cyclopenten-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine 20h (190 mg, white solid) Yield: 44.7%.

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

Step 9

(1 2 3R,5 -3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2 ,3]triazolo[4,5-d]pyrimidin-3-yl)-5-fluorocyclopentane-1,2-diol

N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-3-((3,4R,6 6^)-6-fluoro-2,2-dimethyl 4-,5,6,6α-tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2 , 3] Triazolo[4,5-d]pyrimidin-7-amine 20h (190 mg, 0.37 mmol) was dissolved in 5 mL of methanol, 10 mL of 2 M hydrochloric acid was added, and the reaction was stirred at 40 ° C for 30 minutes. Concentration under reduced pressure, and the residue obtained was purified eluted eluted eluted elut elut elut elut elut elut elut elut elut -amino group -5-(propylthio)-3H-[1,2,3]triazolo[4,5 pyrimidin-3-yl)-5-fluorocyclopentane-1,2-diol 20 ( 70 mg, white solid), Yield: 40.0%.

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

1H NMR (400 MHz, CDC1 ₃ ) 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). Example 21

(1^2R,5R)-5-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-(2-hydroxyethyl)-3-cyclopentene-1,2-diol

First step

2-((3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6β-dihydro-3flH- ring Pentylene M[l,3]dioxol-4-yl)isoindole-1,3-dione (3aS,4S,6aR)-6-(2-((tert-butyl dimethyl) Silyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH-cyclopenta W][l,3]dioxol-4-ol 21a (240 mg , 0.76 mmol, prepared by a known method "Journal of Medicinal Chemistry, 2005 (48), 5043-5046") dissolved in 10 mL of tetrahydrofuran, followed by the addition of phthalimide (168 mg, 1.14 mmol) Phenylphosphine (300 mg, 1.14 mmol) and diisopropyl azodicarboxylate (231 mg, 1.14 mmol) were stirred for 12 hours. The reaction was concentrated under reduced pressure and purified using silica gel column chromatography The residue obtained gave the title product 2-((3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6? - dihydro-3flH-cyclopenta M[l,3]dioxol-4-yl)isoindole-1,3-dione 21M210 mg, pale yellow oil, yield: 61.9% .

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

Second step

(3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6α-dihydro-3flH-cyclopenta

M[l,3]dioxol-4-amine

2-((3aS,4R,6aR)-6-(2-((tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3oH- Cyclopenta M[l,3]dioxol-4-yl)isoindole-1,3-dione 21b (210 mg, 0.47 mmol) was dissolved in 5 mL of ethanol and added to hydrazine hydrate (118). Mg, 2.37 mmol), stir the reaction at 70 ° C for 3 hours. The filtrate was filtered, and the filtrate was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssss -4,6a-dihydro-3flH-cyclopenta M[l,3]dioxol-4-amine 21c (142 mg, yellow oil), yield: 95.9%.

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

third step

A^- Pa^lR^aR-P-((tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH-cyclopenta M[l ,3]dioxol-4-yl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine (3aS,4R,6aR)-6-(2-(( tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH-cyclopenta W][l,3]dioxol-4- Amine 21c (140 mg, 0.45 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by 4,6-dichloro-2-(propylthio)pyrimidine-5-amine lv (159 mg, 0.67 mmol) and N,N-diisopropylethylamine (173 mg, 1.34 mmol), and stirred for 12 hours at 100 ° C. After cooling to room temperature, a saturated ammonium chloride solution (40 mL) was added to the reaction mixture. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) The obtained residue was purified to give the titled product: ?????? -3oH-cyclopenta M[l,3]dioxa Penten-4-yl) -6-chloro-2- (; propylthio) pyrimidine-4,5-diamine 21d (93 mg, reddish-brown solid), yield: 40.4%.

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

the fourth step

3-((3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH- ring Pentyl M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7 -amine will be A^- Pa^lR^aR-P-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3oH-cyclopenta M[l,3]dioxol-4-yl)-6-chloro-2-(;propylthio)pyrimidine-4,5-diamine 21d (85 mg, 0.17 mmol) dissolved in 3.3 mL In a mixed solution of acetic acid and water (V/V = 10:1), sodium nitrite (12 mg, 0.17 mmol) was added under ice water bath, and the reaction was stirred for 30 minutes in an ice water bath. Water (40 mL) was added to the reaction mixture, and the mixture was combined with ethyl acetate (15 mL×3), and the organic phase was washed successively with saturated sodium hydrogen carbonate solution (40 mL) and saturated sodium chloride solution (40 mL) Drying over sodium sulfate, filtration, and EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Dimethyl-4,6a-dihydro-3flH-cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2, 3] Triazolo[4,5-d]pyrimidin-7-amine 21e (70 mg, colorless oil), Yield: 80.5%.

the fifth step

3-((3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH- ring Pentylene M[l,3]dioxol-4-yl)-N-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)-5- (propyl sulfide

-3Η-[1,2,3]triazolo[4,5-d]pyrimidine-7-amine

3-((3aS,4R,6aR)-6-(2-((tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3oH- Cyclopenta M[l,3]dioxol-4-yl)-5-(propylthio)-3Η-[1,2,3]triazolo[4,5-d]pyrimidine -7-Amine 21e (65 mg, 0.12 mmol) was dissolved in 5 mL of acetonitrile and (lR,2 -2-(3,4-difluorophenyl)cyclopropylamine hydrochloride l li (33 mg, 0.16) Methyl) and triethylamine (37 mg, 0.37 mmol) were stirred for 6 h. The reaction mixture was evaporated.jjjjjjjjjjjj 4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH-cyclopenta M[l, 3]dioxol-4-yl)-N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3Η- [1,2,3] Triazolo[4,5-d]pyrimidin-7-amine 21f (60 mg, colorless oil).

Step 6

(1^2R,5R)-5-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-(2-hydroxyethyl)-3-cyclopentene-1,2-diol 3-(( 3aS,4R,6aR)-6-(2-((tert-butyldimethylsilyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3flH-cyclopenta M[ l,3]dioxol-4-yl)-N-((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)- 3Η-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine 21f (55 mg, 0.08 mmol) was dissolved in 5 mL of methanol, 0.5 mL 3 M hydrochloric acid was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Phenyl) cyclopropyl)amino) -5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-(2-hydroxyl Ethyl)-3-cyclopentene-1,2-diol 21 (25 mg, colorless oil), yield: 40.0%.

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

1H NMR (400 MHz, CDC1 ₃ ) δ 6.91 - 7.13 (m, 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). Example 22

(1 2 3R,5 -3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino)-5-((propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)cyclopentane-1,2-diol

step

First step

2-(2-((3aR,4S,6R,6a -6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino) -5- ( Propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3oH-cyclopenta M[l, 3]dioxol-4-yl)oxy)ethoxy)ethyl acetate

2-(((3aR,4 6R,6a -6-(7-(((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio) -3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3oH-cyclopenta M[l,3] Olelenone-4-yl)oxy)ethanol 22a (562 mg, 1 mmol, prepared by the well-known method patent "WO2011017108") dissolved in 10 mL of tetrahydrofuran, cooled to 0 ° C, added to the tertidine Potassium alkoxide (180 mg, 1.60 mmol), stirred for 15 minutes, 2 mL of ethyl bromoacetate (200 mg, 1.20 mmol) in tetrahydrofuran was added dropwise, and the reaction was stirred for 2 hr. The residue obtained was purified by EtOAc EtOAc (EtOAc) Difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- Dimethyltetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)oxy)ethoxy)ethyl acetate 22b (60 mg, light yellow oil) Rate: 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-difluorophenyl)cyclopropyl)amino) -5- ( (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3oH-cyclopenta M[l ,3]dioxol-4-yl)oxy)ethoxy)ethanol

2-(2-((3aR,4S,6R,6a -6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino) -5- (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3oH-cyclopenta M[l ,3]dioxol-4-yl)oxy)ethoxy)ethyl acetate 22b (60 mg, 0.09 mmol) was dissolved in 2 mL of THF, and lithium borohydride (11 mg, 0.50 mmol) The reaction was stirred for 0.5 hours. 1 mL of water was added to the reaction mixture, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2-(2-(;(3aR,^6R,6a -6-(;7-( (; iW) , 2 -2-(;3,4-difluorophenyl)cyclopropyl)amino) -5-((propylthio)-3H-[1,2,3]triazolo[4,5-d Pyrimidine-3-yl)-2,2-dimethyl Tetrahydro-3oH-cyclopenta M[l,3]dioxol-4-yl)oxy)ethoxy)ethanol 22c (54 mg, colorless oil), yield: 99%.

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

third step

(1 2 3R,5 -3-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino)-5-((propylthio)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)cyclopentane-1,2-diol 2-(2-((3aR,4S,6R,6a -6-(7-((lR,2 -2-(3,4-difluorophenyl)cyclopropyl)amino) -5- ((propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3oH-cyclopenta M[ l,3]dioxol-4-yloxy)ethoxy)ethanol 22c (50 mg, 0.08 mmol) was dissolved in 1.5 mL of tetrahydrofuran, 1 mL of 2.5 M hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. Add 4 M saturated sodium carbonate solution to the reaction solution until the reaction solution is 77, extract with ethyl acetate (30 mL X 3 ), combine the organic phase, wash with saturated sodium chloride solution (20 mL X 2), anhydrous The residue was dried (MgSO4), filtered ,4-difluorophenyl)cyclopropyl)amino)-5-((propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl) - 5-(2-(2-hydroxyethoxy) ) Ethoxy) cyclopentane-1,2-diol 22 (20 mg, white solid), yield: 13.5%.

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

1H NMR (400 MHz, CD ₃ OD) 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) Example 23

(1S,2R,3 4R)-4-(5-((cyclopropylmethyl)thio)-7-(((lR,2 -2-(3,4-difluorophenyl)cyclopropyl) Amino) -3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol

third step

First step

(1 2R,3 4R)-4-Aminocyclopentane-1,2,3-triol hydrochloride (3aR,4S,6R,6a -6-amino-2,2-dimethyl-4, 5,6,6a-tetrahydro-3flH-cyclopentenyl M[l,3]dioxol-4-ol L-(-)-dibenzoyl tartrate 5a (6.10 g, 11.50 mmol After adding 10 mL of methanol, 20 mL of 12 M hydrochloric acid was added, and the reaction was stirred at 40 ° C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to give the title product (1S, 2R, 3 4 R)-4-aminocyclopentane-1 2,3-triol hydrochloride 23a (1.53 g, yellow oil), yield: 100%.

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

Second step

(1 2R,3^4R)-4-((5-Amino-6-chloro-2-((cyclopropylmethyl)thio)pyrimidin-4-yl)amino)cyclopentane-1,2, 3-triol

(1 2R,3 4R)-4-Aminocyclopropane-1,2,3-triol 23a (1.53 g, 11.50 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by 4, 6-Dichloro-2-(cyclopropylmethylsulfanyl)pyrimidine-5-amine 2p (3.45 g, 13.80 mmol) and N,N-diisopropylethylamine (10.40 g, 80.50 mmol), 100° The reaction was stirred for 12 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness. - ((cyclopropylmethyl)thio)pyrimidin-4-yl)amino)cyclopentane-1,2,3-triol 23b (3.01 g, yellow oil), yield: 77.2%.

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

third step

(1^2R,3S,4R)-4-(7-chloro-5-((cyclopropylmethyl)thio)-3H-[1,2,3]triazolo[4,5-d] Pyrimidin-3-yl)cyclopentane-1,2,3-triol

(1 2R,3 4R)-4-((5-Amino-6-chloro-2-((cyclopropylmethyl)thio)pyrimidin-4-yl)amino)cyclopentane-1,2, 3-triol 23b (3.01 g, 8.68 mmol) was dissolved in 30 mL of a mixed solution of acetic acid and water (V/V = 2:1), and sodium nitrite (898 mg, 13.02 mmol) was added in an ice water bath, 0 ° C The reaction was stirred for 35 minutes. 80 mL of a saturated potassium carbonate solution was added dropwise to the reaction mixture ρ Η 8 and extracted with ethyl acetate (30 mL X 4 ). The organic phase was combined, washed with a saturated sodium chloride solution (40 mL X 2 ) and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure to give the title Product (1^2R,3S,4R)-4-(7-chloro-5-((cyclopropylmethyl)thio)-3H-[1,2,3]triazolo[4,5-d Pyrimidine-3-yl)cyclopentane-1,2,3-triol 23c (2.20 g, yellow solid), Yield: 70.8%.

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

the fourth step

(1 2R,3 4R)-4-(5-((cyclopropylmethyl)thio)-7-(((lR,2^-2-(3,4-difluorophenyl)cyclopropyl) )amino) -3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (1^2R,3^4R )-4-(7-chloro-5-((cyclopropylmethyl)thio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopenta Alkanol-1,2,3-triol 23c (2.20 g, 6.15 mmol) was dissolved in 25 mL of acetonitrile, and then added with GR, 2 -2-C3,4-difluorophenyl)cyclopropylamine hydrochloride. l li (2.23 g, 9.22 mmol) and N,N-diisopropylethylamine (3.18 g, 24.60 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj ((lR,2^-2-(3,4-difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3- Cyclopentane-1,2,3-triol 23 (1.24 g, white solid), yield 41.3%.

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

1H NMR (400 MHz, CD ₃ OD) 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) _: 1.49 (m, 1H), 1.35 (m, 3H), 1.03 (m , 1H), 0.46 (d, 2H), 0.12 (d, 2H). Test example:

Biological evaluation

Test example 1

The following method was used to determine the inhibitory effect of the compounds of the present invention on ADP-induced rat and human platelet aggregation.

The experimental method is briefly described as follows:

After anesthesia in rats, blood was taken from the abdominal aorta, and the whole blood was centrifuged at 200 g for 10 minutes (22 ° C) to remove the upper platelet-rich plasma (PRP). PRP was resuspended by washing with buffer (Taiwan buffer solution) (NaCl 129 mM, KCl 2.8 mM, KH ₂ P0 ₄ 0.8 mM, MgCl ₂ 0.8 mM, NaHC0 ₃ 8.9 mM, HEPEs 10 mM, glucose 5.5 mM). A platelet rich buffer is obtained. Platelet aggregation was measured using a 96-well plate reader: 188 prepared platelet-rich buffer, 4 μL of CaCl ₂ , 2 DMSO-dissolved compound or 2 DMSO (blank control), 37 ° incubation After 2 minutes, after measuring the absorbance at 0 minutes, add 10 μLAΌP (final concentration 20 μΜ), and oscillate for 2 to 3 minutes and measure the OD ₄₅₀ value at ₅ minutes.

The ADP-induced platelet aggregation rate is expressed as Aggregation% (% agglutination):

Aggregation %=(A _T oA _T5 )/A _TO * 100 %.

The time point when adding ADP is recorded as T0, Α _τ . OD ₄₅ when representing TO. _{The nm} reading, A _T5, represents the OD _{45Q nm} reading at 5 minutes of induction with ADP.

The inhibitory effect of the compound on platelet aggregation is expressed as: inhibition rate (%) = 100% - agglutination rate % The ic _5Q value of the compound can be calculated from the inhibition rate at each concentration.

The inhibition of ADP-induced inhibition of human platelet aggregation is the same as above, and human platelets are taken from venous blood of healthy volunteers.

The IC _5Q values of the test compounds are shown in Table 1 below:

Table 1. Inhibition of ADP-induced rat and human platelet aggregation by the compounds of the present invention.

Conclusion: The test compound of the present invention has obvious and auxiliary effects on ADP-induced rat and human platelet aggregation. Test Example 2

The following method was used to determine the binding of the compound of the present invention to the P2Y12 receptor.

The experimental method is briefly described as follows:

The CHO-K1 cell line (CH0-K1/P2Y12) expressing P2Y12 was constructed using a retroviral transfection method commonly used by those skilled in the art. CHO-Kl was purchased from the Cell Bank of the Institute of Culture Collection of the Chinese Academy of Sciences, Cat. GNHa 7. P2Y12 was purchased from origene, Cat. SC319680.

The constructed CHO-K1/P2Y12 cells were collected with a cell scraper and resuspended in homogenization buffer (10 mM Hepes, 10 mM NaCK ImM EDTA pH 7.4) and incubated on ice for 15 minutes. The cells were homogenized 3 times on ice for 10 seconds each at intervals of 10 seconds. The homogenate was centrifuged at 2000 g for 15 minutes at 4 ° C; the supernatant was collected and centrifuged at 30000 rpm for 1 hour. The supernatant was discarded, and the pellet was resuspended in a reaction buffer (10 mM Hepes, 138 mM NaCl, H 7.4), and the membrane protein concentration was measured by the Bradford method, and stored at -80 °C.

P2Y12 membrane protein was diluted to 1 μ _§ /μΙ^ with reaction buffer, and the reaction system was prepared according to the following table: Membrane protein 100 g/well

[ ³ H] 2-Mes-ADP 0.2 μα/2 μΙ7 well

Compound 10 hole

Reaction buffer 88 μΐ /孑 L

The reaction system was incubated for 2 hours at room temperature, and membrane proteins were collected on a Perkin Elmer GF/B membrane using a 96-well cell harvester. After washing the GF/B membrane 5 times with ice-cold reaction buffer, the GF/B membrane was dried in an environment of 70 ° C for one hour. The membrane was sealed in a nylon bag, force B lO mL scintillation fluid, and read in a Perkin Elmer counter. The read data was analyzed by IC _5Q using Graphpad software.

The IC _5Q values of the test compounds are shown in Table 2 below:

Table 2 Inhibition of P2Y12 receptor by the compound of the present invention

Conclusion: The compounds of the present invention have a significant inhibitory effect on the P2Y12 receptor. Pharmacokinetic evaluation

Test Example 3. Pharmacokinetic test of the compound of the present invention

1, abstract

Rats were used as test animals, and the compound of Example 2, the compound of Example 8, the compound of Example 9, the compound of Example 12, the compound of Example 17, and Example 20 were intragastrically administered to the rats by LC/MS/MS method. The concentration of the drug in the plasma at different times after the compound and the compound of Example 23. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Test drugs

Example 2 compound, Example 8 compound, Example 9 compound, Example 12 compound, Example 17 compound, Example 20 compound and Example 23 compound.

2.2 Test animals Twenty-eight healthy adult SD rats, male and female, were divided into 7 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 Drug preparation

An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication.

2.4 Administration

Twenty-eight SD rats, male and female, were divided into 7 groups. After fasting overnight, they were intragastrically administered at a dose of 10.0 mg/kg and a dose of 10 ml/kg.

3, operation

The compound of Example 2, the compound of Example 8, the compound of Example 9, the compound of Example 12, the compound of Example 17, the compound of Example 20 and the compound of Example 23 were administered by gavage to rats before administration and 0.5 after administration. , 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours of blood sampling 0.1 ml, placed in heparinized tubes, centrifuged at 3500 rpm for 5 min, and stored at 20 °C. Eat 2 hours after administration.

The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method. The linear range of the method was 1.00~2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.

4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The pharmacokinetics of the compound of the present invention is well absorbed, with obvious advantages pharmacokinetic _t

Claims

Claims:

A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Its pharmaceutically acceptable salt,

Its towel _:

^ is a single key or double key;

R ^{1 is} selected from cycloalkyl or heteroaryl;

When R ^{1 is} selected from heteroaryl, the heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) Substituted by a substituent of _m R ⁹ or -S(0) _m NR ⁸ R ⁹ ;

When = is a single bond, R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl, alkoxy are each independently optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, cycloalkane Substituted with a substituent of OR ⁷ or a heterocyclic group; or R ³ and R ^{4 together} form =0 or an alkenyl group; when = is a double bond, R ³ is absent and conforms to the valence bond theory;

The condition is, when R ^{2 is} selected from unsubstituted alkyl, R ^{3 is} selected from alkoxy or hydroxy, wherein alkoxy is substituted by one hydroxy group, R ^{4 is} selected from a hydrogen atom, and R ^{5 is} selected from a hydrogen atom, R ¹ is not a C ₃ -C ₈ naphthenic substituted by a phenyl group Base

R ^{6 is} selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, and ring. Alkyl, heterocyclic, -C(0)R ⁷ , -C(0)OR ⁷ , -S(0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR Substituted by a substituent of ⁸ C(0)R ⁹ , -NR ⁸ S(0) _m R ⁹ or -S(0) _m NR ⁸ R ⁹ ;

RR ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

m is 0, 1, or 2.

2. The compound of the formula (I) according to claim 1, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II) or

( II

Wherein: 1^~1 ⁵ is as defined in claim 1.

3. A compound of the formula (I) according to claim 1 or 2 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (III)

( III

Wherein: 1^~1 ⁵ is as defined in claim 1.

The compound of the formula (I) according to any one of claims 1 to 3, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. isomers thereof, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ¹ is cycloalkyl, said cycloalkyl optionally further substituted with one or more independently substituted by R ^6; R ⁶ is defined as Said in claim 1.

5. The compound of the formula (I) according to claim 4, or a tautomer thereof, a mesogen thereof, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein

R ^{1 is} selected from, —, '"'A, R ⁶ , R ^{6 is} selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently optionally further selected from one or more selected from the group consisting of an alkane Substituted by a substituent of a halogen or a halogen.

The compound of the formula (I) according to any one of claims 1 to 3, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Isomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ^{3 is} selected from the group consisting of a hydrazine, a hydroxy group, an alkyl group or an alkoxy group, each of which is optionally independently further one or A plurality of substituents selected from a hydroxyl group, OR ⁷ or a halogen are substituted.

7. The compound of the formula (I) according to claim 1 or 2 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And mixtures thereof, and pharmaceutically acceptable salts thereof, and towels thereof:

R ^{1 is} selected from cycloalkyl or heteroaryl;

When = is a single bond and R ⁵ is a hydrogen atom:

R ⁴ is a hydrogen atom;

When = is a double bond: R ³ is absent and conforms to the valence bond theory; R ⁴ and R ^{5 are} selected from a hydrogen atom; R ^{6 is} selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is is further selected from one or more selected from alkyl, halo, alkoxy, nitro, cyano, cycloalkyl, ^{heterocyclyl, -C (0) R 7,} -C (0) oR 7, -S (0) _m R ⁷ , -NR ⁸ R ⁹ , -C(0)NR ⁸ R ⁹ , -NR ⁸ C(0)R ⁹ , -NR ⁸ S(0) _M R ⁹ or -S(0) _M NR ⁸ R ⁹ substituent Replaced

R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is 0, 1 or 2.

8. The compound of the formula (I) according to claim 1, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV) or

Its towel:

The definition of RR ² is as described in claim 1.

9. The compound of the formula (I) according to claim 1, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (V) or

(V

Its towel:

R ^{3 is} selected from the group consisting of an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently advanced by at least two selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ group or a heterocyclic group. Substituted by a substituent;

The definition of RR ² is as described in claim 1.

10. The compound of the formula (I) according to claim 1, or a tautomer thereof, a mesogen thereof, a racemic form, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) or

(VI)

Wherein: RR ² is as defined in claim 1.

11. The compound of the formula (I) according to claim 1, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (VD) or

( VH

Its towel:

R ¹ is as defined in claim 1.

The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 or 2. And mixtures thereof, and pharmaceutically acceptable salts thereof,

HO OH or HO OH

13. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a process for preparing the pharmaceutically acceptable salt thereof, comprising the steps of:

( IA )

The compound of the formula (IA) is reacted with hydrazine ₂ , optionally further deprotecting the protecting groups P and P' of the hydroxy group to give a compound of the formula (I);

Wherein: L is a leaving group, preferably a halogen;

P and P' are a protecting group or a hydrogen atom of a hydroxyl group, and the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a silyl group or an acetyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic ring. Further, the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from alkyl, halogen, hydroxy or alkoxy;

The definition of RR ^{2 to} R ⁵ is as set forth in claim 1.

14. A compound of the formula (I) according to claim 2 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And a mixture thereof, and a process for preparing the pharmaceutically acceptable salt thereof, comprising the steps of:

( II A)

The compound of the formula (ΠΑ) is reacted with Ι^ΝΗ ₂ , optionally further deprotecting the protecting group Ρ and Ρ' of the hydroxy group to obtain a compound of the formula (II);

Wherein: L is a leaving group, preferably a halogen;

The definition of RR ² -R ⁵ is as set forth in claim 1.

A pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) according to claim 1 or a tautomer thereof, a mesogen, racemization thereof , enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable carriers, diluents and excipients.

16. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And a mixture thereof, and a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 15 in the manufacture of a medicament for a P2Y12 receptor antagonist.

17. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And a mixture thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the treatment or prevention of myocardial infarction, embolic episode, transient ischemic attack, peripheral vascular disease or angina pectoris Use in medicine.

18. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. And a mixture thereof, and a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 15 for the preparation of a medicament for treating or preventing a disease of platelet aggregation disorder.