TW201311692A - Triazolopyrimidine derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to triazolopyrimidine derivatives, preparation processes and pharmaceutical use thereof. Specifically, the present disclosure relates to triazolopyrimidine derivatives presented by formula (I), and their use as therapeutic agents, especially use as P2Y12 receptor agonists, wherein each substitute group of general formula (I) is as defined in the specification.

Description

Triazolopyrimidine derivatives, preparation method thereof and application thereof in medicine

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.

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, thereby realizing various biological effects processes. Signal transduction is transmitted by 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 coupled G protein species: 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 eukaryotes. 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 now use G-protein coupled receptors as targets.

There are numerous subfamilies of Gq/Gi-coupled receptors, including: (1) Purinergic receptors, members including P1, P2; and (2) Adenosine receptors. Members include A1, A2A, A2B, A3, which are one of the P1 subfamilies of the purinoceptor family. The purine receptor family plays a key role in regulating myocardial 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, P2Z, P2U and P2T. Among them, P2X and P2Z belong to ion channel type receptors, and P2Y, P2U and P2T belong to G protein coupled receptors.

The P2Y receptor family of G protein-coupled receptors has been found to include nine (P2Y1, 2, 4, 6, 11-14) subtypes, widely distributed in a variety of cells and tissues, with low homology between subtypes. Therefore, different subtypes have high selectivity for ligands. P2Y1, 2, 6, and 14 bind Gq and initiate 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 and 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 stimulating factor ADP, and the like.

The co-priming of the P2Y1 and P2Y12 receptors is indispensable during platelet aggregation. The P2Y1 receptor causes aggregation of platelet deformation by releasing Ca ²⁺ by initiating the PI3K pathway. P2Y1 knockout mice 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 the initiation of fibrinogen receptors, 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. The binding of endogenous stimulating factors such as ADP to P2Y12 receptors initiates pathways such as PI3K and initiates Rap1b, Akt, and ERK pathways to cause fibrinogen receptors to initiate binding to fibrinogen to initiate thrombosis or platelet aggregation. This process must be achieved when the P2Y1 receptor is simultaneously activated. 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 a serine protease such as thrombin to be activated by itself, thereby exerting coagulation. Activation of the Akt pathway initiated by the initiation must also rely on the initiation of the P2Y12 receptor and amplify the signal by the G12/13 pathway. Blocking the P2Y12 receptor can significantly inhibit platelet aggregation and thrombosis induced by ADP and other stimulating factors such as the PAR-1 promoter peptide SFLLRN, 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.

The object of the present invention is to provide a novel triazolopyrimidine derivative represented by the general formula (I) or a tautomer, a mesogen, a racemate, an enantiomer and a diastereomer thereof. a construct, a mixture thereof, and a pharmaceutically acceptable salt thereof, among them: Is a single bond or a double bond; R ^{1 is} selected from a cycloalkyl or a heteroaryl group; when R ^{1 is} selected from a cycloalkyl group, the cycloalkyl group is further substituted by one or more of the respective independent R ⁶ , or R ^{1 is} selected from cycloalkyl fused to an aryl or heteroaryl group, wherein the cycloalkyl group fused to the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, a halogen, and an alkoxy group. Base, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C( O) NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ substituted; when R ^{1 is} selected from hetero In the case of an aryl group, the heteroaryl group is further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(O)R ⁷ , -C(O)OR ⁷ as needed. , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S( O) is substituted with a substituent of _m NR ⁸ R ⁹ ; R ^{2 is} selected from an alkyl group, which alkyl group is further substituted by one or more substituents selected from a cycloalkyl group; When it is a single bond, R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently further optionally one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, and an OR. Substituting ⁷ or a substituent of a heterocyclic group; or R ³ and R ⁴ together form an =0 or an alkenyl group; When it is a double bond, R ³ does not exist and conforms to the valence bond theory; When it is a single bond, R ^{4 is} selected from a hydrogen atom or an alkyl group, or R ³ and R ⁴ together form an =0 or an alkenyl group, wherein the alkenyl group is further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy. Substituted by a substituent of a nitro group or a cyano group; or R ⁴ and R ^{5 are} optionally substituted into a cycloalkyl group, and the ring formation conforms to the valence bond theory; When it 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 it is a single bond, R ⁵ and R ^{4 are} optionally substituted into a cycloalkyl group, and ring formation conforms to the valence bond theory; provided that when R ^{2 is} selected from unsubstituted alkyl groups, R ^{3 is} selected from alkoxy groups or hydroxyl groups, wherein The alkoxy group is substituted by a hydroxyl group, R ^{4 is} selected from a hydrogen atom, and when R ^{5 is} selected from a hydrogen atom, R ¹ is not a C ₃ to C ₈ cycloalkyl group substituted by a phenyl group; and R ^{6 is} selected from an aryl group or a heteroaryl group. a group wherein the aryl or heteroaryl group is further independently 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, and a -C(O). R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ Substituted by a substituent of S(O) _m R ⁹ or -S(O) _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 , heterocyclyl, aryl or heteroaryl; 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 or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ are 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 or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ are 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 or a diastereomer thereof a form, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ^{1 is} selected from cycloalkyl, which is further substituted by one or more of the respective independently R ⁶ as desired; R ⁶ is as defined above Said in 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 or a diastereomer thereof a construct, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from R ^{6 is} selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is each independently substituted with one or more substituents selected from an alkyl group or a halogen, as needed.

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 thereof And a mixture thereof, wherein R ^{3 is} selected from the group consisting of halogen, hydroxy, alkyl or alkoxy, said alkyl, alkoxy, each independently being further protected by one or more Substituted by a hydroxyl group, OR ⁷ or a halogen.

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from cycloalkyl or heteroaryl; when R ^{1 is} selected from cycloalkyl, the cycloalkyl is further required to be further one or more Substituted by each independently R ⁶ , or R ^{1 is} selected from cycloalkyl fused to an aryl or heteroaryl group, wherein the cycloalkyl group fused to the aryl or heteroaryl group is further required to be further one or more Selected from alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ Substituted; when R ^{1 is} selected from heteroaryl, the heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(O). R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S (O) _m R ^9, or -S (O) _m NR ⁸ R ⁹ taken The substituent group; R ² is selected from alkyl, the alkyl optionally further substituted with one or more cycloalkyl; when Is a single bond, R ^{5 is} selected from an alkyl group, a hydroxyl group or a halogen, or R ^{4 is} optionally substituted into a cycloalkyl group, and the ring is in the valence bond theory: R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group. Wherein the alkyl group and the alkoxy group are each independently further substituted with at least two substituents selected from a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ group or a heterocyclic group; R ^{4 is} selected from a hydrogen atom, or is R ⁵ Need to form a cycloalkyl group, and the ring formation is in accordance with the valence bond theory; When it is a single bond, when R ⁵ is a hydrogen atom: R ³ is an alkoxy group, wherein the alkoxy group is further substituted by at least two substituents each independently selected from a hydroxyl group, a halogen, a cycloalkyl group, a hydroxyalkyl group or a heterocyclic group. Substituted; R ⁴ is a hydrogen atom; When it 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; and R ^{6 is} selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further required by one Or a plurality selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ Substituted by a substituent; 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 or a diastereomer thereof a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof: Wherein: R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl, alkoxy are each independently further optionally one or more selected from the group consisting of hydroxyl, halogen, cycloalkyl, OR ⁷ or hetero Substituted by a substituent of a cyclic group; R ^{4 is} selected from an alkyl group, a hydrogen atom, or R ^{5 is} optionally substituted into 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 is} optionally substituted into a cycloalkyl group, and the ring-forming is in accordance with 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; and R ¹ and R ² are as defined above. Said in 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 or a diastereomer thereof a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (v) or a pharmaceutically acceptable salt thereof: Wherein R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl, alkoxy are each independently further selected from at least two selected from the group consisting of hydroxyl, halogen, cycloalkyl, OR ⁷ or heterocyclic. Substituted by a substituent; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; and R ¹ and R ² are as defined above for the definition of the general 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 or a diastereomer thereof a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ² are 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 or a diastereomer thereof a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (VII) or a pharmaceutically acceptable salt thereof: Wherein R ^{2 is} selected from an alkyl group, the alkyl group is further substituted by one or more cycloalkyl groups; R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently Further destined to be further substituted by one or more substituents selected from a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ or a heterocyclic group; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a hetero Cyclo, aryl or heteroaryl; R ¹ is as defined above for the definition of formula (I).

In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein, further preferably, R ¹ is a cycloalkyl group which is further substituted by one or more independently R ⁶ as required; R ^{2 is} selected from An alkyl group, which is further substituted by one or more cycloalkyl groups, preferably a cyclopropyl group; R ^{3 is} selected from an alkoxy group or a hydroxyl group, wherein the alkoxy group is further subjected to a need Or a plurality of substituents selected from a hydroxyl group or a halogen; the R ^{6 is} selected from an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group is independently further optionally selected from one or more selected from the group consisting of an alkyl group and a halogen. , alkoxy, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , Substituted with a substituent of -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ ; preferably Halophenyl.

Typical compounds of the invention include, but are not limited to: Or tautomers, meso-forms, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof.

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

The compound of the formula (IA) is reacted with R ¹ NH ₂ , and the protecting groups P and P' of the hydroxyl group are further removed as needed to obtain a compound of the formula (I); wherein: L is a leaving group, preferably a halogen; And P' is a protecting group or a hydrogen atom of a hydroxyl group, the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a decyl group or an ethyl fluorenyl 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 further substituted by one or more substituents selected from an alkyl group, a halogen group, a hydroxyl group or an alkoxy group; and R ¹ , R ² to R ⁵ are as defined above. As stated in the definition of (I).

The present invention further relates to a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A method for preparing a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of the formula (IIA) is reacted with R ¹ NH ₂ , and the protecting groups P and P′ of the hydroxyl group are further removed as needed to obtain a compound of the formula (II); wherein: L is a leaving group, preferably a halogen; And P' is a protecting group or a hydrogen atom of a hydroxyl group, the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a decyl group or an ethyl fluorenyl 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 further substituted by one or more substituents selected from an alkyl group, a halogen, a hydroxyl group or an alkoxy group; and R ¹ , R ^{2 -} R ⁵ are as defined above. As stated in the definition of (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, a mesomer, a racemate, an enantiomer thereof, Diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.

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

The present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for 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 present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment or prevention of a disease of platelet aggregation disorder.

Detailed description of the invention

Terms used in the specification and patent 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 a non-limiting example includes a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl Propyl, 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-dimethyl Hexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-B Hexyl, 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; More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-di Methyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Butyl, 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. , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon The substituent contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably the cycloalkyl ring contains 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl and the like. Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

"Spirocycloalkyl" refers to a polycyclic group of 5 to 20 members, which shares a carbon atom (called a spiro atom) between the monocyclic rings, which may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 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 ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

"Fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

"Bridge cycloalkyl" refers to 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-electron 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. Non-limiting examples of bridged cycloalkyl groups include:

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, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl 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, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio group, heterocycloalkylthio group, pendant oxy group, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ , -S(O) _m NR ⁸ R ⁹ , -C(O)R ¹⁰ , -C(O)OR ¹⁰ 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, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, 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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl 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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _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(O) _m ( Wherein m is an integer from 0 to 2), but does not include a ring moiety of -OO-, -OS- 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, and 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" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _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 monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

"Fused heterocyclyl" refers to 5 to 20 members, each ring in the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more A 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(O) _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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic group. . Non-limiting examples of fused heterocyclic groups include:

"Bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a fully conjugated A π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, 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 group, non-limiting examples include: 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, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, heterocycloalkylthio, pendant oxy, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _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 of a carbon atom is preferably a 6 to 10 member such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached 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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _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 Wait. 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, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Sulfuryl, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

"Alkoxy" means -O-(alkyl) 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, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Sulfuryl, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

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

"Hydroxy" refers to 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 -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Sideoxy" means =0.

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

"Carboxylic acid ester group" means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

"As needed" or "as needed" 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, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with 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 possible chemical positions, and 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, having a tour The amine or hydroxyl group from the 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, and to facilitate the absorption of the active ingredient to exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

R ⁷ to R ⁹ are as defined in the compound of the formula (I), 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 employs the following synthetic technical scheme: a method for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

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) and R ¹ NH ₂ are reacted under basic conditions to obtain the compound of the formula (IE); the compound of the formula (IE) is further dehydroxylated. The protecting groups P and P' give the compound of the formula (I). 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; the reducing reagent includes but not Limited to iron powder; reagents providing basic conditions include, but are not limited to, organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, Potassium butoxide, including but 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 adjusted from 1 minute to 72 hours, preferably 15 minutes to 24 hours; wherein: R ¹ to R ⁵ are as defined in the general formula (I); L and L' are leaving groups a 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 decyl group or an ethyl fluorenyl group, or P and P' and the atom to which they are attached Forming a 5- to 6-membered heterocyclic group together, the 5 to 6-membered heterocyclic group being further selected from one or more selected from the group consisting of an alkyl group, a halogen, and a hydroxy group. The substituted or unsubstituted alkoxy group. Wherein the 5- to 6-membered heterocyclic group is reacted under acidic conditions as needed, and the protecting group is removed to obtain a compound of the formula (I).

A method for preparing a compound of the formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

The aromatic compound (IB) and the compound of the formula (VIA) are subjected to an 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) and R ¹ NH ₂ are reacted under basic conditions to obtain the compound of the formula (VID); the compound of the formula (VID) is in the triphenyl group. The phosphine and the azodicarboxylate diester (preferably diisopropyl azodicarboxylate) are reacted to obtain the compound of the formula (VIE); the compound of the formula (VIE) further deprotects the protecting group P and P' of the hydroxy group. The compound of the formula (VI) is obtained.

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; the reducing reagent includes but not Limited to hydrogen, iron powder or zinc powder; reagents providing basic conditions include, but are not limited to, organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, Butyl lithium, potassium butoxide, 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 regulated at -80 ° C to 200 ° C, Preferably, the reaction time is 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; wherein: R ¹ to R ² are as defined in the general formula (I); L and 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 decyl group or an ethyl group, or P and P' The atoms to which they are attached together form a 5 to 6 membered heterocyclic group which is further optionally selected from one or more selected from the group consisting of alkane. , Halogen, hydroxy or alkoxy substituents.

A method for preparing a compound of the formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

The aromatic compound nucleophilic substitution reaction of the compound of the formula (IVB) with the compound of the formula (IVC) is carried out in a solvent to obtain the compound of the formula (IVD); the compound of the formula (IVD) is dissolved in a solvent to reduce the nitro group under acidic conditions. The compound of the formula (IVF) is obtained; the compound of the formula (IVF) is dissolved in a solvent, and sodium nitrite is added and reacted under ice bath to obtain a compound of the formula (IVA); the compound of the formula (IVA) and R ¹ NH ₂ The reaction is carried out under basic conditions to give the compound of the formula (IVE); the compound of the formula (IVE) is further deprotected from the protecting groups P and P' of the hydroxy group to give the compound of the formula (IV).

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; the reducing reagent includes but not Limited to iron powder; reagents providing basic conditions include, but are not limited to, organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, Potassium butoxide, including but not limited to sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or carbonic acid; the reaction temperature is controlled at -80 ° C to 200 ° C, preferably 0 ° C to 100 ° C; the reaction time is generally adjusted from 1 minute to 72 hours, preferably 15 minutes to 24 hours; wherein: R ¹ to R ⁵ are as defined in the general formula (I); L and L' are leaving groups a 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 decyl group or an ethyl fluorenyl group, or P and P' and the atom to which they are attached Forming a 5- to 6-membered heterocyclic group together, the 5 to 6-membered heterocyclic group being further selected from one or more selected from the group consisting of an alkyl group, a halogen, and a hydroxy group. The substituted or unsubstituted alkoxy group.

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 according to the conditions recommended by the raw material or the manufacturer of the commodity. Reagents without specific source are routine reagents purchased from the market.

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS). ^{The 1} H NMR shift (δ) is given in parts per million (ppm). ^{The 1} H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and deuterated dimethyl hydrazine (DMSO- d ₆ ). Marked as tetramethyl decane (TMS).

The measurement of the MS was carried out using a FINNIGAN 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 C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany).

The thin layer chromatography tannin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 tannin sheet. The thin layer chromatography (TLC) uses a silicone sheet with a specification of 0.15 mm to 0.2 mm. The thin layer chromatography separation and purification product uses a silicone sheet size of 0.4 mm. Up to 0.5 mm.

The rubber hose column is generally made of Yantai Huanghai Silicone 200 to 300 mesh silicone. Carrier.

The basic alumina column generally uses FCP 200 to 300 mesh basic alumina as a carrier for the chromatography of the national medicine.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be used by ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc and Companies such as Rui Chemicals buy.

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 having a volume of about 1 L.

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

The hydrogenation reaction is usually evacuated, charged with hydrogen, and the operation is repeated 3 times.

Unless otherwise stated in the examples, 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 using the purified compound and the system of the thin layer chromatography developing agent include: A: dichloromethane and methanol system, B: N-hexane and ethyl acetate systems, C: dichloromethane and acetone systems, D: methanol system, E: petroleum ether and ethyl acetate system, F: ethyl acetate and methanol system, the volume ratio of the solvent is different depending on the polarity of the compound For adjustment, a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid may be added for adjustment.

Example 1 (1 S , 2 S , 3 S , 4 S )-5-{7-[[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]amino]-5 -propyl mercapto-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

first step 2-chloro-1-(3,4-difluorophenyl)ethanone

Add aluminum trichloride (26.3 g, 197 mmol) to 1,2-difluorobenzene (25 g, 219 mmol), heat to 50 ° C, and slowly add dropwise chloroethyl chloride (17.5 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, and the layers were separated, and the organic phase was saturated with chlorine. sodium solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product, 2-chloro-1- (3,4-difluorophenyl) ethanone 1a (37 g, as a yellow solid ), yield: 88.7%.

GC-MS m/z: 190.0 [M ⁺ ]

Second step (1 S )-2-chloro-1-(3,4-difluorophenyl)ethanol

( S )-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 reacted at 40 ° C for 1.5 hours. Add dimethyl sulfide borane at a temperature between 35 ° C and 45 ° C, react at 40 ° C for 1 hour, and maintain a temperature of 35 ° C to 45 ° C to add 75 mL of 2-chloro-1-(3,4-difluorophenyl) A solution of ethyl ketone 1a (26 g, 136 mmol) in toluene was continued to react at 40 ° C for 1 hour. The reaction solution was cooled to 10 ° C, the temperature was kept below 35 ° C, 25 mL of methanol was added, and the reaction mixture was cooled to 20 ° C and stirred for 30 minutes. The reaction mixture was concentrated under reduced EtOAc.jjjjjjjjjjjjjjjjj The crude title product 60 mL ( 1S )-2-chloro-1-(3,4-difluorophenyl)ethanol 1b (26.3 g) in toluene was obtained.

GC-MS m/z: 192.0 [M ⁺ ]

third step Ethyl (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxylate

60% sodium hydride (10.9 g, 273 mmol) was suspended in 100 mL of toluene, heated to 40 ° C, and 60 mL (diethoxy-phosphate)-ethyl acetate (33.7 g, 150 mmol) was added dropwise. The toluene solution was reacted at 40 ° C for 1 hour, and 60 mL of (1 S )-2-chloro-1-(3,4-difluorophenyl)ethanol 1b (26.3 g, 137 mmol) in toluene solution was added below 60 ° C. Stir at 60 ° C for 12 hours. To the reaction mixture was added 150 mL of water, separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (1 R, Ethyl 2R )-2-(3,4-difluorophenyl)cyclopropylcarboxylate 1c (13.8 g, pale yellow solid), yield: 44.7%.

MS m/z (ESI): 227.0 [M+1]

the fourth step (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid

Ethyl (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxylate 1c (13.8 g, 61 mmol) was dissolved in 90 mL of methanol and then 30% sodium hydroxide (4.39) g, 109 mmol) solution, reacted at 65 ° C for 2 hours. Concentrate under reduced pressure, add 100 mL of toluene and 100 mL of water, layer, adjust pH with 35% hydrochloric acid 7, layers were separated and extracted with toluene (500 mL × 2), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product (1 R, 2 R) -2- (3,4- Difluorophenyl)cyclopropylcarboxylic acid 1d (12.1 g, yellow liquid), the product was taken to the next step without purification.

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

the fifth step (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxamide

Dissolve (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid 1d (12.1 g, 61 mmol) in 100 mL of toluene and add dichlorohydrazine (5.4 mL, 73.9). Methyl), reacted at 35 ° C for 6 hours, concentrated under reduced pressure, and added to the residue, 28% aqueous ammonia (14.9 g, 244 mmol), 35 mL of water and 100 mL of ethyl acetate. Adjust pH with 35% hydrochloric acid 7. The layers were separated and extracted with ethyl acetate (100 mL). EtOAcjjjjjjjjjjjjjjjjjjjjjjjj The title product (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxamide 1e (9.8 g, white solid).

MS m/z (ESI): 198.0 [M+1]

Step 6 (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine

Add (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarbamimidamine 1e (9 g, 45.64 mmol) to a solution of 30% sodium hydroxide (16.43 g, 411 mmol) The mixture was heated to 20 to 25 ° C, and a 13% sodium hypochlorite (8.49 g, 114 mmol) solution was added dropwise thereto, 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 organic phase concentrated under reduced pressure to give the crude title product (1 R, 2 S) -2- (3,4- difluorophenyl) cyclopropanamine 1f (7.29 g, dark red liquid) was used without purification for the next step reaction.

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

Seventh step (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate

(1 R , 2 S )-2-(3,4-Difluorophenyl)cyclopropylamine 1f (7.29 g, 43.1 mmol) was dissolved in 100 mL of ethyl acetate and methanol (V/V=7:3) In a mixed solvent, L-(+)-tartaric acid (3.88 g, 25.9 mmol) was added under stirring, and the mixture was stirred for 12 hours to precipitate a solid. Filtered, and solid was isolated and purified by silica gel column chromatography to elute the surfactant system D, to give the title product (1 R, 2 S) -2- (3,4- difluorophenyl) cyclopropylamine L - (+) - Tartrate 1 g (3.70 g, yellow solid), yield: 44.8%.

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

¹ H 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 [(3a R ,4 R ,6 R ,6a R )-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d ][1,3 Dioxol-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 and add 30 mL (3 R , 4 S , 5 R )-5-( A solution of methylol)tetrahydrofuran-2,3,4-triol in 1 h (22.5 g, 150 mmol) in acetone was reacted at 70 ° C for 5 hours. The reaction was quenched by the addition of 6 mL of pyridine and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). ×2) Washing, drying over anhydrous sodium sulfate, filtration, and the filtrate are concentrated under reduced pressure, and the residue obtained is purified by eluent column chromatography to afford the title product [(3a R , 4 R , 6 R , 6a R - 6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d ][1,3]dioxol-4-yl]methanol 1i (15.5 g, light brown oil), yield: 50.6%.

¹ H NMR (400 MHz, CDCl 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 (3a S , 4 S , 6 R , 6a R )-4-(iodomethyl)-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuran [3,4 - d ][1,3]dioxole

[(3a R , 4 R , 6 R , 6a R )-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d ][1, 3] Dioxol-4-yl]methanol 1i (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 mmol) and imidazole (7.75 g, 114 mmol) were added iodine (23 g, 91 mmol) in portions and stirred 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×2), water (60 mL) and saturated sodium chloride solution (60 mL×2). sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (3a S, 4 S, 6 R, 6a R) -4- ( iodomethyl - 6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d ][1,3]dioxole 1j (22.2 g, yellow Oil), yield: 93.3%.

Step 10 (4 R ,5 R )-2,2-methyl-5-vinyl-1,3-dioxolane-4-carbaldehyde

(3a S , 4 S , 6 R , 6a R )-4-(iodomethyl)-6-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuran [3, 4- d ][1,3]dioxole 1j (83 g, 264 mmol) was dissolved in 500 mL of isopropanol, zinc powder (25.7 g, 396 mmol) was added, and acetic acid was added to the ice bath (26.4). g, 462 mmol), reacted at 30 ° C for 4 hours. Add saturated sodium bicarbonate solution to adjust pH The organic layer was washed with ethyl acetate (100 mL×2), and the organic phase was combined with water (60 mL), saturated sodium bicarbonate (60 mL) and saturated sodium chloride solution (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (4 R, 5 R )-2,2-Dimethyl-5-vinyl-1,3-dioxolane-4-carbaldehyde 1k (31 g, colorless oil), yield: 75.3%.

¹ H NMR (400 MHz, CDCl 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 1-[(4 S ,5 R )-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]prop-2-en-1-ol

(4 R ,5 R )-2,2-Dimethyl-5-vinyl-1,3-dioxolane-4-carbaldehyde 1k (30 g, 192 mmol) was dissolved in 50 mL of tetrahydrofuran A solution of 1 M vinylmagnesium bromide in tetrahydrofuran (550 mL, 384 mmol) was quickly added at -78 ° C, and the reaction was kept at -78 ° C for 1 hour, and allowed to warm to room temperature, and the reaction was continued for 30 minutes. Add 120 mL of saturated ammonium chloride solution, add crepe, filter, filter cake with ethyl acetate (200 mL×4), and combine the organic phase, then use water (60 mL) and saturated sodium chloride solution (60 mL×2) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 1 - [(4 S, 5 R) -2,2- two Methyl-5-vinyl-1,3-dioxolane-4-yl]prop-2-en-1-ol 1 m (20 g, mp.

Step 12 (3a S ,4 R ,6a R )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4- alcohol

Add bis(tricyclohexylphosphine)benzylidene dichloride (444 mg, 0.54 mmol) to the reaction flask and add 100 mL of 1-[(4 S ,5 R )-2,2-dimethyl in a syringe. -5-Vinyl-1,3-dioxol-4-yl]prop-2-en-1-ol 1 m (10 g, 54 mmol) in chloroform. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (3a S, 4 R, 6a R) -2,2- dimethyl two -4,6a- Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-4-ol 1 n (4.5 g, light brown oil), yield: 53.2%.

Step 13 2-((3a R ,4 R ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxole -4-yl)isoindoline-1,3-dione

(3a S ,4 R ,6a R )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole-4 - alcohol 1n (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 azodicarboxylic acid was added. A solution of isopropyl ester (1.9 mL, 9 mmol) in tetrahydrofuran was reacted at 20 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - ((3a R, 4 R, 6a S) -2,2- dimethyl-4, 6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)isoindoline-1,3-dione 1o (1.4 g, white solid) , Yield: 82.3%.

¹ H NMR (400 MHz, CDCl 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-((3a R , 4 S , 5 S , 6 S , 6a S )-4,5-dihydroxy-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1, 3]dioxol-6-yl)isoporphyrin-1,3-dione

2-((3a R ,4 R ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxole Iso-4-yl)isoindoline-1,3-dione 1o (500 mg, 1.75 mmol) was dissolved in 10 mL of tetrahydrofuran, and a catalytic amount of ruthenium tetroxide was added and reacted at room temperature for 24 hours. The reaction mixture was combined with EtOAc (EtOAc) (EtOAc m. (3a R , 4 S , 5 S , 6 S , 6a S )-4,5-dihydroxy-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1,3] Oxocyclo-6-yl)isoindoline-1,3-dione 1p (558 mg, colorless oil).

Step fifteenth 2-((3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene[1,2- d :3,4- d ']Lian([1,3]dioxole)-7-yl)isoindoline-1,3-dione

2-((3a R , 4 S , 5 S , 6 S , 6a S )-4,5-Dihydroxy-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1 , 3]dioxol-6-yl)isoindoline-1,3-dione 1p (558 mg, 1.75 mmol) was dissolved in 10 mL of acetone, and p-toluenesulfonic acid monohydrate was added. 4 mg, 0.02 mmol), heated to 50 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - ((3a S, 3b S, 6a S, 7a S) -2,2,5,5 -tetramethyltetrahydro-3a H -cyclopenta[1,2- d :3,4- d ']bi[(1,3]dioxole-7-yl)isoindole Porphyrin-1,3-dione 1q (230 mg, white solid), yield: 36.6%.

Step 16 (3a S , 3b S , 6a S , 7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene[1,2- d :3,4- d '] ([1,3]dioxole)-7-amine

2-((3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene[1,2- d :3,4- d ']Lian([1,3]dioxole)-7-yl)isoindoline-1,3-dione 1q (220 mg, 0.61 mmol) was dissolved in 10 mL of ethanol and added to hydrate肼 (0.36 mL, 6.12 mmol), heated to 70 ° C for 2.5 h. The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, the concentrated residue was dissolved in dichloromethane, filtered and the filtrate was concentrated under reduced pressure to give the crude title product (3a S, 3b S, 6a S, 7a S) - 2,2,5,5-tetramethyltetrahydro-3a H -cyclopenta[1,2- d :3,4- d ']-([1,3]dioxole)- 7-Amine 1r (130 mg, pale yellow liquid), yield: 93.1%.

¹ H NMR (400 MHz, CDCl 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 -[(3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene And [1,2-d:3,4-d']-([1,3]dioxole-7-yl]pyrimidine-4,5-diamine

4,6-Dichloro-2-propylindenyl-pyrimidin-5-amine 1 s (162 mg, 0.68 mmol, prepared by the known method "Patent WO2001092263") and (3a S , 3b S , 6a S , 7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopenta[1,2- d :3,4- d ']-([1,3]dioxole Pentene)-7-amine 1r (130 mg, 0.57 mmol) was dissolved in 5 mL of ethylene glycol and heated to 100 ° C for 24 hours. 30 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (10 mL×3) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by de-bending system B to give the title product 6-chloro-2-(propyl decyl)-N ⁴ - ((3a S , 3b S , 6a S , 7a S )-2,2,5,5- Tetramethyltetrahydro-3a H -cyclopenta[1,2- d :3,4- d' ]-([1,3]dioxol-7-yl)pyrimidine-4, 5-Diamine 1t (80 mg, yellow solid), yield: 32.6%.

MS m/z (ESI): 431.0 [M+1]

Eighteenth step 7-Chloro-5-(propylindolyl)-3-[(3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene [1,2- d :3,4- d' ]-([1,3]dioxole-7-yl]-3 H- [1,2,3]triazolo[4, 5-d]pyrimidine

6-Chloro-2-(propylindenyl)-N ⁴ -((3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a under ice bath H -cyclopentene[1,2- d :3,4- d' ]-([1,3]dioxole-7-yl)pyrimidine-4,5-diamine 1t (80 Mg, 0.19 mmol) was dissolved in a mixed solvent of 1.5 mL of acetic acid and water (V/V = 2:1), sodium nitrite (12 mg, 0.20 mmol) was added, and the mixture was 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, and the mixture was stirred for 10 minutes, and the mixture was separated and extracted with ethyl acetate (10 mL×2). , 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 7-chloro-5- (propyl-mercapto) -3 - ((3a S, 3b S, 6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene[1,2- d :3,4- d' ]([1,3] dioxole) 7-yl) -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-1u (82 mg, brown oil), was used without purification for The next step is to react.

MS m/z (ESI): 442.1 [M+1]

Step 19 N-{[(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropyl]-5-(propylindolyl)-3-[(3a S ,3b S ,6a S , 7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene[1,2- d :3,4- d' ]-([1,3]dioxole Pentene]-7-yl)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine

7-Chloro-5-(propylindolyl)-3-((3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene And [1,2- d :3,4- d' ]-([1,3]dioxole-7-yl)-3 H- [1,2,3]triazolo[4 ,5- d ]pyrimidine 1u (82 mg, 0.19 mmol) and (1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (83 Mg, 0.26 mmol) was dissolved in 10 mL of acetonitrile, and triethylamine (0.09 mL, 0.67 mmol) was added and reacted for 24 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product N - {[(1 R, 2 S) -2- (3,4- difluorophenyl) Cyclopropyl]-5-(propylindolyl)-3-[(3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopentene And [1,2- d :3,4- d' ]-([1,3]dioxole-7-yl}-3 H -[1,2,3]triazolo[4 , 5- d ]pyrimidin-7-amine 1v (80 mg, yellow oil), yield: 73.4%.

MS m/z (ESI): 575.1 [M+1]

Step 20 (1 S , 2 S , 3 S , 4 S )-5-{7-[[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]amino]-5 -propyl mercapto-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

N-{[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]-5-(propylindolyl)-3-[(3a S ,3b S ,6a S ,7a S )-2,2,5,5-tetramethyltetrahydro-3a H -cyclopenta[1,2- d :3,4- d' ]-([1,3]diox Cyclopentene)-7-yl]-3 H- [1,2,3]triazolo[4,5- d ]pyrimidin-7-amine 1v (80 mg, 0.14 mmol) was dissolved in 3 mL of methanol. 5 M hydrochloric acid (0.3 mL, 1.5 mmol) was added and the reaction was carried out for 48 hours. Add saturated sodium carbonate solution, adjust pH=8, stir for 5 minutes, concentrate under reduced pressure, extract with ethyl acetate (10 mL×5), and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, The obtained residue was purified by preparative chromatography to afford the title product ( 1S , 2S , 3S , 4S )-5-{7-[[(1 R , 2S )-2-(3,4-difluoro Phenyl)cyclopropyl]amino]-5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol 1 (18 Mg, white solid), Yield: 25.7%.

MS m/z (ESI): 495.1 [M+1]

¹ H NMR (400 MHz, CDCl 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 (1 R , 2 R , 3 S , 5 R )-3-{5-(cyclopropylmethylhydrazino)-7-[[(1 R ,2 S )-2-(3,4-difluorobenzene Cyclopropyl]amino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (1 S , 2 S , 3 R , 5 S )-3-{5-(cyclopropylmethylhydrazino)-7-[[(1 R ,2 S )-2-(3,4-difluorobenzene) Cyclopropyl]amino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 3

first step Benzyl N-hydroxycarbamate

Hydroxylamine (7.65 g, 0.11 mol) and sodium bicarbonate (58.8 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) The residue was dissolved in 270 mL of a mixed solvent of dichloromethane and n-hexane (V/V = 5.5:8) at 45 ° C, and then cooled and crystallized to give the title product N-hydroxyaminocarbamate 2a (15.48 g). , white solid), Yield: 92.6%.

MS m/z (ESI): 168.1 [M+1]

Second step (1 R , 4 S /1 S , 4 R )-2-oxa-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester

Benzyl N-hydroxycarbamate 2a (20.4 g, 0.12 mol) was dissolved in a mixed solvent of 800 mL of methanol and water (V/V = 3:1), and cyclopentadiene (22.98 g, 0.35 mol) and sodium periodate (25.3 g, 0.12 mol), kept at 0 ° C to 5 ° C for 10 minutes, and reacted 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) Drying in vacuo gave the crude title product (1 R , 4 S /1 S , 4 R )-2-oxa-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester 2b ( 32.39 g, black oil). The product was taken to the next step without purification.

MS m/z (ESI): 232.0 [M+1]

third step (1 S ,4 R ,6 S/ 1 R ,4 S ,6 R )-5,6-Dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptane-3-carboxylic acid benzyl ester

The crude product (1 R , 4 S /1 S , 4 R )-2-oxa-3-azabicyclo[2.2.1]heptane-5-ene-3-carboxylic acid benzyl ester 2b (32.39 g, 0.12 mol Dissolved in 600 mL of tetrahydrofuran, adding N-methyl oxidized morpholine (57.2 g, 0.24 mol) and osmium tetroxide (100 mg, 0.39 mmol) for 1.5 hours, adding sodium dithionite (63.7 g, 0.37 mol) , reaction for 30 minutes. The THF was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) dryness to give the crude title product (1 S, 4 R, 6 S / 1 R, 4 S, 6 R) -5,6- dihydroxy-2-oxa-3-azabicyclo [2.2.1] heptane Benzyl-3-carboxylate 2c (31.73 g, yellow oil).

¹ H NMR (400 MHz, CDCl 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 (3a S , 4 S , 7 R , 7a S/ 3a R , 4 R , 7 S , 7a R )-2,2-dimethyldihydro-3a H -4,7-methylene [1,3 Dioxol-[4,5- d ][1,2]oxazine-6( 4H )-benzyl carboxylate

The crude product (1 S , 4 R , 6 S/ 1 R , 4 S , 6 R )-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptane-3-carboxylic acid Benzyl ester 2c (31.73 g, 0.12 mol) was dissolved in 150 mL of acetone, and p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) was added and reacted at 30 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (3a S, 4 S, 7 R, 7a S / 3a R, 4 R, 7 S, 7a R -2,2-Dimethyldihydro-3a H -4,7-methylene[1,3]dioxol[4,5- d ][1,2]oxazine-6 ( 4H )-Benzyl carboxylate 2d (27.8 g, white solid), yield: 76.1%.

¹ H NMR (400 MHz, CDCl 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 (3a R , 4 S , 6 R , 6a S/ 3a S , 4 R , 6 S , 6a R )-6-amino-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-4-ol

(3a S , 4 S , 7 R , 7a S/ 3a R , 4 R , 7 S , 7a R )-2,2-dimethyldihydro-3a H -4,7-methylene [1, 3] Dioxe[4,5- d ][1,2]oxazine-6( 4H )-formic acid benzyl ester 2d (27.8 g, 91.06 mmol) dissolved in 400 mL of methanol, palladium /Carbon (10%, 1.4 g), three times of hydrogen, and reacted at 50 ° C for 40 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude title product (3a R , 4 S , 6 R , 6a S/ 3a S , 4 R , 6 S , 6a R )-6-amino-2,2-dimethyltetra Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-4-ol 2e (16.8 g, yellow solid).

MS m/z (ESI): 174.1 [M+1]

Step 6 N-[(3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetra Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl carbamate

The crude product (3a R , 4 S , 6 R , 6a S/ 3a S , 4 R , 6 S , 6a R )-6-amino-2,2-dimethyl 4,5,6,6a-tetrahydro -3a H -cyclopenteno[ d ][1,3]dioxol-4-ol 2e (16.8 g, 91.06 mmol) was dissolved in 195 mL of 4-methyl-2-pentanone and water ( Potassium carbonate (22.65 g, 163.9 mmol) was added to a mixed solvent of V/V = 3:1), and benzylphosphonium chloride (27 mL, 0,87 mol) was added dropwise, and the mixture was reacted 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 solution (100 mL×2), dried over anhydrous magnesium sulfate A mixture of 200 mL of n-hexane and dichloromethane (V/V = 20:1) was added to the residue, and the mixture was filtered, and dried in vacuo to give the title product N-[(3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-hydroxy-2,2-dimethyl 4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1, 3] Benzyl dioxol-4-yl]carbamate 2f (18.82 g, off-white solid), yield: 77.3%.

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

Seventh step 2-((3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S -6-(benzyloxycarbonylamino-2,2-dimethyltetrahydro-3aH-cyclo) Ethyl penteno[ d ][1,3]dioxol-4-yl)oxyacetate

N-[(3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-hydroxy-2,2-dimethyl-4,5,6,6a- Benzyl tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]carbamate 2f (2 g, 6.51 mmol) dissolved in 100 mL of tetrahydrofuran, dry ice The bath was cooled to below -22 ° C (internal temperature), kept for 30 minutes, 10 mL of potassium t-butoxide (3.65 g, 9.76 mmol) in tetrahydrofuran solution was added, and kept at -22 ° C for 30 minutes (internal temperature), at - After stirring at 30 ° C for 30 minutes, a solution of ethyl bromoacetate (1.09 mL, 9.76 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was kept at -22 ° C for 1 hour, and then allowed to react to room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - ((3a S, 4 R, 6 S, 6a R / 3a R, 4 S, 6 R ,6a S )-6-(Benzyloxycarbonylamino-2,2-dimethyltetrahydro-3a H -cyclopenta[d][1,3]dioxol-4- Ethyl acetate 2 g (2.16 g, pale yellow oil), yield: 84.4%.

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

Eighth step (3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl carbamate

2-((3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-(benzyloxycarbonylamino-2,2-dimethyltetrahydro-3a Ethyl H -cyclopenteno[d][1,3]dioxol-4-yl)oxyacetate 2 g (8 g, 20.34 mmol) was dissolved in 60 mL of tetrahydrofuran, and lithium tetrahydroborate was added. (887 mg, 40.7 mmol), stirred at room temperature overnight. The mixture was poured into water (150 mL) and extracted with ethyl acetate (60 mL×3). saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure to give the title product N - [(3a S, 4 R, 6 S, 6a R / 3a R, 4 S, 6 R, 6a S )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxo Benzene heterocyclopenten-4-yl]carbamate 2h (6.82 g, colorless mp.), yield 49.7%.

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

Step 9 2-{[(3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-Amino-2,2-dimethyl-4,5,6,6a -tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol

N-[(3a S , 4 R , 6 S , 6a R /3a R , 4 S , 6 R , 6a S )-6-(2-hydroxyethoxy)-2,2-dimethyl 4, 5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 2h (6.8 g, 19.35 mmol) dissolved in Palladium on carbon (10%, 600 mg) was added to 150 mL of methanol, three times with hydrogen, and stirred at room temperature for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude title product 2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-amino-2,2- Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 2i (4.43 g, Light yellow liquid), the product was directly subjected to the next reaction without purification.

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

¹ H NMR (400 MHz, CDCl 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, and 20 mL of water was added, followed by 1 -methylpyrrol-2-one (20.6 g, 207.9 mmol), bromomethylcyclopropane (9.6 g, 71.4 mmol), stirred at 20 ° C for 12 hours, then added 30 mL of 1 M hydrochloric acid and then 15 mL of 6 M hydrochloric acid. After stirring for 12 hours, it was filtered, washed 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+1]

The eleventh step 2-(cyclopropylmethylmercapto)-5-( p -toluene azide)pyrimidine-4,6-diol

Dissolve 4-methylaniline (6.7 g, 62 mmol) and 36% hydrochloric acid (18.7 mL, 224 mmol) in 20 mL water, and add 20 mL of sodium nitrite solution (4.5 g, 65 mmol) dropwise on ice. After the addition is completed, the solution is kept in the ice bath condition and the solution is reserved.

Dissolve 2-(cyclopropylmethylhydrazino)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 the pH = 1 and a solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried in vacuo to give the title product 2-(cyclopropylmethylmethyl)-5-( p -toluene Nitrogen)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-(cyclopropylmethylmercapto)pyrimidin-5-yl]-( p -toluene)肼

2-(cyclopropylmethylmercapto)-5-( p -toluene azide)pyrimidine-4,6-diol 2m (12.2 g, 39 mmol) was suspended in 40 mL of toluene, and pyridine was added at 70 °C. mL, 77 mmol), phosphorus oxychloride (44 mL, 482 mmol) was added dropwise below 94 ° C and allowed to react 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 mL×3), and the organic phase was combined with saturated sodium chloride solution (200 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (E) - [4,6- dichloro-2- (cyclo Propylmethylmercapto)pyrimidin-5-yl]-( p -toluene)oxime 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-(cyclopropylmethylmercapto)pyrimidin-5-yl]-( p -toluene)肼2n (9.5 g, 27 mmol) was dissolved in 190 mL of ethyl acetate To the ester, palladium on carbon (10%, 2.56 g) was added, and the hydrogen was replaced three times, and the mixture was 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×2), pH = 1.5 to 2 with 3 M hydrochloric acid, and the filtrate was concentrated under reduced pressure to give the 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+1]

Fourteenth step 2-{[(3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-[[5-Amino-6-chloro-2-(cyclopropyl) mercapto-yl) pyrimidin-4-yl] amino] -2,2-dimethyl-tetrahydro -4,5,6,6a- -3a H - cyclopenta [d] [1,3] dioxa Cyclopentene-4-yl]oxy}ethanol

4,6-Dichloro-2-(cyclopropylmethylmercapto)pyrimidine-5-amine 2p (700 mg, 2.8 mmol) and 2-{[(3a R , 4 S , 6 R , 6a S /3a S ,4 R ,6 S ,6a R )-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3 Dioxol-4-yl]oxy}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×3) and saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. Chromatography of the residue obtained by eluent B to give the title product 2-{[3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R ]-6-[[5 -amino-6-chloro-2-(cyclopropylmethyldecyl)pyrimidin-4-yl]amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethanol 2q (250 mg, dark red oil), yield: 25.2%.

MS m/z (ESI): 431.1 [M+1]

Step fifteenth 2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[7-chloro-5-(cyclopropylmethyldecyl)triazole [4,5- d ]pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxo Heterocyclopenten-4-yl]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[[5-Amino-6-chloro-2-) (cyclopropylmethylhydrazino)pyrimidin-4-yl]amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1, 3] Dioxol-4-yl]oxy}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×2), and the organic phase was combined with saturated sodium carbonate (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by column chromatography on silica gel eluting with system B agent resulting solid was purified to give the crude title product was 2 - {[(3a R, 4 S, 6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-[7-Chloro-5-(cyclopropylmethylhydrazino)triazolo[4,5- d ]pyrimidine-3- -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy Ethanol 2r (212 mg, pale yellow oil), yield: 82.8%.

MS m/z (ESI): 442.1 [M+1]

Step 16 2-{[((3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-[5-(cyclopropylmethylhydrazino)-7-[[( 1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl]-2,2-dimethyl- 4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy)ethanol

2-{[(3a S , 4 S , 6 R /3a R , 4 S , 6 R )-6-[7-chloro-5-(cyclopropylmethylhydrazino)triazolo[4,5- d ] pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole- 4-yl]oxy}ethanol 2r (212 mg, 0.48 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (207 mg, 0.65 mmol) was dissolved in 15 mL of acetonitrile and triethylamine (170 mg, 1.68 mmol) was added and reacted for 24 hours. The reaction solution was concentrated under reduced pressure. 50 mL of ethyl acetate and 50 mL of water were added, and pH was adjusted by adding 2.5 M hydrochloric acid. 4, the liquid phase was extracted with ethyl acetate (300 mL×2), and the organic phase was combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, The resulting solid was purified by column chromatography using eluent B to give the title product 2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[5 -(cyclopropylmethylhydrazino)-7-[[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ] Pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4- Base oxy}ethanol 2s (225 mg, pale yellow solid), yield: 81.5%.

MS m/z (ESI): 575.3 [M+1]

Step 17 (1 R , 2 R , 3 S , 5 R/ 1 S , 2 S , 3 R , 5 S )-3-{5-(cyclopropylmethylindolyl)-7-[(1 R ,2 S ) -2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl- 1,2-diol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[5-(cyclopropylmethylhydrazino)-7-[[( 1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl]-2,2-dimethyl- 4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 2s (225 mg, 0.39 mmol) dissolved 2.5 M hydrochloric acid (4.5 mL, 11.25 mmol) was added to 15 mL of methanol for 24 hours. Add saturated sodium hydroxide solution to adjust pH 7. Add 60 mL of ethyl acetate and 20 mL of water, stir for 15 minutes, separate the layers, and extract the aqueous phase with ethyl acetate (300 mL×2). The organic phase is combined and washed with saturated brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then recrystallized from 4.7 chloro chloroform, and the obtained solid was purified by eluent column chromatography with eluent system B to obtain the racemic product (1 R , 2 R , 3 S ,5 R/ 1 S ,2 S ,3 R ,5 S )-3-{5-(cyclopropylmethylhydrazino)-7-[(1 R ,2 S )-2-(3,4-di Fluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2s (149 Mg, colorless oil), yield: 71.5%.

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

¹ H 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 R , 2 R , 3 S , 5 R )-3-{5-(cyclopropylmethylhydrazino)-7-[(1 R ,2 S )-2-(3,4-difluorophenyl Cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (1 S , 2 S , 3 R , 5 S )-3-{5-(cyclopropylmethylhydrazino)-7-[(1 R ,2 S )-2-(3,4-difluorophenyl Cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 3

Mixture of diastereomers (1 R , 2 R , 3 S , 5 R/ 1 S , 2 S , 3 R , 5 S )-3-{5-(cyclopropylmethylindenyl)-7- [(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyl Ethoxy)cyclopentyl-1,2-diol 2s (149 mg, colorless oil) was isolated from the chiral isomers using the HPLC method to give the title product (1 R , 2 R , 3 S , 5 R )-3-{5-(cyclopropylmethylhydrazino)-7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropane Amino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol 2 (61.8 mg, colorless oil ), yield: 41.5%; (1 S , 2 S , 3 R , 5 S )-3-{5-(cyclopropylmethylhydrazino)-7-[(1 R , 2 S )-2-( 3,4-difluorophenyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2- Glycol 3 (61.5 mg, colorless oil), yield: 41.3%.

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

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

Example 4 (1 S , 2 S , 3 R , 5 S )-3-{7-[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyl Gentyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

first step 2-chloro-1-(5-chloro-2-thienyl)ethanone

2-Chloroacetonitrile chloride (22.5 g, 0.2 mol) was dissolved in 100 mL of dichloromethane, and aluminum trichloride (24 g, 0.18 mol) was added, stirred at room temperature, and 150 mL of 2-chlorothiophene (23.72) was added dropwise. g, 0.2 mol) of dichloromethane solution, reacted for 3.5 hours. The mixture was stirred for 30 minutes, and the organic layer was washed with saturated sodium chloride solution The title product, 2-chloro-1-(5-chloro-2-thienyl)ethanone 4a (32 g, m.

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

Second step (1 S )-2-chloro-1-(5-chloro-2-thienyl)ethanol

(S)-Diphenyl-pyrrolidin-2-yl-methanol (2.08 g, 8.2 mmol) was dissolved in 45 mL of toluene, trimethyl borate (1.1 g, 11.5 mmol) was added and reacted at 40 ° C for 1.5 hours. , keep dimethyl sulfide borane (65.5 mL, 131 mmol) dropwise at 35 ° C to 45 ° C, react at 40 ° C for 1 hour, keep 35 ° C to 45 ° C, add 150 mL of 2-chloro in 1.5 hours - A solution of 1-(5-chloro-2-thienyl)ethanone 4a (32 g, 0.16 mol) in toluene was reacted 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, washed with 10% acetic acid (100 mL × 4), and combined with water. phase with toluene (60 mL) extracted with saturated sodium chloride solution (150 mL), and concentrated to give the crude title product (1 S) -2- chloro-1- (5-chloro-2-thienyl) ethanol 4b (32.3 g, yellow oil).

MS m/z (ESI): 196.0 [M-1]

third step (1 R , 2 R )-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, heated to 40 ° C, and a solution of ethyl 2-diethoxyphosphonate (40.5 g, 0.18 mol) in toluene was added dropwise. The reaction was carried out at 40 ° C for 1 hour, and a solution of (1 S )-2-chloro-1-(5-chloro-2-thienyl)ethanol 4b (32.3 g, 0.16 mol) was added dropwise, stirred at 60 ° C for 12 hours, and 150 mL of water was added. , liquid separation, the organic phase was added over anhydrous sodium sulfate, and column chromatography with silica gel in the eluent system B resulting residue, to give the title product (1 R, 2 R) -2- (5- chloro-2-thienyl Ethyl cyclopropylcarboxylate 4c (10.9 g, yellow liquid), yield: 28.8%.

¹ H NMR (400 MHz, CDCl 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, J = 7.14 Hz, 3H), 1.28-1.23 (m, 1H).

the fourth step (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylcarboxylic acid

Ethyl (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylcarboxylate 4c (10.9 g, 0.047 mol) was dissolved in 80 mL of ethanol, and a 30% sodium hydroxide solution was added ( 3.4 g, 0.085 mol), stir for 4.5 hours, concentrate most of the ethanol under reduced pressure, add 100 mL of water and 100 mL of toluene, add concentrated hydrochloric acid dropwise, adjust pH 7, separated and the aqueous phase was extracted with toluene (100 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the title product (1 R, 2R )-2-(5-Chloro-2-thienyl)cyclopropylcarboxylic acid 4d (7.8 g, yellow liquid), yield: 81.6%.

MS m/z (ESI): 201.0 [M-1]

the fifth step (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylcarboxamidine chloride

(1 R , 2 R )-2-(5-Chloro-2-thienyl)cyclopropylcarboxylic acid 4d (3.24 g, 16 mmol) was dissolved in 10 mL of toluene, and dichlorothylene (3.04 g, 25.6 mmol), stirring at 25 ° C for 24 hours, the reaction mixture was concentrated under reduced pressure to remove the dichloromethane to give the crude title product 5 mL (1 R , 2 R ) -2-(5-chloro-2-thienyl) A solution of cyclopropylguanidinium chloride 4e (3.53 g) in toluene was taken directly to the next reaction without purification.

Step 6 (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropadienyl azide

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) were dissolved in 10 mL water, cooled to 0 ° C, and the crude product was added dropwise. mL (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylmethylhydrazine chloride 4e (3.53 g, 16 mmol) in toluene, stirring at 0 ° C for 3 hours, to the reaction mixture 10 mL of ice water was added, the layers were separated, and the aqueous phase was extracted with toluene (20 mL). The organic phase was combined, washed sequentially with ice water (25 mL) and saturated sodium chloride (20 mL) and dried over anhydrous sodium sulfate. A crude toluene solution of 35 mL (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylamidine azide 4f was obtained as a crude title product.

Seventh step (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylamine

Place 20 mL of toluene in a 250 mL 3-neck flask, heat to 100 ° C, and add 35 mL of the crude (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropadienamide of the above procedure. A toluene solution of 4f azide 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, kept at 80 ° C dropwise into the above standby solution, the mixed solution was reacted at 80 ° C for 1.5 hours, added 45 mL of water, cooled to room temperature, separated, discarded Toluene layer, the aqueous phase is adjusted with saturated sodium hydroxide solution 12, (35mL × 2) and extracted with ethyl acetate, the organic phase washed with water (45mL × 2), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the title product (1 R, 2 R) -2- (5- chloro 2-Thienyl)cyclopropylamine 4g (715 mg, yellow oil), yield: 25.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.66 (d, J = 3.76 Hz, 1H), 6.46 (d, J = 3.72 Hz, 1H), 2.54-2.51 (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-{[(3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-[(5-Amino-6-chloro-2-propylindenyl-pyrimidine) 4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole- 4-based]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-amino-2,2-dimethyl-4,5,6, 6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 2i (1.95 g, 9 mmol) dissolved in 30 mL of ethylene glycol 4,6-Dichloro-2-propylindenyl-pyrimidin-5-amine 1 s (2.6 g, 10.8 mmol) and triethylamine (4.5 g, 45 mmol) were added and reacted at 100 ° C for 12 hours, cooled to At room temperature, 150 mL of ethyl acetate and 150 mL of saturated sodium chloride solution were added, stirred for 20 minutes, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phase was combined and washed with saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - {[(3a R, 4 S, 6 R, 6a S /3a S , 4 R , 6 S , 6a R )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl 4-,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 4h (1.8 g, brownish yellow oil (form), yield: 47.6%.

MS m/z (ESI): 419.2 [M+1]

Step 9 2-{[(3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-(7-chloro-5-propylindolyl-3 H -[1,2 ,3]-triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ] [1,3]dioxol-4-yl]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[(5-Amino-6-chloro-2-) Propylmercapto-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxo Heterocyclopenten-4-yl]oxy}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 and added dropwise to the above. After stirring for 30 minutes, add 60 mL of ethyl acetate, then add 30 mL of saturated potassium carbonate solution, quench the reaction, separate the liquid, extract the aqueous phase with ethyl acetate (50 mL×2), combine the organic phases, and use sequentially. The mixture was washed with aq. EtOAc (EtOAc) (EtOAc) {[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-(7-chloro-5-propylindolyl-3 H -[1,2,3 Triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1, 3] Dioxol-4-yl]oxy}ethanol 4j (1.27 g, pale yellow solid), yield: 69.0%.

MS m/z (ESI): 430.2 [M+1]

¹ H NMR (400 MHz, CDCl 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, J = 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, J = 7.36 Hz, 3H).

Step 10 2-{[(3a R ,4 S ,6 R ,6a S /3a S ,4 R ,6 S ,6a R )-6-[7-[[(1 R ,2 R )-2-(5- Chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl]-2,2-dimethyl-4,5, 6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-4-yl]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-(7-chloro-5-propylindolyl-triazolo[4, 5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole Ethyl-4-yl]oxy}ethanol 4j (215 mg, 0.5 mmol) was dissolved in 15 mL of acetonitrile and (1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropylamine 4 g ( 117 g, 0.68 mmol), stirring at 25 ° C or less, triethylamine (177.1 mg, 1.75 mmol) was added dropwise, stirring at 25 ° C for 12 hours, concentrated acetonitrile, and 30 mL of water and 30 mL of ethyl acetate Adjust pH with 2.5 M hydrochloric acid 4, liquid separation, the aqueous phase was extracted with ethyl acetate (20 mL), and the organic phase was combined, washed with water (40 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product 2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[7-[[(1 R , 2 R )-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-4-yl]oxy}ethanol 4k (245 mg, light Yellow solid), Yield: 86.6%.

¹ H NMR (400 MHz, CDCl 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, 1H), 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, J = 7.28 Hz, 3H).

The eleventh step (1 S , 2 S , 3 R , 5 S /1 R , 2 R , 3 S , 5 R )-3-{7-[[(1 R ,2 R )-2-(5-chloro-2- thienyl) cyclopropyl] amino] -5-propyl-mercapto -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-3-yl} -5- (2-hydroxy Ethoxy)cyclopentane-1,2-diol

2-{[(3a R , 4 S , 6 R , 6a S /3a S , 4 R , 6 S , 6a R )-6-[7-[[(1 R , 2 R )-2-(5 -chloro-2-thienyl)cyclopropyl]amino]-5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl]-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-4-yl]oxy}ethanol 4k (245 mg, 0.43 mmol) dissolved in 15 mL of methanol 5 mL of 2.5 M hydrochloric acid was added dropwise at 20 ° C, and stirred at 20 ° C for 12 hours. The pH of the reaction solution was adjusted with saturated sodium hydroxide solution. The extract was extracted with ethyl acetate (35 mL × 3), EtOAc (EtOAc m. After stirring at 57 ° C for 10 minutes, 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 S , 2 S , 3 R , 5 S / 1 R , 2 R , 3 S ,5 R ) -3-{7-[[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazole [4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 4 m (190 mg, pale yellow solid), yield: 83.7%.

¹ H NMR (400 MHz, DMSO- d 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, J = 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, J = 7.32 Hz, 3H).

Step 12 (1 S , 2 S , 3 R , 5 S )-3-{7-[[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5 -propyl mercapto-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

(1 S , 2 S , 3 R , 5 S /1 R , 2 R , 3 S , 5 R )-3-{7-[[(1 R , 2 R )-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, 0.36 mol), which was isolated by chiral column chromatography using the HPLC method to give the title product ( 1S , 2S , 3R , 5S )- 3-{7-[[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5-propylindolyl-triazolo[4,5- d 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 ⁺ ]

¹ H NMR (400 MHz, DMSO- d 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, J = 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, J = 7.32 Hz, 3H).

Example 5 (1 S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5-{7-(indanyl-2-ylamino)-5-propylindenyl-triazole And [4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2-diol

first step (3a R , 4 S , 6 R , 6a S )-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1 , 3]dioxol-4-ol L-(-)-benzophenone tartrate

(3a S , 4 S , 7 R , 7a S/ 3a R , 4 R , 7 S , 7a R )-2,2-dimethyldihydro-3a H -4,7-methylene [1, 3] Dioxe[4,5- d ][1,2]oxazine-6( 4H )-formic acid benzyl ester 2d (20 g, 65.5 mmol) was added to 400 mL of methanol and palladium was added. /carbon (1 g, 5%), three times of hydrogen, reacted at 50 ° C for 24 hours, filtered, added L-(-)-dibenzidal tartaric acid (23.4 g, 65.5 mmol), concentrated under reduced pressure, added to the crude 262 mL of acetonitrile and 43.7 mL of water were stirred at 60 ° C for 1 hour, then cooled to room temperature, and the solid was slowly precipitated and stirred at room temperature for 12 hours to give the title product (3a R , 4 S , 6 R , 6a S )-6- Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol L-( -)-Dibenzoyl tartaric acid salt 5a (11.8 g, off-white solid), yield: 33.9%.

MS m/z (ESI): 174.1 [M+1]

Second step N-[(3a S ,4 R ,6 S ,6a R )-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ] [1,3]dioxol-4-yl]benzyl carbamate

(3a R , 4 S , 6 R , 6a S )-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][ 1,3]dioxol-4-ol L-(-)-dibenzidal tartrate 5a (11.8 g, 22.2 mmol) dissolved in 195 mL of tetrahydrofuran and water (V/V = 10:3) To the mixed solvent, potassium carbonate was added dropwise, and benzyl chloroformate (7.57 g, 22.2 mmol) was slowly added dropwise, and the reaction was carried out for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran and ethyl acetate (50 mL×3) The organic phase was combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was mixed with 63 mL of n-hexane and dichloromethane (V/V=20:1) It is beaten, filtered, and the filter cake is dried in vacuo to give the title product N-[(3a S , 4 R , 6 S , 6a R )-6-hydroxy-2,2-dimethyl-4,5,6,6a- Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 5b (6.51 g, white solid), yield: 95.4%.

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

¹ H NMR (400 MHz, CDCl 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-[[(3a R ,4 S ,6 R ,6a S )-6-benzyloxycarbonylamino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - ring Ethyl penteno[ d ][1,3]dioxol-4-yl]oxy]acetate

N-[(3a S ,4 R ,6 S ,6a R )-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d] ][1,3]Dioxol-4-yl]carbamic acid benzyl ester 5b (2 g, 6.51 mmol) was dissolved in 20 mL of tetrahydrofuran, and potassium butoxide (3.65 g) was added dropwise in a dry ice bath. , 9.76 mmol), after completion, the reaction was carried out at -20 ° C for 1 hour, and ethyl bromoacetate (1.63 g, 9.76 mmol) was added dropwise at -20 ° C or lower, and the reaction was carried out at -20 ° C for 1 hour, and the temperature was naturally raised to room temperature and stirred. 12 hours, the reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - [[(3a R, 4 S, 6 R, 6a S) -6- benzyl Oxycarbonylamino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl Ethyloxyacetate 5c (2.16 g, pale yellow oil), yield: 84.2%.

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

¹ H NMR (400 MHz, CDCl 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-[(3a S ,4 R ,6 S ,6a R )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopentene[ d ][1,3]dioxol-4-yl]carbamic acid benzyl carbamate

2-{[(3a R ,4 S ,6 R ,6a S )-6-benzyloxyguanamine-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -ring Ethyl penteno [ d ][1,3]dioxol-4-yl]oxy}acetate 5c (8 g, 20.34 mmol) was dissolved in 60 mL of tetrahydrofuran, and lithium borohydride (887 mg) After stirring for 12 hours, the reaction mixture was poured into 150 mL of water, EtOAc (EtOAc (EtOAc) The crude title product N-[(3a S ,4 R ,6 S ,6a R )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydrol was obtained. -3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 5d (7.04 g, pale yellow). The next step is to react.

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

the fifth step 2-{[(3a R ,4 S ,6 R ,6a S )-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-4-yl]oxy}ethanol

N-[(3a S ,4 R ,6 S ,6a R )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 5d (7.04 g, 20.03 mmol) dissolved in 100 mL of methanol, palladium/carbon (350) Mg, 5%), three times of hydrogen, stirred for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 2-{[(3a R , 4 S , 6 R , 6a S )-6-amino-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 5e (4.54 g, light yellow oil), the product was directly subjected to next reaction without purification.

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

Step 6 2-{[(3a R ,4 S ,6 R ,6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol

The crude product is 2-{[(3a R , 4 S , 6 R , 6a S )-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene And [ d ][1,3]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) Methyl) and 4,6-dichloro-2-propylindenyl-pyrimidin-5-amine 1s (1.98 g, 8.28 mmol), reacted at 100 ° C for 12 hours, cooled to room temperature, added 100 mL of ethyl acetate and 100 mL Saturated sodium chloride solution, stirred for 20 minutes, liquid separation, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate Concentration by pressure, the residue obtained was purified by eluent column chromatography using eluent system B to give the title product 2-{[(3a R , 4 S , 6 R , 6a S )-6-[(5-Amino- 6-Chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][ 1,3]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-{[(3a R , 4 S , 6 R , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino group under ice bath ]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy} Ethanol 5f (1.6 g, 3.8 mmol) was dissolved in 6.5 mL of acetic acid, stirred, and 3 mL of sodium nitrite (277 mg, 4 mmol) was added dropwise. Stirring was continued for 30 minutes in ice bath, and 50 mL of ethyl acetate and 30 were added. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; , dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 2 - {[(3a R, 4 S, 6 R, 6a S) - 6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethanol 5 g (1.18 g, pale yellow thick), yield: 72.4%.

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

Eighth step 2-{[(3a R ,4 S ,6 R ,6a S )-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5- d Pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4 -oxy]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2 ,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 5g ( 100 mg, 0.23 mmol) was dissolved in 8 mL of acetonitrile, 2-aminopurine (418 mg, 0.31 mmol) was added, stirred, triethylamine (82.2 mg, 0.81 mmol) was added dropwise, and stirred at room temperature for 24 hours. Add 15 mL of water to the solution and adjust the pH with 2.5 M hydrochloric acid. 4, ethyl acetate (25 mL × 2) was extracted, the organic phase was combined, washed with a saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give crude title product 2-{[( 3a R , 4 S , 6 R , 6a S )-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3- -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy }Ethanol 5h (100 mg, light yellow solid). The product was taken to the next step without purification.

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

Step 9 (1 S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5-[7-(indanyl-2-ylamino)-5-propylindenyl-triazole And [4,5- d ]pyrimidin-3-yl]cyclopentyl-1,2-diol

The crude product is 2-{[(3a S ,4 R ,6 S ,6a R )-6-[7-(indanyl-2-ylamino)-5-propylindolyl-triazolo[4,5 - d ] pyrimidin-3-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole -4-yl]oxy}ethanol 5h (100 mg, 0.19 mmol) was dissolved in 5 mL of methanol, hydrochloric acid (4 mL, 2.5 M) was added dropwise, stirred for 12 hours, and saturated sodium hydroxide solution was added to the reaction mixture to adjust pH. 9. Ethyl acetate (30 mL×2) was extracted, and the organic phase was combined, washed with saturated sodium chloride solution (25 mL×2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. F initiator system resulting residue was purified to give the title product (1 S, 2 S, 3 S, 5 R) -3- (2- hydroxyethoxy) -5- [7- (indan-2-yl-amine 5-)-5-propyldecyl-triazolo[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]

¹ H NMR (400 MHz, DMSO- d 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, J =7.18 Hz, 3H).

Example 6 (1 S , 2 S , 3 S , 4 S )-5-{7-[[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropyl]amino]-5 -propyl mercapto-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

first step 5-nitro-2-propylindolyl-pyrimidine-4,6-diol

2-propylmercapto-pyrimidine-4,6-diol 6a (prepared by the known method "Patent WO2001092263") (8.0 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 until the pH of the reaction solution was 1 to 2, a large amount of solid was precipitated, and the filter cake was washed with water (50 mL×2). Drying gave the crude title product, 5-nitro-2-propyl-decyl-pyrimidine-4,6-diol 6b (11.1 g, yellow powdery solid), yield: 100%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.27-3.17 (t, 2H), 1.90-1.74 (m, 2H), 1.11 (t, 3H).

Second step 4,6-dichloro-5-nitro-2-propylindenyl-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 the mixture was stirred for 20 min, EtOAc (EtOAc) The title product was 4,6-dichloro-5-nitro-2-propylindolyl-pyrimidine 6c (0.45 g, m.

third step (3a R ,6 S )-2,2-dimethyl-6,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-6-ol

Add bis(tricyclohexylphosphine)benzylidene ruthenium dichloride 6d (177 mg, 0.216 mmol) to the reaction flask and add 40 mL of 1-[(4 S ,5 R )-2,2-dimethyl A solution of benzyl-5-vinyl-1,3-dioxol-4-yl]prop-2-en-1-ol 1 m (2 g, 10.8 mmol) in chloroform was reacted for 2 hr. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (3a R, 6 S) -2,2- dimethyl-dihydro -3a -6,6a- H -cyclopenteno[ d ][1,3]dioxol-6-ol 6e (450 mg, brownish black oil), yield: 26.7%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.01-6.02 (m, 1H), 5.88-5.90 (m, 1H), 5.25-5.28 (m, 1H), 4.78 (m, 1H), 4.50-4.51 (d, 1H), 2.23 (br, 1H), 1.39 (s, 3H), 1.34 (s, 3H).

the fourth step (4 R ,6a R )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]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, dropwise. 20 mL (3a R , 6 S )-2,2-dimethyl-6,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-6-ol 6e (1.77 g, 11.3 mmol) in tetrahydrofuran, react at -20 ° C for 30 minutes, warm to 0 ° C, add diphenyl azide (3.73 g, 13.56 mmol), react at 0 ° C for 7 hours, add triphenyl The phosphine (3.26 g, 12.43 mmol) was reacted 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 R , 6a R ) 2,2-Dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-amine 6f (1.7 g, colorless oil) The product was directly subjected to the next reaction without purification.

¹ H NMR (400 MHz, CDCl 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-[(3a R ,6 R )-2,2-dimethyl-6,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-6- Benzyl carbamide

(4 R ,6a R )-2,2-Dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-amine 6f (1.7 g, 11 mmol) dissolved in 20 mL of tetrahydrofuran, 10 mL of water and potassium carbonate (3.04 g, 22 mmol), benzyl chloroformate (4.5 mL, 13.2 mmol). (20 mL × 2), the organic phase was combined and concentrated under reduced pressure. The residue obtained was purified eluting with eluent column chromatography to afford the title product N-[(3a R , 6 R )-2,2 - Benzyl-6,6a-dihydro-3a H -cyclopenta[ d ][1,3]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 ((3a S , 4 R , 5 S , 6 S , 6a R )-5,6-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene[ d ][1,3] Benzyl oxol-4-yl)carbamate

N-[(3a R ,6 R )-2,2-dimethyl-6,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxole-6 - benzyl benzyl carbamate 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 teoxide (102 mg, 0.4 mmol). After reacting for 12 hours, 30 mL of water and ethyl acetate (60 mL×3) were added, and the organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate The resulting residue was purified by chromatography to afford the title product ((3a S , 4 R , 5 S , 6 S , 6a R ) -5,6-dihydroxy-2,2-dimethyltetrahydro -3aH-cyclopenteno[ d ][1,3]dioxol-4-yl)carbamate benzyl ester 6h (500 mg, colourless oil), yield: 78.0%.

MS m/z (ESI): 324.3 [M+1]

¹ H NMR (400 MHz, CDCl 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), 4.17-4.21 (m, 1H), 4.05-4.09 (m, 1H), 1.43 (s, 3H), 1.25 (s, 3H).

Seventh step (3a R , 4 S , 5 S , 6 R , 6a S )-6-Amino-2,2-dimethyltetrahydro-3a H -cyclopenteno[ d ][1,3]dioxa Cyclopentene-4,5-diol

((3a S , 4 R , 5 S , 6 S , 6a R )-5,6-dihydroxy-2,2-dimethyltetrahydro-3aH-cyclopentene[ d ][1,3] Benzyl dioxol-4-yl)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 , adding diatomaceous earth, filtering, and concentrating the filtrate under reduced pressure to give the crude title product (3a R , 4 S , 5 S , 6 R , 6a S )-6-amino-2,2-dimethyltetrahydro-3a H -cyclopenteno[ d ][1,3]dioxole-4,5-diol 6j (270 mg, mp.

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

¹ H NMR (400 MHz, CDCl 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 (3a R , 4 S , 5 S , 6 R )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl -4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 S , 6 R , 6a S )-6-Amino-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1,3]dioxo Heterocyclopentene-4,5-diol 6j (270 mg, 1.42 mmol) was dissolved in 15 mL of ethanol and added triethylamine (0.4 mL, 2.84 mmol) and 4,6-chloro-5-nitro-2 - mercapto propyl - pyrimidin-6b (419 mg, 1.57 mmol) , 12 hours, the reaction solution was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a R, 4 S , 5 S , 6 R )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl-4,5, 6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 6k (390 mg, yellow solid), yield: 65.4%.

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

Step 9 (3a R , 4 S , 5 S , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2- Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 S , 6 R )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl Base-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol 6k (390 mg, 0.93 mmol) dissolved To 10 mL of acetic acid, iron powder (260 mg, 4.64 mmol) was added, and the reaction was carried out for 12 hours. 50 mL of ethyl acetate was added, stirred, filtered, and the filter cake was washed with ethyl acetate (40 mL×2). The mixture was washed with water (50 mL×2), EtOAc (EtOAcjjjjjjjjj Product (3a R , 4 S , 5 S , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 6m (200 mg, brown Solid), yield: 55%.

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

¹ H NMR (400 MHz, DMSO- d 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 (3a R , 4 S , 5 S , 6 R )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl 4-,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 S , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 6m (200 mg, 0.51 Methyl acetate was dissolved in 4 mL of acetic acid, 0.5 mL water was added, 0.5 mL of sodium nitrite (38.9 mL, 0.56 mmol) in ice water was added dropwise, stirred for 5 minutes, and 60 mL of ethyl acetate was added, followed by saturated sodium bicarbonate solution. (10 mL), water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title product (3a R, 4 S, 5 S, 6 R) -6 -(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxole-4,5-diol 6n (220 mg) as a brown oil.

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

The eleventh step (3a R , 4 S , 5 S , 6 R )-6-{7-[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyl Keto-triazolo[4,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][ 1,3]dioxol-4,5-diol

(3a R , 4 S , 5 S , 6 R )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2,2-di Methyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 6n (80 mg, 0.2 mmol) Dissolved in 10 mL of acetonitrile, added (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (58.8 mg, 0.28 mmol), stirred, dripped triethylamine (0.1 mL, 0.7 mmol), for 12 hours, the reaction mixture was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a R, 4 S, 5 S ,6 R )-6-{7-[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propylindolyl-triazolo[4 ,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole Pentene-4,5-diol 6p (107 mg, light yellow oil), yield 100%.

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

Step 12 (1 S , 2 S , 3 S , 4 S )-5-{7-[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropylamino]-5-propyl Gentyl-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

(3a R , 4 S , 5 S , 6 R )-6-{7-[(1 R ,2 R )-2-(5-chloro-2-thienyl)cyclopropylamino]-5- Propylmercapto-triazolo[4,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ] [1,3]dioxole-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 hours with saturated sodium carbonate Adjust pH 8, concentrated under reduced pressure to remove methanol and extracted with ethyl acetate (60 mL × 3), dried over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, further separated by HPLC preparative chromatography, to give the title product (1 S, 2 S, 3 S ,4 S )-5-{7-[(1 R ,2 R )-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]

¹ H 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. 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 (1 S , 2 S , 3 S , 4 R )-5-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propyl Gentyl-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2,3,4-tetraol

first step (3a R ,6 R ,6a R )-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-ol

(3 R , 4 S , 5 R )-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol 1 h (20 g, 133 mmol) was dissolved in 250 mL of acetone, and 0.6 mL of concentrated sulfuric acid was added. The reaction was carried out for 4 hours at room temperature. The solid sodium hydrogencarbonate solid was added to the reaction mixture until pH = 7 and filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified eluting with eluent column chromatography to afford the title product (3a R , 6 R , 6a R - 6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-ol 7a (17.8 g, colorless oil ), the yield was 70.4%.

Second step ( R )-1-((4 R ,5 S )-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethane-1,2- Glycol

Methyltriphenylphosphonium 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 min. Raise to room temperature for 1 hour, add 200 mL (3a R , 6 R , 6a R )-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran [3,4- d ][1 , 3] Dioxol-4-ol 7a (18 g, 95 mmol) in tetrahydrofuran, stirred at room temperature for 12 h. The reaction mixture was added with 150 mL of water, and the solid was dissolved, and the mixture was evaporated to ethyl acetate (100 mL×4). The combined organic phase was washed with saturated sodium chloride (100 mL×2) and dried over anhydrous sodium sulfate. filtered and concentrated under reduced pressure to give crude (R) -1 - ((4 R, 5 S) -2,2- dimethyl-5-vinyl-1,3-dioxolan-4 Ethyl-1,2-diol 7b (17.8 g, brownish red oil), the product was taken to the next step without purification.

third step (4 S ,5 S )-2,2-dimethyl-5-vinyl-1,3-dioxolane-4-carbaldehyde

( R )-1-((4 R ,5 S )-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 (29 g, 135 mmol) was added dropwise. After 30 minutes, the reaction was continued for 30 minutes. The reaction mixture was added with 200 mL of water, and the aqueous layer was extracted with dichloromethane (200 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting eluent B in the residue system, to give the title product (4 S, 5 S) -2,2- dimethyl-5-vinyl-1,3-dioxolane-4-carbaldehyde 7c ( 7.5 g, colorless oil), yield 53.4%.

the fourth step 1-((4 R ,5 S )-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-en-1-ol

(4 S , 5 S )-2,2-Dimethyl-5-vinyl-1,3-dioxolane 4-carbaldehyde 7c (25 g, 160 mmol) was dissolved in 300 mL of tetrahydrofuran. The solution was cooled to -78 ° C, 1 M vinylmagnesium bromide (320 mL, 320 mmol) was added dropwise, and after the addition was completed, the reaction was carried out at -78 ° C for 1 hour, and the reaction was carried out at 0 ° C for 30 minutes. The reaction mixture was stirred and dried under reduced pressure. The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product 1-((4 R , 5S )-2,2-dimethyl-5-vinyl-1,3-di Oxapentan-4-yl)prop-2-en-1-ol 7d (18 g, colorless oil), yield 61%.

the fifth step (3a R ,4 R ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4- alcohol

Add bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (0.5 g, 0.63 mmol) to a 1000 mL single-mouth bottle, and add 450 mL of 1-((4 R , 5 S )-2,2-two to the syringe. Methyl-5-vinyl-1,3-dioxol-4-yl)prop-2-en-1-ol 7d (11.5 g, 62.5 mmol) in chloroform, mp. The reaction mixture was concentrated under reduced pressure, by silica gel chromatography to B the resulting residue was purified eluent system, to give the title product (3a R, 4 R, 6a S) -2,2- dimethyl--4,6a- dihydro - 3a H -cyclopenteno[ d ][1,3]dioxol-4-ol 7e (3.2 g, light brown-black oil), yield 50%.

Step 6 (3a R , 4 S , 6a S )-4-benzyloxy-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]diox Cyclopentene

(3a R , 4 R , 6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxole-4 - Alcohol 7e (2.5 g, 16 mmol) was dissolved in 30 mL of DMF, 60% sodium hydride (1.28 g, 32 mmol) was added portionwise at 0 ° C, and allowed to react at room temperature for 30 minutes, and benzyl bromide (2.85 mL, 24) was added. (mmol), the reaction was carried out for 12 hours, and the reaction was quenched with EtOAc. EtOAc (EtOAc) The resulting residue was purified with EtOAc (EtOAc) eluting to afford the title product (3a R , 4 S , 6a S ) -4-benzyloxy-2,2-dimethyl-4,6a-dihydro-3a H - ring Penteno[ d ][1,3]dioxole 7f (3.9 g, colorless oil), yield: 100%.

Seventh step (1 S , 2 S , 5 S )-5-benzyloxycyclopentene-3-ene-1,2-diol

(3a R , 4 S , 6a S )-4-benzyloxy-2,2-dimethyl-4,6a-dihydro-3a H -cyclopentene[ d ][1,3]dioxo Heterocyclopentene 7f (3.9 g, 16 mmol) was dissolved in 20 mL of methanol, and Dowex 50 cation resin (3 g) was added and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified to give the title compound ( 1S , 2S , 5S )-5-benzyloxycyclopentene-3-ene-1,2-diol 7 g (2.2 g, pale yellow oil) , Yield: 66.6%.

Eighth step (1 R , 2 R , 3 S , 4 R , 5 R )-4-benzyloxy-6-oxabicyclo[3.1.0]hexane-2,3-diol

Dissolve (1 S , 2 S , 5 S )-5-benzyloxycyclopentene-3-ene-1,2-diol 7 g (2.2 g, 10.67 mmol) in 50 mL of dichloromethane and add m-chloro oxybenzoate (4.74 g, 19.2 mmol), reacted for 24 hours, the reaction solution was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product (1 R, 2 R, 3 S, 4 R ,5 R )-4-benzyloxy-6-oxabicyclo[3.1.0]hexane-2,3-diol 7h (2.14 g, pale yellow oil), yield: 90.3 %.

Step 9 (1 S , 2 S , 3 S , 4 R , 5 S )-3-azido-5-benzyloxy-cyclopentyl-1,2,4-triol

(1 R , 2 R , 3 S , 4 R , 5 R )-4-benzyloxy-6-oxabicyclo[3.1.0]hexane-2,3-diol 7h (2.14 g, 9.63 mmol) dissolved in 30 mL of a mixed solvent of N,N-dimethylformamide and water (V/V=5:1), sodium azide (940 mg, 14.5 mmol) at 80 ° C After the reaction was carried out for 16 hours, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Crude title product (1 S , 2 S , 3 S , 4 R , 5 S )-3-azido-5-benzyloxy-cyclopentyl-1,2,4-triol 7j (2.55 g, light Yellow oil), the product was directly subjected to the next reaction without purification.

Step 10 (3a S , 4 R , 5 R , 6 S , 6a S )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-5-ol

(1 S , 2 S , 3 S , 4 R , 5 S )-3-azido-5-benzyloxy-cyclopentyl-1,2,4-triol 7j (2.55 g, 9.63 mmol) Dissolved in 20 mL of acetone, 2,2-dimethoxypropane (2.36 mL, 19.3 mmol) and p-toluenesulfonic acid (750 mg, 4.4 mmol) were reacted for 4 hours. The reaction solution was concentrated under reduced pressure. B to column chromatography eluting agent system resulting residue, to give the title product (3a S, 4 R, 5 R, 6 S, 6a S) -4- azido-6-benzyloxy-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-5-ol 7k (1.78 g, white solid) Rate: 60.5%.

The eleventh step (3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-5-ol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-5-ol 7k (400 mg, 1.31 mmol) and triphenylphosphine (490 mg, 1.86 mmol) were dissolved in 6 mL of tetrahydrofuran and added 1.2 mL of water was reacted at 30 ° C for 12 hours, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product (3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxo Heterocyclopenten-5-ol 7m (340 mg, white solid), yield: 93%.

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

¹ H NMR (400 MHz, DMSO- d 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 (3a R , 4 S , 5 R , 6 R , 6a S )-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-4,5-diol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-5-ol 7m (340 mg, 1.22 mmol) was dissolved in 8 mL of methanol and palladium hydroxide (600 mg, 4.27 mmol). the reaction at 1 atm 12 hours, the reaction mixture was concentrated under reduced pressure to give the crude title product (3a R, 4 S, 5 R, 6 R, 6a S) -6- amino-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 7n (230 mg, white viscous solid), product not The next reaction was carried out directly by purification.

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

Step 13 (3a R , 4 S , 5 R , 6 R , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2- Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 R , 6 R , 6a S )-6-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxole-4,5-diol 7n (230 mg, 1.22 mmol) and 4,6-chloro-5-nitro-2-propylindenyl-pyrimidine 6b (423.5 Mg, 1.6 mmol) was dissolved in 15 mL of ethanol, triethylamine (0.34 mL, 2.44 mmol) was added dropwise, and the reaction was carried out for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by eluent column chromatography with eluent system A. The title product (3a R , 4 S , 5 R , 6 R , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino] -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 7p ( 310 mg, pale yellow solid), yield: 60.5%.

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

Fourteenth step (3a R , 4 S , 5 R , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2- Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 R , 6 R , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol 7p (310 mg, 0.74 Methyl acetate was dissolved in 10 mL of acetic acid, iron powder (207 mg, 3.7 mmol) was added, and the reaction was carried out for 3 hours. 20 mL of ethyl acetate was added, stirred for 5 minutes, filtered, and the filter cake was washed with a large amount of ethyl acetate. (20 mL × 2) and saturated sodium bicarbonate solution (20 mL × 2), dried combined aqueous phase was extracted with ethyl acetate (20 mL × 2) and the combined organic phase was concentrated under reduced pressure to give the title product (3a R , 4 S , 5 R , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2-dimethyl -4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 7q (210 mg, yellow solid) The rate is 93%.

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

Step fifteenth (3a R , 4 S , 5 R , 6 R , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 R , 6 R , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 7q (270 mg, 0.7 Ment) dissolved in a mixed solvent of 4.5 mL of acetic acid and water (V/V = 2:1), added sodium nitrite (53.2 mg, 0.77 mL) under ice bath, reacted at 0 ° C for 5 minutes, added 20 mL of acetic acid Ethyl acetate and 20 mL of saturated sodium carbonate solution were stirred for 5 minutes, and the organic phase was washed successively with saturated sodium carbonate (10 mL) and saturated sodium chloride (10 mL). (10 mL × 2), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude title product (3a R, 4 S, 5 R, 6 R, 6a S) -6- (7- chloro-5-mercapto -Triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1, 3] Dioxol-4,5-diol 7r (281 mg, brown oil).

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

Step 16 (3a R , 4 S , 5 R , 6 R , 6a S )-6-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-4,5-diol

(3a R , 4 S , 5 R , 6 R , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4,5-diol 7r (281.3 mg, 0.7 mmol), (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (312.9 mg, 0.98 mmol) dissolved in 10 mL acetonitrile was added dropwise triethylamine (0.34 mL, 2.45mmol), 16 hours of reaction, the reaction solution was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a R, 4 S , 5 R , 6 R , 6a S )-6-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindenyl- Triazolo[4,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3] Dioxol-4,5-diol 7s (310 mg, white solid), yield: 83%.

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

Step 17 (1 S , 2 S , 3 S , 4 R )-5-[7-[[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]amino]-5 -propyl decyl-triazolo[4,5- d ]pyrimidin-3-yl]cyclopentyl-1,2,3,4-tetraol

(3a R , 4 S , 5 R , 6 R , 6a S )-6-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino] -5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxole-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 added Dowex50 (300 mg), 16 hours of reaction, the reaction solution was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (1 S, 2 S, 3 S, 4 R) - 5-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidine -3-yl}cyclopentyl-1,2,3,4-tetraol 7 (260 mg, white solid), yield: 91%.

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

¹ H 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 (1 R , 2 S , 3 S , 4 S , 5 S )-4-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-fluoro-cyclopentyl-1,2,3-triol

first step (3a S , 4 S , 5 R , 6 R , 6a S )-4-azido-6-(benzyloxy)-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-5-yltrifluoromethanesulfonate

(3a S , 4 R , 5 R , 6 S , 6a S )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-5-ol 7k (0.10 g, 0.33 mmol) was dissolved in 5 mL dichloromethane, then pyridine (39 mg, 0.50 mmol) Trifluoromethanesulfonic anhydride (113 mg, 0.40 mmol) was reacted for 1 hour. 5 mL of saturated sodium bicarbonate solution and 10 mL of dichloromethane were added, and the organic phase was washed successively with saturated sodium bicarbonate solution (10 mL) and saturated copper sulfate (10 mL×2) and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded crude title product (3a S , 4S , 5 R , 6 R , 6a S )-4-azido-6-(benzyloxy)-2,2-dimethyltetra Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-5-yl trifluoromethanesulfonate 8a (145 mg, light yellow oil), product Carry out the next reaction.

Second step (3a S , 4 R , 5 S , 6 S , 6a S )-6-azido-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetra Hydrogen-3a H -cyclopenta[ d ][1,3]dioxole

(3a S , 4 S , 5 R , 6 R , 6a S )-4-azido-6-(benzyloxy)-2,2-dimethyltetrahydro-3a H -cyclopentene[ d ][1,3]dioxole-5-yltrifluoromethanesulfonate 8a (136 mg, 0.33 mmol) was dissolved in 5 mL of tetrahydrofuran, and 0.5 mL of 1 M tetrabutylammonium fluoride trihydrate was added. A solution of the compound in tetrahydrofuran was reacted for 3 hours. After adding 10 mL of water and 10 mL of ethyl acetate, the mixture was separated and washed with ethyl acetate (10 mL×2). The organic phase was combined, washed with saturated sodium chloride (10 mL) the filtrate was concentrated under reduced pressure, by silica gel column chromatography to E eluent system resulting residue, to give the title product (3a S, 4 R, 5 S, 6 S, 6a S) -6- azido-4 -benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole 8b (0.10 g, colorless oil), yield: 99.0%.

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

third step (3a S , 4 R , 5 S , 6 S , 6a S )-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -ring Penteno[ d ][1,3]dioxol-6-amine

(3a S , 4 R , 5 S , 6 S , 6a S )-6-azido-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a- Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole 8b (0.60 g, 1.96 mmol) was dissolved in 10 mL of tetrahydrofuran, followed by triphenylphosphine (0.66 g, 2.54) Methyl) and 2 mL water for 48 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the crude title product (3a S, 4 R, 5 S, 6 S, 6a S) -4- benzyloxy - 5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-amine 8c ( 0.60 g, colorless oil), the product was taken to the next step without purification.

MS m/z (ESI): 282.2 [M+1]

the fourth step N-[(3a S ,4 R ,5 S ,6 S ,6a S )-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a Benzyl H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamate

The crude product (3a S , 4 R , 5 S , 6 S , 6a S )-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][1,3]dioxol-6-amine 8c (550 mg, 1.90 mmol) was dissolved in 10 mL of tetrahydrofuran and 3 mL of water, then potassium carbonate (525 mg, 3.80 mmol) Benzyl chloroformate (0.5 mL, 3 mmol) was added dropwise and reacted for 1 hour. The organic layer was extracted with ethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system E , the title product N-[(3a S , 4 R , 5 S , 6 S , 6a S )-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a- Benzyl tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamate 8d (590 mg, colorless oil), yield: 75.0% .

MS m/z (ESI): 416.1 [M+1]

the fifth step (3a R , 4 R , 5 S , 6 S , 6a S )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentyl Oxo[ d ][1,3]dioxol-4-ol

N-[(3a S , 4 R , 5 S , 6 S , 6a S )-4-benzyloxy-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 8d (788 mg, 1.90 mmol) dissolved in 20 mL of methanol, added palladium hydroxide /Carbon (1.20 g, 7.83 mmol), three times of hydrogen, and reacted for 16 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3a R , 4 R , 5 S , 6 S , 6a S )-6-amino-5-fluoro-2,2-dimethyl-4,5,6, 6a-Tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-ol 8e (270 mg, colorless oil), yield: 72.0%.

MS m/z (ESI): 192.35 [M+1]

Step 6 (3a R , 4 R , 5 S , 6 S , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol

(3a R , 4 R , 5 S , 6 S , 6a S )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -ring Penteno[ d ][1,3]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 and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (3a R, 4 R, 5 S, 6 S, 6a S) -6 - [(6- chloro -5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentyl Iso[ d ][1,3]dioxol-4-ol 8f (0.10 g, yellow solid), yield: 56.5%.

MS m/z (ESI): 423.1 [M+1]

Seventh step (3a R , 4 R , 5 S , 6 S , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol

(3a R , 4 R , 5 S , 6 S , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][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 for 1.5 hours. 20 mL of ethyl acetate, filtered, and the filtrate washed with water (10 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product (3a R, 4 R, 5 S, 6 S, 6a S -6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol 8 g (93 mg, mp.

MS m/z (ESI): 393.41 [M+1]

Eighth step (3a R , 4 R , 5 S , 6 S , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol

(3a R , 4 R , 5 S , 6 S , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol 8 g (93 mg, 0.43 mmol) was dissolved in a mixed solvent of 4 mL of acetic acid and water (V/V = 1:1), and sodium nitrite (18 mg, 0.47 mnol) was added at 0 ° C for 10 minutes. Add 15 mL of ethyl acetate, then add 10 mL of saturated sodium carbonate solution to the reaction solution pH=7, separate the liquid, and wash the organic phase with saturated sodium carbonate solution (10 mL) and saturated sodium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product (3a R, 4 R, 5 S, 6 S, 6a S) -6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6a Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol 8h (96 mg, mp.

MS m/z (ESI): 404.1 [M+1]

Step 9 (3a R , 4 R , 5 S , 6 S , 6a S )-6-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -ring Penteno[ d ][1,3]dioxol-4-ol

The crude product (3a R , 4 R , 5 S , 6 S , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5-d]pyrimidin-3-yl)-5 -fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol 8h (96 Mg, 0.24 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (106 mg, 0.33 mmol) dissolved in 5 mL Triethylamine (86 mg, 0.85 mmol) was added dropwise to acetonitrile for 48 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (3a R, 4 R, 5 S, 6 S, 6a S) -6- {7 - [( 1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl}-5 -fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol 8i (0.10 g, white solid), Yield: 78.7%.

MS m/z (ESI): 537.2 [M+1]

Step 10 (1 R , 2 S , 3 S , 4 S , 5 S )-4-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-fluoro-cyclopentyl-1,2,3-triol

(3a R , 4 R , 5 S , 6 S , 6a S )-6-{7-[(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino] -5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-4-ol 8i (0.10 g, 0.19 mmol) was dissolved in 6 mL of a mixed solvent of methanol and water (V/V = 5:1) Dowex 50 cationic resin (0.15 g) was added and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (1 R, 2 S, 3 S, 4 S, 5 S) -4- [7 - [[ (1 R , 2 S )-2-(3,4-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+1]

¹ H 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 (1 S , 2 S , 3 S , 4 S , 5 R )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

first step N-[(3a S ,4 S ,5 S ,6 R ,6a R )-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopentene[ d ][1,3]dioxol-4-yl]carbamic acid benzyl carbamate

(3a R , 4 R , 5 S , 6 S , 6a S )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -ring Penteno[ d ][1,3]dioxol-4-ol 8e (0.19 g, 1 mmol) was dissolved in 10 mL of methanol and 3 mL of water and potassium carbonate (276 mg, 2 mmol). Benzyl chloroformate (0.24 g, 1.40 mmol) was added dropwise at 0 ° C and allowed to react at room temperature for 1 hour. The mixture was separated, and the aqueous layer was evaporated, evaporated, evaporated, evaporated, evaporated To give the title product N-[(3a S , 4 S , 5 S , 6 R , 6a R )-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro -3a H -cyclopenta[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 9a (0.28 g, colorless oil), yield: 86.0%.

MS m/z (ESI): 282.2 [M-43]

Second step 2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-benzyloxycarbonylamino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetra Ethyl-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethyl acetate

N-[(3a S ,4 S ,5 S ,6 R ,6a R )-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-4-yl]carbamic acid benzyl ester 9a (0.28 g, 0.86 mmol) was dissolved in 10 mL of tetrahydrofuran and added dropwise at 0 °C. A solution of potassium terp-butoxide in tetrahydrofuran (0.7 mL, 1.30 mmol) was reacted for 30 minutes. Ethyl 2-bromoacetate (217 mg, 1.30 mmol) was added dropwise and allowed to react for 30 min. The temperature was raised to room temperature and reacted for 16 hours. 10 ml of water was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj (3a S , 4 R , 5 S , 6 S , 6a S )-6-benzyloxycarbonylamino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}acetate 9b (0.36 g, colorless oil). .

third step N-[(3a S ,4 R ,5 S ,6 S ,6a S )-5-fluoro-4-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a - tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl carbamate

2-{[(3a S , 4 R , 5 S , 6 S , 6a S )-6-benzyloxycarbonylamino-5-fluoro-2,2-dimethyl-4,5,6,6a- Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}acetate 9b (354 mg, 0.86 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium borohydride (38 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 aqueous layer was separated with ethyl acetate (10 mL×3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the titled product N-[(3a S , 4 R , 5 S , 6 S , 6a S )-5-fluoro-4-(2-hydroxyethoxy)-2,2 - dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 9c (0.29 g, colorless oil), yield: 91.3%.

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

the fourth step 2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol

N-[(3a S , 4 R , 5 S , 6 S , 6a S )-5-fluoro-4-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6, 6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 9c (0.29 g, 0.79 mmol) dissolved in 10 mL of methanol Palladium on carbon (10%, 0.30 g) was added and the hydrogen was replaced three times for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure to give the crude title product was 2 - [[(3a S, 4 R, 5 S, 6 S, 6a S) -6- fluoro-2,2-dimethyl-amino-5- -4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]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+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.06-5.04 (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-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]- 5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy Ethanol

2-{[(3a S , 4 R , 5 S , 6 S , 6a S )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 9d (185 mg, 0.79 mmol) and 4,6-chloro-5-nitro- 2-propyl mercapto-pyrimidine 6b (315 mg, 1.18 mmol) was dissolved in 10 mL of ethanol, and triethylamine (0.16 g, 1.58 mmol) was added and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product 2 - {[(3a S, 4 R, 5 S, 6 S, 6a S) -6- [ (6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethanol 9e (0.20 g, yellow oil), yield: 54.3%.

MS m/z (ESI): 467.42 [M+1]

Step 6 2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]- 5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy Ethanol

2-{[(3a S , 4 R , 5 S , 6 S , 6a S )-6-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino] -5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl] Ethoxy}ethanol 9e (0.20 g, 0.43 mmol) was dissolved in 6 mL of acetic acid, and iron powder (123 mg, 2.20 mmol) was added and reacted for 2 hours. 20 mL of ethyl acetate, filtered, and the filtrate washed with water (10 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product was 2 - {[(3a S, 4 R, 5 S, 6 S ,6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-5-fluoro-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethanol 9f (188 mg, yellow oil), product The next reaction was carried out without purification.

MS m/z (ESI): 437.1 [M+1]

Seventh step 2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl) -5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl] Oxygen}ethanol

2-{[(3a S , 4 R , 5 S , 6 S , 6a S )-6-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino] -5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl] Ethoxy}ethanol 9f (188 mg, 0.43 mmol) was dissolved in a mixed solvent of 4.5 mL of acetic acid and water (V/V = 2:1). Sodium nitrite (33 mg, 0.47 mmol) was added at 0 ° C for 10 minutes. 20 mL of ethyl acetate was added to the reaction solution, and saturated sodium carbonate solution was added to the reaction solution at pH=7, and the organic phase was washed successively with saturated sodium carbonate solution (10 mL) and saturated sodium chloride solution (10 mL). dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product was 2 - {[(3a S, 4 R, 5 S, 6 S, 6a S) -6- (7- chloro-5-mercapto - tris Zizo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ][ 1,3]dioxol-4-yl]oxy}ethanol 9 g (0.20 g, yellow oil).

MS m/z (ESI): 448.41 [M+1]

Eighth step 2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-[7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl Amino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol

2-{[(3a S ,4 R ,5 S ,6 S ,6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl -5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl ]oxy}ethanol 9g (193 mg, 0.43 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+)-tartrate 1 g (0.19 g , 0.60 mmol) was dissolved in 10 mL of acetonitrile, and triethylamine (0.15 g, 1.50 mmol) was added dropwise for 16 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product 2 - {[(3a S, 4 R, 5 S, 6 S, 6a S) -6- [ 7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidine-3- 5-ylfluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4- Ethyl]oxy}ethanol 9h (0.17 g, colorless oil), yield: 68.0%.

MS m/z (ESI): 581.2 [M+1]

Step 9 (1 S , 2 S , 3 S , 4 S , 5 R )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-4-fluoro-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol

2-{[(3a S , 4 R , 5 S , 6 S , 6a S )-6-[7-[(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropane Amino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl]-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro -3a H -cyclopenteno[ d ][1,3]dioxol-4-yl]oxy}ethanol 9h (0.17 g, 0.29 mmol) dissolved in 11 mL of methanol and water (V/V = To a mixed solvent of 10:1), Dowex 50 cationic resin (0.2 g) was added and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (1 S, 2 S, 3 S, 4 S, 5 R) -3- {7 - [( 1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]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+1]

¹ H 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), 0.91 (t, 3H).

Example 10 (1 S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5{7-[(1 R ,2 R/ 1 S ,2 S )-2-(4-A Thiazole-5-yl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2-diol

(1 R , 2 R/ 1 S , 2 S )-2-(4-Methylthiazol-5-yl)cyclopropanecarboxylic acid ethyl ester

4-Methyl-5-vinyl-thiazole 10a (5 g, 40 mmol) was heated to 135 ° C, and ethyl diazoacetate (2.28 g, 20 mmol). Cooled to room temperature, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (1 R, 2 R / 1 S, 2 S) -2- (4- methylthiazol-5 Ethyl cyclopropanecarboxylate 10b (2.01 g, pale yellow oil), yield: 47.6%.

MS m/z (ESI): 212.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 4.19 - 4.14 (q, J = 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, J = 7.12 Hz, 3H), 1.23-1.17 (m, 1H).

Second step (1 R , 2 R/ 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropanecarboxylic acid

Ethyl (1 R , 2 R / 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropanecarboxylate 10b (2.01 g, 9.50 mmol) was dissolved in 30 mL of methanol. 2.5 mL of 30% sodium hydroxide solution for 12 hours. Concentrated under reduced pressure, 40 mL of ethyl acetate and 30 mL of water were added, and 37% hydrochloric acid was added dropwise to pH = 4. The mixture was separated and dried with EtOAc EtOAc. (1 R , 2 R / 1 S , 2 S ) -2-(4-methylthiazol-5-yl)cyclopropanecarboxylic acid 10c (1.54 g, pale yellow solid).

third step N-[(1 R , 2 R/ 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropanyl]aminobutyl methacrylate

Dissolve (1 R , 2 R / 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropanecarboxylic acid 10c (732 mg, 4 mmol) in 20 mL of tert-butanol, Diphenylphosphoryl azide (1.10 g, 4 mmol) and triethylamine (485.70 mg, 4.80 mmol) were added. The reaction was carried out at 83 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained was purified by column chromatography eluting to afford the title product N-[(1 R , 2 R / 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropane. Tert-butyl carbazate 10d (390 mg, white solid), yield: 38.6%.

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

the fourth step (1 R , 2 R/ 1 S , 2 S )-2-(4-methylthiazol-5-yl)cyclopropylamine hydrochloride

N-[(1 R ,2 R/ 1 S ,2 S )-2-(4-methylthiazol-5-yl)cyclopropanyl]carbamic acid tert-butyl ester 10d (254 mg, 1 mmol) Dissolved in 5 mL of ethyl acetate, and added 3 mL of a 6.8 M solution of hydrogen chloride in ethyl acetate for 3.5 hours. Concentrated under reduced pressure to give the crude title product (1 R, 2 R / 1 S, 2 S) -2- (4- methylthiazol-5-yl) propylamine hydrochloride ring 10e (180 mg, white solid), product The next reaction was carried out without purification.

MS m/z (ESI): 155.1 [M+1]

the fifth step 2-{[(3a S ,4 R ,6 S ,6a R )-2,2-dimethyl-4-[7-[(1 R ,2 R/ 1 S ,2 S )-2-(4 -methylthiazole-5-yl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl]-4,5,6,6a-tetrahydro- 3a H -cyclopenta[ d ][1,3]dioxol-6-yl]oxy}ethanol

2-{[(3a R , 4 S , 6 R , 6a S )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2 ,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 5g ( 254 mg, 1 mmol) was dissolved in 5 mL of acetonitrile and 5 mL (1 R , 2 R / 1 S , 2 S ) -2-(4-methylthiazol-5-yl)cyclopropylamine hydrochloride 10e ( A solution of 100 mg, 0.65 mmol) in acetonitrile was added dropwise triethylamine (51.70 mg, 0.51 mmol) for 12 hours. Concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product 2 - {[(3a S, 4 R, 6 S, 6a R) -2,2- dimethyl - 4-[7-[(1 R ,2 R/ 1 S ,2 S )-2-(4-methylthiazol-5-yl)cyclopropylamino]-5-propylindolyl-triazolo[ 4,5- d ]pyrimidin-3-yl]-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl] Oxygen}ethanol 10f (140 mg, pale yellow solid), yield: 100%.

MS m/z (ESI): 548.56 [M+1]

Step 6 (1 S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5-{7-[(1 R ,2 R/ 1 S ,2 S )-2-(4- Methylthiazole-5-yl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2-diol

2-{[(3a S ,4 R ,6 S ,6a R )-2,2-Dimethyl-4-[7-[(1 R ,2 R/ 1 S ,2 S )-2-( 4-methylthiazole-5-yl)cyclopropylamino]-5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl]-4,5,6,6a-tetrahydro -3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]oxy}ethanol 10f (140 mg, 0.26 mmol) dissolved in 8 mL of methanol, 3 mL 2.5 M hydrochloric acid, reacted for 12 hours. 4 M sodium hydroxide solution was added dropwise to the reaction solution, pH=8, and extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL×2) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, column chromatography on silica gel using the eluent system F The resulting residue was purified to give the title product (1 S, 2 S, 3 S, 5 R) -3- (2- hydroxyethoxy -5-{7-[(1 R ,2 R/ 1 S ,2 S )-2-(4-methylthiazol-5-yl)cyclopropylamino]-5-propyldecyl-triazole And [4,5- d ]pyrimidin-3-yl}cyclopentyl-1,2-diol 10 (100 mg, white solid), yield: 76.9%.

MS m/z (ESI): 508.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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, J = 7.36 Hz, 3H).

Example 11 (1 S , 2 S , 3 R , 5 S )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propyl Thiol-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2,3-dihydroxypropoxy)cyclopentyl-1,2-diol

first step N-[(3a R ,4 S ,6 R ,6a S )-4-allyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene [ d ][1,3]dioxol-6-yl]carbamic acid benzyl carbamate

N-[(3a R , 4 S , 6 R , 6a S )-6-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d] [[,3]Dioxol-4-yl]carbamic acid benzyl ester 5b (1 g, 3.20 mmol) was dissolved in 20 mL of tetrahydrofuran, and potassium tert-butoxide (0.73 g, 6.50 mmol) was added. After stirring for 20 minutes, 3-bromopropene (1.1 mL, 13 mmol) was added dropwise, and the mixture was reacted for 16 hours. After adding 10 mL of water, the mixture was extracted with ethyl acetate (30 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system E The title product N-[(3a R , 4 S , 6 R , 6a S )-4-allyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H - Cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 11a (0.40 g, colorless oil), yield: 35.0%.

Second step N-[(3a R , 4 S , 6 R , 6a S )-4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl carbamate

N-[(3a R ,4 S ,6 R ,6a S )-4-allyloxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene And [ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 11a (0.40 g, 1.15 mmol) was dissolved in 10 mL of tetrahydrofuran, and N-methylmorpholine-N- was added. Oxide (0.54 g, 2.30 mmol) and osmium tetroxide (59 mg, 0.23 mmol) were reacted for 5 hours. Add 10 mL of saturated sodium thiosulfate solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product N - [(3a R, 4 S , 6 R , 6a S )-4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ] [1,3]dioxol-6-yl]carbamic acid benzyl ester 11b (0.45 g, pale yellow oil), yield: 99.0%.

third step N-{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl}carbamic acid benzyl carbamate

N-[(3a R , 4 S , 6 R , 6a S )-4-(2,3-dihydroxypropoxy)-2,2-dimethyl-4,5,6,6a-tetrahydrogen -3a H -cyclopenteno[ d ][1,3]dioxol-6-yl]carbamic acid benzyl ester 11b (0.45 g, 1.20 mmol) dissolved in 10 mL 2,2-dimethyl To the oxypropane, p-toluenesulfonic acid monohydrate (13 mg, 0.068 mmol) was added and reacted for 30 minutes. Add 10 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (30 mL×3), and then the organic phase is combined, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified to give the title product N - [(3a R, 4 S, 6 R, 6a S) -4 - [(2,2- dimethyl-1,3-dioxolan-4 Methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-6- Benzyl carbazide 11c (0.41 g, light yellow oil), yield: 82.0%.

MS m/z (ESI): 422.2 [M+1]

the fourth step (3a R , 4 S , 6 R , 6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2- Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-amine

N-{(3a R , 4 S , 6 R , 6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-6-yl}carbamic acid benzyl carbamate 11c (0.41 g, 1 mmol) was dissolved in 10 mL of ethanol, palladium/carbon (10%, 0.10 g) was added, and the mixture was replaced with hydrogen three times for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3a R , 4 S , 6 R , 6a S ) -4-[(2,2-dimethyl-1,3-dioxolan-4-yl) )methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-amine 11d (0.22 g, light yellow oil). Yield: 81.0%.

the fifth step N-{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-6-chloro-5 -nitro-2-propylindolyl-pyrimidine-4-amine

(3a R , 4 S , 6 R , 6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2 -Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-amine 11d (0.11 g, 0.38 mmol) dissolved 4,6-chloro-5-nitro-2-propylindenyl-pyrimidine 6b (0.11 g, 0.42 mmol) was added to 8 mL of tetrahydrofuran, and triethylamine (0.2 mL, 1.15 mmol) was added dropwise for 1 hour. . The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product N - {(3a R, 4 S, 6 R, 6a S) -4 - [(2,2 -Dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopentene And [ d ][1,3]dioxol-6-yl}-6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-amine 11e (134 mg, yellow oil ), yield: 38.0%.

MS m/z (ESI): 519.1 [M+1]

Step 6 N ⁴ -{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-6-chloro- 2-propyl mercapto-pyrimidine-4,5-diamine

N-{(3a R , 4 S , 6 R , 6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-6-chloro- 5-Nitro-2-propylindolyl-pyrimidin-4-amine 11e (134 mg, 0.26 mmol) was dissolved in 5 mL of acetic acid, and iron powder (116 mg, 2.10 mmol) was added and reacted for 2.5 hours. After adding 10 mL of water, the mixture was extracted with ethyl acetate (30 mL×3). ⁴ -{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-6-chloro-2 -propylmercapto-pyrimidine-4,5-diamine 11f (134 mg, brown oil).

MS m/z (ESI): 490.52 [M+1]

Seventh step 3-{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-7-chloro-5 -propyl decyl-triazolo[4,5- d ]pyrimidine

N ⁴ -{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy] -2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-6-chloro 2-propylmercapto-pyrimidine-4,5-diamine 11f (0.25 g, 0.50 mmol) was dissolved in 2 mL of acetic acid. An aqueous solution of 0.4 mL of sodium nitrite (36 mg, 0.53 mnol) was added at 0 ° C for 10 minutes. 15 mL of ethyl acetate and 10 mL of saturated potassium carbonate solution were added, and the aqueous layer was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phase was combined and washed with saturated sodium chloride (10 mL) Drying, filtration and concentrating the filtrate under reduced pressure afforded the crude title product 3-{(3a R , 4S ,6 R ,6a S )-4-[(2,2-dimethyl-1,3-dioxacyclohexane) Pentane-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxole Pentene-6-yl}-7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidine 11 g (0.25 g, brown oil).

MS m/z (ESI): 500.1 [M+1]

Eighth step T -butyl N-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]carbamic acid

Dissolve (1 R , 2 R )-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid 1d (12 g, 60.55 mmol) in 600 mL of tert-butanol, and sequentially add azide diphenyl phosphate Ester (16.70 g, 60.55 mmol) and triethylamine (6.20 g, 60.55 mmol). The reaction was carried out at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product N - [(1 R, 2 S) -2- (3,4- difluorophenyl) cycloalkyl Propyl] butyl methacrylate, 13 h (1.90 g, white solid), yield: 11.7%.

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

Step 9 (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride

Dissolving tert- butyl N-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]carbamate 11h (1.90 g, 7.05 mmol) in 38 mL ethyl acetate Into the solution, 38 mL of a 5 M solution of hydrogen chloride in ethyl acetate was added dropwise, and the mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure to give the crude title product (1 R, 2 S) -2- (3,4- difluorophenyl) cyclopropanamine hydrochloride 11i (1.40 g, yellow solid) was used without purification for The next step is to react.

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

Step 10 3-{(3a R , 4 S , 6 R , 6a)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2, 2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl}-N-[(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropyl]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-7-amine

3-{(3a R ,4 S ,6 R ,6a S )-4-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]- 2,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl}-7-chloro- 5-propyldecyl-triazolo[4,5- d ]pyrimidine 11g (126 mg, 0.25 mmol) and (1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamine Hydrochloride 11i (67 mg, 0.33 mmol) was dissolved in 5 mL of acetonitrile and triethylamine (0.2 mL, 0.88 mmol) The reaction solution was concentrated under reduced pressure, 10 m water was added, 2.5 M hydrochloric acid was added dropwise to pH < 4, and the aqueous phase was extracted with ethyl acetate (15 mL×3), and the organic phase was combined with saturated sodium chloride solution (10 mL) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by eluent column chromatography with eluent system E to give the title product 3-{(3a R , 4 S , 6 R , 6a) -6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2,2-dimethyl-4,5,6,6a-tetra Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl}-N-[(1 R ,2 S )-2-(3,4-difluorobenzene Cyclopropyl]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-7-amine 11j (75 mg, yellow oil), yield: 47.0%.

MS m/z (ESI): 633.63 [M+1]

The eleventh step (1 S , 2 S , 3 R , 5 S )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]-5-propyl Thiol-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2,3-dihydroxypropoxy)cyclopentyl-1,2-diol

3-{(3a R , 4 S , 6 R , 6a)-6-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2 ,2-Dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-4-yl}-N-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-7-amine 11j (0.15 g, 0.24 Methyl) was dissolved in 8 mL of methanol, and 2 mL of 2.5 M hydrochloric acid was added dropwise for 16 hours. The reaction solution was concentrated under reduced pressure and then 10 mL water was added. After adding a saturated sodium carbonate solution to the reaction mixture, pH=7, and ethyl acetate (30 mL×3), and the organic phase was washed with saturated sodium chloride (10 mL) by column chromatography on silica gel eluting agent system E resulting residue, to give the title product (1 S, 2 S, 3 R, 5 S) -3- {7 - [(1 R, 2 S) -2- (3,4-difluorophenyl)cyclopropylamino]-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2,3-dihydroxypropane Oxy)cyclopentyl-1,2-diol 11 (134 mg, yellow solid), yield: 99.0%.

MS m/z (ESI): 553.55 [M+1]

¹ H NMR (400 MHz, CDCl 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 (1 S , 2 S , 3 S , 4 R , 5 S )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol

first step 2-{[(3a R ,4 S ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole Ethyl-4-yl]oxy}ethyl acetate

(3a S ,4 R ,6a R )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole-4 - Alcohol 1 n (1.22 g, 7.82 mmol) was dissolved in 50 mL of tetrahydrofuran. A 20% potassium butoxide potassium tetrahydrofuran solution (7.2 mL, 11.73 mmol) was added dropwise at 0 ° C for 30 minutes. Ethyl bromoacetate (1.3 mL, 11.73 mmol) was added dropwise, and the mixture was reacted for 30 min. 10 mL of water, separated, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product was 2 - {[(3a R , 4 S , 6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy Ethyl acetate 12a (1.90 g, brown oil).

Second step 2-{[(3a R ,4 S ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole Alk-4-yl]oxy}ethanol

2-{[(3a R ,4 S ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole Ethylpenta-4-yl]oxy}acetate 12a (1.90 g, 7.82 mmol) was dissolved in 40 mL of THF, and lithium borohydride (341 mg, 15.64 mmol) was added and reacted for 2 hours. 10 mL of water, separated, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product was 2 - {[(3a R , 4 S , 6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy Ethanol 12b (1.56 g, yellow oil), product was taken to the next step without purification.

third step (3a R , 4 S , 6a S )-4-(2-Benzyloxyethoxy)-2,2-dihydro-4,6a-dihydro-3a H -cyclopentene[ d ][1 ,3]dioxole

2-{[(3a R ,4 S ,6a S )-2,2-dimethyl-4,6a-dihydro-3a H -cyclopenteno[ d ][1,3]dioxole Penten-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. ), react at room temperature for 30 minutes. Benzyl bromide (1.4 mL, 11.73 mmol) was added at 0 ° C and allowed to react at room temperature for 16 h. After adding 10 mL of methanol, and concentrating under reduced pressure, 50 mL of ethyl acetate and 15 mL of water were added and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phase was combined and washed with water (20 mL×2). dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (3a R, 4 S, 6a S) -4- (2- benzyloxy Ethyloxy)-2,2-dihydro-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxole 12c (1.60 g, colorless oil ), yield: 70.0%.

¹ H NMR (400 MHz, CDCl 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 S , 2 S , 5 S )-5-(2-Benzyloxyethoxy)cyclopent-3-ene-1,2-diol

(3a R , 4 S , 6a S )-4-(2-Benzyloxyethoxy)-2,2-dihydro-4,6a-dihydro-3a H -cyclopentene[ d ][ 1,3]dioxole 12c (1.60 g, 5.50 mmol) was dissolved in 22 mL of a mixed solvent of methanol and water (V/V = 1:1), and Dowex 50 cationic resin (3.50 g) was added. 72 hours. Concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (1 S, 2 S, 5 S) -5- (2- benzyloxy-ethoxy) cyclopentyl - 3-ene-1,2-diol 12d (1.37 g, colorless oil), yield: 100%.

the fifth step (1 R , 2 R , 3 S , 4 R , 5 R )-4-(2-Benzyloxyethoxy)-6-oxabicyclo[3.1.0]hexane-2,3-diol

(1 S , 2 S , 5 S )-5-(2-Benzyloxyethoxy)cyclopent-3-ene-1,2-diol 12d (1.35 g, 5.40 mmol) was dissolved in 40 mL two To the methyl chloride, 70% m-chloroperoxybenzoic acid (2.40 g, 9.72 mmol) was added and the reaction was carried out for 24 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (1 R, 2 R, 3 S, 4 R, 5 R) -4- (2- benzyloxy Ethyl ethoxy)-6-oxabicyclo[3.1.0]hexane-2,3-diol 12e (630 mg, yellow oil), yield: 44%.

¹ H NMR (400 MHz, CDCl 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 S , 2 S , 3 S , 4 R , 5 S )-3-azido-5-(2-benzyloxyethoxy)cyclopentane-1,2,4-triol

(1 R , 2 R , 3 S , 4 R , 5 R )-4-(2-Benzyloxyethoxy)-6-oxabicyclo[3.1.0]hexane-2,3-di Alcohol 12e (630 mg, 2.36 mmol) was dissolved in 12 mL of a mixture of N,N-dimethylformamide and water (V/V = 5:1) and sodium azide (230 mg, 3.54 mmol) ). The reaction was carried out at 80 ° C for 16 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) pressure and concentrated to give the crude title product (1 S, 2 S, 3 S, 4 R, 5 S) -3- azido-5- (2-benzyloxy-ethoxy) cyclopentane-1,2, 4-triol 12f (730 mg, yellow oil).

Seventh step (3a S , 4 R , 5 R , 6 S , 6a S )-4-azido-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6, 6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol

(1 S , 2 S , 3 S , 4 R , 5 S )-3-azido-5-(2-benzyloxyethoxy)cyclopentane-1,2,4-triol 12f ( 730 mg, 2.36 mmol) was dissolved in 10 mL of acetone, and then 2,2-dimethoxypropane (0.6 mL, 4.72 mmol) and p-toluenesulfonic acid monohydrate (180 mg, 0.94 mmol) were added and reacted for 3 hours. Concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (3a S, 4 R, 5 R, 6 S, 6a S) -4- azido-6- ( 2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole -5-Alcohol 12 g (470 mg, colorless oil), yield: 57.0%.

¹ H NMR (400 MHz, CDCl 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. (m, 2H), 3.77-3.60 (m, 5H), 1.51 (s, 3H), 1.28 (s, 3H).

Eighth step (3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a -tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-azido-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6 , 6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol 12g (460 mg, 1.32 mmol) was dissolved in 15 mL of tetrahydrofuran, and triphenylphosphine was added. (450 mg, 1.71 mmol), 3 mL of water was added dropwise and the reaction was carried out for 16 hours. Concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a S, 4 R, 5 R, 6 S, 6a S) -4- amino-6- (2 -benzyloxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole- 5-Alcohol 12h (427 mg, yellow oil), yield: 100%.

MS m/z (ESI): 324.50 [M+1]

Step 9 (3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetra Hydrogen-3a H -cyclopenteno[ d ][1,3]dioxol-5-ol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-(2-benzyloxyethoxy)-2,2-dimethyl-4,5,6, 6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol 12h (427 mg, 1.32 mmol) was dissolved in 20 mL of methanol and palladium hydroxide was added. Carbon (0.80 g, 5.69 mmol) was replaced with hydrogen three times for 16 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-(2-hydroxyethoxy)-2,2-dimethyl -4,5,6,6a-tetrahydro-3a H -cyclopenteno[ d ][1,3]dioxol-5-ol 12i (250 mg, colorless oil), yield : 81.2%.

MS m/z (ESI): 234.44 [M+1]

Step 10 (3a S , 4 R , 5 R , 6 S , 6a S )-4-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2 -hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5- alcohol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-amino-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a- Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol 12i (250 mg, 1.07 mmol) and 4,6-chloro-5-nitro-2- Propylmercapto-pyrimidine 6b (430 mg, 1.60 mmol) was dissolved in 20 mL of ethanol, and triethylamine (0.3 mL, 2.14 mmol) was added and reacted for 16 hours. Concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a S, 4 R, 5 R, 6 S, 6a S) -4 - [(6- chloro-5 -nitro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -cyclopenteno[ d ][1,3]dioxol-5-ol 12j (320 mg, yellow oil), yield: 64.3%.

MS m/z (ESI): 465.1 [M+1]

The eleventh step (3a S , 4 R , 5 R , 6 S , 6a S )-4-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6-(2 -hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5- alcohol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-[(6-chloro-5-nitro-2-propylindolyl-pyrimidin-4-yl)amino]-6-( 2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5 - Alcohol 12j (320 mg, 0.69 mmol) was dissolved in 10 mL of acetic acid, and iron powder (200 mg, 3.50 mmol) was added and reacted for 4 hours. 20 mL of ethyl acetate was added, and the filtrate was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give the title. Product (3a S , 4 R , 5 R , 6 S , 6a S )-4-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6-( 2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5 - alcohol 12k (200 mg, yellow oil), yield: 66.6%.

MS m/z (ESI): 435.45 [M+1]

Step 12 (3a S , 4 R , 5 R , 6 S , 6a S )-4-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-6-( 2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5 -alcohol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-[(5-Amino-6-chloro-2-propylindolyl-pyrimidin-4-yl)amino]-6-( 2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5 - Alcohol 12k (200 mg, 0.46 mmol) was dissolved in 3 mL of acetic acid and 1.5 mL of water, and sodium nitrite (35 mg, 0.51 mnol) was added at 0 ° C for 10 minutes. Add 20 mL of ethyl acetate, then add 10 mL of saturated sodium carbonate solution to the reaction solution pH=7, separate the liquid, and wash the organic phase with saturated sodium carbonate solution (10 mL), ethyl acetate (10 mL×2) The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product (3a S, 4 R, 5 R, 6 S, 6a S) -4- (7- chloro-5-propoxy Gentyl-triazolo[4,5- d ]pyrimidin-3-yl)-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro- 3a H -Cyclopentene[ d ][1,3]dioxol-5-ol 12m (205 mg, yellow solid).

MS m/z (ESI): 446.43 [M+1]

Step 13 (3a S , 4 R , 5 R , 6 S , 6a S )-4-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a- Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-6- (2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole- 5-Alcohol 12m (205 mg, 0.46 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i (132 mg, 0.64 mmol) dissolved in 10 mL of acetonitrile Triethylamine (0.2 mL, 1.60 mmol) was added dropwise and the mixture was reacted for 16 hours. Concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product (3a S, 4 R, 5 R, 6 S, 6a S) -4- {7 - [(1 R , 2 S )-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-3a H -cyclopenta[ d ][1,3]dioxol-5 - alcohol 12n (230 mg, yellow oil), yield: 86.5%.

MS m/z (ESI): 577.2 [M-1]

Fourteenth step (1 S , 2 S , 3 S , 4 R , 5 S )-3-{7-[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino]- 5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentyl-1,2,4-triol

(3a S , 4 R , 5 R , 6 S , 6a S )-4-{7-[(1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino] -5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a -Tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol 12n (230 mg, 0.40 mmol) was dissolved in 10 mL of methanol and 1 mL of water, and Dowex 50 was added. A cationic resin (500 mg) was reacted for 16 hours. The filtrate was concentrated under reduced pressure and purified by preparative HPLC resulting residue was chromatographed to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -3- {7 - [(1 R, 2 S) -2-(3,4-difluorophenyl)cyclopropylamino]-5-propyldecyl-triazolo[4,5- d ]pyrimidin-3-yl}-5-(2-hydroxyethyl Oxy)cyclopentyl-1,2,4-triol 12 (130 mg, white solid), yield: 60.0%.

MS m/z (ESI): 539.1 [M+1]

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

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. A solution of 10 mL 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. Add 100 mL of water, extract with ethyl acetate (50 mL×4), and the organic phase is combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, method E to the resulting residue was purified eluent system, to give the title product (E) -3- (3- pyridyl) prop-2-enoic acid ethyl ester 13b (6.90 g, colorless oil). yield: 80.0 %.

MS m/z (ESI): 178.1 [M+1]

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

Ethyl ( E )-3-(3-pyridyl)prop-2-enoate 13b (6.90 g, 38.90 mmol) was dissolved in 50 mL of methanol and then 10 mL sodium hydroxide (3.40 g, 85 mmol) , the reaction was 1.5 hours. The organic layer was extracted with ethyl acetate (200 mL×4). The title compound ( E )-3-(3-pyridyl)prop-2-enoic acid 13c (5.80 g, white solid).

MS m/z (ESI): 150.1 [M+1]

third step [(1R,2 S ,5 R )-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 (6.6 g, N,N'-Dicyclohexylcarbodiimide (12.03 g, 58.30 mmol) and 4-dimethylaminopyridine (5.22 g, 42.80 mmol) were reacted for 12 hours. By column chromatography on silica gel eluting agent system E resulting residue, to give the title product [(1R, 2 S, 5 R) -2- isopropyl-5-methyl - cyclohexyl] (E) -3 -(3-Pyridyl)prop-2-enoate 13d (5 g, colorless oil), yield: 50.0%.

MS m/z (ESI): 288.2 [M+1]

the fourth step [(1 R , 2 S , 5 R )-2-isopropyl-5-methyl-cyclohexyl](1 R ,2 R/ 1 S ,2 S )-2-(3-pyridyl)cyclopropane Formate

Dissolve trimethyl iodide (9.57 g, 43.5 mmol) and potassium t-butoxide (4.88 g, 43.50 mmol) in 40 mL of dimethyl hydrazine and add 20 mL [(2 S , 5 R ) 2-Isopropyl-5-methyl-cyclohexyl]( E )-3-(3-pyridyl)prop-2-enoate 13d (5 g, 17.40 mmol) in dimethyl sulfonium. 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), and combine the organic phase. , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product [(1 R, 2 S, 5 R) -2- isopropyl -5-Methyl-cyclohexyl](1 R , 2 R/ 1 S , 2 S )-2-(3-pyridyl)cyclopropanecarboxylate 13e (3.58 g, colorless oil). 68.0%.

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

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

[(1 R , 2 S, 5 R )-2-isopropyl-5-methyl-cyclohexyl](1 R , 2 R/ 1 S , 2 S )-2-(3-pyridyl) ring Propane formate 13e (3.58 g, 11.90 mmol) was dissolved in 100 mL of methanol, and a solution of 10 mL of sodium hydroxide (3.80 g, 95 mmol) was added and reacted for 20 minutes. The reaction was carried out at 40 ° C for 1.5 hours. The organic layer was extracted with ethyl acetate (150 mL×7), and the organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the title product (1 R, 2 R / 1 S, 2 S) -2- (3- pyridyl) cyclopropanecarboxylic acid 13f (1.80 g, pale yellow oil). yield: 92.0%.

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

Step 6 N-[(1 R , 2 S/ 1 S , 2 R )-2-(3-pyridyl)cyclopropyl]carbamic acid tert-butyl ester

(1 R , 2 R / 1 S , 2 S )-2-(3-pyridyl)cyclopropanecarboxylic acid 13f (407 mg, 2.50 mmol) was dissolved in 15 mL of tert-butanol, followed by azidophosphoric acid Phenyl ester (0.8 mL, 3.75 mmol), triethylamine (0.5 mL, 3.75 mmol). The reaction was carried out at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue to give the title product N - [(1 R, 2 S / 1 S, 2 R) -2- (3- pyridyl Tributyl butyl propyl] carbamic acid 13 g (335 mg, pale yellow oil), yield: 57.0%.

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

Seventh step (1 R , 2 S/ 1 S , 2 R )-2-(3-pyridyl)cyclopropylamine

13 g (300 mg, 1.28 mmol) of N-[(1 R , 2 S/ 1 S , 2 R )-2-(3-pyridyl)cyclopropyl]carbamic acid tert- butyl ester was dissolved in 2 mL of acetic acid To the ethyl ester, 6 mL of a 5 M aqueous solution of hydrogen chloride was added dropwise, and the mixture was reacted for 2 hours. Add saturated sodium carbonate solution to the reaction solution pH=9, add 50 mL of ethyl acetate, and separate the liquid. The aqueous phase is extracted with ethyl acetate (50 mL×4), the organic phase is combined, dried over anhydrous sodium sulfate, filtered, filtrate reduced concentrated under pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (1 R, 2 S / 1 S, 2 R) -2- (3- pyridyl) cyclopropanamine 13h (60 mg, Colorless oil), Yield: 35%.

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

Eighth step 2-{[(3a R ,4 S ,6 R ,6a S )-2,2-dimethyl-6-[5-propylindol-7-[[(1 R , 2 S )-2-( 3-pyridyl)cyclopropyl]amino]triazolo[4,5- d ]pyrimidin-3-yl}-4,5,6,6a-tetrahydro-3a H -cyclopentene[ d ] [1,3]dioxol-4-yl]oxy]ethanol

2-{[(3a S ,4 R ,6 S ,6a R )-6-(7-chloro-5-propylindolyl-triazolo[4,5- d ]pyrimidin-3-yl)-2 ,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy}ethanol 5g ( 80 mg, 0.19 mmol) dissolved in 4 mL of tetrahydrofuran, followed by the addition of triethylamine (0.3 mL, 0.67 mmol) and 2 mL (1 R , 2 S / 1 S , 2 R )-2-(3-pyridyl) A solution of cyprolide 13h (30 mg, 0.22 mmol) in tetrahydrofuran was reacted for 12 hours. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 2 - {[(3a R, 4 S, 6 R, 6a S) -2,2- dimethyl-6- [5-propyldecyl-7-[[(1 R , 2 S/ 1 S , 2 R )-2-(3-pyridyl)cyclopropyl]amino]triazolo[4,5- d ] Pyrimidin-3-yl}-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl]oxy]ethanol 13i ( 45 mg, colorless oil), yield: 45.8%.

MS m/z (ESI): 528.54 [M+1]

Step 9 (1 S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5-{5-propylindolyl-7-[[(1 R ,2 S/ 1 S ,2 R )-2-(3-pyridyl)cyclopropyl]amino]triazolo[4,5- d ]pyrimidin-3-yl}cyclopentane-1,2-diol

2-{[(3a R ,4 S ,6 R ,6a S )-2,2-dimethyl-6-[5-propylindolyl-7-[(1 R , 2 S/ 1 S , 2 R )-2-(3-pyridyl)cyclopropylamino]triazolo[4,5- d ]pyrimidin-3-yl]-4,5,6,6a-tetrahydro-3a H -cyclopentyl Iso[ d ][1,3]dioxol-4-yl]oxy}ethanol 13i (45 mg, 0.085 mmol) was dissolved in 4 mL of methanol, and 1 mL of 2 M hydrochloric acid was added for 4 hours. . The saturated sodium carbonate solution was added dropwise to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. S , 2 S , 3 S , 5 R )-3-(2-hydroxyethoxy)-5-{5-propylindolyl-7-[(1 R ,2 S/ 1 S ,2 R )-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+1]

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

first step 4-nitrobenzoic acid ((3a S , 4 S , 5 S , 6 S , 6a S )-4-azido-6-(benzyloxy)-2,2-dimethyl-4,5, 6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-5-yl)ester

(3 aS , 4 R , 5 R , 6 S , 6 aS )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-5-ol 7e (1.20 g, 4 mmol), p-nitrobenzoic acid (1.34 g, 8 mmol) and triphenylphosphine (2.15 g, 8 mmol) was dissolved in 60 mL of tetrahydrofuran, diisopropyl azodicarboxylate (1.6 mL, 8 mmol) was added, and the reaction was stirred at 55 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product 4-nitrobenzoic acid ((3 aS, 4 S, 5 S, 6 S, 6aS) -4 -azido-6-(benzyloxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxa Cyclopentene-5-yl)ester 14a (1.32 g, yellow oil), yield: 73.0%.

Second step (3 aS , 4 R , 5 S , 6 S , 6 aS )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-5-ol

4-Nitrobenzoic acid ((3 aS , 4 S , 5 S , 6 S , 6aS )-4-azido-6-(benzyloxy)-2,2-dimethyl-4,5, 6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-5-yl)ester 14a (1.32 g, 3 mmol) was dissolved in 24 mL of methanol and water ( Potassium hydroxide (337 mg, 6 mmol) was added to the mixed solution of V/V = 5:1), and the reaction was stirred for 1 hour. The organic layer was combined with EtOAc (EtOAc)EtOAc. Title product (3 aS , 4 R , 5 S , 6 S , 6 aS )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6 a -tetrahydro -3a H -cyclopenta[ d ][1,3]dioxol-5-ol 14b (870 mg, pale yellow oil), yield: 95.0%.

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

third step (3 aS , 4 S , 5 R , 6 R , 6 aS )-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6 A -tetrahydro-3 aH -cyclopenta[d][1,3]dioxole

(3 aS , 4 R , 5 S , 6 S , 6 aS )-4-azido-6-benzyloxy-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-5-ol 14b (750 mg, 2.50 mmol) was dissolved in 40 mL of dichloromethane, and diethylamine trifluoride was added dropwise. Sulfur (0.5 mL, 3.70 mmol) was stirred for 3 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. aS ,4 S ,5 R ,6 R ,6 aS )-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6 a - Tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxole 14c (380 mg, colorless oil), yield: 50%.

the fourth step (3 aS , 4 S , 5 R , 6 R , 6 aS )-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine

(3 aS , 4 S , 5 R , 6 R , 6 aS )-4-azido-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6, 6 a -Tetrahydro -3 aH -cyclopenta[ d ][1,3]dioxole 14c (480 mg, 1.56 mmol) was dissolved in 30 mL of methanol and 5% Pd/CaCO ₃ ( 900 mg), the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the title product (3 aS, 4 S, 5 R, 6 R, 6 aS) -6- ( benzyloxy) -5-fluoro-2,2-dimethyl-4,5 ,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine 14d (430 mg, colorless oil), product The next step is to react.

MS m/z (ESI): 282.2 [M+1]

the fifth step (3 aR , 4 R , 5 R , 6 S , 6 aS )-6-amino-5-fluoro-2,2-dimethyl-4,5,6,6a-tetrahydro-3 aH -cyclopentyl And [ d ][1,3]dioxol-4-ol

(3 aS , 4 S , 5 R , 6 R , 6 aS )-6-(benzyloxy)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-4-amine 14d (430 mg, 1.56 mmol) was dissolved in 15 mL of methanol and 20% Pd/C (900 mg) was added. The hydrogen was replaced three times, and the reaction was stirred for 12 hours. The filtrate was concentrated under reduced pressure to give the title product (3 aR, 4 R, 5 R, 6 S, 6 aS) -6- amino-5-fluoro-2,2-dimethyl -4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 14e (300 mg, colorless oil). .

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

Step 6 (3 aS , 4 S , 5 R , 6 R , 6 aR )-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopentyl And [ d ][1,3]benzyl dioxol-4-ylcarbamate

(3 aR , 4 R , 5 R , 6 S , 6 aS )-6-amino-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH - Cyclopenta[ d ][1,3]dioxol-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). Potassium carbonate (290 mg, 2.10 mmol) was added, benzyl chloroformate (215 mg, 1.26 mmol) was added dropwise, and the reaction was stirred for 12 hours. Ethyl acetate (10 mL) and water (10 mL) were added toEtOAc. The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product (3 aS , 4 S , 5 R , 6 R , 6 aR )-5-fluoro-6-hydroxy-2,2- Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamic acid benzyl ester 14f (260 mg, White solid), Yield: 76.2%.

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

Seventh step 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(benzyloxyindenyl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxyacetate

(3 aS , 4 S , 5 R , 6 R , 6 aR )-5-fluoro-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH - ring Benzyl [ d ][1,3]dioxol-4- ylaminocarbamate 14f (260 mg, 0.80 mmol) was dissolved in 10 mL of tetrahydrofuran, and 20% tributyl was added dropwise at 0 °C. The potassium alkoxide solution (0.7 mL, 1.20 mmol) was stirred at 0 ° C for 30 min, and ethyl bromoacetate (0.1 mL, 1.20 mmol) was added dropwise. A saturated ammonium chloride solution (10 mL) was added to the mixture, and the mixture was evaporated. Product 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(benzyloxyindenyl)-5-fluoro-2,2-dimethyl-4,5,6,6 A -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxyacetate ethyl ester 14 g (328 mg, colorless oil) Carry out the next reaction.

Eighth step (3 aS , 4 S , 5 R , 6 R , 6 aS )-5-fluoro-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6 a -four Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylaminocarbamate

2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(benzyloxyindenyl)-5-fluoro-2,2-dimethyl-4,5,6,6 A -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxyacetate ethyl acetate 14g (328 mg, 0.80 mmol) was dissolved in 10 mL of tetrahydrofuran and added Lithium borohydride (35 mg, 1.60 mmol) was stirred for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product (3 aS, 4 S, 5 R, 6 R, 6 aS) -5- fluoro-6- (2-hydroxyethoxy) -2,2-dimethyl-4, 5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamate benzyl ester 14h (170 mg, colorless oil) Yield: 57.6%.

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

Step 9 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)ethanol

(3 aS , 4 S , 5 R , 6 R , 6 aS )-5-fluoro-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6 a - Benzyl tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamate 14h (170 mg, 0.46 mmol) dissolved in 8 mL of methanol, 10% Pd/C (170 mg) 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 2-((3 aS , 4 R , 5 R , 6 S , 6 aS )-6-amino-5-fluoro-2,2-dimethyl-4,5 ,6,6 a -tetrahydro-3 aH -cyclopenta[d][1,3]dioxol-4-yloxy)ethanol 14i (108 mg, colorless oil), product Purification proceeds directly to the next reaction.

MS m/z (ESI): 236.1 [M+1]

Step 10 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro -2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)ethanol

2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-Amino-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)ethanol 14i (108 mg, 0.46 mmol), 4,6-dichloro-2-propylindenyl-pyrimidine -5-Amine 1s (220 mg, 0.92 mmol) and N , N -diisopropylethylamine (0.24 mL, 1.38 mmol) were dissolved in 5 mL of N , N -dimethylformamide and stirred at 100 °C Reaction for 12 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to A resulting residue was purified by developing solvent system, to give the title product 2 - ((3 aS, 4 R, 5 R, 6 S, 6 aS) -6- (5- Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -ring Pentero[ d ][1,3]dioxol-4-yloxy)ethanol 14j (65 mg, brown oil), yield: 36.0%.

MS m/z (ESI): 437.3 [M+1]

The eleventh step 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4 ,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3] Dioxol-4-oxy)ethanol

2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5- Fluorin-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)ethanol 14j (65 mg, 0.15 mmol) was dissolved in 3 mL of a mixed solution 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 saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 7 and the organic phase was washed with saturated sodium carbonate solution (15 mL). acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2 - ((3 aS, 4 R, 5 R, 6 S, 6 aS) -6- (7-Chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl 4-,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)ethanol 14k (67 mg, reddish brown oily The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 448.2 [M+1]

Step 12 2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino) -5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4, 5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)ethanol

2-((3 aS , 4 R , 5 R , 6 S , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[ 4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3 Dioxol-4-oxy)ethanol 14k (67 mg, 0.15 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i ( 40.10 mg, 0.20 mmol) was dissolved in 5 mL of acetonitrile, triethylamine (53.13 mg, 0.53 mmol) was added and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product 2 - ((3 aS, 4 R, 5 R, 6 S, 6 aS) -6- (7- ((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4, 5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3] Cyclohexene -4-oxy)ethanol 14 l (43 mg, pale yellow oil), yield: 50%.

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

Step 13 (1 S , 2 S , 3 S , 4 R , 5 R )-3-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-4-fluoro-5-(2-hydroxyethoxy)cyclopentane -1,2-diol

2-((3 aS ,4 R ,5 R ,6 S ,6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino) -5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4 ,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)ethanol 14 l (43 mg, 0.07 mmol) dissolved in 5.5 mL In a mixed solution of methanol and water (V/V = 10:1), dowex 50 ion exchange resin (50 mg) was added, and the reaction was stirred for 60 hours. The filtrate was concentrated under reduced pressure to give the title product (1 S, 2 S, 3 S, 4 R, 5 R) -3- (7 - ((1 R, 2 S) -2- (3,4- difluoro Phenyl)cyclopropylamino)-5-(propylthio)-3 H -[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]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.23-7.09 (m, 3H), 5.50-5.47 (m, 0.5H), 5.36-5.31 (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 (1 R , 2 S , 3 S , 4 S , 5 R )-4-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluorocyclopentane-1,2,3-triol

first step (3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2, 2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 R , 5 R , 6 S , 6 aS )-6-amino-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH - Cyclopenta[ d ][1,3]dioxol-4-ol 14e (100 mg, 0.52 mmol) was dissolved in 3 mL of N , N -dimethylformamide, followed by 4,6 -Dichloro-2-propylthio-pyrimidin-5-amine 1s (250 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.57 mmol). The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 aR, 4 R, 5 R, 6 S, 6 aS) -6- (5- amino - 6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 15a (100 mg, brownish red oil), yield: 50%.

MS m/z (ESI): 393.1 [M+1]

Second step (3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ] pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxa Cyclopenten-4-ol

(3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2 ,2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 15a (200 mg, 0.51 mmol Dissolved in a mixed solution of 4.5 mL of acetic acid and water (V/V = 2:1), 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 layer was washed with saturated sodium carbonate (10 mL). ×3), the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to give the title product (3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(7-chloro-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6 , 6 a - tetrahydro -3 aH - cyclopenta [d] [1,3] dioxol-4-ol 15b (180 mg, reddish brown oil) yield: 87.5%.

MS m/z (ESI): 404.2 [M+1]

third step (3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl) Cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl 4-,5,6,6 a -tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5- d ] pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxa Cyclopenten-4-ol 15b (180 mg, 0.45 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i (120 mg, 0.58 mmol) dissolved Triethylamine (159 mg, 1.58 mmol) was added to 8 mL of acetonitrile, and the reaction was stirred for 48 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 aR, 4 R, 5 R, 6 S, 6 aS) -6- (7 - ((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d Pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxole Penten-4-ol 15c (160 mg, pale yellow oil), yield: 66.3%.

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

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

(3 aR , 4 R , 5 R , 6 S , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5 -(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluoro-2,2-dimethyl-4,5, 6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 15c (160 mg, 0.30 mmol) dissolved in 5.5 mL of methanol and water (V/ In the mixed solution of 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 obtained residue was purified to silica gel column chromatography to afford the title product (1 R , 2 S , 3 S , 4 S , 5 R ) -4- (7-(( 1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[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]

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

first step (3 aS , 4 R , 6 S , 6 aR )-6-(allyloxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]benzyl dioxol-4-ylcarbamate

N -[(3 aS ,4 R ,6 S ,6 aR )-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d [[,3]Dioxol-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), and stirred for 12 hours. Water (20 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated. The resulting residue was purified by silica gel column chromatography eluting to afford to afford the title product (3 aS , 4 R , 6 S , 6 aR )-6-(allyloxy)-2,2-dimethyl- 4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamic acid benzyl ester 16a (2.10 g, colorless oil ), yield: 48.0%.

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

Second step (3 aS , 4 R , 6 S , 6 aR )-2,2-dimethyl-6-(oxirane-2-methoxy)-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylaminocarbamate

(3 aS , 4 R , 6 S , 6 aR )-6-(allyloxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta [ d ][1,3]Benzyl dioxol-4-ylcarbamate 16a (2.10 g, 6 mmol) was dissolved in 15 mL of dichloromethane, and m-chloroperoxybenzoic acid was added at 0 °C. 2.10 g, 12.17 mmol), the reaction was stirred for 12 hours. Filtration, the filtrate was washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained gave the title product (3 as , 4 R , 6 S , 6 aR )-2,2-dimethyl-6-(oxirane-2-methoxy)-4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamate benzyl ester 16b (2.16 g, pale yellow oil), yield: 98.0%.

MS m/z (ESI): 364.1 [M+1]

third step (3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)-2-hydroxypropoxy)-2,2-dimethyl-4,5,6,6 a - Benzene tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamate

The benzyl alcohol (0.7 mL, 6.90 mmol) was dissolved in 5 mL of tetrahydrofuran, and 60% sodium hydrogen (60 mg, 1.50 mmol), (3 aS , 4 R , 6 S , 6 aR )-2 was added in sequence at 0 °C. 2-Dimethyl-6-(oxirane-2-methoxy)-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxa Benzyl cyclopenten-4-ylcarbamate 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 until the pH of the reaction mixture was 7 and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title product (3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)- 2-hydroxypropoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxole-4 Benzyl carbazide 16c (0.35 g, colorless oil), yield: 57.0%.

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

the fourth step (3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)-2-fluoropropoxy)-2,2-dimethyl-4,5,6,6 a - Benzene tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamate

(3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)-2-hydroxypropoxy)-2,2-dimethyl-4,5,6,6 a - tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamic acid benzyl ester 16c (330 mg, 0.70 mmol) was dissolved in 10 mL dichloromethane. Diethylaminosulfur trifluoride (0.2 mL, 1.67 mmol) was added dropwise at -78 ° C, and the mixture was stirred at room temperature for 6 hr. Water (15 mL) was added to the mixture and the mixture was evaporated, evaporated, evaporated, evaporated The residue obtained was purified by silica gel column chromatography to afford titled product (3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)-2-fluoropropoxy -2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylaminocarbamate benzyl Ester 16d (260 mg, brownish red oil), yield: 79.0%.

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

the fifth step 3-((3 aR ,4 S ,6 R ,6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol

(3 aS , 4 R , 6 S , 6 aR )-6-(3-(benzyloxy)-2-fluoropropoxy)-2,2-dimethyl-4,5,6,6 a - tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ylcarbamic acid benzyl ester 16d (260 mg, 0.55 mmol) dissolved in 10 mL of methanol, added 10 % Pd/C (100 mg) was replaced with hydrogen three times and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the title product 3 - ((3 aR, 4 S, 6 R, 6 aS) -6- amino-2,2-dimethyl -4,5,6,6 a - four Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol 16e (100 mg, brown oil), yield : 74.0%.

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

Step 6 3-((3 aR ,4 S ,6 R ,6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2, 2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)-2-fluoropropane- 1-alcohol

3-((3 aR , 4 S , 6 R , 6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol 16e (100 mg, 0.40 mmol), 4,6-dichloro-2-propylthio - Pyrimidine-5-amine 1s (143 mg, 0.60 mmol) and N,N -diisopropylethylamine (0.2 mL, 1.20 mmol) dissolved in 5 mL of N,N -dimethylformamide, 100 The reaction was stirred at ° C for 12 hours. Water (10 mL) was added to the mixture and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated by column chromatography on silica gel B resulting residue was purified by developing solvent system, to give the title product 3 - ((3 aR, 4 S, 6 R, 6 aS) -6- (5- chloro-2-6- -(propylthio)pyrimidin-4-amino)-5-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1, 3] Dioxol-4-oxy)-2-fluoropropan-1-ol 16f (45 mg, brown oil), yield: 25.1%.

MS m/z (ESI): 451.1 [M+1]

Seventh step 3-((3 aR ,4 S ,6 R ,6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ] pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3a H -cyclopenta[ d ][1,3]dioxole- 4-oxy)-2-fluoropropan-1-ol

3-((3 aR , 4 S , 6 R , 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-5-fluoro-2, 2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yloxy)-2-fluoropropane- 1-Alcohol 16f (45 mg, 0.10 mmol) was dissolved in 2 mL of acetic acid, and 0.1 mL of sodium nitrite (7.2 mg, 0.10 mmol) was added at 0 ° C, and the reaction was stirred at 0 ° C for 20 minutes. 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×3). , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product 3 - ((3 aR, 4 S, 6 R, 6 aS) -6- (7- chloro-5- (propylthio) -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH - ring Pentero[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol 16 g (50 mg, red brown oil). One step reaction.

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

Eighth step 3-((3 aR ,4 S ,6 R ,6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a - Tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol

3-((3 aR ,4 S ,6 R ,6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5 - d ] pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxole -4-oxy)-2-fluoropropan-1-ol 16g (50 mg, 0.11 mmol) and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i (29 mg, 0.14 mmol) was dissolved in 5 mL of acetonitrile, triethylamine (38 mg, 0.38 mmol) was added and the reaction was stirred for 12 hours. The reaction mixture was concentrated and extracted with ethyl acetate (10 mL) under reduced pressure, water (10 mL), 2.5 M hydrochloric acid was added dropwise to the reaction solution to pH 4, separated, the organic phase was washed with saturated sodium chloride solution (10 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product 3 - ((3 aR, 4 S, 6 R, 6 aS) - 6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3] Zoxa[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3] Dioxol-4-oxy)-2-fluoropropan-1-ol 16h (24 mg, orange-brown oil), yield: 38.0%.

MS m/z (ESI): 595.2 [M+1]

Step 9 (1 S , 2 S , 3 R , 5 S )-3-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl sulfide -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-(2-fluoro-3-hydroxypropoxy)cyclopentane-1, 2-diol

3-((3 aR ,4 S ,6 R ,6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5 -(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-oxy)-2-fluoropropan-1-ol 16h (24 mg, 0.04 mmol) dissolved in 8 In mL 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 solution to pH 7 and extracted with ethyl acetate (10 mL×3). The organic phase was combined with saturated sodium chloride solution (10 mL) ), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product (1 S, 2 S, 3 R, 5 S) -3- ( 7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[ 4,5- d ]pyrimidin-3-yl)-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 S , 2 R , 5 R )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)- 3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol

first step (3 aR , 4 S , 6 R , 6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1 ,3]dioxol-4-ol

((3 aS , 4 R , 6 S , 6 aR )-6-hydroxy-2,2-dimethyl-tetrahydro-3 aH -cyclopenteno[ d ][1,3]dioxole Benzene-4-ylaminocarbamate 5b (3 g, 9.80 mmol) was dissolved in 100 mL of methanol, 10% Pd/C (600 mg) was added, three times with hydrogen, and the reaction was stirred for 12 hours. concentrated under reduced pressure to give the title product (3 aR, 4 S, 6 R, 6 aS) -6- amino-2,2-dimethyl -4,5,6,6 a - tetrahydro -3 aH - ring Pentero[ d ][1,3]dioxol-4-ol 17a (1.60 g, pale yellow oil), yield: 94.0%.

Second step (3 aR , 4 S , 6 R , 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl-4 ,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 S , 6 R , 6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][ 1,3]dioxol-4-ol 17a (1.60 g, 9.20 mmol), 4,6-dichloro-2-propylthio-pyrimidin-5-amine 1 s (2.60 g, 11 mmol) N,N -diisopropylethylamine (3.60 g, 27.60 mmol) was dissolved in 20 mL of N,N -dimethylformamide, and the reaction was stirred at 100 ° C for 5 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). solution of sodium (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 aR, 4 S, 6 R, 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 17b (1.85 g, orange solid), yield: 55.0%.

MS m/z (ESI): 375.1 [M+1]

third step (3 aR , 4 S , 6 R , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidine -3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 S , 6 R , 6 aS )-6-(5-Amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl- 4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 17b (1.85 g, 4.90 mmol) was dissolved in 30 mL of acetic acid and In a mixed solution of water (V/V = 1:1), 1 mL of an aqueous solution of sodium nitrite (0.38 g, 5.40 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes. Ethyl acetate (50 mL) was added to the mixture, and the mixture was evaporated. mjjjjjjjjjjjjjjj The sodium solution (50 mL) was washed with anhydrous sodium sulfate and filtered, and then filtered and evaporated to give the title product (3 aR , 4 S , 6 R , 6 aS )-6-(7-chloro-5-(propyl sulfide) -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -Cyclopenta[ d ][1,3]dioxol-4-ol 17c (1.90 g, brown oil).

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

the fourth step (3 aR , 4 S , 6 R , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl sulfide -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 S , 6 R , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ] Pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4- Alcohol 17c (1.90 g, 4.90 mmol) was dissolved in 50 mL of acetonitrile and ( 1R , 2S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i (1.30 g, 6.40 mmol) And triethylamine (1.70 g, 17 mmol), and stirred for 12 hours. The reaction mixture was concentrated under reduced vacuo. ethyl acetate (EtOAc) (EtOAc) (EtOAc) The title product (3 aR , 4 S , 6 R , 6 aS )-6 was obtained by washing with EtOAc. -(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazole And [4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3] Oxocyclo-4-ol 17d (2 g, orange solid), yield: 80%.

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

the fifth step N -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)-3-((3 aS ,4 R ,6 aR )-2,2-dimethyl- 4,6 a -dihydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2, 3] Triazolo[4,5- d ]pyrimidin-7-amine

(3 aR , 4 S , 6 R , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl Thio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 17d (130 mg, 0.25 mmol) and triphenylphosphine (263 mg, 1 mmol) dissolved in 2 mL toluene Diisopropyl azodicarboxylate (200 mg, 1 mmol) was added dropwise, and the mixture was stirred at 80 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography and the obtained residue was purified by developing solvent system B to give the title product N -) ((1 R, 2 S -2- (3,4- difluorophenyl) cycloprop -3((3 aS ,4 R ,6 aR )-2,2-dimethyl-4,6 a -dihydro-3 aH -cyclopenta[ d ][1,3]dioxa Cyclopenten-4-yl)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine 17e (125 mg, colorless oil ()), yield: 99%.

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

Step 6 (1 S , 2 R , 5 R )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)- 3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)cyclopent-3-ene-1,2-diol

N -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)-3-((3 aS ,4 R ,6 aR )-2,2-dimethyl -4,6a-dihydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[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=1:1.33), and 4 mL was added dropwise. 2.5 M hydrochloric acid, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. water (15 mL) was added, and saturated sodium hydroxide solution was added dropwise to pH 6 of the reaction mixture, extracted with ethyl acetate (15 mL×3), and the organic phase was combined with saturated sodium chloride solution ( The title product (1 S , 2 R , 5 R )-5-(7) was obtained after purification. -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[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]

¹ H NMR (400 MHz, DMSO- d 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), 0.71 (t, 3H)

Example 18 (1 S , 2 S , 3 S , 5 R )-3-(2,2-difluoroethoxy)-5-(7-((1 R ,2 S )-2-(3,4-di) Fluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)cyclopentane-1,2 -diol

first step (3 aS , 4 R , 6 S , 6 aR )-2,2-dimethyl-6-(2-oxoethoxy)-4,5,6,6 a -tetrahydro-3 aH - ring Pentero[ d ][1,3]dioxol-4-yl-carbamic acid benzyl ester

(3 aS , 4 R , 6 S , 6 aR )-6-(2-hydroxyethoxy)-2,2-dimethyl-4,5,6,6a-tetrahydro-3 aH -cyclopentyl Benzene [ d ][1,3]dioxol-4-yl-carbamic acid benzyl ester 5d (2 g, 5.69 mmol) was dissolved in 20 mL of dichloromethane and added to Days-Martin at 0 °C. The oxidizing agent (2.90 g, 6.83 mmol) 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 concentrated to give the title product (3 aS, 4 R, 6 S, 6 aR) -2,2- dimethyl-6- (2-oxo-ethoxy) -4,5,6,6 a - tetrahydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-yl-carbamic acid benzyl ester 18a (1.46 g, yellow oil). reaction.

Second step (3 aS , 4 R , 6 S , 6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH - Cyclopenta[ d ][1,3]dioxol-4-yl-carbamic acid benzyl carbamate

(3 aS , 4 R , 6 S , 6 aR )-2,2-dimethyl-6-(2-oxoethoxy)-4,5,6,6 a -tetrahydro-3 aH - Cyclopenta[ d ][1,3]dioxol-4-yl-carbamic acid benzyl ester 18a (1.46 g, 4.18 mmol) was dissolved in 15 mL of dichloromethane, then diethylamine Sulfur fluoride (1.01 g, 6.27 mmol) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 aS, 4 R, 6 S, 6 aR) -6- (2,2- difluoro-ethoxy -2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl-amino Benzyl formate 18b (925 mg, pale yellow oil), yield: 59.7%. MS m/z (ESI): 372.45 [M+1]

third step (3 aS , 4 R , 6 S , 6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine

(3 aS , 4 R , 6 S , 6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl-carbamic acid benzyl ester 18b (925 mg, 2.50 mmol) was dissolved in 20 mL of methanol and 10% Pd/ was added. C (100 mg) was replaced with hydrogen three times, and the reaction was stirred for 3 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3 as , 4 R , 6 S , 6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5, 6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine 18c (565 mg, colorless oil), yield: 95.3%.

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

the fourth step 6-Chloro- N ⁴ -((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-2-(propylthio)pyrimidine-4,5-diamine

(3 aS , 4 R , 6 S , 6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine 18c (365 mg, 1.54 mmol) was dissolved in ethylene glycol, followed by 4,6-dichloro-2-propane The thiol-pyrimidine-5-amine 1s (550 mg, 2.31 mmol) and triethylamine (778 mg, 7.69 mmol) were 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. Concentration, the residue obtained was purified by silica gel column chromatography eluting to afford to afford the title product 6-chloro- N ⁴ -((3 aS ,4 R ,6 S ,6 aR )-6-(2,2- Difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4- 2-(propylthio)pyrimidine-4,5-diamine 18d (250 mg, dark red oil), yield: 37.6%.

MS m/z (ESI): 439.1 [M+1]

the fifth step 7-Chloro-3-((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 A -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2,3] Zoxa[4,5- d ]pyrimidine

6-Chloro-N ⁴ -((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6 , 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-2-(propylthio)pyrimidine-4,5-diamine 18d ( 250 mg, 0.57 mmol) was dissolved in 1 mL of acetic acid, and 0.4 mL of water, sodium nitrite (42 mg, 0.60 mmol) was added in sequence, 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 mixture was separated, and the aqueous phase was extracted with ethyl acetate (45 mL×2). The solution (45 mL) was washed with EtOAc EtOAc (EtOAc m. Chloro-3-((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a - Tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2,3]triazole [4,5- d ]pyrimidine 18e (128 mg, pale yellow oil), yield: 50.0%.

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

Step 6 3-((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) -N -((1 R ,2 S )-2-(3,4-difluorophenyl) Cyclopropane)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine

7-Chloro-3-((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2,3] Triazolo[4,5- d ]pyrimidine 18e (128 mg, 0.29 mmol) was dissolved in 15 mL of tetrahydrofuran and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine salt was added. The acid salt 11i (79 mg, 0.38 mmol) was added dropwise triethylamine (101 mg, 1 mmol). The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product 3 - ((3 aS, 4 R, 6 S, 6 aR) -6- (2,2- two Fluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl ) -N -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropanyl)-5-(propylthio)-3 H -[1,2,3]triazole And [4,5- d ]pyrimidin-7-amine 18f (108 mg, colorless oil), yield: 65.0%.

MS m/z (ESI): 583.2 [M+1]

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

3-((3 aS ,4 R ,6 S ,6 aR )-6-(2,2-difluoroethoxy)-2,2-dimethyl-4,5,6,6 a -tetra Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) -N -((1 R ,2 S )-2-(3,4-difluorophenyl) ) cyclopropyl) -5- (propylthio) -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-7-amine 18f (108 mg, 0.19 mmol) was dissolved in 3.2 In mL methanol, 2.2 mL of 2.5 M hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. 4 M sodium hydroxide solution was added to the reaction solution until the pH of the reaction solution was 8 and extracted with ethyl acetate (25 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. method B in the resulting residue was purified by developing solvent system, to give the title product (1 S, 2 S, 3 S, 5 R) -3- (2,2- difluoro-ethoxy) -5- (7 - ((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d Pyrimidin-3-yl)cyclopentane-1,2-diol 18 (99 mg, pale white solid), yield: 99.0%.

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

¹ H NMR (400 Hz, CDCl 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, 1H), 2.10-2.22 (m, 1H), 1.20-1.70 (m, 6H), 0.97 (t, 3H)

Example 19 (1 R , 2 R , 3 S , 4 R , 5 S )-4-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane -2,3-diol

first step (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(1,3-indol-2-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4 ]cyclopenta[1,2-d][1,3]dioxol-3 b -formic acid ethyl ester

(3 aR , 3 bS , 4 aS , 5 S , 5 aS )-5-hydroxy-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-d] [1,3]dioxole-3 b -ethyl formate 19a (370 mg, 1.53 mmol, using a known method "Nucleosides, Nucleotides & Nucleic Acids (2008), 27(3), 279-291" Prepared by dissolving in 20 mL of tetrahydrofuran, adding triphenylphosphine (400 mg, 1.53 mmol) and phthalimide (225 mg, 1.53 mmol), and adding 10 mL of azodicarboxylic acid. A solution of propyl ester (309 mg, 1.53 mmol) in tetrahydrofuran was stirred for 12 hours. The reaction mixture was purified by silica gel column chromatography to give the title product (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(1,3-indol-2-yl). -2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylic acid ethyl ester 19b (420 Mg, slightly pink solid), yield: 74.0%.

Second step (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-amino-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d] [1,3]dioxole-3b-carboxylic acid ethyl ester

(3 aR , 3b S , 4 aS , 5 R , 5 aS )-5-(1,3-indol-2-yl)-2,2-dimethyl-hexahydrocyclopropyl[3, 4] cyclopenta[1,2-d][1,3]dioxole-3 b -formic acid ethyl ester 19b (420 mg, 1.11 mmol) dissolved in 8 mL of ethanol, 85% hydrated The hydrazine monohydrate (653 mg, 11.10 mmol) was stirred at 70 ° C for 2 hours. The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to give the title product (3 aR, 3 bS, 4 aS, 5 R, 5 aS) -5- amino-2,2-dimethyl - hexahydro- Cyclopropyl[3,4]cyclopenta[1,2-d][1,3]dioxole-3 b -carboxylic acid ethyl ester 19c (220 mg, white oil), yield: 82.0%.

third step (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl Ethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylate

(3 aR , 3b S , 4 aS , 5 R , 5 aS )-5-amino-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-d ][1,3]dioxole-3b-formic acid ethyl ester 19c (140 mg, 0.58 mmol) was dissolved in 15 mL of ethanol and then added 4,6-chloro-5-nitro-2-propyl Mercapto-pyrimidine 6b (170 mg, 0.64 mmol) and triethylamine (117 mg, 1.16 mmol) were stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 aR, 3 bS, 4 aS, 5 R, 5 aS) -5- (6- chloro-5- Nitro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3 Dioxetane- 3b -ethyl ester 19d (160 mg, brown oil), yield: 58.6%.

the fourth step (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-dimethyl Ethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylate

(3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amino)-2,2-di Methyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylic acid ethyl ester 19d (200 mg, 0.42 mmol) dissolved Iron powder (190 mg, 3.40 mmol) was added to 3 mL of acetic acid, and the reaction was stirred for 2 hours. The celite was filtered, and saturated sodium bicarbonate (30 mL) was added to the filtrate. The mixture was separated and washed with ethyl acetate (20 mL×2). The organic phase was combined and washed with saturated sodium chloride (20 mL) Drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give the title product (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(5-amino-6-chloro-2-(propyl sulfide) Pyrimido-4-amino)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-d][1,3]dioxole- 3b -ethyl formate 19e (300 mg, brown oil).

MS m/z (ESI): 441.1 [M+1]

the fifth step (3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ] pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-d][1,3]dioxole-3 B -ethyl formate

(3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-amino)-2,2-di Methyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylate 19e (300 mg, 0.42 mmol) dissolved To 2 mL of acetic acid, 0.5 mL of water was added, and 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 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×2). solution (25 mL), saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (3 aR, 3 bS, 4 aS, 5 R, 5 aS) -5 -(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-six Hydrocyclopropazo[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -carboxylate ethyl ester 19f (190 mg, dark brown oil), product The next reaction was carried out without purification.

MS m/z (ESI): 454.1 [M+1]

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

(3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(7-chloro-5-(propylthio)-3 H - [1,2,3]triazolo[4,5 -d ]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4]cyclopenta[1,2-d][1,3]dioxole- 3 b -ethyl formate 19f (190 mg, 0.42 mmol) was dissolved in 20 mL of acetonitrile and (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine L-(+ )-Tartrate 1 g (181 mg, 0.57 mmol), triethylamine (148 mg, 1.47 mmol) was added dropwise, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc m. 3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-( Propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3,4] Ethylcyclopenta[1,2-d][1,3]dioxole-3 b -carboxylate 19 g (215 mg, off-white solid), yield: 87.3%.

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

Seventh step ((3 aR , 3 bR , 4 aS , 5 R , 5 aS )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5 -(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3, 4] cyclopenta[1,2-d][1,3]dioxol-3 b -yl)methanol

(3 aR , 3 bS , 4 aS , 5 R , 5 aS )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5 -(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3, 4] Cyclopenta[1,2-d][1,3]dioxole-3 b -formic acid ethyl ester 19 g (215 mg, 0.37 mmol) dissolved in 10 mL of tetrahydrofuran, 1.5 mL 1 M A solution of lithium aluminum hydride in tetrahydrofuran was stirred for 12 hours. Saturated sodium potassium tartrate solution (3 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. Filtration and concentration of the filtrate under reduced pressure, ethyl acetate (25 mL) and water (20 mL), and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (15 mL×2). 15 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product ((3 aR, 3 bR, 4 aS, 5 R, 5 aS) -5- (7 - ((1 R, 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidine-3 -yl)-2,2-dimethyl-hexahydrocyclopropan[3,4]cyclopenta[1,2-d][1,3]dioxol-3 b -yl)methanol 19 h (260 mg, light yellow solid).

Eighth step (1 R , 2 R , 3 S , 4 R , 5 S )-4-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5- (propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane -2,3-diol

((3 aR , 3 bR , 4 aS , 5 R , 5 aS )-5-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)- 5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopropyl[3 , 4] cyclopenta[1,2-d][1,3]dioxol-3 b -yl)methanol 19h (260 mg, 0.37 mmol) dissolved in 15 mL of methanol, 4 mL 2 .5 M hydrochloric acid, stirring reaction for 12 hours. Add 1 M sodium hydroxide solution to the reaction solution until the pH of the reaction solution was 7. Add ethyl acetate (20 mL) and water (10 mL), and the mixture was evaporated. The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, separated by HPLC preparative chromatography to give the title product (1 R, 2 R, 3 S, 4 R, 5 S ) -4-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2 ,3]triazolo[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]

¹ H NMR (400 MHz, CDCl 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, 2H), 3.79-3.74 (m, 1H), 3.54-3.51 (d, 1H), 3.14-3.13 (m, 1H), 3.10-3.00 (m, 1H), 2.91-2.80 (m, 1H), 2.20-2.12(m,1H),1.70-1.65(m,1H),1.60-1.55(m,2H),1.50-1.45(m,1H),1.40-1.30(m,1H),1.30-1.26(t , 1H), 0.88 (m, 3H), 0.85-0.80 (m, 1H).

Example 20 (1 S , 2 S , 3 R , 5 S )-3-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-( Propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluorocyclopentane-1,2-diol

first step ((3 aS ,4 R ,6 aS )-2,2-dimethyl-6-oxo-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3 Benzyl dioxol-4-yl)carboxylate

((3 aS , 4 R , 6 S , 6 aR )-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopentene[ d ] Benzyl [1,3]dioxol-4-yl)carbamate 5b (5 g, 16.3 mmol) was dissolved in 150 mL of dichloromethane, 4A molecular sieve (5 g) was added, and chlorochrome was slowly added. The acid pyridinium salt (10.50 g, 48.80 mmol) was stirred for 60 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product ((3 aS , 4 R , 6 aS )-2,2-dimethyl-6-oxo-4,5,6,6 a -tetrahydro-3 aH - Benzyl bromide [ d ][1,3]dioxol-4-yl)carboxylate 20a (3.10 g, mp.

Second step ((3 aS ,4 R ,6 R ,6 aR )-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopentene[ d ][ Benzyl 1,3]dioxol-4-yl)carbamate

((3 aS , 4 R , 6 aS )-2,2-dimethyl-6-oxo-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1, 3] Benzyl dioxol-4-yl)carboxylate 20a (1 g, 3.30 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium borohydride (495 mg, 13.10 mmol) was added at -78 ° C, and stirred at -78 ° C. Reaction for 1 hour. The reaction mixture was purified by silica gel column chromatography to afford title product ((3 aS , 4 R , 6 R , 6 aR )-6-hydroxy-2,2-dimethyl-4,5,6 , 6 a - tetrahydro-3 aH - cyclopenta[ d ][1,3]dioxol-4-yl)carbamic acid benzyl ester 20b (510 mg, white solid), yield: 51.0%.

third step (3 aR , 4 R , 6 R , 6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1 ,3]dioxol-4-ol

((3 aS ,4 R ,6 R ,6 aR )-6-hydroxy-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopentene[ d ] Benzyl [1,3]dioxol-4-yl)carbamate 20b (800 mg, 2.60 mmol) was dissolved in 50 mL of methanol, 10% Pd/C (80 mg) was added, and hydrogen was replaced. Three times, the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (3 aR , 4 R , 6 R , 6 aS ) 6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20c (410 mg, orange solid), yield: 91.0%.

the fourth step (3 aR , 4 R , 6 R , 6 aS )-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyl 4-,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 R , 6 R , 6 aS )-6-amino-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][ 1,3]dioxol-4-ol 20c (410 mg, 2.36 mmol) was dissolved in 30 mL of N,N -dimethylformamide, followed by 4,6-dichloro-2-propene The thiol-pyrimidin-5-amine 1s (676 mg, 2.84 mmol) and N,N -diisopropylethylamine (915 mg, 7.08 mmol) were 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 separated, and the aqueous phase was extracted with ethyl acetate (60 mL×3). ) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by silica gel column chromatography and the obtained residue was purified by developing solvent system B to give the title product (3 aR, 4 R ,6 R ,6 aS )-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyl-4,5, 6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20d (390 mg, orange solid), yield: 44.0%.

MS m/z (ESI): 375.1 [M+1]

the fifth step (3 aR , 4 R , 6 R , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidine -3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 R , 6 R , 6 aS )-6-((5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-di Methyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20d (390 mg, 1.04 mmol) dissolved in 10 In a mixed solution of mL acetic acid and water (V/V = 1:1), 1 mL of an aqueous solution of sodium nitrite (79 mg, 1.15 mmol) was added dropwise to an ice water bath, and the mixture was stirred at 0 ° C for 30 minutes. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL×3). ×2) Washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the title product (3 aR , 4 R , 6 R , 6 aS )-6-(7-chloro -5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20e (340 mg, orange solid), yield: 86.0%.

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

Step 6 (3 aR , 4 R , 6 R , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl sulfide -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro- 3 aH -cyclopenta[ d ][1,3]dioxol-4-ol

(3 aR , 4 R , 6 R , 6 aS )-6-(7-chloro-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ] Pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4- Alcohol 20e (340 mg, 0.88 mmol) was dissolved in 30 mL of acetonitrile and ( 1R , 2S )-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride 11i (235 mg, 1.15 mmol) And triethylamine (311 mg, 3.10 mmol), and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (60 mL) and water (60 mL) was evaporated. mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (3 aR, 4 R, 6 R, 6 aS) -6- (7 - ((1 R, 2 S) -2- ( 3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2 ,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20f (480 mg, brown solid The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 519.4 [M+1]

Seventh step Trifluoromethanesulfonic acid ((3 aS , 4 R , 6 R , 6 aS )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)) -5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6, 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)ester

(3 aR , 4 R , 6 R , 6 aS )-6-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propyl Thio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 20f (320 mg, 0.62 mmol) was dissolved in 20 mL of dichloromethane, pyridine (198 mg, 2.48 mmol), trifluoromethanesulfonic anhydride (350 mg, 1.24 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, trifluoromethanesulfonic acid to give the title product ((3 aS, 4 R, 6 R, 6 aS) -6- (7- ((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4, 5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxole Ethyl-4-yl) ester 20 g (320 mg, colorless oil), yield: 79.0%.

Eighth step N -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)-3-((3 aS ,4 R ,6 S ,6 aS )-6-fluoro-2 ,2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propyl sulfide -3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine

Trifluoromethanesulfonic acid ((3 aS , 4 R , 6 R , 6 aS )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamino) )-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl-4,5,6 , 6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) ester 20 g (320 mg, 0.49 mmol) dissolved in 20 mL of tetrahydrofuran, -40 Tris(dimethylamino)phosphonium difluoro(trimethyl) decanoate (165 mg, 0.60 mmol) was added at ° C, and the reaction 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 and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product N - ((1 R, 2 S) -2- (3,4- difluorophenyl) cyclopropyl )-3-((3 aS ,4 R ,6 S ,6 aS )-6-fluoro-2,2-dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidine-7 -amine 20h (190 mg, white solid), yield: 44.7%.

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

Step 9 (1 S , 2 S , 3 R , 5 S )-3-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropylamino)-5-( Propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-fluorocyclopentane-1,2-diol

N -((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)-3-((3 aS ,4 R ,6 S ,6 aS )-6-fluoro- 2,2-Dimethyl-4,5,6,6 a -tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propyl thio) -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-7-amine 20h (190 mg, 0.37 mmol) was dissolved in 5 mL methanol was added 10 mL 2 M HCl The reaction was stirred at 40 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, separated by HPLC resulting residue was preparative chromatography to give the title product (1 S, 2 S, 3 R, 5 S) -3- (7 - ((1 R, 2 S) -2- ( 3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl) 5-5-fluorocyclopentane-1,2-diol 20 (70 mg, white solid), yield: 40.0%.

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

¹ H NMR (400 MHz, CDCl 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), 2.94-2.91 (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 S , 2 R , 5 R )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propyl Thio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-3-(2-hydroxyethyl)-3-cyclopentene-1,2 -diol

first step 2-((3a S ,4 R ,6a R )-6-(2-((t-butyldimethyl methoxy)ethyl)-2,2-dimethyl-4,6 a - Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)isoindole-1,3-dione

(3a S , 4 S , 6a R )-6-(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-ol 21a (240 mg, 0.76 mmol, using the well-known method "Journal of Medicinal Chemistry, 2005 (48), 5043-5046" Prepared in 10 mL of tetrahydrofuran, followed by the addition of xylylenediamine (168 mg, 1.14 mmol), triphenylphosphine (300 mg, 1.14 mmol) and diisopropyl azodicarboxylate (231 mg) , 1.14 mmol), stirred for 12 hours The reaction solution was concentrated under reduced pressure, silica gel column chromatography to B resulting residue was purified by developing solvent system, to give the title product 2 -. ((3a S, 4 R, 6a R) -6 -(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6 a -dihydro-3 aH -cyclopenta[ d ][1,3 Dioxol-4-yl)isoindole-1,3-dione 21b (210 mg, pale yellow oil), yield: 61.9%.

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

Second step (3a S , 4 R , 6a R )-6-(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6 a -dihydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-amine

2-((3a S ,4 R ,6a R )-6-(2-((Tert-Butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a-di Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)isoindole-1,3-dione 21b (210 mg, 0.47 mmol) dissolved in 5 mL ethanol The hydrazine hydrate (118 mg, 2.37 mmol) was added, and the reaction was stirred at 70 ° C for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to give the title product (3a S , 4 R , 6a R )-6-(2-(( Tert-butyldimethyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3 aH -cyclopenta[ d ][1,3]dioxole 4-Amine 21c (142 mg, yellow oil), yield: 95.9%.

MS m/z (ESI): 314.1 [M+1]

third step N ⁴ -((3a S ,4 R ,6a R )-6-(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a-di Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine

(3a S , 4 R , 6a R )-6-(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3 aH -cyclopenta[ d ][1,3]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 1v (159 mg, 0.67 mmol) and N,N -diisopropylethylamine (173 mg, 1.34 mmol), stirred at 120 °C 12 After cooling to room temperature, a saturated aqueous solution of ammonium chloride (40 mL) was added, and ethyl acetate (20 mL×3) was evaporated. dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product ^{N 4 - ((3a S,} 4 R, 6a R) -6- (2 -((t-butyldimethyl methoxy)ethyl)-2,2-dimethyl-4,6a-dihydro-3 aH -cyclopenta[ d ][1,3]dioxa Cyclopenten-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-((3a S ,4 R ,6a R )-6-(2-((Tertiary butyldimethyl methoxy)ethyl)-2,2-dimethyl-4,6a-dihydro -3 aH - cyclopenta [d] [1,3] dioxol-4-yl) -5- (propylthio) -3 H - [1,2,3] triazolo [4 ,5- d ]pyrimidin-7-amine

N ⁴ -((3a S ,4 R ,6a R )-6-(2-(( T -butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a- Dihydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine 21d ( 85 mg, 0.17 mmol) was dissolved in 3.3 mL of a mixed solution of acetic acid and water (V/V = 10:1). Sodium nitrite (12 mg, 0.17 mmol) was added in an ice water bath, and the reaction was stirred for 30 minutes in an ice water bath. Water (40 mL) was added to the mixture, and the mixture was combined with ethyl acetate (15 mL×3). The organic phase was combined and washed with saturated sodium bicarbonate (40 mL) and saturated sodium chloride (40 mL) sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product 3 - ((3a S, 4 R, 6a R) -6- (2 - (( tert-butyl-dimethyl silicon) ethyl) -2 ,2-Dimethyl-4,6a-dihydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3 H -[1,2,3] Triazolo[4,5- d ]pyrimidin-7-amine 21e (70 mg, colorless oil), yield: 80.5%.

the fifth step 3-((3a S ,4 R ,6a R )-6-(2-((Tertiary butyldimethyl methoxy)ethyl)-2,2-dimethyl-4,6a-dihydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) -N -((1 R ,2 S )-2-(3,4-difluorophenyl) Cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine

3-((3a S ,4 R ,6a R )-6-(2-((Tertylbutyldimethyloxy)ethyl)-2,2-dimethyl-4,6a-di Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4 ,5- d ]pyrimidine-7-amine 21e (65 mg, 0.12 mmol) was dissolved in 5 mL of acetonitrile, followed by (1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropylamine salt The acid salt 11i (33 mg, 0.16 mmol) and triethylamine (37 mg, 0.37 mmol) were stirred for 6 hr. The reaction mixture was concentrated under reduced pressure. The product 3-((3a S ,4 R ,6a R )-6-(2-((t-butyldimethylmethyloxy)ethyl)-2,2-dimethyl-4,6a-di Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) -N -((1 R ,2 S )-2-(3,4-difluorophenyl) Cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine 21f (60 mg, colorless oil).

Step 6 (1 S , 2 R , 5 R )-5-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propyl Thio)-3 H -[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-(2-hydroxyethyl)-3-cyclopentene-1,2 -diol

3-((3a S ,4 R ,6a R )-6-(2-((Tertylbutyldimethyloxy)ethyl)-2,2-dimethyl-4,6a-di Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl) -N -((1 R ,2 S )-2-(3,4-difluorophenyl) Cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5- d ]pyrimidin-7-amine 21f (55 mg, 0.08 mmol) dissolved in 5 mL methanol, was added 0.5 mL3 M hydrochloric acid and stirred for 12 hours. the reaction solution was concentrated under reduced pressure, the resulting thin layer chromatography in a developing solvent system B and the residue was purified to give the title product (1 S, 2 R, 5 R) -5 -(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3 H -[1,2, 3] Triazolo[4,5- d ]pyrimidin-3-yl)-3-(2-hydroxyethyl)-3-cyclopentene-1,2-diol 21 (25 mg, colorless oil ), yield: 40.0%.

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

¹ H NMR (400 MHz, CDCl 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 S , 2 S , 3 R , 5 S )-3-(7-((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5 -((propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy Cyclopentane-1,2-diol

first step 2-(2-((3a R , 4 S , 6 R , 6a S )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropane) Amino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyltetrahydro -3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)ethoxy)ethyl acetate

2-(((3a R , 4 S , 6 R , 6a S )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropyl)) Amino)-5-(propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)ethanol 22a (562 mg, 1 mmol, prepared by the known method patent "WO2011017108") dissolved in In 10 mL of tetrahydrofuran, cool to 0 ° C, add potassium butoxide (180 mg, 1.60 mmol), stir the reaction for 15 minutes, add 2 mL of ethyl bromoacetate (200 mg, 1.20 mmol) in tetrahydrofuran, stir the reaction 2 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product 2- (2 - (((3a R, 4 S, 6 R, 6a S) -6- (7 -(((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3 H -[1,2,3] Zizo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl Ethoxy)ethoxy)ethyl acetate 22b (60 mg, pale yellow oil), yield: 9.2%.

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

Second step 2-(2-((3a R , 4 S , 6 R , 6a S )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)cyclopropane) Amino)-5-((propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyltetra Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)ethoxy)ethanol

2-(2-((3a R , 4 S , 6 R , 6a S )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)) ring) propyl) amino) -5- (propylthio) -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-3-yl) -2,2-dimethyl-four Hydrogen-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)ethoxy)acetate 22b (60 mg, 0.09 mmol) dissolved in 2 mL of tetrahydrofuran Lithium borohydride (11 mg, 0.50 mmol) was added, and the reaction was stirred for 0.5 hour. To the reaction solution was added 1 mL of water, filtered and the filtrate was concentrated under reduced pressure to give the title product 2- (2- (((3a R , 4 S, 6 R, 6a S) -6- (7 - (((1 R, 2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-((propylthio)-3 H -[1,2,3]triazolo[4,5 - d ] pyrimidin-3-yl)-2,2-dimethyltetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)ethoxy Ethyl alcohol 22c (54 mg, colorless oil), yield: 99%.

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

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

2-(2-((3a R , 4 S , 6 R , 6a S )-6-(7-((1 R , 2 S )-2-(3,4-difluorophenyl)) ring) Propyl)amino)-5-((propylthio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)-2,2-dimethyl Tetrahydro-3 aH -cyclopenta[ d ][1,3]dioxol-4-yl)oxy)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. 4 M saturated sodium carbonate solution was added to the reaction solution until the pH of the reaction solution was 7, and extracted with ethyl acetate (30 mL×3), and the organic phase and saturated chlorine were combined. sodium solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the resulting residue was by preparative HPLC to give the title product (1 S, 2 S, 3 R, 5 S) -3- ( 7-(((1 R ,2 S )-2-(3,4-Difluorophenyl)cyclopropyl)amino)-5-((propylthio)-3 H -[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] ¹ H 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), 2.10-2.21 (m, 1H), 1.80-1.25 (m, 6H), 1.01 (m, 3H)

Example 23 (1 S , 2 R , 3 S , 4 R )-4-(5-((cyclopropylmethyl)thio)-7-(((1 R ,2 S )-2-(3,4- Difluorophenyl)cyclopropyl)amino)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)cyclopentane-1,2,3-tri alcohol

first step (1 S , 2 R , 3 S , 4 R )-4-Aminocyclopentane-1,2,3-triol hydrochloride

(3a R , 4 S , 6 R , 6a S )-6-Amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3 aH -cyclopentene[ d ][ 1,3]dioxol-4-ol L-(-)-dibenzidal tartrate 5a (6.10 g, 11.50 mmol) was added to 10 mL of methanol, 20 mL of 12 M hydrochloric acid was added, and stirred at 40 ° C. 12 hours, filtered, the filtrate was concentrated under reduced pressure to give the title product (1 S, 2 R, 3 S, 4 R) -4- amino-cyclopentane-1,2,3-triol hydrochloride 23a (1.53 g, yellow oil), yield: 100%.

MS m/z (ESI): 134.2 [M+1]

Second step (1 S , 2 R , 3 S , 4 R )-4-((5-Amino-6-chloro-2-((cyclopropylmethyl)thio)pyrimidin-4-yl)amino) ring Pentane-1,2,3-triol

(1 S , 2 R , 3 S , 4 R )-4-Aminocyclopropane-1,2,3-triol 23a (1.53 g, 11.50 mmol) was dissolved in 15 mL of N,N -dimethyl In the decylamine, 4,6-dichloro-2-(cyclopropylmethylsulfanyl)pyrimidine-5-amine 2p (3.45 g, 13.80 mmol) and N,N -diisopropylethylamine (10.40) were sequentially added. g, 80.50 mmol), and the reaction was stirred at 100 ° C for 12 hours. Cooled to room temperature, the reaction solution was concentrated under reduced pressure, silica gel column chromatography to A resulting residue was purified by developing solvent system, to give the title product (1 S, 2 R, 3 S, 4 R) -4 - ((5- Amino-6-chloro-2-((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-1]

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

(1 S , 2 R , 3 S , 4 R )-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) was added in an ice water bath. , 13.02 mmol), stir the reaction at 0 ° C for 35 minutes. Add 80 mL of saturated potassium carbonate solution to the pH of the reaction solution 8, (30 mL × 4) was extracted with EtOAc, the combined organic phases were washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (1 S , 2 R , 3 S , 4 R )-4-(7-chloro-5-((cyclopropylmethyl)thio)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-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 S , 2 R , 3 S , 4 R )-4-(5-((cyclopropylmethyl)thio)-7-(((1 R ,2 S )-2-(3,4- Difluorophenyl)cyclopropyl)amino)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-3-yl)cyclopentane-1,2,3-tri alcohol

(1 S , 2 R , 3 S , 4 R )-4-(7-chloro-5-((cyclopropylmethyl)thio)-3 H -[1,2,3]triazolo[ 4,5- d ]pyrimidin-3-yl)cyclopentane-1,2,3-triol 23c (2.20 g, 6.15 mmol) was dissolved in 25 mL of acetonitrile and added in an ice water bath (1 R , 2 S 2-(3,4-Difluorophenyl)cyclopropylamine hydrochloride 11i (2.23 g, 9.22 mmol) and N,N -diisopropylethylamine (3.18 g, 24.60 mmol), stirred at room temperature 12 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography to A resulting residue was purified by developing solvent system, to give the title product (1 S, 2 R, 3 S, 4 R) -4- (5 - (( cyclopropylmethyl Thio)-7-(((1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl)amino)-3 H -[1,2,3]triazole And [4,5- d ]pyrimidin-3-yl)cyclopentane-1,2,3-triol 23 (1.24 g, white solid), yield 41.3%.

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

¹ H 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 case: Biological evaluation Test example 1

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

The experimental method is briefly described as follows: After anesthesia, the rats were bled by 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). The PRP was resuspended by washing with buffer (Taiwan buffer solution) (NaCl 129 mM, KCl 2.8 mM, KH ₂ PO ₄ 0.8 mM, MgCl ₂ 0.8 mM, NaHCO ₃ 8.9 mM, HEPEs 10 mM, glucose 5.5 mM). A platelet rich buffer is obtained. The platelet aggregation rate was measured by a 96-well plate reader: 188 μL of prepared platelet-rich buffer, 4 μL of CaCl ₂ , 2 μL of compound dissolved in DMSO or 2 μL of DMSO (blank control) were added to each well, and cultured at 37 degrees for 2 minutes. After detecting the absorbance at 0 minutes, 10 μL of ADP (final concentration 20 μM) was added, and after shaking for 2 to 3 minutes, the value of OD _{450 nm} at T ₅ minutes was measured.

The ADP-induced platelet aggregation rate is expressed as Aggregation % (aggregation %): Aggregation% = (A _{T0 -} A _T5 ) / A _T0 * 100%.

The time point at which ADP was added was recorded as T0, A _T0 represents the OD _{450 nm} reading at T0, and A _T5 represents the OD _{450 nm} reading at 5 minutes of induction of ADP addition.

The inhibitory effect of the compound on platelet aggregation is expressed as: inhibition rate (%) = 100% - agglutination rate %

IC ₅₀ values of the compounds obtained Keji inhibition rate at each concentration is calculated.

Inhibition of ADP-induced human platelet aggregation The experimental method was the same as above, and human platelets were taken from venous blood of healthy volunteers.

The IC ₅₀ values of the test compounds are shown in Table 1 below: Conclusion: The test compound of the present invention has a significant inhibitory effect on ADP-induced rat and human platelet aggregation.

Test example 2

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

The experimental method is briefly described as follows: A CHO-K1 cell line (CHO-K1/P2Y12) expressing P2Y12 was constructed using a retroviral transfection method commonly used by those skilled in the art. CHO-K1 was purchased from the Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences, Cat. GNHa 7. P2Y12 was purchased from origene, Cat. SC319680.

The constructed CHO-K1/P2Y12 cells were harvested with a cell scraper and resuspended in homogenization buffer (10 mM Hepes, 10 mM NaCl, 1 mM 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 reaction buffer (10 mM Hepes, 138 mM NaCl, pH 7.4), and the membrane protein concentration was measured by the Bradford method, and stored at -80 °C.

The P2Y12 membrane protein was diluted to 1 μg/μL with reaction buffer, and the reaction system was prepared according to the following table:

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 and 10 mL of scintillation fluid was added and read in a Perkin Elmer counter. The data read was analyzed by IC ₅₀ using Graphpad software.

The IC ₅₀ values of the test compounds are shown in Table 2 below: Conclusion: The compounds of the present invention have a significant inhibitory effect on the P2Y12 receptor.

Pharmacokinetic evaluation Test Example 3, Pharmacokinetic Testing of Compounds of the Invention

1. Summary

Rats were used as test animals, and the compounds of Example 2, the compound of Example 8, the compound of Example 9, the compound of Example 12, the compound of Example 17, and the Example 20 were intragastrically administered to the rats by LC/MS/MS method. Compound 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, the test plan

2.1 test drugs

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.

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 to separate blood The slurry was 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 to 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 compounds of the present invention have good drug metabolism absorption and have obvious pharmacokinetic advantages.

Claims (20)

a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound thereof salt, among them: Is a single bond or a double bond; R ^{1 is} selected from a cycloalkyl or a heteroaryl group; when R ^{1 is} selected from a cycloalkyl group, the cycloalkyl group is further substituted by one or more of the respective independent R ⁶ , or R ^{1 is} selected from cycloalkyl fused to an aryl or heteroaryl group, wherein the cycloalkyl group fused to the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, a halogen, and an alkoxy group. Base, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C( O) NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ substituted; when R ^{1 is} selected from hetero In the case of an aryl group, the heteroaryl group is further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(O)R ⁷ , -C(O)OR ⁷ as needed. , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S( O) substituted with a substituent of _m NR ⁸ R ⁹ ; R ^{2 is} selected from an alkyl group, which alkyl group is further substituted by one or more cycloalkyl groups as needed; When it is a single bond, R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently further optionally one or more selected from the group consisting of a hydroxyl group, a halogen, a cycloalkyl group, and an OR. Substituting ⁷ or a substituent of a heterocyclic group; or R ³ and R ⁴ together form an =0 or an alkenyl group; When it is a double bond, R ³ does not exist and conforms to the valence bond theory; When it is a single bond, R ^{4 is} selected from a hydrogen atom or an alkyl group, or R ³ and R ⁴ together form an =0 or an alkenyl group, wherein the alkenyl group is further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy. Substituted by a substituent of a nitro group or a cyano group; or R ⁴ and R ^{5 are} optionally substituted into a cycloalkyl group, and the ring formation conforms to the valence bond theory; When it 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 it is a single bond, R ⁵ and R ^{4 are} optionally substituted into a cycloalkyl group, and ring formation conforms to the valence bond theory; provided that when R ^{2 is} selected from unsubstituted alkyl groups, R ^{3 is} selected from alkoxy groups or hydroxyl groups, wherein The alkoxy group is substituted by a hydroxyl group, R ^{4 is} selected from a hydrogen atom, and when R ^{5 is} selected from a hydrogen atom, R ¹ is not a C ₃ to C ₈ cycloalkyl group substituted by a phenyl group; and R ^{6 is} selected from an aryl group or a heteroaryl group. a group wherein the aryl or heteroaryl group is further independently 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, and a -C(O). R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ Substituted by a substituent of S(O) _m R ⁹ or -S(O) _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 , heterocyclyl, aryl or heteroaryl; m is 0, 1 or 2. a compound represented by the formula (I) 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 of the formula (II) or a pharmaceutically acceptable salt thereof: Wherein: R ¹ to R ⁵ are as defined in the first item of the patent application. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 1 or 2 of the patent application. And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof: Wherein: R ¹ to R ⁵ are as defined in the first item of the patent application. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 3. enantiomers thereof, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ¹ is cycloalkyl, the cycloalkyl optionally further substituted by one or more substituents independently by R ^6; R ⁶ is defined as The scope of patent application is as described in item 1. a compound of the formula (I), or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from R ^{6 is} selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is each independently substituted with one or more substituents selected from an alkyl group or a halogen, as needed. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 3. And a mixture thereof, wherein R ^{3 is} selected from halogen, hydroxy, alkyl or alkoxy, the alkyl, alkoxy are each independently further optionally one or more Substituted by a substituent selected from a hydroxyl group, OR ⁷ or a halogen. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 1 or 2 of the patent application. And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein: R ^{1 is} selected from cycloalkyl or heteroaryl; when R ^{1 is} selected from cycloalkyl, the cycloalkyl is further required to be further one or more Substituted independently by R ⁶ , or R ^{1 is} selected from cycloalkyl fused to an aryl or heteroaryl group, wherein the cycloalkyl group fused to an aryl or heteroaryl group is further selected by one or more From alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ ,- Substituents for NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ Substituted; when R ^{1 is} selected from heteroaryl, the heteroaryl is further optionally one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, nitro, cyano, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O Substituting _m R ⁹ or -S(O) _m NR ⁸ R ⁹ R ^{2 is} selected from an alkyl group which is further substituted by one or more cycloalkyl groups as needed; Is a single bond, R ^{5 is} selected from an alkyl group, a hydroxyl group or a halogen, or R ^{4 is} optionally substituted into a cycloalkyl group, and the ring is in the valence bond theory: R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group. Wherein the alkyl group and the alkoxy group are each independently further substituted with at least two substituents selected from a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ group or a heterocyclic group; R ^{4 is} selected from a hydrogen atom, or is R ⁵ Need to form a cycloalkyl group, and the ring formation is in accordance with the valence bond theory; When it is a single bond, when R ⁵ is a hydrogen atom: R ³ is an alkoxy group, wherein the alkoxy group is further substituted by at least two substituents each independently selected from a hydroxyl group, a halogen, a cycloalkyl group, a hydroxyalkyl group or a heterocyclic group. Substituted; R ⁴ is a hydrogen atom; When it 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; and R ^{6 is} selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further required by one Or a plurality selected from the group consisting of alkyl, halogen, alkoxy, nitro, cyano, cycloalkyl, heterocyclic, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ Substituted by a substituent; 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. a compound represented by the formula (I) 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 of the formula (IV) or a pharmaceutically acceptable salt thereof: Wherein: R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl, alkoxy are each independently further optionally one or more selected from the group consisting of hydroxyl, halogen, cycloalkyl, OR ⁷ or hetero Substituted by a substituent of a cyclic group; R ^{4 is} selected from an alkyl group, a hydrogen atom, or R ^{5 is} optionally substituted into 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 is} optionally substituted into a cycloalkyl group, and ring-forming is in accordance with 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; and R ¹ and R ² are as defined above; The scope of patent application is as described in item 1. a compound represented by the formula (I) 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 of the formula (V) or a pharmaceutically acceptable salt thereof: Wherein R ^{3 is} selected from halogen, alkyl, alkoxy or hydroxy, wherein the alkyl, alkoxy are each independently further selected from at least two selected from the group consisting of hydroxyl, halogen, cycloalkyl, OR ⁷ or heterocyclic. Substituted by a substituent; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; and R ¹ and R ² are as defined in the first item of the patent application. a compound represented by the formula (I) 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 of the formula (VI) or a pharmaceutically acceptable salt thereof: Wherein: R ¹ and R ² are as defined in the first item of the patent application. a compound represented by the formula (I) 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 of the formula (VII) or a pharmaceutically acceptable salt thereof: Wherein: R ^{2 is} selected from an alkyl group, the alkyl group is further substituted by one or more cycloalkyl groups; R ^{3 is} selected from a halogen, an alkyl group, an alkoxy group or a hydroxyl group, wherein the alkyl group and the alkoxy group are each independently Further substituted with one or more substituents selected from a hydroxyl group, a halogen, a cycloalkyl group, an OR ⁷ or a heterocyclic group, if necessary; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a heterocyclic ring A aryl group, an aryl group or a heteroaryl group; R ¹ is as defined in the first item of the patent application. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 1 or 2 of the patent application. And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of: A compound represented by the formula (I) according to the first aspect of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form thereof, and a preparation method of the pharmaceutically acceptable salt thereof, comprising the steps of: The compound of the formula (IA) is reacted with R ¹ NH ₂ , and the protecting groups P and P' of the hydroxyl group are further removed as needed to obtain a compound of the formula (I): wherein: L is a leaving group; P and P' are a hydroxyl group. Protecting group or hydrogen atom, the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a decyl group or an ethyl fluorenyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic group. The 6-membered heterocyclic group is further substituted by one or more substituents selected from an alkyl group, a halogen group, a hydroxyl group or an alkoxy group; and R ¹ , R ² to R ⁵ are as defined in the first item of the patent application. Said. The production method according to claim 13, wherein L is a halogen. a compound of the formula (I) according to the second aspect of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form thereof, and a preparation method of the pharmaceutically acceptable salt thereof, comprising the steps of: The compound of the formula (IIA) is reacted with R ¹ NH ₂ , and the protecting groups P and P′ of the hydroxyl group are further removed as needed to obtain a compound of the formula (II); wherein: L is a leaving group; P and P′ are a hydroxyl group. Protecting group or hydrogen atom, the protecting group of the hydroxyl group is selected from an alkyl group, a benzyl group, a decyl group or an ethyl fluorenyl group, or P and P' together with the atom to which they are attached form a 5- to 6-membered heterocyclic group. The 6-membered heterocyclic group is further substituted by one or more substituents selected from an alkyl group, a halogen group, a hydroxyl group or an alkoxy group; and R ¹ , R ² to R ⁵ are as defined in the first item of the patent application. Said. The production method according to claim 15, wherein L is a halogen. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, or a compound of the formula (I) described in claim 1 The enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable carriers, diluents and excipients. A compound represented by the formula (I) according to the first aspect of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use thereof in the form of a mixture, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 17 of the patent application, for use in the preparation of a P2Y12 receptor antagonist. A compound represented by the formula (I) according to the first aspect of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 17, which is used for the preparation of a medicament for treating or preventing myocardial infarction, embolic episodes, transient ischemic attack , peripheral vascular disease or angina drugs. A compound represented by the formula (I) according to the first aspect of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use thereof in the form of a mixture, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 of the invention, for use in the preparation of a medicament for treating or preventing a disorder of platelet aggregation disorder.