TW201713659A - Pyrrolopyrimidine compound, application thereof and pharmaceutical composition serving as a TLR7 agonist containing the compound and an application of the compound to preparation of an antiviral drug - Google Patents

Pyrrolopyrimidine compound, application thereof and pharmaceutical composition serving as a TLR7 agonist containing the compound and an application of the compound to preparation of an antiviral drug Download PDF

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TW201713659A
TW201713659A TW104133088A TW104133088A TW201713659A TW 201713659 A TW201713659 A TW 201713659A TW 104133088 A TW104133088 A TW 104133088A TW 104133088 A TW104133088 A TW 104133088A TW 201713659 A TW201713659 A TW 201713659A
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methyl
pyrrolo
amine
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TWI558709B (en
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Zhao Zhong Ding
Hao Wu
Fei Sun
li-fang Wu
Ling Yang
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The present invention relates to a pyrrolopyrimidine compound serving as a TLR7 agonist, and more particularly to a compound as shown in formula (I) or a pharmaceutically acceptable salt and a preparation method thereof, a pharmaceutical composition containing the compound and an application of the compound to preparation of an antiviral drug.

Description

吡咯并嘧啶環化合物、其用途及藥物組合物 Pyrrolopyrimidine ring compound, use thereof and pharmaceutical composition

本發明關於新穎的作為TLR7促效劑的吡咯并嘧啶環化合物或其藥學上可接受的鹽，具體關於式(I)所示化合物或其藥學上可接受的鹽。 The present invention relates to a novel pyrrolopyrimidine ring compound as a TLR7 agonist or a pharmaceutically acceptable salt thereof, particularly to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

Toll樣受體表達於複數種免疫細胞。Toll樣受體識別高度保守結構基序(motif)：由微生物病原體表達的病原體相關的微生物模式(PAMP)或由壞死細胞釋放的損傷相關分子模式(DAMP)。通過相應的病原體相關的微生物模式(PAMP)或損傷相關分子模式(DAMP)刺激Toll樣受體引發信號級聯導致轉錄因子如AP-1、NF-κ B和干擾素調節因子(脈衝回應函數)的啟動。這導致複數種細胞反應，包括生產干擾素、促炎性細胞因子和效應細胞因子，從而產生免疫反應。迄今為止，哺乳動物中有13種Toll樣受體已被發現。Toll樣受體1、2、4、5和6主要表達在細胞表面上，Toll樣受體3、7、8和9表達在內體中。不同的 Toll樣受體識別不同病原體衍生的配體。對於Toll樣受體7(TLR7)，它主要是由漿細胞樣樹突細胞(pDC)表達和配體識別而誘導干擾素-α(IFN-α)的分泌。Toll樣受體7(TLR7)和Toll樣受體8(TLR8)高度同源。因此TLR7配體在大多數情況下也是TLR8配體。TLR8刺激主要誘導產生細胞因子如腫瘤壞死因子-α(TNF-α)和趨化因子。干擾素α是治療慢性乙型肝炎或丙型肝炎的主要藥物之一，而TNF-α是一種促炎細胞因子，過多分泌可能導致嚴重的副作用。所以對TLR7和TLR8的選擇性對於開發TLR7促效劑用於治療病毒感染性疾病至關重要。幾個TLR7促效劑已有報導，如咪喹莫特、瑞喹莫德、GS-9620。但具備更好的選擇性、活性和安全性的新的TLR7促效劑仍然有很大需求。我們發現了一系列的新穎的吡咯并嘧啶衍生物是TLR7的促效劑。背景研發資料參照如下的期刊文章：Hoffmann,J.A.,Nature,2003,426,p33-38；Akira,S.,Takeda,K.,and Kaisho,T.,Annual.Rev.Immunology,2003,21,335-376；Ulevitch,R.J.,Nature Reviews：Immunology,2004,4,512-520；Coffman,R.L.,Nat.Med.2007,13,552-559；Paul A.Roethle,J.Med.Chem.2013,56(18),7324-7333。 Toll-like receptors are expressed in a plurality of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Stimulation of Toll-like receptors by a corresponding pathogen-associated microbial pattern (PAMP) or damage-associated molecular pattern (DAMP) triggers a signal cascade leading to transcription factors such as AP-1, NF-κB and interferon regulatory factors (pulse response function) Startup. This results in a number of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines to produce an immune response. To date, 13 Toll-like receptors have been discovered in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are mainly expressed on the cell surface, and Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. different Toll-like receptors recognize ligands derived from different pathogens. For Toll-like receptor 7 (TLR7), it is mainly induced by plasma cell-like dendritic cell (pDC) expression and ligand recognition to induce secretion of interferon-α (IFN-α). Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8) are highly homologous. Thus the TLR7 ligand is in most cases also a TLR8 ligand. TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and chemokines. Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C, and TNF-α is a pro-inflammatory cytokine, and excessive secretion may cause serious side effects. Therefore, the selectivity for TLR7 and TLR8 is critical for the development of TLR7 agonists for the treatment of viral infectious diseases. Several TLR7 agonists have been reported, such as imiquimod, resiquimod, and GS-9620. However, there is still a great need for new TLR7 agonists with better selectivity, activity and safety. We have discovered a series of novel pyrrolopyrimidine derivatives that are agonists of TLR7. Background research and development materials are referred to the following journal articles: Hoffmann, JA, Nature, 2003, 426, p33-38; Akira, S., Takeda, K., and Kaisho, T., Annual. Rev. Immunology, 2003, 21, 335-376 ; Ulevitch, RJ, Nature Reviews: Immunology, 2004, 4, 512-520; Coffman, RL, Nat. Med. 2007, 13, 552-559; Paul A. Roethle, J. Med. Chem. 2013, 56 (18), 7324 7333.

本發明的目的在於提供一種式(I)所示化合物或其藥學上可接受的鹽， It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

式中，L1、L2分別獨立地選自-O-、-CH2-、-S-、-NH-、-NHC(=O)-、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O)2-、-NHS(=O)2-或-S(=O)2NH-，其中上述之-CH2-、-NH-、-NHC(=O)-、-C(=O)NH-、-NHS(=O)2-或-S(=O)2NH-任選被一種或複數種R4取代；R1選自氫、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基，其中上述之C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；R2選自氫、鹵素、氰基、羥基、巰基、胺基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基，其中上述之羥基、巰基、胺基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；B選自C3-10環烴基、3-10員雜環烴基、芳基、雜芳基；L3選自C0-6亞烷基、亞胺基、-O-、-S-、-S(=O)-或-S(=O)2-，其中上述之C0-6亞烷基、亞胺基任選被一種或複數種R4取代；R3選自氫、胺基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴 基、3-10員雜環烴基、芳基、雜芳基，其中上述之胺基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；或R3、L3與B環上鄰位原子一起形成飽和或不飽和的5-8員環，上述之5-8員環任選被一種或複數種R4取代；n為0、1、2、3、4或5；R4選自鹵素、氰基、-R、-OR、=O、-SR、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、-NRC(=O)R、-NRC(=O)OR、-NRC(=O)NRR、-C(=O)NRR、-C(=O)OR、-OC(=O)NRR、-OC(=O)OR、-C(=O)R、-S(=O)2OR、-S(=O)2R、-OS(=O)2OR、-S(=O)2NRR、-S(=O)R、-NRS(=O)2R、-NRS(=O)2NRR、-NRS(=O)2OR、-OP(=O)(OR)2、-P(=O)(OR)2、-C(=O)R、-C(=S)R、-C(=O)OR、-C(=S)OR、-C(=O)SR、-C(=S)SR、-C(=O)NRR、-C(=S)NRR、-C(=NR)NRR或-NRC(=NR)NRR；R獨立地選自H、C1-8烷基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基、芳基烷基、雜芳基烷基；並且，當L1為-CH2-或-NH-時，R3不為H。 Wherein L 1 and L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-, -NHC(=O)-, -C(=O)-, -C(= O) NH-, -S(=O)-, -S(=O) 2 -, -NHS(=O) 2 - or -S(=O) 2 NH-, wherein -CH 2 -, - NH-, -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 - or -S(=O) 2 NH- are optionally substituted by one or a plurality of R 4 ; 1 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally substituted by one or more R 4 is substituted; R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, amine, COOH, -CONH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C a 3-10 cycloalkyl group, a 3-10 membered heterocycloalkyl group, an aryl group, a heteroaryl group, wherein the above-mentioned hydroxyl group, mercapto group, amine group, COOH, -CONH 2 , C 1-10 alkyl group, C 2-10 alkenyl group , C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally substituted by one or more R 4 ; B is selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, An aryl group; L 3 is selected from C 0-6 alkylene, group, -O -, - S -, - S (= O) - or -S (= O) 2 -, wherein the above-described C 0- 6 alkylene, imido group optionally substituted by one or more of R 4 ; R 3 is selected from hydrogen, amine, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10cycloalkyl , 3-10 membered heterocycloalkyl, aryl, heteroaryl, wherein the above amino group, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 a -10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally substituted by one or more R 4 groups; or R 3 , L 3 together with an ortho atom on the B ring to form a saturated or unsaturated 5-8 member ring, the above 5-8 member ring is optionally substituted by one or more kinds of R 4 ; n is 0, 1, 2, 3, 4 or 5; R 4 is selected from halogen, cyano, -R, -OR, =O, -SR, -NR 2 , =NR, -C(halogen) 3 , -CR(halogen) 2 , -CR 2 (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) 2 OR, -S(=O) 2 R, -OS(=O) 2 OR , -S(=O) 2 NRR, -S(=O)R, -NRS(=O) 2 R, -NRS(=O) 2 NRR, -NRS(=O) 2 OR, -OP(= O)(OR) 2 , -P(=O)(OR) 2 , -C(=O)R, -C(=S)R, -C(=O)OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR)NRR or -NRC(=NR)NRR; R independent Is selected from H, C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and, when L 1 When it is -CH 2 - or -NH-, R 3 is not H.

在式(I)化合物的一些實施方案中，L1、L2分別獨立地選自-O-、-CH2-、-S-、-NH-、-C(=O)-、-S(=O)-或-S(=O)2-，其中上述之-CH2-、-NH-任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，L1、L2分別獨立地選自-O-、-CH2-、-S-、-NH-，其中上述之-CH2-、-NH-任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，L1、L2分別獨立地選自-O-、-CH2-，其中上述之-CH2-任選被一種或複數種R4取代。 In some embodiments of the compound of Formula (I), L 1 , L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-, -C(=O)-, -S ( =O)- or -S(=O) 2 -, wherein -CH 2 -, -NH- described above are optionally substituted by one or a plurality of R 4 . In some embodiments of the compound of Formula (I), L 1 , L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-, wherein -CH 2 -, -NH- Optionally substituted with one or more of R 4 . In some embodiments of a compound of Formula (I), L 1 , L 2 are each independently selected from -O-, -CH 2 -, wherein -CH 2 - is optionally substituted with one or more R 4 .

在式(I)化合物的一些實施方案中，R1選自氫、C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基，其中上述之C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，R1選自C1-6烷基，其中上述之C1-6烷基任選被一種或複數種R4取代。 In some embodiments of a compound of Formula (I), R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, wherein the above-described C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, The aryl or heteroaryl group is optionally substituted by one or a plurality of R 4 groups. In some embodiments of a compound of Formula (I), R 1 is selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 4 .

在式(I)化合物的一些實施方案中，R2選自氫、鹵素、氰基、羥基、巰基、胺基、CHO、COOH、-CONH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基，其中上述之羥基、巰基、胺基、CHO、COOH、-CONH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，R2選自氫、鹵素、氰基、羥基、胺基、-CONH2、C1-6烷基，其中上述之羥基、胺基、-CONH2、C1-6烷基任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，R2選自氫、氰基、-CONH2，其中上述之-CONH2任選被一種或複數種R4取代。 In some embodiments of a compound of Formula (I), R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, amine, CHO, COOH, -CONH 2 , C 1-6 alkyl, C 2-6 olefin a group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, a 3-6 membered heterocycloalkyl group, an aryl group, a heteroaryl group, wherein the above-mentioned hydroxyl group, mercapto group, amine group, CHO, COOH, -CONH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl optionally substituted by one or more R 4 Replace. In some embodiments of compounds of formula (I), R 2 is selected from hydrogen, halo, cyano, hydroxy, amino, -CONH 2, C 1-6 alkyl, wherein the above-described hydroxyl, amine, -CONH 2 The C 1-6 alkyl group is optionally substituted by one or a plurality of R 4 groups. In some embodiments of a compound of Formula (I), R 2 is selected from the group consisting of hydrogen, cyano, and -CONH 2 , wherein -CONH 2 described above is optionally substituted with one or more R 4 groups.

在式(I)化合物的一些實施方案中，B選自芳基、雜芳基。在式(I)化合物的一些實施方案中，B選自5-7員芳基、5-7員雜芳基。在式(I)化合物的一些實施方案中，B選自苯基、吡啶基嘧啶基、縫嗪基(pyridazinyl)、吡嗪基(pyrazine)、噻吩基、噻唑基、呋喃基、噁唑基(Oxazole)、噻二唑基、異噁唑基、噁二唑基、吡咯基、咪唑基、吡唑基、異噻唑基、***基。在式(I)化合物的一些實施方案中，B選自苯基、吡啶基。 In some embodiments of a compound of Formula (I), B is selected from aryl, heteroaryl. In some embodiments of a compound of Formula (I), B is selected from the group consisting of 5-7 membered aryl, 5-7 membered heteroaryl. In some embodiments of a compound of Formula (I), B is selected from the group consisting of phenyl, pyridylpyrimidinyl, pyridazinyl, pyrazine, thienyl, thiazolyl, furyl, oxazolyl ( Oxazole), thiadiazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl. In some embodiments of a compound of Formula (I), B is selected from the group consisting of phenyl, pyridyl.

在式(I)化合物的一些實施方案中，L3選自C0-6亞烷基，其中上 述之C0-6亞烷基任選被一種或複數種R4取代。 In some embodiments of compounds of formula (I) is, L 3 is selected from C 0-6 alkylene group, wherein the above-described C 0-6 alkylene group optionally substituted with a plurality of kinds by one or R 4.

在式(I）化合物的一些實施方案中，R3選自氫、胺基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基，其中上述之胺基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；或R3、L3與B環上鄰位原子一起形成飽和或不飽和的5-8員環，上述之5-8員環任選被一種或複數種R4取代。在式(I)化合物的一些實施方案中，R3選自氫、胺基、C1-6烷基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基，其中上述之胺基、C1-6烷基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；或R3、L3與B環上鄰位原子一起形成飽和或不飽和的5-8員環，上述之5-8員環任選被一種或複數種R4取代。 In some embodiments of a compound of Formula (I), R 3 is selected from the group consisting of hydrogen, amine, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, aryl, heteroaryl, wherein the above amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 3- The 8-membered heterocycloalkyl, aryl, heteroaryl is optionally substituted with one or more R 4 groups; or R 3 , L 3 together with the ortho atom of the B ring form a saturated or unsaturated 5-8 membered ring, The 5-8 member ring is optionally substituted with one or more R 4 groups. In some embodiments of a compound of Formula (I), R 3 is selected from the group consisting of hydrogen, amine, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, Wherein the above-mentioned amine group, C 1-6 alkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocycloalkyl group, aryl group, heteroaryl group are optionally substituted by one or more kinds of R 4 ; or R 3 , L 3 together with the ortho atom on the B ring form a saturated or unsaturated 5-8 membered ring, and the above 5-8 membered ring is optionally substituted with one or more of R 4 .

在式(I)化合物的一些實施方案中，R4選自鹵素、氰基、-R、-OR、=O、-SR、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、-NRC(=O)R、-C(=O)NRR、-C(=O)OR、-OC(=O)NRR、-C(=O)R、-S(=O)2OR、-S(=O)2R、-OS(=O)2OR、-S(=O)2NRR、-S(=O)R、-NRS(=O)2R、-C(=O)R、-C(=O)OR或-C(=O)NRR。在式(I)化合物的一些實施方案中，R4選自鹵素、氰基、-R、-OR、=O、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)。在式(I)化合物的一些實施方案中，R4選自鹵素、-R、-OR、=O。 In some embodiments of a compound of Formula (I), R 4 is selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR 2 , =NR, -C(halogen) 3 , -CR ( Halogen) 2 , -CR 2 (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , -NRC(=O)R, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -C(=O)R, -S(=O) 2 OR, -S(=O) 2 R, -OS(=O) 2 OR , -S(=O) 2 NRR, -S(=O)R, -NRS(=O) 2 R, -C(=O)R, -C(=O)OR or -C(=O)NRR . In some embodiments of a compound of Formula (I), R 4 is selected from the group consisting of halogen, cyano, -R, -OR, =O, -NR 2 , =NR, -C(halogen) 3 , -CR(halogen) 2 , -CR 2 (halogen). In some embodiments of a compound of Formula (I), R 4 is selected from the group consisting of halogen, -R, -OR, =O.

在一些實施方案中，式(I)化合物選自以下化合物： In some embodiments, the compound of formula (I) is selected from the group consisting of:

本發明另一方面提供了一種治療病毒感染的方法，該方法包括給予治療有效量的式(I)化合物或其藥學上可接受的鹽。 Another aspect of the invention provides a method of treating a viral infection, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

本發明的另一個方面提供了一種式(I)化合物或其藥學上可接受的鹽在製備治療病毒感染的藥物的用途。 Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a viral infection.

在本發明的一些實施方案中，該病毒感染是登革熱病毒、黃熱病毒、西尼祿病毒、日本腦炎病毒、蜱傳腦炎病毒、昆津病毒、墨累山谷腦炎病毒、聖路易腦炎病毒、鄂木斯克出血熱病毒、牛病毒性腹瀉病毒、濟卡病毒、肝炎病毒感染。在本發明的一個實施方案中，該病毒感染是肝炎病毒感染。在本發明的一個實施方案中，該病毒感染是乙型或丙型肝炎病毒感染。 In some embodiments of the invention, the viral infection is dengue virus, yellow fever virus, sinuo virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis brain Inflammatory virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, hepatitis virus infection. In one embodiment of the invention, the viral infection is a hepatitis virus infection. In one embodiment of the invention, the viral infection is a hepatitis B or hepatitis C virus infection.

本發明的另一方面提供了一種藥物組合物，其包含治療有效量的式(I)化合物或其藥學上可接受的鹽；和一種或複數種藥學上可接受的載體或賦形劑。本發明的藥物組合物可以進一步含有一種或複數種額外的治療劑。 Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions of the invention may further comprise one or more additional therapeutic agents.

本發明的藥物組合物可通過將本發明的化合物或其鹽與適宜的藥學上可接受的載體組合而製備，例如可配製成固態、半固態、液態或氣態製劑，如片劑、丸劑、膠囊劑、粉劑、顆粒劑、膏劑、乳劑、懸浮劑、溶液劑、栓劑、注射劑、吸入劑、凝膠劑、微球及氣溶膠等。 The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, Capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.

給予本發明的化合物或其藥物可接受的鹽或其立體異構體或其藥物組合物的典型途徑包括但不限於口服、直腸、透黏膜、經腸給 藥，或者局部、經皮、吸入、腸胃外、舌下、***內、鼻內、眼內、腹膜內、肌內、皮下、靜脈內給藥。 Typical routes for administration of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration Drug, or topical, transdermal, inhaled, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.

本發明的藥物組合物可以採用本領域眾所周知的方法製造，如常規的混合法、溶解法、製粒法、製糖衣藥丸法、磨細法、乳化法、冷凍乾燥法等等。 The pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.

對於口服給藥，可以通過將活性化合物與本領域熟知的藥學上可接受的載體混合來配製該藥物組合物。這些載體能使本發明的化合物被配製成片劑、丸劑、錠劑、糖衣劑、膠囊劑、液體、凝膠劑、漿劑、懸浮劑等，用於對患者的口服給藥。 For oral administration, the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

可以通過常規的混合、填充或壓片方法來製備固體口服組合物。例如，可通過下述方法獲得：將所述的活性化合物與固體賦形劑混合，任選地碾磨所得的混合物，如果需要則加入其它合適的輔劑，然後將該混合物加工成顆粒，得到了片劑或糖衣劑的核心。適合的輔料包括但不限於：黏合劑、稀釋劑、崩解劑、潤滑劑、助流劑、甜味劑或矯味劑等。如微晶纖維素、葡萄糖溶液、***膠漿、明膠溶液、蔗糖和澱粉糊；滑石、澱粉、硬脂酸鎂、硬脂酸鈣或硬脂酸；乳糖、蔗糖、澱粉、甘露糖醇、山梨糖醇或磷酸二鈣；二氧化矽；交聯羧甲基纖維素鈉、預交化澱粉、澱粉羥乙酸鈉、藻酸、玉米澱粉、馬鈴薯澱粉、甲基纖維素、瓊脂、羧甲基纖維素、交聯聚乙烯吡咯烷酮等。可以根據通常藥物實踐中公知的方法任選地對糖衣劑的核心進行包衣，尤其使用腸溶包衣。 Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; cerium oxide; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone. The core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.

藥物組合物還可適用於腸胃外給藥，如合適的單位劑型的無菌溶液劑、混懸劑或凍乾產品。能夠使用適當的賦形劑，例如填充劑、緩衝劑或表面活性劑。 The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form. Suitable excipients such as fillers, buffers or surfactants can be used.

本文所述的式(I)化合物或其藥學上可接受的鹽可以通過任何適用的途徑和方法給藥，例如通過口服或腸胃外(例如，靜脈內)給藥。式(I)化合物的治療有效量為從約0.0001到20mg/Kg體重/天，例如從0.001到10mg/Kg體重/天。 The compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, can be administered by any suitable route and method, for example by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound of formula (I) is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.

式(I)化合物的劑量頻率由患者個體的需求決定，例如，每天1次或2次，或每天更多次。給藥可以是間歇性的，例如，其中在若干天的期間內，患者接受式(I)化合物的每日劑量，接著在若干天或更多天的期間，患者不接受式(I)化合物的每日劑量。 The dosage frequency of the compound of formula (I) is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of a compound of formula (I), followed by a patient who does not receive a compound of formula (I) for a period of several days or more Daily dose.

有關定義：Related definitions:

除非另有說明，本文所用的下列術語和短語具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。 The following terms and phrases used herein have the following meanings unless otherwise indicated. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

術語“任選”或“任選地”是指隨後描述的事件或情況可能發生或可能不發生，該描述包括發生所述事件或情況和不發生所述事件或情況。例如，乙基“任選”被鹵素取代，指乙基可以是未被取代的(CH2CH3)、單取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本領域技術人員可理解，對於包含一個或多個取代基的任何基團，不會引入任何在空間上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, an ethyl group "optionally" substituted with halo, refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.

本文所用的Cm-n指該部分中具有m-n個碳原子。例如，“C3-10環烷基”指該環烷基具有3-10個碳原子。“C0-6亞烷基”指該亞烷基具有0-6個碳原子，當亞烷基具有0個碳原子時，該基團為鍵。 As used herein, C mn means having mn carbon atoms in this moiety. For example, "C 3-10 cycloalkyl" means that the cycloalkyl group has 3 to 10 carbon atoms. The "C 0-6 alkylene group" means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.

本文中的數字範圍，是指給定範圍中的各個整數。例如“C1-10” 是指該基團可具有1個碳原子、2個碳原子、3個碳原子、4個碳原子、5個碳原子、6個碳原子、7個碳原子、8個碳原子、9個碳原子或10個碳原子。 The numerical range in this document refers to each integer in a given range. For example, "C 1-10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.

術語“被取代”是指特定原子上的任意一個或多個氫原子被取代基取代，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為酮基(即=O)時，意味著兩個氫原子被取代，酮取代不會發生在芳香基上。 The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are substituted, and the ketone substitution does not occur on the aryl group.

當任何變數(例如R)在化合物的組成或結構中出現一次以上時，其在每一種情況下的定義都是獨立的。因此，例如，如果一個基團被0-2個R所取代，則所述基團可以任選地至多被兩個R所取代，並且每種情況下的R都有獨立的選項。此外，取代基及/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。 When any variable (e.g., R) occurs more than once in the composition or structure of the compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

除非另有規定，術語“雜”表示雜原子或雜原子團(即含有雜原子的原子團)，即碳和氫以外的原子或含有這些原子的原子團，雜原子獨立地選自氧、氮、硫、磷、矽、鍺、鋁、硼。在出現兩個或更多雜原子的實施方式中，所述兩個或更多雜原子可彼此相同，或者所述兩個或更多雜原子中的部分或全部彼此不同。 Unless otherwise specified, the term "hetero" means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, antimony, bismuth, aluminum, boron. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

術語“鹵”或“鹵素”是指氟、氯、溴和碘。 The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

術語“羥基”指-OH基團。 The term "hydroxy" refers to an -OH group.

術語“氰基”指-CN基團。 The term "cyano" refers to a -CN group.

術語“巰基”指-SH基團。 The term "mercapto" refers to a -SH group.

術語“胺基”指-NH2基團。 The term "amino" refers to a -NH 2 group.

術語“烷基”是指由碳原子和氫原子組成的直鏈或支鏈的飽和的 脂肪烴基團，其通過單鍵與分子的其餘部分連接。烷基的非限制性實例包括但不限於甲基、乙基、丙基、2-丙基、正丁基、異丁基、第三-丁基、正-戊基、2-甲基丁基、新戊基、正己基、2-甲基己基、-CH2-環丙基等。 The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl , neopentyl, n-hexyl, 2-methylhexyl, -CH 2 -cyclopropyl, and the like.

術語“亞烷基”是指飽和的直鏈或支鏈或環狀烴基，其具有2個從母體烷的相同碳原子或兩個不同的碳原子上除去兩個氫原子所衍生出的殘基。亞烷基的非限制性實例包括但不限於亞甲基(-CH2-)、1,1-亞乙基(-CH(CH3)-)、1,2-亞乙基(-CH2CH2-)、1,1-亞丙基(-CH(CH2CH3)-)、1,2-亞丙基(-CH2CH(CH3)-)、1,3-亞丙基(-CH2CH2CH2-)、1,4-亞丁基(-CH2CH2CH2CH2-)等。 The term "alkylene" refers to a saturated straight or branched or cyclic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. . Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 ) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.

術語“亞胺基”指-NH-。 The term "imino" refers to -NH-.

術語“烯基”是指由碳原子和氫原子組成的直鏈或支鏈的具有至少一個雙鍵的不飽和脂肪族烴基。烯基的非限制性實例包括但不限於乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、異丁烯基、1,3-丁二烯基等。 The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

術語“炔基”是指由碳原子和氫原子組成的直鏈或支鏈的具有至少一個三鍵的不飽和脂肪族烴基。炔基的非限制性實例包括但不限於乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。 The term "alkynyl" means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡CC≡CH) or the like.

術語“環烴基”是指由碳原子和氫原子組成的飽和的或不飽和的非芳香性的環狀烴基，較佳包含1或2個環。所述環烴基可以是單環、稠合多環、橋環或螺環結構。環烴基的非限制性實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、雙環[2.2.1]庚基和螺[3.3]庚基等。 The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cyclic hydrocarbon group may be a monocyclic, fused polycyclic, bridged or spiro ring structure. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl, and the like.

術語“雜環烴基”是指無芳香性的單環、稠合多環、橋環或螺環體系基團，其中部分環原子是選自N、O、S(O)n(其中n為0、1或2)的雜原子，其餘環原子為C。這樣的環可以是飽和的或不飽和的(例如具有一個或多個雙鍵)，但是不具有完全共軛的π-電子體系。3員雜環烴基的實例包括但不限於環氧乙烷基、環硫乙烷基、環氮乙烷基，4員雜環烴基的實例包括但不限於吖丁啶基、噁丁環基、噻丁環基，5員雜環烴基的實例包括但不限於四氫呋喃基、四氫噻吩基、吡咯烷基、異噁唑烷基、噁唑烷基、異噻唑烷基、1,1-二氧代異噻唑烷基、噻唑烷基、咪唑烷基、四氫吡唑基、吡咯啉基、二氫呋喃基、二氫噻吩基，6員雜環烴基的實例包括但不限於呱啶基、四氫吡喃基、四氫噻喃基、嗎啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六環基、硫代嗎啉基、1,2-、1,4-二噻烷基、二氫吡啶基、四氫吡啶基、二氫吡喃基、四氫吡喃基、二氫噻喃基，7員雜環烴基的實例包括但不限於氮雜環庚烷基、氧雜環庚烷基、硫雜環庚烷基、氧雜氮雜雙環[2.2.1]庚基和氮雜螺[3.3]庚基等。 The term "heterocycloalkyl" refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system wherein some of the ring atoms are selected from N, O, S(O) n (where n is 0) a hetero atom of 1 or 2), the remaining ring atoms being C. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated π-electron system. Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an oxiranyl group, an ethylenethio group, a cycloalkylethane group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, acetobutyl, thidium Examples of ring-based, 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxo Examples of thiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl include, but are not limited to, acridinyl, tetrahydropyridyl Cyclol, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiazolidine, 1,4-dioxacyclyl, thiomorpholinyl, 1,2-, 1,4 -Dithiaalkyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, examples of 7-membered heterocycloalkyl, including but not limited to azepane Alkyl, oxetanyl, thiaheptanyl, oxazabicyclo[2.2.1]heptyl and azaspiro[3.3]heptyl, and the like.

術語“芳基”是指具有共軛的π電子體系的全碳單環或稠合多環的芳香環基團。例如，芳基可以具有6-20個碳原子，6-14個碳原子或6-12個碳原子。芳基的非限制性實例包括但不限於苯基、萘基和蒽基等。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

術語“雜芳基”是指單環或稠合多環體系，其中含有至少一個選自N、O、S的環原子，其餘環原子為C，並且具有至少一個芳香環。雜芳基的非限制性實例包括但不限於吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、異喹啉基、四唑基、***基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚 基、異吲哚基等。 The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, anthracene Base, isomeric base, etc.

術語“藥學上可接受的”，是針對那些化合物、材料、組合物及/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。 The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

作為藥學上可接受的鹽，例如，可以提及金屬鹽、銨鹽、與有機鹼形成的鹽、與無機酸形成的鹽、與有機酸形成的鹽、與鹼性或者酸性胺基酸形成的鹽等。金屬鹽的非限制性實例包括但不限於鹼金屬的鹽，例如鈉鹽、鉀鹽等；鹼土金屬的鹽，例如鈣鹽、鎂鹽、鋇鹽等；鋁鹽等。與有機鹼形成的鹽的非限制性實例包括但不限於與三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、環己胺、二環己基胺等形成的鹽。與無機酸形成的鹽的非限制性實例包括但不限於與鹽酸、氫溴酸、硝酸、硫酸、磷酸等形成的鹽。與有機酸形成的鹽的非限制性實例包括但不限於與甲酸、乙酸、三氟乙酸、富馬酸、草酸、蘋果酸、馬來酸、酒石酸、檸檬酸、琥珀酸、甲磺酸、苯磺酸、對甲基苯磺酸等形成的鹽。與鹼性胺基酸形成的鹽的非限制性實例包括但不限於與精胺酸、離胺酸、鳥胺酸等形成的鹽。與酸性胺基酸形成的鹽的非限制性實例包括但不限於與天冬胺酸、麩胺酸等形成的鹽。 As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, and a basic or acidic amino acid may be mentioned. Salt and so on. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like. Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.

本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物通過常規化學方法合成。一般情況下，這樣的鹽的製備方法是：在水或有機溶劑或兩者的混合物中，經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。一般地，較佳為醚、乙酸乙酯、乙醇、異丙醇或乙腈等非水介質。 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

本發明的某些化合物可以以非溶劑化形式或者溶劑化形式存在，包括水合物形式。一般而言，溶劑化形式與非溶劑化的形式相當，都包含在本發明的範圍之內。本發明的某些化合物可以以多晶或無定形形式存在。 Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.

本發明的某些化合物可以具有不對稱碳原子(光學中心)或雙鍵。外消旋體、非對映異構體、幾何異構體和單個的異構體都包括在本發明的範圍之內。 Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

本文中消旋體、兩可非外消旋(ambiscalemic)及非外消旋(scalemic)或者對映異構體純的化合物的圖示法來自Maehr,J.Chem.Ed.1985,62：114-120。除非另有說明，用楔形鍵和虛線鍵表示一個立體中心的絕對構型。當本文所述化合物含有烯屬雙鍵或其它幾何不對稱中心，除非另有規定，它們包括E、Z幾何異構體。同樣地，所有的互變異構形式均包括在本發明的範圍之內。 Graphical representations of racemates, ambiscalemic and non-racemic or enantiomerically pure compounds from Maehr, J. Chem. Ed. 1985, 62: 114. -120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

本發明的化合物可以存在特定的幾何或立體異構體形式。本發明設想所有的這類化合物，包括順式和反式異構體、(-)-和(+)-對對映異構體、(R)-和(S)-對映異構體、非對映異構體、(D)-異構體、(L)-異構體，及其外消旋混合物和其他混合物，例如對映異構體或非對映異構體富集的混合物，所有這些混合物都屬於本發明的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構體以及它們的混合物，均包括在本發明的範圍之內。 The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the ( R )- and ( S )-enantiomers, Diastereomers, ( D )-isomers, ( L )-isomers, and racemic mixtures thereof, and other mixtures, such as enantiomers or diastereomeric enriched mixtures All such mixtures are within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

可以通過的手性合成或手性試劑或者其他常規技術製備光學活性的(R)-和(S)-異構體以及D和L異構體。如果想得到本發明某化合物的一種對映異構體，可以通過不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映異構體混合物分離，並且輔助基 團裂開以提供純的所需對映異構體。或者，當分子中含有鹼性官能團(如胺基)或酸性官能團(如羧基)時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後通過本領域所公知的分步結晶法或色譜法進行非對映異構體拆分，然後回收得到純的對映異構體。此外，對映異構體和非對映異構體的分離通常是通過使用色譜法完成的，所述色譜法採用手性固定相，並任選地與化學衍生法相結合(例如由胺生成胺基甲酸鹽)。 The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved The pure desired enantiomer is provided. Alternatively, when a molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, and then is known in the art. The diastereomeric resolution is carried out by step crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amine from an amine) Carbamate).

本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚(3H)、碘-125(125I)或C-14(14C)。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

術語“藥學上可接受的載體”是指對有機體無明顯刺激作用，而且不會損害該活性化合物的生物活性及性能的那些載體。“藥學上可接受的載體”是指與活性成份一同給藥的、有利於活性成份給藥的惰性物質，包括但不限於國家食品藥品監督管理局許可的可接受的用於人或動物(例如家畜)的任何助流劑、增甜劑、稀釋劑、防腐劑、染料/著色劑、矯味增強劑、表面活性劑、潤濕劑、分散劑、崩解劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。所述載體的非限制性實例包括碳酸鈣、磷酸鈣、各種糖和各類澱粉、纖維素衍生物、明膠、植物油和聚乙二醇等。關於載體的其他資訊，可以參考Remington：The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams & Wilkins(2005)，該文獻的內容通過引用的方式併入本文。 The term "pharmaceutically acceptable carrier" refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, etc. Penetrant, solvent or emulsifier. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

術語“賦形劑”通常是指配製有效的藥物組合物所需要載體、稀釋劑及/或介質。 The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

針對藥物或藥理學活性劑而言，術語“有效量”或“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。對於本發明中的口服劑型，組合物中一種活性物質的“有效量”是指與該組合物中另一種活性物質聯用時為了達到預期效果所需要的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本領域技術人員根據常規試驗確定。 The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

術語“活性成分”、“治療劑”，“活性物質”或“活性劑”是指一種化學實體，它可以有效地治療目標紊亂、疾病或病症。 The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

本發明的化合物可以通過本領域技術人員所熟知的複數種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，較佳的實施方式包括但不限於本發明的實施例。 The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, including but not limited to embodiments of the invention.

本發明具體實施方式的化學反應是在合適的溶劑中完成的，所述的溶劑須適合於本發明的化學變化及其所需的試劑和物料。為了獲得本發明的化合物，有時需要本領域技術人員在已有實施方式的基礎上對合成步驟或者反應流程進行修改或選擇。 The chemical reaction of a particular embodiment of the invention is carried out in a suitable solvent which is suitable for the chemical changes of the invention and the reagents and materials required thereof. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.

本領域任何合成路線規劃中的一個重要考量因素是為反應性官能團(如本發明中的胺基)選擇合適的保護基。對於經過訓練的從業者來說，Greene and Wuts的Protective Groups In Organic Synthesis,Wiley and Sons,1991是這方面的權威。本發明引用的所有參考文獻整體上併入本發明。 An important consideration in any synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group such as an amine group in the present invention. For trained practitioners, Greene and Wuts' Protective Groups In Organic Synthesis, Wiley and Sons, 1991 is the authority in this regard. All references cited in the present invention are incorporated by reference in their entirety.

本發明通式(II)的化合物可以由有機合成領域技術人員通過下述路線1用本領域的標準方法來製備： The compounds of the formula (II) of the present invention can be prepared by those skilled in the art of organic synthesis by standard methods in the art using the following Scheme 1:

通用流程1General process 1

從2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1-1)(商品化試劑)出發，用SEM保護，然後用NH3取代得到2-氯-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(1-2)。使用不同種類的醇(通式R1OH)、比如正丁醇，在鈉的作用下形成醇鈉，然後發生取代反應生成中間體(1-3)。然後與NBS反應，得到溴化物(1-4)。溴化物(1-4)在正丁基鋰作用下溴被交換成鋰鹽，然後與醛(R5選自甲醛基或任選帶有保護基的L3-R3)反應，得到仲醇(1-5)。仲醇(1-5)經過0-3步轉 化，然後用三氟乙酸、三乙基矽烷還原同時脫除保護基，生成最終產物(II)。 Starting from 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (1-1) (commercial reagent), protected by SEM, then substituted with NH 3 to give 2-chloro-5-(( 2-(Trimethylcarbinyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (1-2). A different type of alcohol (formula R 1 OH), such as n-butanol, is used to form sodium alkoxide under the action of sodium, followed by a substitution reaction to form an intermediate (1-3). It is then reacted with NBS to give bromide (1-4). The bromide (1-4) is exchanged for lithium salt under the action of n-butyllithium, and then reacted with an aldehyde (R 5 is selected from a formaldehyde group or optionally a protecting group L 3 -R 3 ) to obtain a secondary alcohol. (1-5). The secondary alcohol (1-5) is converted in steps 0-3, and then reduced with trifluoroacetic acid and triethyldecane while the protecting group is removed to give the final product (II).

本發明通式(III)的化合物可以由有機合成領域技術人員通過下述路線2用本領域的標準方法來製備： The compounds of the formula (III) according to the invention can be prepared by the skilled artisan by standard methods in the art by the following Scheme 2:

通用流程2General process 2

從按照路線1製備的中間體(2-1)(R6選自羧酸甲酯)出發，用NBS反應得到溴化物(2-2)。溴化物(2-2)進一步通過1到3步反應(比如用DIBAL-H還原成醛，然後與吡咯在甲醇溶劑中用NaBH3CN還原胺化)得到另一種溴化物(2-3)。溴化物(2-3)在Zn(CN)2/Zn/Pd2(dba)3/dppf/DMF條件下轉化成2-氰基化合物(2-4)。用三氟乙酸 脫除SEM得到最終產物(III)。 Starting from the intermediate (2-1) prepared according to Scheme 1 (R 6 is selected from methyl carboxylate), bromide (2-2) is obtained by reaction with NBS. The bromide (2-2) is further subjected to a 1 to 3 step reaction (for example, reduction to an aldehyde with DIBAL-H, followed by reductive amination with a pyrrole in a methanol solvent with NaBH 3 CN) to give another bromide (2-3). The bromide (2-3) is converted to the 2-cyano compound (2-4) under Zn(CN) 2 /Zn/Pd 2 (dba) 3 /dppf/DMF conditions. The SEM was removed with trifluoroacetic acid to give the final product (III).

本領域技術人員應該知道，為了製備本發明化合物，反應路線1和2中反應步驟的順序可以是不同的，這也屬於本發明的範圍。 It will be appreciated by those skilled in the art that the order of the reaction steps in Schemes 1 and 2 can be varied for the preparation of the compounds of the invention, and is also within the scope of the invention.

為清楚起見，發明進一步用實施例來闡述。但是實施例不局限於定義或者指定發明範圍。 For the sake of clarity, the invention is further illustrated by the examples. However, the embodiments are not limited to the definition or the scope of the invention.

本發明所使用的所有溶劑是市售的，無需進一步純化即可使用。反應一般是在惰性氮氣下、無水溶劑中進行的。質子核磁共振資料記錄在Bruker Avance III 400(400MHz)分光儀上，化學位移以四甲基矽烷低場處的(ppm)表示。質譜是在安捷倫1200系列加6110(&1956A)上測定。LC/MS或Shimadzu MS包含一個DAD：SPD-M20A(LC)和Shimadzu Micromass 2020檢測器。質譜儀配備有一個正或負模式下操作的電噴霧離子源(ESI)。 All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out under an inert nitrogen atmosphere in an anhydrous solvent. Proton nuclear magnetic resonance data was recorded on a Bruker Avance III 400 (400 MHz) spectrometer with chemical shifts expressed in ppm at the low field of tetramethyl decane. Mass spectra were measured on an Agilent 1200 Series Plus 6110 (&1956A). LC/MS or Shimadzu MS contains a DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in either positive or negative mode.

本發明採用下述縮略詞：aq代表含水的；SEMCl代表(2-(氯甲氧基)乙基)三甲基矽烷；eq代表當量；1,3-DPPP代表1,3-雙(二苯基膦基)丙烷；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲醯胺；NMP代表N-甲基吡咯烷酮；EtOAc代表乙酸乙酯；i-PrOH代表異丙醇；EtOH代表乙醇；MeOH是甲醇；THF代表四氫呋喃；BPO代表過氧苯甲醯；BOC代表第三丁氧羰基；HOAc為乙酸；NaCNBH3是氰基硼氫化鈉；LAH為氫化鋁鋰；9-BBN是9-硼二環壬烷；MsCl是甲磺醯氯；RT為室溫；O/N為過夜；Boc2O是二碳酸二第三丁酯；TFA為三氟乙酸；TFAA為三氟乙酸酐；TEA是三乙胺；DIBAL-H為二異丁基氫化鋁；NBS為溴代丁二醯胺；DPPF是1,1'-雙(二苯基膦基)二茂鐵；Ph3P是三苯基膦；Pd(OAc)2是乙酸鈀；Pd(PPh3P)2CL2是雙(三苯基膦)氯化鈀；Pd2(dba)3是三(亞 苄基丙酮)二鈀；XANTPHOS是4,5-雙(二苯基膦基)-9,9-二甲基氧雜蒽；n-BuLi是正丁基鋰。 The present invention employs the following abbreviations: aq for aqueous; SEMCl for (2-(chloromethoxy)ethyl)trimethylnonane; eq for equivalent; 1,3-DPPP for 1,3-double (two Phenylphosphino)propane; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc stands for ethyl acetate; i-PrOH stands for Propanol; EtOH for ethanol; MeOH for methanol; THF for tetrahydrofuran; BPO for benzophenone; BOC for third butoxycarbonyl; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride; LAH for lithium aluminum hydride; 9-BBN is 9-borobicyclononane; MsCl is methanesulfonium chloride; RT is room temperature; O/N is overnight; Boc 2 O is dibutyl butyl carbonate; TFA is trifluoroacetic acid; Trifluoroacetic anhydride; TEA is triethylamine; DIBAL-H is diisobutylaluminum hydride; NBS is bromobutane; DPPF is 1,1'-bis(diphenylphosphino)ferrocene; Ph 3 P is triphenylphosphine; Pd(OAc) 2 is palladium acetate; Pd(PPh 3 P) 2 CL 2 is bis(triphenylphosphine)palladium chloride; Pd 2 (dba) 3 is tris (benzylidene) Acetone) dipalladium; XANTPHOS is 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime n-BuLi is n-butyllithium.

化合物經手工或者ChemDraw®軟體命名，市售化合物採用供應商目錄名稱。 Compounds are named by hand or by ChemDraw® software, and commercial compounds are listed under the supplier's catalogue.

用配有ShimadzuSIL-20A自動進樣器和日本島津DAD：SPD-M20A探測器的島津LC20AB系統進行高效液相色譜分析，採用XtimateC18(3m填料，規格為2.1x300mm)色譜柱。0-60AB_6分鐘的方法：應用線性梯度，以100%A(A為0.0675%TFA的水溶液)開始洗脫，並以60%B(B為0.0625%TFA的MeCN溶液)結束洗脫，整個過程為4.2分鐘，然後以60%B洗脫1分鐘。將色譜柱再平衡0.8分鐘達到100：0，總執行時間為6分鐘。10-80AB_6分鐘的方法：應用線性梯度，以90%A(A為0.0675%TFA的水溶液)開始洗脫，並以80%B(B為0.0625%TFA的乙腈溶液)結束洗脫，整個過程為4.2分鐘，然後以80%B洗脫1分鐘。將色譜柱再平衡0.8分鐘達到90：10，總執行時間為6分鐘。柱溫為50℃，流速為0.8mL/min。二極體陣列檢測器掃描波長為200-400nm。 High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector, using a Xtimate C18 (3 m packing, size 2.1 x 300 mm) column. 0-60AB_6 min method: Apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN solution). The whole process is 4.2 minutes, then eluted with 60% B for 1 minute. The column was equilibrated for 0.8 minutes to reach 100:0 with a total execution time of 6 minutes. 10-80AB_6 min method: Apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end the elution with 80% B (B in 0.0625% TFA in acetonitrile). 4.2 minutes, then eluted with 80% B for 1 minute. The column was equilibrated for 0.8 minutes to reach 90:10 with a total execution time of 6 minutes. The column temperature was 50 ° C and the flow rate was 0.8 mL/min. The diode array detector has a scanning wavelength of 200-400 nm.

在Sanpont-group的矽膠GF254上進行薄層色譜分析(TLC)，常用紫外光燈照射檢出斑點，在某些情況下也採用其他方法檢視斑點，在這些情況下，用碘(10g矽膠中加入約1g碘並徹底混合而成)、香草醛(溶解大約1g香草醛於100mL 10% H2SO4中製得)、茚三酮(從Aldrich購得)或特殊顯色劑(徹底混合(NH4)6Mo7O24˙4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2O和50mL濃H2SO4而製得)展開薄層板，檢視化合物。採用Still,W.C.；Kahn,M.；and Mitra,M.Journal of Organic Chemistry,1978,43,2923-2925中所公開技術的類似方 法，在Silicycle的40-63μm(230-400目)矽膠上進行快速柱色譜。快速柱色譜或薄層色譜的常用溶劑是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯的混合物。 Thin layer chromatography (TLC) was performed on Sanpont-group gelatin GF254. Spots were detected by ultraviolet light irradiation. In some cases, spots were also observed by other methods. In these cases, iodine (10 g of silicone was added). About 1 g of iodine and thoroughly mixed), vanillin (dissolved in about 1 g of vanillin in 100 mL of 10% H 2 SO 4 ), ninhydrin (purchased from Aldrich) or special developer (completely mixed (NH) 4 ) 6 Mo 7 O 24 ̇ 4H 2 O, 5g(NH 4 ) 2 Ce(IV)(NO 3 ) 6 , 450mL H 2 O and 50mL of concentrated H 2 SO 4 are prepared) to develop a thin layer plate and to inspect the compound . A similar method of the technique disclosed in Still, WC; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923-2925 was carried out on a 40-63 μm (230-400 mesh) silicone of Silicycle. Fast column chromatography. A common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.

在Gilson-281 Prep LC 322系統上採用吉爾森UV/VIS-156探測器進行製備色譜分析，所採用的色譜柱是Agella Venusil ASB Prep C18,5m、150×21.2mm；Phenomenex Gemini C18、5m、150×30mm；Boston Symmetrix C18,5m、150×30mm；或者Phenomenex Synergi C18、4m、150×30mm。在流速約為25mL/min時，用低梯度的乙腈/水洗脫化合物，其中水中含有0.05% HCl、0.25% HCOOH或0.5% NH3˙H2O，總執行時間為8-15分鐘。 Preparative chromatographic analysis was performed on a Gilson-281 Prep LC 322 system using a Gilson UV/VIS-156 detector using Agella Venusil ASB Prep C18, 5 m, 150 x 21.2 mm; Phenomenex Gemini C18, 5 m, 150 × 30 mm; Boston Symmetrix C18, 5 m, 150 x 30 mm; or Phenomenex Synergi C18, 4 m, 150 x 30 mm. When a flow rate of about 25mL / min, with a low gradient of acetonitrile / water elution compound, wherein water containing 0.05% HCl, 0.25% HCOOH or 0.5% NH 3 ˙H 2 O, the total execution time of 8-15 minutes.

圖1：HDI乙型肝炎感染小鼠模型體內藥效學試驗藥效結果(血漿)。 Figure 1: Pharmacodynamic test results (plasma) in a mouse model of HDI hepatitis B infection.

圖2：HDI乙型肝炎感染小鼠模型體內藥效學試驗藥效結果(肝臟)。 Figure 2: Pharmacodynamic test results (liver) in a mouse model of HDI hepatitis B infection.

下面的具體實施例，其目的是使本領域的技術人員能更清楚地理解和實施本發明。它們不應該被認為是對本發明範圍的限制，而只是本發明的示例性說明和典型代表。 The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They are not to be considered as limiting the scope of the invention, but are merely illustrative and representative of the invention.

實施例1Example 1 2-丁氧基-7-(3-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

反應流程： Reaction process:

實施例1流程Example 1 process

步驟A：將2,4-二氯-5H-吡咯并[3,2-d]嘧啶(4克，21.4毫莫耳)溶解在無水四氫呋喃(30mL)中，然後在0攝氏度向其中分批加入氫化鈉(1.03克，60%的礦物油混合物，25.6毫莫耳)。反應液在室溫下攪拌30分鐘，將(2-(氯甲氧基)乙基)三甲基矽烷(3.9克，23.5毫莫耳)逐滴加入。室溫下再攪拌2小時，然後，用水(120毫升)稀釋，並用乙酸乙酯(100毫升×2)萃取。將合併的有機層用飽和碳酸鈉水溶液和鹽水洗滌，用無水硫酸鈉乾燥，並減壓濃縮。殘餘物用矽膠柱純化(洗脫劑：乙酸乙酯/石油醚5%至10%)，得到2,4-二氯-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(5.8克，85%)，為黃色固體。 Step A: 2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine (4 g, 21.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and then added portionwise at 0 ° C. Sodium hydride (1.03 g, 60% mineral oil mixture, 25.6 mmol). The reaction solution was stirred at room temperature for 30 minutes, and (2-(chloromethoxy)ethyl)trimethylnonane (3.9 g, 23.5 mmol) was added dropwise. After stirring at room temperature for further 2 hours, it was diluted with water (120 ml) and extracted with ethyl acetate (100 ml). The combined organic layers were washed with EtOAc EtOAc. The residue was purified with a silica gel column (eluent: ethyl acetate / petroleum ether 5% to 10%) to give 2,4-dichloro-5-((2-(trimethylmethylmethyl) ethoxy) Methyl)-5 H -pyrrolo[3,2-d]pyrimidine (5.8 g, 85%) as a yellow solid.

MS(ESI)M/Z：318[M+H+]。 MS (ESI) M / Z: 318 [M+H + ].

步驟B：在1000毫升高壓反應器中，將2,4-二氯-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(5克，15.8毫莫耳)、異丙醇(15毫升)和氨水(250毫升)混合，在100-110攝氏度下攪拌3小時。在冷卻到室溫後，將該混合物用水稀釋(250毫升)並過濾，得到2-氯-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，85%)，無需進一步純化。 Step B: 2,4-Dichloro-5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2 in a 1000 mL high pressure reactor -d] Pyrimidine (5 g, 15.8 mmol), isopropanol (15 ml) and aqueous ammonia (250 ml) were mixed and stirred at 100-110 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with water (250 ml) and the filtered to give 2-chloro-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrole [3,2-d]pyrimidin-4-amine (4 g, 85%) without further purification.

MS(ESI)M/Z：299[M+H+]。 MS (ESI) M / Z: 299 [M+H + ].

步驟C：將2-氯-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，13.4毫莫耳)和丁醇鈉(5.15克，53.6毫莫耳)溶於正丁醇(55毫升)。混合物在氮氣保護下加熱到100攝氏度，攪拌8小時。在冷卻到室溫後，將該混合物用水稀釋(200毫升)，用乙酸乙酯(100毫升×3)萃取。將合併的有機層用鹽水洗滌，用無水硫酸鈉乾燥，並減壓濃縮。將殘餘物用矽膠柱層析純化(洗脫劑：乙酸乙酯/石油醚15%至25%)，得到2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4.1克，91%)，為黃色固體。 Step C: 2-Chloro-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine (4 g (13.4 mmol) and sodium butoxide (5.15 g, 53.6 mmol) were dissolved in n-butanol (55 mL). The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred for 8 hours. After cooling to room temperature, the mixture was diluted with H.sub.2 (200 mL). The combined organic layers were washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 15% to 25%) to give 2-butoxy-5-((2-(trimethylmethyl)alkyl) ethoxy Methyl)-5- H -pyrrolo[3,2-d]pyrimidin-4-amine (4.1 g, 91%) as a yellow solid.

MS(ESI)M/Z：337[M+H+]。 MS (ESI) M / Z: 337 [M+H + ].

步驟D：將2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，12毫莫耳)溶解在無水四氫呋喃(40mL中。把NBS(2.2克，12.5毫莫耳)配成無水四氫呋喃的飽和溶液，在20分鐘內低於0攝氏度下加入到上述溶液中。加完後，該反應混合物在0攝氏度下攪拌30分鐘，然後用鹽水(150毫升)稀釋，並用乙酸乙酯(100毫升×3)萃取。將合併的有機層經無水硫酸鈉乾燥並減壓濃縮。將殘餘物用矽膠柱層析純化(洗脫劑：乙酸乙酯/石油醚5%至 15%)得到7-溴-2-丁氧基-5-(2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(3.85克，78%)，為白色固體。 Step D: 2-Butoxy-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine ( 4 g, 12 mmoles, dissolved in anhydrous tetrahydrofuran (40 mL). NBS (2.2 g, 12.5 mmol) was added to a saturated solution of anhydrous tetrahydrofuran and added to the above solution at less than 0 degrees Celsius in 20 minutes. After the addition, the reaction mixture was stirred at 0 ° C for 30 min then diluted with brine (150 mL) The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 5% to 15%) to give 7-bromo-2-butoxy-5-(2-(trimethylmethyl) ) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine (3.85 g, 78%) as a white solid.

MS(ESI)M/Z：415，417[M+H+]。 MS (ESI) M/Z: 415, 417 [M+H + ].

步驟E：在-78攝氏度，向攪拌的7-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(3克，7.25毫莫耳)的無水四氫呋喃(40毫升)溶液中在氮氣保護下加入正丁基鋰(2.5M，12毫升，30毫莫耳)。將反應混合物在-78攝氏度下攪拌1小時。然後，將間苯二甲醛(1.26克，9毫莫耳)的無水四氫呋喃(5毫升)溶液緩慢加入。此混合物在-78攝氏度下再攪拌30分鐘後，倒入飽和氯化銨水溶液(15毫升)中，並用乙酸乙酯(60毫升×2)萃取。將合併的有機層減壓濃縮，殘餘物經製備型HPLC純化，得到3-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羥基)甲基)苯甲醛鹽共1.1克。 Step E: Stirring 7-bromo-2-butoxy-5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3] at -78 ° C To a solution of 2-pyrpyrimidine-4-amine (3 g, 7.25 mmol) in anhydrous tetrahydrofuran (40 mL) was added n-butyllithium (2.5M, 12 mL, 30 mmol). The reaction mixture was stirred at -78 ° C for 1 hour. Then, a solution of isophthalic acid (1.26 g, 9 mmol) in anhydrous tetrahydrofuran (5 ml) was slowly added. The mixture was stirred at -78.degree. C. for a further 30 min. The combined organic layers were concentrated under reduced pressure and purified ethyl purified ethylamine A total of 1.1 g of methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzaldehyde salt.

MS(ESI)M/Z：471[M+H+]。 MS (ESI) M / Z: 471 [M+H + ].

步驟F：在0攝氏度下，向正在攪拌的3-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羥基)甲基)苯甲醛(200毫克，0.43毫莫耳)和1-甲基哌嗪(87毫克，0.87毫莫耳)的乙醇(2.5毫升)的溶液中分批加入氰基硼氫化鈉(40毫克，0.64毫莫耳)。該反應混合物在室溫下攪拌2小時，然後用水(10ml)稀釋，並用乙酸乙酯(15毫升×2)萃取。將合併的有機層經無水硫酸鈉乾燥並在減壓濃縮，得到粗品(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-((4-甲基哌嗪-1-基)甲基)苯基)甲醇，直接用於下一步。 Step F: 3-((4-Amino-2-butoxy-5-((2-(trimethylmethyl)alkyl)ethoxy)methyl)-5 is being stirred at 0 degrees Celsius H -pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzaldehyde (200 mg, 0.43 mmol) and 1-methylpiperazine (87 mg, 0.87 mmol) A solution of ethanol (2.5 ml) was added portionwise with sodium cyanoborohydride (40 mg, 0.64 mmol). The reaction mixture was stirred at room temperature for 2 hr then diluted with EtOAc (EtOAc) The combined organic layers were dried over anhydrous sodium ) -5 H - pyrrolo [3,2-d] pyrimidin-7-yl) (3 - ((4-methyl-piperazin-1-yl) methyl) phenyl) methanol was used directly in the next step.

MS(ESI)M/Z：555[M+H+]。 MS (ESI) M/Z: 555 [M+H + ].

步驟G：向正在攪拌的(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-((4-甲基哌嗪-1-基)甲基)苯基)甲醇(100毫克)的三氟乙酸(2毫升)溶液中分批加入三乙基矽烷(0.4毫升)。此反應混合物在55攝氏度在氮氣保護下攪拌1小時，並減壓濃縮。將殘餘物溶解在無水碳酸鉀(100毫克)的甲醇(5毫升)溶液中。此混合物於50℃再攪拌30分鐘並過濾。將濾液在減壓下濃縮，殘餘物經製備HPLC純化，得到36毫克2-丁氧基-7-(3-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺三氟乙酸鹽。 Step G: to a stirred suspension of (4-amino-2-butoxy-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3,2 -d]pyrimidin-7-yl)(3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol (100 mg) in trifluoroacetic acid (2 mL) Ethyl decane (0.4 ml). The reaction mixture was stirred at 55 ° C under nitrogen for 1 hour and concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL)EtOAcEtOAc This mixture was stirred at 50 ° C for another 30 minutes and filtered. The filtrate was concentrated under reduced pressure and the residue was purified mjjjjjj H -pyrrolo[3,2-d]pyrimidin-4-amine trifluoroacetate.

1 HNMR(Methanol-d4,400MHz)：δ7.33-7.21(m,4H),4.55(t,J=6.8Hz,2H),4.01(s,2H),3.67(s,2H),3.29-3.24(m,4H),2.87-2.80(m,7H),1.87-1.80(m,2H),1.56-1.49(m,2H),1.02(t,J=6.8Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.33 - 7.21 (m, 4H), 4.55 (t, J = 6.8 Hz, 2H), 4.01 (s, 2H), 3.67 (s, 2H), 3.29-3.24 (m, 4H), 2.87-2.80 (m, 7H), 1.87-1.80 (m, 2H), 1.56-1.49 (m, 2H), 1.02 (t, J = 6.8 Hz, 3H).

MS(ESI)m/z：409[M+H+]。 MS (ESI) m / z: 409 [M+H + ].

實施例2Example 2 2-丁氧基-7-(3-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例1，在步驟F中用嗎啉替代1-甲基哌嗪，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(嗎啉代甲基)苯基)甲醇。 Step A: According to Example 1, substituting morpholine for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylmethyl)alkyl) Ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(3-(morpholinomethyl)phenyl)methanol.

LCMS(ESI)m/z：542[M+H+]。 LCMS (ESI) m / z: 542 [M + H +].

步驟B：根據實施例1，用步驟G中所用的方法製得2-丁氧基-7-(3-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 1, 2-butoxy-7-(3-(morpholinomethyl)benzyl)-5 H -pyrrolo[3,2-d was obtained by the method used in Step G. Pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.41(s,2H),7.35-7.24(m,5H),4. 49(t,J=6.8Hz,2H),4.03(s,2H),3.82(s,2H),3.77-3.75(m,4H),2.77-2.73(m,4H),1.83-1.79(m,2H),1.55-1.49(m,2H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.41 (s, 2H), 7.35-7.24 (m, 5H), 4. 49 (t, J = 6.8 Hz, 2H), 4.03 (s, 2H), 3.82 (s, 2H), 3.77-3.75 (m, 4H), 2.77-2.73 (m, 4H), 1.83-1.79 (m, 2H), 1.55-1.49 (m, 2H), 1.01 (t, J = 6.8 Hz) , 3H).

MS(ESI)m/z：396[M+H+]。 MS (ESI) m / z: 396 [M+H + ].

實施例3Example 3 7-(3-(胺基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺 7-(3-(Aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例1，在步驟F中用乙酸銨替代1-甲基哌嗪，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(胺基甲基)苯基)甲醇。 Step A: According to Example 1, substituting ammonium acetate for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylmethyl)alkyl) Ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(3-(aminomethyl)phenyl)methanol.

LCMS(ESI)m/z：472[M+H+]。 LCMS (ESI) m / z: 472 [M + H +].

步驟B：根據實施例1，用步驟G中所用的方法製備7-(3-(胺基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: Preparation of 7-(3-(Aminomethyl)benzyl)-2-butoxy- 5H -pyrrolo[3,2-d]pyrimidine according to the procedure used in Step G. 4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.31-7.15(m,4H),7.06(s,1H),4.32(t,J=6.6Hz,2H),4.00(s,2H),3.80(s,2H),1.79-1.73(m,2H),1.56-1.50(m,2H),1.01(t,J=7.4Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.31-7.15 (m, 4H), 7.06 (s, 1H), 4.32 (t, J = 6.6 Hz, 2H), 4.00 (s, 2H), 3.80 (s) , 2H), 1.79-1.73 (m, 2H), 1.56-1.50 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：326[M+H+]。 MS (ESI) m / z: 326 [M+H + ].

實施例4Example 4 2-丁氧基-7-(3-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4胺 2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4amine

步驟A：根據實施例1，在步驟F中用吡咯烷替代1-甲基哌嗪，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(吡咯烷-1-基甲基)苯基)甲醇。 Step A: According to Example 1, substituting pyrrolidine for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylmethyl)alkyl) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-7-yl) (3- (pyrrolidin-1-ylmethyl) phenyl) methanol.

步驟B：根據實施例1，用步驟G中所用的方法製得2-丁氧基-7-(3-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 1, prepared by the method used in Step G to give 2-butoxy-7- (3- (pyrrolidin-1-ylmethyl) benzyl) -5 H - pyrrolo [3, 2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.50(s,2H),7.41-7.28(m,5H),4.45(t,J=6.8Hz,2H),4.31(s,2H),4.06(s,2H),3.31-3.29(m,4H),2.10-2.07(m,4H),1.81-1.76(m,2H),1.54-1.49(m,2H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.50 (s, 2H), 7.41-7.28 (m, 5H), 4.45 (t, J = 6.8 Hz, 2H), 4.31 (s, 2H), 4.06 (s) , 2H), 3.31-3.29 (m, 4H), 2.10-2.07 (m, 4H), 1.81-1.76 (m, 2H), 1.54-1.49 (m, 2H), 1.01 (t, J = 6.8 Hz, 3H ).

MS(ESI)m/z：380[M+H+]。 MS (ESI) m/z: 380[M+H + ].

實施例5Example 5 2-丁氧基-7-(4-((3,3-二氟吡咯烷-1-基)甲基)苄基-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl- 5H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例1，在步驟E中用對苯二甲醛替代間苯二甲醛，製備4-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羥基)甲基)苯甲醛。 Step A: According to Example 1, 4-((4-amino-2-butoxy-5-((2-(trimethylmethyl)) was prepared by substituting terephthalaldehyde for isophthalaldehyde in step E).矽alkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzaldehyde.

LCMS(ESI)m/z：471[M+H+]。 LCMS (ESI) m / z: 471 [M + H +].

步驟B：根據實施例1，在步驟F中用3,3-二氟吡咯烷替代1-甲基哌嗪，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3,3-二氟吡咯烷-1-基)甲基)苯基)甲醇。 Step B: According to Example 1, substituting 3,3-difluoropyrrolidine for 1-methylpiperazine in step F, (4-amino-2-butoxy-5-((2-(3) alkyl methyl silicone) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-7-yl) (4 - ((3,3-difluoro-pyrrolidin-1-yl) Methyl)phenyl)methanol.

LCMS(ESI)m/z：562[M+H+]。 LCMS (ESI) m / z: 562 [M + H +].

步驟C：根據實施例1，用步驟G中所用的方法製備2-丁氧基-7-(4-((3,3-二氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step C: Preparation of 2-butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl)-5 according to the procedure used in Step G H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.28-7.15(m,4H),7.04(s,1H),4.30(t,J=6.4Hz,2H),3.97(s,2H),3.59(s,2H),2.88-2.71(m,4H),2.30-2.19(m,2H),1.78-1.71(m,2H),1.55-1.46(m,2H),0.98(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.28-7.15 (m, 4H), 7.04 (s, 1H), 4.30 (t, J = 6.4 Hz, 2H), 3.97 (s, 2H), 3.59 (s) , 2H), 2.88-2.71 (m, 4H), 2.30-2.19 (m, 2H), 1.78-1.71 (m, 2H), 1.55-1.46 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H ).

MS(ESI)m/z：416[M+H+]。 MS (ESI) m / z: 416 [M+H + ].

實施例6Example 6 2-丁氧基-7-(4-((3-氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用3-氟吡咯烷替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3-氟吡咯烷-1-基)甲基)苯基)甲醇。 Step A: According to Example 5, in the step B, 3-fluoropyrrolidine was used instead of 3,3-difluoropyrrolidine to prepare (4-amino-2-butoxy-5-((2-(tri)) Methyl decyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((3-fluoropyrrolidin-1-yl)methyl)benzene Base) methanol.

LCMS(ESI)m/z：544[M+H+]。 LCMS (ESI) m / z: 544 [M + H +].

步驟B：根據實施例5，用步驟C中所用的方法製備2-丁氧基-7-(4-((3-氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: Preparation of 2-butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5 H -pyrrole according to the procedure used in Step C And [3,2-d]pyrimidine-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.30-7.24(m,4H),7.06(s,1H),5.24-5.08(m,1H),4.32(t,J=6.4Hz,2H),3.99(s,2H),3.69-3.57(m,2H),2.88-2.65(m,4H),2.45-2.43(m,1H),2.25-2.11(m,1H),2.02-1.91(m,1H),1.78-1.73(m,2H),1.57-1.50(m,2H),1.01(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.30-7.24 (m, 4H), 7.06 (s, 1H), 5.24-5.08 (m, 1H), 4.32 (t, J = 6.4 Hz, 2H), 3.99 (s, 2H), 3.69-3.57 (m, 2H), 2.88-2.65 (m, 4H), 2.45-2.43 (m, 1H), 2.25-2.11 (m, 1H), 2.02-1.91 (m, 1H) , 1.78-1.73 (m, 2H), 1.57-1.50 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：398[M+H+]。 MS (ESI) m / z: 398[M+H + ].

實施例7Example 7 1-(4-((4-胺基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苄基)吡咯烷-3-醇 1-(4-((4-Amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)benzyl)pyrrolidin-3-ol

步驟A：根據實施例5，在步驟B中用吡咯烷-3-醇替代3,3-二氟吡咯烷，製備1-(4-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羥基)甲基)苄基)吡咯烷-3-醇。 Step A: According to Example 5, in the step B, pyrrolidin-3-ol was used in place of 3,3-difluoropyrrolidine to prepare 1-(4-((4-amino-2-butoxy-5-). ((2-(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzyl)pyrrolidine- 3-ol.

LCMS(ESI)m/z：542[M+H+]。 LCMS (ESI) m / z: 542 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得1-(4-((4-胺基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苄基)吡咯烷-3-醇甲酸鹽。 Step B: According to Example 5, 1-(4-(4-amino-2-butoxy- 5H -pyrrolo[3,2-d]pyrimidin-7-yl was obtained by the method of Step C. )methyl)benzyl)pyrrolidin-3-ol formate.

1 HNMR(Methanol-d4,400MHz)：δ8.43(s,2H),7.45-7.39(m,4H),7.25(s,1H),4.53(m,1H),4.44-4.27(m,2H),4.04(s,2H),3.54-3.47(m,1H),3.38-3.36(m,4H),3.22-3.19(m,1H),2.28-2.24(m,1H),2.05-2.01(m,1H),1.82-1.76(m,2H),1.56-1.50(m,2H),1.01(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d4, 400 MHz): δ 8.43 (s, 2H), 7.45-7.39 (m, 4H), 7.25 (s, 1H), 4.53 (m, 1H), 4.44 - 4.27 (m, 2H) , 4.04 (s, 2H), 3.54-3.47 (m, 1H), 3.38-3.36 (m, 4H), 3.22-3.19 (m, 1H), 2.28-2.24 (m, 1H), 2.05-2.01 (m, 1H), 1.82-1.76 (m, 2H), 1.56-1.50 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：396[M+H+]。 MS (ESI) m / z: 396 [M+H + ].

實施例8Example 8 2-丁氧基-7-(4-(呱啶-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(acridin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用呱啶替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(呱啶-1-基甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-(trimethylmethyl) decane) by substituting acridine for 3,3-difluoropyrrolidine according to Example 5 Ethyl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-(acridin-1-ylmethyl)phenyl)methanol.

LCMS(ESI)m/z：540[M+H+]。 LCMS (ESI) m / z: 540 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-(呱啶-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: Preparation of 2-butoxy-7-(4-(acridin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d according to the procedure of Example 5 Pyrimidine-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.28(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.04(s,1H),4.30(t,J=6.6Hz,2H),3.98(s,2H),3.47(s,2H),2.42(s,4H),1.77-1.73(m,2H),1.60-1.57(m,4H),1.52-1.46(m,4H),0.99(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.28 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.98 (s, 2H), 3.47 (s, 2H), 2.42 (s, 4H), 1.77-1.73 (m, 2H), 1.60-1.57 (m, 4H), 1.52-1.46 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：394[M+H+]。 MS (ESI) m / z: 394 [M+H + ].

實施例9Example 9 2-丁氧基-7-(4-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(morpholinomethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用嗎啉替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(嗎啉代甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-(trimethylmethane)) by substituting morpholine for 3,3-difluoropyrrolidine according to Example 5 Ethyl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-(morpholinomethyl)phenyl)methanol.

LCMS(ESI)m/z：542[M+H+]。 LCMS (ESI) m / z: 542 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: Preparation of 2-butoxy-7-(4-(morpholinomethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidine according to the procedure of Example 5 4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.28(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.03(s,1H),4.29(t,J=6.6Hz,2H),3.96(s,2H),3.67-3.64(m,4H),3.46(s,2H),2.43(s,4H),1.77-1.72(m,2H),1.55-1.45(m,2H),0.98(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.28 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.96 (s, 2H), 3.67-3.64 (m, 4H), 3.46 (s, 2H), 2.43 (s, 4H), 1.77-1.72 (m, 2H), 1.55-1.45 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：396[M+H+]。 MS (ESI) m / z: 396 [M+H + ].

實施例10Example 10 2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7- (4 - ((4-methylpiperazin-1-yl) methyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用1-甲基哌嗪替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲基哌嗪-1-基)甲基)苯基)甲醇。 Step A: Preparation of (4-Amino-2-butoxy-5-((2-(3))), in Example B, substituting 1-methylpiperazine for 3,3-difluoropyrrolidine in Step B alkyl methyl silicone) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-7-yl) (4 - ((4-methyl-piperazin-1-yl) methyl Phenyl)methanol.

LCMS(ESI)m/z：555[M+H+]。 LCMS (ESI) m/z: 555 [M+H + ].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: According to Example 5, 2-butoxyethanol was prepared by the method of Step C 7- (4 - ((4-methylpiperazin-1-yl) methyl) benzyl) -5 H - pyrrolo [3,2-d]pyrimidine-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.29(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.04(s,1H),4.31(t,J=6.6Hz,2H),3.97(s,2H),3.50(s,2H),2.49-2.26(m,11H),1.79-1.72(m,2H),1.56-1.47(m,2H),0.99(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.29 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.97 (s, 2H), 3.50 (s, 2H), 2.49-2.26 (m, 11H), 1.79-1.72 (m, 2H), 1.56-1.47 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：409[M+H+]。 MS (ESI) m / z: 409 [M+H + ].

實施例11Example 11 2-丁氧基-7-(4-((二甲基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((dimethylamino)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用二甲基胺替代3,3-二氟代吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲 基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二甲基胺基)甲基)苯基)甲醇。 Step A: According to Example 5, in the step B, dimethylamine was used instead of 3,3-difluoropyrrolidine to prepare (4-amino-2-butoxy-5-((2-(tri)) Methyl decyl) ethoxy) methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((dimethylamino)methyl)phenyl)methanol.

LCMS(ESI)m/z：500[M+H+]。 LCMS (ESI) m / z: 500 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-((二甲基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: Preparation of 2-butoxy-7-(4-((dimethylamino)methyl)benzyl)-5 H -pyrrolo[3,2- according to the procedure of Example 5 d] Pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.48(s,2H),7.41(s,4H),7.26(s,1H),4.43(t,J=6.8Hz,2H),4.22(s,2H),4.06(s,2H),2.79(s,6H),1.79(m,J=6.8Hz,2H),1.55-1.49(m,2H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.48 (s, 2H), 7.41 (s, 4H), 7.26 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 4.22 (s, 2H) ), 4.06 (s, 2H), 2.79 (s, 6H), 1.79 (m, J = 6.8 Hz, 2H), 1.55-1.49 (m, 2H), 1.01 (t, J = 6.8 Hz, 3H).

MS(ESI)m/z：354[M+H+]。 MS (ESI) m / z: 356 [M+H + ].

實施例12Example 12 2-丁氧基-7-(4-((二乙基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((diethylamino)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5製備，在步驟B中用二乙胺代3,3-二氟代吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二乙基胺基)甲基)苯基)甲醇。 Step A: Prepared according to Example 5, using 4-ethylamino-3,3-difluoropyrrolidine in step B to prepare (4-amino-2-butoxy-5-((2-(tri)) Methyl decyl) ethoxy) methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((diethylamino)methyl)phenyl)methanol.

LCMS(ESI)m/z：528[M+H+]。 LCMS (ESI) m / z: 528 [M + H +].

步驟B：根據實施例5,用步驟C的方法製得2-丁氧基-7-(4-((二乙基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, 2-butoxy-7-(4-((diethylamino)methyl)benzyl)-5 H -pyrrolo[3,2 -d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.48(s,2H),7.42(s,4H),7.25(s,1H),4.41(t,J=6.8Hz,2H),4.28(s,2H),4.06(s,2H),3.20-3.15(m,4H),1.82-1.77(m,2H),1.55-1.49(m,2H),1.34(t,J=6.8Hz,6H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.48 (s, 2H), 7.42 (s, 4H), 7.25 (s, 1H), 4.41 (t, J = 6.8 Hz, 2H), 4.28 (s, 2H) ), 4.06 (s, 2H), 3.20-3.15 (m, 4H), 1.82-1.77 (m, 2H), 1.55-1.49 (m, 2H), 1.34 (t, J = 6.8 Hz, 6H), 1.01 ( t, J = 6.8 Hz, 3H).

MS(ESI)m/z：382[M+H+]。 MS (ESI) m / z: 382 [M+H + ].

實施例13Example 13 2-丁氧基-7-(4-((二丙基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((dipropylamino)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用二丙胺替代3,3-二氟代吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二丙基胺基)甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-(trimethylmethyl)) according to Example 5, substituting dipropylamine for 3,3-difluoropyrrolidine in step B矽alkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((dipropylamino)methyl)phenyl)methanol.

LCMS(ESI)m/z：556[M+H+]. LCMS (ESI) m/z: 556[M+H + ].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-((二丙基胺基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: According to Example 5, 2-butoxy-7-(4-((dipropylamino)methyl)benzyl)-5 H -pyrrolo[3,2- d] pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.29-7.19(m,4H),7.04(s,1H),4.32(t,J=6.5Hz,1H),3.99(s,2H),3.55(s,2H),2.41-2.37(m,4H),1.78-1.74(m,2H),1.57-1.47(m,6H),1.00(t,J=7.4Hz,3H),0.87(t,J=7.4Hz,6H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.29-7.19 (m, 4H), 7.04 (s, 1H), 4.32 (t, J = 6.5 Hz, 1H), 3.99 (s, 2H), 3.55 (s) , 2H), 2.41-2.37 (m, 4H), 1.78-1.74 (m, 2H), 1.57-1.47 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.4 Hz, 6H).

MS(ESI)m/z：410[M+H+]。 MS (ESI) m / z: 410 [M+H + ].

實施例14Example 14 7-(4-(氮雜環丁烷-1-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺 7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用氮雜環丁烷替代3,3-二氟代吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(氮雜環丁烷-1-基甲基)苯基)甲 醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-(3))), in Example B, substituting azetidine for 3,3-difluoropyrrolidine in step B alkyl methyl silicone) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-7-yl) (4- (azetidin-1-ylmethyl) phenyl ) Methanol.

LCMS(ESI)m/z：512[M+H+]。 LCMS (ESI) m / z: 512 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備7-(4-(氮雜環丁烷-1-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: According to Example 5, 7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5 H -pyrrolo[3, 2-d]pyrimidine-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.28(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),7.04(s,1H),4.31(t,J=6.8Hz,2H),3.98(s,2H),3.59(s,2H),3.30-3.27(m,4H),2.15-2.10(m,2H),1.78-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.98 (s, 2H), 3.59 (s, 2H), 3.30-3.27 (m, 4H), 2.15-2.10 (m, 2H), 1.78-1.73 (m, 2H), 1.56-1.52 ( m, 2H), 1.01 (t, J = 6.8 Hz, 3H).

MS(ESI)m/z：366[M+H+]。 MS (ESI) m / z: 366 [M+H + ].

實施例15Example 15 2-丁氧基-7-(4-((3-甲氧基氮雜環丁烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((3-methoxyazetidin-1-yl)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidine-4 -amine

步驟A：根據實施例5，在步驟B中用3-甲氧基氮雜環丁烷替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3-甲氧基氮雜環丁烷-1-基)甲基)苯基)甲醇。 Step A: According to Example 5, in the step B, 3-methoxy-2-butoxy-5-( 2-(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((3-methoxyazetidine) Alkyl-1-yl)methyl)phenyl)methanol.

LCMS(ESI)m/z：542[M+H+]。 LCMS (ESI) m / z: 542 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-((3-甲氧基氮雜環丁烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: Preparation of 2-butoxy-7-(4-((3-methoxyazetidin-1-yl)methyl)benzyl)-5 according to the procedure of Example 5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.28(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),7.04(s,1H),4.31(t,J=6.8Hz,2H),4.06-4.04(m,1H),3.98(s,2H),3 .60(s,2H),3.54-3.52(m,2H),3.24(s,3H),3.04-3.02(m,2H),1.78-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J=6.8Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 4.31 (t, J = 6.8 Hz, 2H), 4.06-4.04 (m, 1H), 3.98 (s, 2H), 3.60 (s, 2H), 3.54-3.52 (m, 2H), 3.24 (s, 3H), 3.04-3.02 ( m, 2H), 1.78-1.73 (m, 2H), 1.56-1.52 (m, 2H), 1.01 (t, J = 6.8 Hz, 3H).

MS(ESI)m/z：396[M+H+]。 MS (ESI) m / z: 396 [M+H + ].

實施例16Example 16 2-丁氧基-7-(4-((4-甲基-1,4-二氮雜環庚烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5 H -pyrrolo[3,2- d]pyrimidine-4-amine

步驟A：根據實施例5，在步驟B中用1-甲基-1,4-二氮雜環庚烷替代3,3-二氟吡咯烷，製備((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲基-1,4-二氮雜環庚烷-1-基)甲基)苯基)甲醇。 Step A: Preparation of ((4-Amino-2-butoxy) according to Example 5, substituting 1-methyl-1,4-diazacycloheptane for 3,3-difluoropyrrolidine in Step B 5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-A) Base-1,4-diazepan-1-yl)methyl)phenyl)methanol.

LCMS(ESI)m/z：569[M+H+]。 LCMS (ESI) m / z: 569 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得2-丁氧基-7-(4-((4-甲基-1,4-二氮雜環庚烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, 2-butoxy-7-(4-((4-methyl-1,4-diazepan-1-yl)methyl) was obtained by the method of Step C Benzyl)-5 H -pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.41(s,3H),7.34-7.24(m,5H),4.52(t,J=6.8Hz,2H),3.99(s,2H),3.76(s,2H),3.38-3.36(m,2H),3.29-3.27(m,2H),2.95(s,2H),2.87-2.84(m,5H),2.07-2.05(m,2H),1.84-1.80(m,2H),1.55-1.49(m,2H),1.03-0.99(t,J=8.0Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.41 (s, 3H), 7.34-7.24 (m, 5H), 4.52 (t, J = 6.8 Hz, 2H), 3.99 (s, 2H), 3.76 (s) , 2H), 3.38-3.36 (m, 2H), 3.29-3.27 (m, 2H), 2.95 (s, 2H), 2.87-2.84 (m, 5H), 2.07-2.05 (m, 2H), 1.84-1.80 (m, 2H), 1.55-1.49 (m, 2H), 1.03-0.99 (t, J = 8.0 Hz, 3H).

MS(ESI)m/z：423[M+H+]。 MS (ESI) m / z: 422 [M+H + ].

實施例17Example 17 2-丁氧基-7-(4-((2,6-二甲基嗎啉基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((2,6-dimethylmorpholinyl)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用2,6-二甲基嗎啉替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((2,6-二甲基嗎啉基)甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-(2) according to Example 5, substituting 2,6-dimethylmorpholine for 3,3-difluoropyrrolidine in Step B -(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((2,6-dimethylmorpholinyl) )methyl)phenyl)methanol.

LCMS(ESI)m/z：570[M+H+]。 LCMS (ESI) m / z: 570 [M + H +].

步驟B：根據實施例5，用步驟C的方法製備2-丁氧基-7-(4-((2,6-二甲基嗎啉基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step B: According to Example 5, 2-butoxyethanol was prepared by the method of Step C 7- (4 - ((2,6-dimethyl-morpholinyl) methyl) benzyl) -5 H - pyrrolo [3,2-d]pyrimidine-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.30-7.28(d,J=8.0Hz,2H),7.23-7.21(d,J=8.0Hz,2H),7.06(s,1H),4.34-4.30(t,J=8.0Hz,2H),3.99(s,2H),3.69-3.64(m,2H),3.47(s,2H),2.73(d,J=12.0Hz,2H),1.77-1.70(m,4H),1.54-1.51(m,2H),1.11(d,J=10.4Hz,6H),1.00(t,J=8.0Hz,3H). 1 H NMR (Methanol- d 4, 400 MHz): δ 7.30-7.28 (d, J = 8.0 Hz, 2H), 7.23 - 7.21 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 4.34 - 4.30 (t, J = 8.0 Hz, 2H), 3.99 (s, 2H), 3.69-3.64 (m, 2H), 3.47 (s, 2H), 2.73 (d, J = 12.0 Hz, 2H), 1.77-1.70 ( m, 4H), 1.54-1.51 (m, 2H), 1.11 (d, J = 10.4 Hz, 6H), 1.00 (t, J = 8.0 Hz, 3H).

MS(ESI)m/z：424[M+H+]。 MS (ESI) m / z: 422 [M+H + ].

實施例18Example 18 7-(4-((1S,4S)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺 7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl)benzyl)-2-butoxy-5 H -pyrrole And [3,2-d]pyrimidine-4-amine

步驟A：根據實施例5，在步驟B中用(1S,4S)-2-氧雜-5-氮雜雙 環[2.2.1]庚烷替代3,3-二氟吡咯烷，製備(4-((1S,4S)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基甲基)苯基)(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲醇。 Step A: Preparation of (4-S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane in place of 3,3-difluoropyrrolidine according to Example 5, (4- ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl)phenyl)(4-amino-2-butoxy-5-(( 2-(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)methanol.

LCMS(ESI)m/z：554[M+H+]。 LCMS (ESI) m / z: 554 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得7-(4-((1S,4S)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-D]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, 7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl) was obtained by the procedure of Step C. Benzyl)-2-butoxy-5 H -pyrrolo[3,2-D]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ：8.38(brs,2H),7.45(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.29(s,1H),4.66(s,1H),4.47(t,J=6.8Hz,2H),4.36-4.27(m,1H),4.24-4.23(m,2H),4.16-4.13(m,1H),4.04(s,2H),3.82-3.81(m,1H),3.33-3.31(m,2H),2.33-2.29(m,1H),2.14-2.11(m,1H),1.83-1.76(m,2H),1.56-1.48(m,2H),1.01(t,J=7.2Hz,3H). 1 H NMR (Methanol-d 4, 400 MHz): δ: 8.38 (brs, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 4.66(s,1H), 4.47(t, J = 6.8Hz, 2H), 4.36-4.27(m,1H), 4.24-4.23(m,2H), 4.16-4.13(m,1H),4.04(s, 2H), 3.82-3.81 (m, 1H), 3.33-3.31 (m, 2H), 2.33-2.29 (m, 1H), 2.14-2.11 (m, 1H), 1.83-1.76 (m, 2H), 1.56- 1.48 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：408[M+H+]。 MS (ESI) m / z: 408 [M+H + ].

實施例19Example 19 2-丁氧基-7-(4-((4-甲氧基呱啶-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-((4-methoxyacridin-1-yl)methyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用4-甲氧基呱啶替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲氧基呱啶-1-基)甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-) according to Example 5, substituting 4-methoxy acridine for 3,3-difluoropyrrolidine in step B. Trimethylmethanealkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-methoxyacridin-1-yl)) Methyl)phenyl)methanol.

LCMS(ESI)m/z：570[M+H+]。 LCMS (ESI) m / z: 570 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得2-丁氧基-7-(4-((4-甲氧基呱啶-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, to give 2-butoxy-7 by the method of Step C (4 - ((4-methoxy-piperidin-1-yl) methyl) benzyl) -5 H - Pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ：8.45(s,2H),7.43-7.38(m,4H),7.28(s,1H),4.45(t,J=6.4Hz,2H),4.21(s,2H),4.05(s,2H),3.52-3.53(m,1H),3.33-3.39(m,3H),3.26-3.24(m,2H),3.13-3.10(m,2H),1.99-1.92(m,4H),1.84-1.77(m,2H),1.56-1.50(m,2H),1.01(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ: 8.45 (s, 2H), 7.43-7.38 (m, 4H), 7.28 (s, 1H), 4.45 (t, J = 6.4 Hz, 2H), 4.21. , 2H), 4.05 (s, 2H), 3.52-3.53 (m, 1H), 3.33-3.39 (m, 3H), 3.26-3.24 (m, 2H), 3.13-3.10 (m, 2H), 1.99-1.92 (m, 4H), 1.84-1.77 (m, 2H), 1.56-1.50 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：424[M+H+]。 MS (ESI) m / z: 422 [M+H + ].

實施例20Example 20 2-丁氧基-7-(4-((4-異丙基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7- (4 - ((4-isopropyl-piperazin-1-yl) methyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用1-異丙基哌嗪替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-異丙基哌嗪-1-基)甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-) by substituting 1-isopropylpiperazine for 3,3-difluoropyrrolidine according to Example 5 Trimethylmethanealkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-isopropylpiperazin-1-yl)) Methyl)phenyl)methanol.

LCMS(ESI)m/z：583[M+H+]。 LCMS (ESI) m / z: 583 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得2-丁氧基-7-(4-((4-異丙基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, to give 2-butoxy by the method of Step C 7- (4 - ((4-isopropyl-piperazin-1-yl) methyl) benzyl) -5 H - Pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,300MHz)：δ：8.45(s,2H),7.31-7.25(m,5H),4.49(t,J=8.4Hz,2H),3.99(s,2H),3.64(s,2H),3.42-3.40(m,1H),3.21-3.25(m,4H),2.66-2.82(m,4H),1.84-1.79(m,2H),1.56-1.51(m,2H),1.35(d,J=8.8Hz,6H),1.04-0.99(t,J=10.0Hz,3H)。 1 H NMR (Methanol-d4, 300 MHz): δ: 8.45 (s, 2H), 7.31-7.25 (m, 5H), 4.49 (t, J = 8.4 Hz, 2H), 3.99 (s, 2H), 3.64 (s) , 2H), 3.42-3.40 (m, 1H), 3.21-3.25 (m, 4H), 2.66-2.82 (m, 4H), 1.84-1.79 (m, 2H), 1.56-1.51 (m, 2H), 1.35 (d, J = 8.8 Hz, 6H), 1.04-0.99 (t, J = 10.0 Hz, 3H).

MS(ESI)m/z：437[M+H+]。 MS (ESI) m / z: 437[M+H + ].

實施例21Example 21 2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例5，在步驟B中用吡咯替代3,3-二氟吡咯烷，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(吡咯烷-1-基甲基)苯基)甲醇。 Step A: Preparation of (4-amino-2-butoxy-5-((2-(trimethylmethyl)alkyl) by substituting pyrrole for 3,3-difluoropyrrolidine according to Example 5 Ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol.

LCMS(ESI)m/z：526[M+H+]。 LCMS (ESI) m / z: 526 [M + H +].

步驟B：根據實施例5，用步驟C的方法製得2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 5, 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2- d] Pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.41(s,2H),7.46(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.30(s,1H),4.48(t,J=6.8Hz,2H),4.33(s,2H),4.05(s,2H),3.32-3.30(m,4H),2.10-2.06(m,4H),1.83-1.89(m,2H),1.55-1.48(m,2H),1.02(t,J=7.2Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 8.41 (s, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 4.48 (t, J = 6.8 Hz, 2H), 4.33 (s, 2H), 4.05 (s, 2H), 3.32-3.30 (m, 4H), 2.10-2.06 (m, 4H), 1.83-1.89 (m, 2H), 1.55-1.48 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：380[M+H+]。 MS (ESI) m/z: 380[M+H + ].

實施例22Example 22 2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

6-(吡咯烷-1-基甲基)煙醛的製備路線： Preparation route of 6-(pyrrolidin-1-ylmethyl)nicaldaldehyde:

步驟A：在室溫下，向6-甲基煙酸甲酯(10克，0.0662莫耳)在CCl4(100毫升)溶液中加入NBS(13.0克，0.0728莫耳)和BPO(1.6克，0.0066莫耳)。將反應混合物加熱至75℃並攪拌12小時。冷卻後，加入水(80毫升)，並用乙酸乙酯(200毫升×2)萃取。將有機層依次用硫代硫酸鈉(80毫升)的飽和水溶液洗滌，用無水硫酸鈉乾燥，並減壓濃縮。殘餘物通過矽膠柱純化(洗脫劑：石油醚/乙酸乙酯=20/1)，得到6-(溴甲基)煙酸甲酯(5.2克，產率34%)，為棕色固體。 Step A: To a solution of methyl 6-methylnicotinate (10 g, 0.0662 mol) in CCl 4 (100 mL) was added NBS (13.0 g, 0.0728 m) and BPO (1.6 g, 0.0066 moles). The reaction mixture was heated to 75 ° C and stirred for 12 hours. After cooling, water (80 ml) was added andEtOAc was evaporated. The organic layer was washed with EtOAc EtOAc. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc)

1 HNMR(CDCl 3 ,400MHz)：δ9.18(d,J=1.6Hz,1H),8.32(dd,J 1 =8.0Hz,J 2 =2.0Hz,1H),7.55(d,J=8.0Hz,1H),4.60(s,2H),3.97(s,3H)。 1 H NMR (CDCl 3 , 400 MHz): δ 9.18 (d, J = 1.6 Hz, 1H), 8.32 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz) , 1H), 4.60 (s, 2H), 3.97 (s, 3H).

MS(ESI)m/z：230,232[M+H+]。 MS (ESI) m/z: 230, 232 [M+H + ].

步驟B：在0攝氏度下，向吡咯烷(3.09克，43.47毫莫耳)和三乙胺(3毫升，21.73毫莫耳)的無水四氫呋喃(100毫升)溶液中分批加入6-(溴甲基)煙酸甲酯(5.0克，21.73毫莫耳)。加完後，將該反應混合物在室溫下攪拌16小時，然後用水(80毫升)稀釋，並用乙酸乙酯(100毫升)萃取。將有機層用無水硫酸鈉乾燥，並減壓濃縮。殘餘物通過矽膠柱純化(洗脫劑：石油醚/乙酸乙酯=10/1)，得到6-(吡咯烷-1-基甲基)煙酸甲酯(4.1克，產率86%)，為棕色固體。 Step B: Add 6-(bromomethyl) in a solution of pyrrolidine (3.09 g, 43.47 mmol) and triethylamine (3 mL, 21.73 mmol) in anhydrous tetrahydrofuran (100 mL). Base) methyl nicotinate (5.0 g, 21.73 mmol). After the addition was completed, the~~~~~~~~~~~~~~~ The organic layer was dried with anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: It is a brown solid.

1 HNMR(CDCl 3 ,400MHz)：δ9.11(d,J=2.0Hz,1H),8.22(dd,J 1 =8.0Hz ,J 2 =2.0Hz,1H),7.48(d,J=8.0Hz,1H),3.91(s,3H),3.81(s,2H),2.58-2.53(m,4H),1.81-1.77(m,4H)。 1 H NMR (CDCl 3 , 400 MHz): δ 9.11 (d, J = 2.0 Hz, 1H), 8.22 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz) , 1H), 3.91 (s, 3H), 3.81 (s, 2H), 2.58-2.53 (m, 4H), 1.81-1.77 (m, 4H).

MS(ESI)m/z：221[M+H+]。 MS (ESI) m/z: 221 [M+H + ].

步驟C：在低於0℃下，向正在攪拌的6-(吡咯烷-1-基甲基)煙酸甲酯(3.0克，13.62毫莫耳)的無水四氫呋喃(70毫升)溶液中分批加入四氫鋰鋁(1.03克，27.24毫莫耳)。在大約0攝氏度反應2小時，並在室溫下進一步反應30分鐘。TLC顯示反應物消失。然後將該混合物冷卻至0℃，並非常緩慢地滴入水(1毫升)。然後，將15%的氫氧化鈉水溶液(1毫升)和外加水(3毫升)分別加入並劇烈攪拌。將所得混合物過濾。將濾液用無水Mg2SO4乾燥並減壓濃縮乾，得到(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇(2.5克)。 Step C: Batchwise to a stirred solution of 6-(pyrrolidin-1-ylmethyl)nicotinic acid methyl ester (3.0 g, 13.62 mmol) in anhydrous tetrahydrofuran (70 mL) at below 0 °C Add lithium aluminum hydride (1.03 g, 27.24 mmol). The reaction was carried out at about 0 ° C for 2 hours and further at room temperature for 30 minutes. TLC showed the disappearance of the reactants. The mixture was then cooled to 0 ° C and water (1 mL) was added very slowly. Then, 15% aqueous sodium hydroxide solution (1 ml) and additional water (3 ml) were separately added and stirred vigorously. The resulting mixture was filtered. The filtrate was dried over anhydrous Mg 2 SO 4 and concentrated to dryness under reduced pressure, to give (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) methanol (2.5 g).

1 HNMR(CDCl 3 ,400MHz)：δ8.41(d,J=1.6Hz,1H),7.67(dd,J 1 =8.0Hz,J 2 =2.0Hz,1H),7.37(d,J=8.0Hz,1H),4.67(s,2H),3.75(s,2H),2.57-2.543(m,4H),1.81-1.76(m,4H)。 1 H NMR (CDCl 3 , 400 MHz): δ 8.41 (d, J = 1.6 Hz, 1H), 7.67 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 7.37 (d, J = 8.0 Hz) , 1H), 4.67 (s, 2H), 3.75 (s, 2H), 2.57-2.543 (m, 4H), 1.81-1.76 (m, 4H).

步驟D：將(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇(2.5克，13毫莫耳)溶解在無水二氯甲烷(50毫升)中。將二氧化錳(5.0克，58毫莫耳)在0攝氏度下分批加入。將反應混合物在室溫下攪拌24小時，過濾。將濾液在真空下濃縮，殘餘物通過矽膠柱純化(洗脫劑：15%乙酸乙酯的石油醚溶劑)，得到6-(吡咯烷-1-基甲基)煙醛(2.2克，粗品)，為黃色油狀物。 Step D: (6-(Pyrrolidin-l-ylmethyl)pyridin-3-yl)methanol (2.5 g, 13 mmol) was dissolved in anhydrous dichloromethane (50 mL). Manganese dioxide (5.0 grams, 58 millimolar) was added in portions at 0 degrees Celsius. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified eluting eluting eluting eluting eluting It is a yellow oil.

LCMS(ESI)m/z：191[M+H+]。 LCMS (ESI) m / z: 191 [M + H +].

2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的製備流程： 2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine Preparation process:

實施例22流程Example 22 process

步驟E：根據實施例1，在步驟E中用6-(吡咯烷-1-基甲基)煙醛替代間二苯甲醛，製備(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇。 Step E: According to Example 1, in the step E, 6-(pyrrolidin-1-ylmethyl)nicaldaldehyde was used in place of m-dibenzaldehyde to prepare (4-amino-2-butoxy-5-(( 2-(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(6-(pyrrolidin-1-ylmethyl)pyridine -3-yl)methanol.

LCMS(ESI)m/z：527[M+H+]。 LCMS (ESI) m/z: 437 [M+H + ].

步驟F：按照實施例1，用步驟G的方法製得2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽，為白色固體。 Step F: as described in Example 1, Step G prepared as 2-butoxy-7 - ((6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) methyl) -5 H - Pyrrolo[3,2-d]pyrimidine-4-amine formate is a white solid.

1 HNMR(Methanol-d4,400MHz)：δ8.62(s,1H),8.40(brs,1H),7.77(d,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),7.35(s,1H),4.48(s,2H),4.45(t,J=6.4Hz,2H),4.08(s,2H),3.42-3.38(m,4H),2.13-2.10(m,4H),1.83-1.76(m,2H),1.5 5-1.49(m,2H),1.01(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.62 (s, 1H), 8.40 (brs, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 4.48 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 4.08 (s, 2H), 3.42-3.38 (m, 4H), 2.13-2.10 (m, 4H) , 1.83-1.76 (m, 2H), 1.5 5-1.49 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：381[M+H+]。 MS (ESI) m / z: 381 [M+H + ].

實施例23Example 23 2-丁氧基-7-(3-(2-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

3-(2-(吡咯烷-1-基)乙基)苯甲醛的製備路線： Preparation route of 3-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde:

步驟A：在氮氣保護下，將3-溴苯甲酸甲酯(17.0克，79.0毫莫耳)、三丁基(乙烯基)錫烷(33克，102毫莫耳)和Pd(PPh3)4(4.5克，4毫莫耳)的二噁烷(200毫升)溶液在110攝氏度下攪拌反應6小時，然後加10%的氟化鉀水溶液(100毫升)淬滅。將所得混合物在室溫下再攪拌10分鐘，並用乙酸乙酯(150毫升×3)萃取。將合併的有機層用鹽水洗滌，用無水硫酸鈉乾燥，並減壓濃縮。將殘餘物用矽膠柱 純化(洗脫劑：25%乙酸乙酯的石油醚溶液)，得到約15克粗品3-乙烯基苯甲酸甲酯，為黃色油狀物。 Step A: Methyl 3-bromobenzoate (17.0 g, 79.0 mmol), tributyl(vinyl)stannane (33 g, 102 mmol) and Pd (PPh 3 ) under nitrogen. A solution of 4 (4.5 g, 4 mmol) of dioxane (200 mL) was stirred at 110 <0>C for 6h then quenched with 10% aqueous potassium fluoride (100 mL). The resulting mixture was stirred at room temperature for additional 10 min and extracted with ethyl acetate (150 mL & The combined organic layers were washed with EtOAc EtOAc. The residue was purified with EtOAc (EtOAc:EtOAc:EtOAc)

MS(ESI)m/z：163[M+H+]。 MS (ESI) m / z: 163 [M+H + ].

步驟B：在氮氣氛圍下，向正在攪拌的3-乙烯基苯甲酸甲酯的無水四氫呋喃(100毫升)溶液中通過滴液漏斗加入9-BBN(0.5M，166毫升，83毫莫耳)並保持溫度低於-30攝氏度。加完後，將反應混合物升溫至室溫並攪拌16小時。然後冷卻至-30攝氏度，滴加H2O2的水溶液(品質比30%，19毫升)，接著慢慢滴加15%氫氧化鈉水溶液(40毫升)。將所得混合物在環境溫度下再攪拌1小時後，加水(200毫升)稀釋，並用乙酸乙酯(200毫升×2)萃取。將合併的有機層用鹽水洗滌，用無水硫酸鈉乾燥，減壓濃縮得到約9克粗品3-(2-羥乙基)苯甲酸甲酯，為淡黃色油狀物，其直接用於下一步驟。 Step B: 9-BBN (0.5 M, 166 mL, 83 mmol) was added to a stirred solution of methyl 3-vinylbenzoate in anhydrous tetrahydrofuran (100 mL). Keep the temperature below -30 degrees Celsius. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 16 hr. Then, it was cooled to -30 ° C, and an aqueous solution of H 2 O 2 (quality ratio: 30%, 19 ml) was added dropwise, followed by dropwise addition of a 15% aqueous sodium hydroxide solution (40 ml). After the mixture was stirred at ambient temperature for additional 1 hour, it was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The combined organic layers were washed with EtOAcq~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ step.

1 HNMR(CDCl 3 ,400MHz)：δ7.92-7.90(m,2H),7.45-7.37(m,2H),3.92(s,3H),3.89(t,J=6.5Hz,2H),2.93(t,J=6.5Hz,2H)。 1 H NMR (CDCl 3 , 400 MHz): δ 7.92-7.90 (m, 2H), 7.45-7.37 (m, 2H), 3.92 (s, 3H), 3.89 (t, J = 6.5 Hz, 2H), 2.93 ( t, J = 6.5 Hz, 2H).

MS(ESI)m/z：181[M+H+]。 MS (ESI) m / z: 181 [M+H + ].

步驟C：在約0攝氏度下，向正在攪拌的3-(2-羥乙基)苯甲酸甲酯(10克)無水二氯甲烷(90mL)溶液中加入甲磺醯氯(34克，299毫莫耳)和三乙胺(12克，118毫莫耳)。反應物在0攝氏度下攪拌1小時，用水淬滅(50毫升)，並用乙酸乙酯(100毫升×3)萃取。將合併的有機層經無水硫酸鈉乾燥並減壓濃縮。將殘餘物用矽膠柱層析純化(洗脫劑：10%乙酸乙酯的石油醚溶液)，得到2.7g的3-(2-((甲基磺醯基)氧基)乙基)苯甲酸甲酯，為無色油狀物。 Step C: To a solution of 3-(2-hydroxyethyl)benzoic acid methyl ester (10 g) in anhydrous dichloromethane (90 mL) was added methanesulfonium chloride (34 g, 299 m) at about 0 °C. Mohr) and triethylamine (12 g, 118 mmol). The reaction was stirred at 0<0>C for 1 h then quenched with EtOAc (EtOAc) The combined organic layers were dried with anhydrous sodium The residue was purified by silica gel column chromatography (eluent: 10% ethyl acetate in petroleum ether) to afford 2.7 g of 3-(2-((methylsulfonyl)oxy)ethyl)benzoic acid Methyl ester is a colorless oil.

MS(ESI)m/z：259[M+H+]。 MS (ESI) m / z: 259 [M+H + ].

步驟D：將吡咯烷(2.3克，31.3毫莫耳)和碳酸鉀(2.2克，16毫 莫耳)溶於無水乙腈(20毫升)并用10分鐘時間向其中加入3-(2-((甲基磺醯基)氧基)乙基)苯甲酸甲酯(2.7克，10.4毫莫耳)的乙腈(5毫升)溶液。將反應液在70℃攪拌16小時，冷卻到室溫後，用水(20毫升)稀釋，並用乙酸乙酯(20毫升×3)萃取。將合併的有機層經無水硫酸鈉乾燥並減壓濃縮。將殘餘物用矽膠柱層析純化(洗脫劑：甲醇/二氯甲烷等於2%至5%)，得到3-(2-(吡咯烷-1-基)乙基)苯甲酸甲酯(1.7克，71%)，為黃色油狀物。 Step D: Pyrrolidine (2.3 g, 31.3 mmol) and potassium carbonate (2.2 g, 16 m) Mol) was dissolved in anhydrous acetonitrile (20 mL) and methyl 3-(2-((methylsulfonyl)oxy)ethyl)benzoate (2.7 g, 10.4 mmol) was added over 10 min. A solution of acetonitrile (5 ml). The reaction mixture was stirred at 70 ° C for 16 hr then cooled to EtOAc. The combined organic layers were dried with anhydrous sodium The residue was purified by silica gel column chromatography (eluent: methanol / methylene chloride to 2% to 5%) to give methyl 3-(2-(pyrrolidin-1-yl)ethyl)benzoate (1.7) Gram, 71%), as a yellow oil.

MS(ESI)m/z：234[M+H+]。 MS (ESI) m / z: 234 [M+H + ].

步驟E：根據實施例22，用步驟C、D方法製備3-(2-(吡咯烷-1-基)乙基)苯甲醛。 Step E: According to Example 22, 3-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde was obtained by the procedure of Steps C and D.

MS(ESI)m/z：204[M+H+]。 MS (ESI) m / z: 204 [M+H + ].

步驟F：根據實施例22，用步驟E、F方法製得2-丁氧基-7-(3-(2-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step F: According to Example 22, 2-butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5 H -pyrrole was obtained by the method of steps E and F. [3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.42(s,2H),7.30-7.13(m,5H),4.38(t,J=6.4Hz,2H),4.01(s,1H),3.41(t,J=7.6Hz,2H),3.35-3.32(m,4H),3.01(t,J=7.6Hz,2H),2.09-2.05(m,4H),1.81-1.74(m,2H),1.57-1.48(m,2H),1.01(t,J=7.6Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.42 (s, 2H), 7.30-7.13 (m, 5H), 4.38 (t, J = 6.4 Hz, 2H), 4.01 (s, 1H), 3.41 (t) , J = 7.6 Hz, 2H), 3.35-3.32 (m, 4H), 3.01 (t, J = 7.6 Hz, 2H), 2.09-2.05 (m, 4H), 1.81-1.74 (m, 2H), 1.57- 1.48 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H).

MS(ESI)m/z：394[M+H+]。 MS (ESI) m / z: 394 [M+H + ].

實施例24Example 24 2-丁氧基-7-(4-(1-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

4-(1-(吡咯烷-1-基)乙基)苯甲醛製備路線： 4-(1-(pyrrolidin-1-yl)ethyl)benzaldehyde preparation route:

步驟A：在攪拌下，向4-氰基苯乙酮(4克，27.56毫莫耳)和吡咯烷(2.94克，41.33毫莫耳)的甲醇(100毫升)溶液中加入醋酸(0.5毫升)以及氰基硼氫化鈉(5.2克，82.67毫莫耳)，並保持溫度低於0攝氏度。將反應物在室溫下攪拌16小時，然後減壓濃縮。將所得油狀物用矽膠柱層析純化(洗脫劑：石油醚/乙酸乙酯=1/3)，得到2.8克4-(1-(吡咯烷-1-基)乙基)苄腈，為無色油狀物。 Step A: To a solution of 4-cyanoacetophenone (4 g, 27.56 mmol) and pyrrolidine (2.94 g, 41.33 mmol) in methanol (100 mL) And sodium cyanoborohydride (5.2 g, 82.67 mmol) and keep the temperature below 0 °C. The reaction was stirred at room temperature for 16 h then concentrated EtOAc. The oil was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1/3) to afford 2.8 g of 4-(1-(pyrrolidin-1-yl)ethyl)benzonitrile. It is a colorless oil.

MS(ESI)m/z：201[M+H+]。 MS (ESI) m / z: 201 [M+H + ].

步驟B：在-20至-10攝氏度向4-(1-(吡咯烷-1-基)乙基)苄腈(2克，10毫莫耳)的無水甲苯(100毫升)溶液中加入DIBAL-H(1M，20毫升，20毫莫耳)的溶液並控制在1小時加完。將反應液再攪拌3小時，然後用氯化銨飽和水溶液淬滅，並用乙酸乙酯萃取。用鹽水洗滌有機層，用無水硫酸鈉乾燥，並減壓濃縮。將所得固體物用矽膠柱層析純化(洗脫劑：石油醚/乙酸乙酯=50/1至10/1)，得到4-(1-(吡咯烷-1-基)乙基)苯甲醛(680毫克，33.5%)，為無色油狀物。 Step B: Add DIBAL to a solution of 4-(1-(pyrrolidin-1-yl)ethyl)benzonitrile (2 g, 10 mmol) in dry toluene (100 mL) from -20 to -10. A solution of H (1 M, 20 mL, 20 mmol) was added over 1 hour. The reaction mixture was stirred for additional 3 hr then EtOAc EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The obtained solid was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50/1 to 10/1) to give 4-(1-(pyrrolidin-1-yl)ethyl)benzaldehyde. (680 mg, 33.5%) as a colorless oil.

(ESI)m/z：204[M+H+]。 (ESI) m/z: 204 [M+H + ].

步驟C：根據實施例22，用步驟E、F的方法製得2-丁氧基 -7-(4-(1-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step C: According to Example 22, 2-butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5 H -pyrrole was obtained by the procedure of steps E and F. And [3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.50(s,2H),7.44-7.38(m,4H),7.27(s,1H),4.45(t,J=6.4,2H),4.33-4.28(m,1H),4.04(s,2H),3.37-3,33(m,2H),3.14-3.11(m,2H),2.04-2.02(m,4H),1.83-1.78(m,2H),1.72-1.70(m,3H),1.55-1.49(m,2H),1.01(t,J=7.4,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.50 (s, 2H), 7.44-7.38 (m, 4H), 7.27 (s, 1H), 4.45 (t, J = 6.4, 2H), 4.33-4.28 ( m,1H), 4.04(s,2H), 3.37-3,33(m,2H),3.14-3.11(m,2H),2.04-2.02(m,4H),1.83-1.78(m,2H), 1.72-1.70 (m, 3H), 1.55-1.49 (m, 2H), 1.01 (t, J = 7.4, 3H).

MS(ESI)m/z：394[M+H+]。 MS (ESI) m / z: 394 [M+H + ].

實施例25Example 25 2-丁氧基-7-(4-(1-甲基呱啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(1-methylacridin-4-yl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

4-(4-甲醯基苯基)呱啶-1-甲酸第三丁酯的製備路線： Preparation route of 4-(4-methylnonylphenyl) acridine-1-carboxylic acid tert-butyl ester:

步驟A：將4-溴吡啶(3.0克，19.0毫莫耳)、(4-(甲氧羰基)苯基)硼酸(2.63克，14.6毫莫耳)、Pd(PPh3)2Cl2(0.35克，0.5毫莫耳)和碳酸鈉(6.91克，65.2毫莫耳)的1,2-二甲氧基乙烷(40毫升)混合物在氮 氣氣氛下加熱至90℃並攪拌10小時。將所得混合物減壓濃縮，殘餘物通過矽膠柱層析純化(洗脫劑：石油醚/乙酸乙酯=6/1至2/1)，得到4-(吡啶-4-基)苯甲酸甲酯(2.7克，收率：86.8%)，為白色固體。 Step A: 4-bromopyridine (3.0 g, 19.0 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2.63 g, 14.6 mmol), Pd(PPh 3 ) 2 Cl 2 (0.35 A mixture of gram (0.5 mmol) and sodium carbonate (6.91 g, 65.2 mmol) of 1,2-dimethoxyethane (40 ml) was heated to 90 ° C under a nitrogen atmosphere and stirred for 10 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified eluted eluted eluted elut elut elut elut elut elut elut (2.7 g, yield: 86.8%) as a white solid.

MS(ESI)m/z：214[M+H+]。 MS (ESI) m / z: 214 [M+H + ].

步驟B：向4-(吡啶-4-基)苯甲酸甲酯(3.8克，17.8毫莫耳)和PtO2(0.2克)的甲醇(40毫升)溶液中加入2毫升鹽酸，加熱到約50攝氏度，在氫氣氛圍下(50psi)攪拌16小時。將所得混合物過濾，濾液減壓濃縮，得到粗品4-(呱啶-4-基)苯甲酸甲酯(4.0克)，為鹽酸鹽，無需進一步純化。 Step B: To a solution of methyl 4-(pyridin-4-yl)benzoate (3.8 g, 17.8 mmol) and PtO 2 (0.2 g) in methanol (40 mL) Celsius was stirred for 16 hours under a hydrogen atmosphere (50 psi). The mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~

MS(ESI)m/z：220[M+H+]。 MS (ESI) m / z: 220 [M+H + ].

步驟C：向正在攪拌的4-(呱啶-4-基)苯甲酸甲酯(5.0克，22.8毫莫耳)和碳酸鉀(25.0克，182.2毫莫耳)的四氫呋喃(50毫升)/水(50毫升)混合溶液中分批加入二碳酸二第三丁酯(10.0克，45.8毫莫耳)並保持溫度低於10℃。加完後，將反應混合物在室溫下攪拌另外0.5小時，然後用水(50毫升)稀釋，並用乙酸乙酯(50毫升×2)萃取。將合併的有機層用鹽水洗滌，用無水硫酸鈉乾燥，並在真空下濃縮。殘餘物通過矽膠柱層析純化(洗脫劑：石油醚/乙酸乙酯=6/1至1/1)，得到4-(4-(甲氧羰基)苯基)呱啶-1-甲酸第三丁酯(1.9克，收率：26.4%)，為白色固體。 Step C: To a stirred solution of methyl 4-(acridin-4-yl)benzoate (5.0 g, 22.8 mmol) and potassium carbonate (25.0 g, 182.2 mmol) in THF (50 mL) / water (30 ml) of the mixed solution was added portionwise to ditributyl dicarbonate (10.0 g, 45.8 mmol) and kept at a temperature below 10 °C. After the addition was completed, the reaction mixture was stirred at room temperature for additional 0.5 hr, then diluted with water (50 ml) and ethyl acetate (50 ml x 2). The combined organic layers were washed with brine w... The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 6/1 to 1 / 1) to afford 4-(4-(methoxycarbonyl)phenyl) a Tributyl ester (1.9 g, yield: 26.4%) was obtained as a white solid.

1 HNMR(CDCl 3 ,400MHz)：δ7.98(d,J=8.4Hz,2H),7.28(d,J=7.6Hz,2H),4.27(s,1H),3.91(s,3H),2.84-2.68(m,3H),1.85(d,J=12.8Hz,2H),1.66-1.59(m,2H),1.49(s,9H)。 1 H NMR (CDCl 3 , 400 MHz): δ 7.98 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 4.27 (s, 1H), 3.91 (s, 3H), 2.84 -2.68 (m, 3H), 1.85 (d, J = 12.8 Hz, 2H), 1.66-1.59 (m, 2H), 1.49 (s, 9H).

MS(ESI)m/z：320[M+H+]。 MS (ESI) m / z: 320 [M+H + ].

步驟D：根據實施例22，用步驟C、D的方法製備4-(4-甲醯基 苯基)呱啶-1-甲酸第三丁酯。 Step D: Preparation of 4-(4-carboxamyl) by the method of Steps C and D according to Example 22. Phenyl) acridine-1-carboxylic acid tert-butyl ester.

MS(ESI)m/z：312.1[M+Na+]。 MS (ESI) m / z: 312.1 [M + Na +].

步驟F：根據實施例22，用步驟E、F的方法製備2-丁氧基-7-(4-(呱啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step F: Preparation of 2-butoxy-7-(4-(acridin-4-yl)benzyl)-5 H -pyrrolo[3,2-d according to the procedure of Steps E and F. Pyrimidine-4-amine.

MS(ESI)m/z：380.2[M+H+]。 MS (ESI) m / z: 380.2 [M+H + ].

2-丁氧基-7-(4-(1-甲基呱啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺的製備： 2-butoxy-7- (4- (1-methyl-piperidin-4-yl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine:

步驟G：在攪拌5分鐘後，向2-丁氧基-7-(4-(呱啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺(100毫克，0.264毫莫耳)和HCHO(20毫克，0.666毫莫耳)的甲醇(5毫升)溶液中加入氰基硼氫化鈉(50毫克，0.796毫莫耳)。此反應物在室溫攪拌0.5小時，用水稀釋，並用乙酸乙酯萃取。將有機層在真空下濃縮，殘餘物經製備型HPLC純化，得到7.48毫克2-丁氧基-7-(4-(1-甲基呱啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Step G: After stirring for 5 minutes, 2-butoxy-7- (4- (piperidin-4-yl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine (100 mg, 0.264 mmol) and a solution of HCHO (20 mg, 0.666 mmol) in methanol (5 mL). The reaction was stirred at room temperature for 0.5 h, diluted with water and EtOAc. The organic layer was concentrated in vacuo < RTI ID =0.0> And [3,2-d]pyrimidine-4-amine.

1 HNMR(Methanol,400MHz)：δ7.21(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),7.00(s,1H),4.32-4.28(m,2H),3.94(s,2H),3.00-2.97(m,2H),2.52-2.47(m,1H),2.32(s,3H),2.19-2.15(m,2H),1.80-1.72(m,6H),1.53-1.48(m,2H),0.98(t,J=7.4Hz,3H)。 1 H NMR (Methanol, 400 MHz): δ 7.21 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 4.32-4.28 (m, 2H), 3.94(s,2H), 3.00-2.97(m,2H), 2.52-2.47(m,1H), 2.32(s,3H), 2.19-2.15(m,2H),1.80-1.72(m,6H), 1.53-1.48 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：394[M+H+]。 MS (ESI) m / z: 394 [M+H + ].

實施例26Example 26 2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

2-(4-甲醯基苯基)吡咯烷-1-甲酸第三丁酯的製備路線： Preparation route of 2-(4-methylnonylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

步驟A：在N2氛圍、0攝氏度下，向NaH(446毫克，18.6毫莫耳)的無水四氫呋喃(20毫升)混合物中加入1-烯丙基-吡咯-2-酮(1.14克，9.11毫莫耳)。然後緩慢加入4-溴苯甲酸甲酯的無水四氫呋喃(10毫升)溶液。此混合物在90攝氏度下攪拌2小時，然後冷卻至室溫，用6N鹽酸稀釋。將所得混合物在110攝氏度下攪拌12小時，然後將水相用乙酸乙酯(50毫升)洗滌。用1N氫氧化鈉溶液鹼化，使pH約為9，再用乙酸乙酯(50毫升×2)萃取。將合併的有機層在真空下濃縮至乾，得到2.0克5-(4-溴苯基)-3,4-二氫-2H-吡咯，為黃色固體，將其直接用於下一步驟。 Step A: N 2 atmosphere at 0 ° C, to NaH (446 mg, 18.6 mmol) in dry tetrahydrofuran (20 ml) was added 1-allyl - pyrrolidin-2-one (1.14 g, 9.11 mmol Moore). A solution of methyl 4-bromobenzoate in anhydrous tetrahydrofuran (10 mL) was then added slowly. The mixture was stirred at 90 ° C for 2 hours, then cooled to room temperature and diluted with 6N hydrochloric acid. The resulting mixture was stirred at 110 ° C for 12 hours then the aqueous was washed with ethyl acetate (50 mL). It was basified with a 1N sodium hydroxide solution to give a pH of about 9 and then extracted with ethyl acetate (50 ml x 2). The combined organic layers were dried < RTI ID =0.0></ RTI> to <RTI ID =0.0></ RTI><RTI ID =0.0>

步驟B：在0攝氏度下，向正在攪拌的5-(4-溴苯基)-3,4-二氫-2H-吡咯(2.0克，9.0毫莫耳)甲醇(20毫升)溶液中慢慢地加入硼氫化鈉(684毫克，18.1毫莫耳)。加完後，將該反應混合物在室溫下攪拌1小時。TLC(石油醚/乙酸乙酯=2：1)顯示原料完全消耗。將得到的混合物用水稀釋(30毫升)。向上述步驟中的混合物加入碳酸鉀(1.51克，10.9毫莫耳)和Boc2O(2.3克，10.5毫莫耳)。將該混合物在20攝氏度下攪拌2小時後，薄層色譜板(展開劑：石油醚/乙酸乙酯=2/1)顯示起始物質被消耗完全。然後用乙酸乙酯(50毫升×2)萃取，萃取液減壓濃縮，用矽膠色譜純化殘餘物，得到2-(4-溴苯基)吡咯烷-1-甲酸第三丁酯(1.5克，收率：51.1%)，為黃色固體。 Step B: Slowly at 0 ° C to a stirred solution of 5-(4-bromophenyl)-3,4-dihydro- 2H -pyrrole (2.0 g, 9.0 mmol) in methanol (20 mL) Sodium borohydride (684 mg, 18.1 mmol) was added slowly. After the addition was completed, the reaction mixture was stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate = 2:1) showed complete consumption of starting material. The resulting mixture was diluted with water (30 mL). Potassium carbonate (1.51 g, 10.9 mmol) and Boc 2 O (2.3 g, 10.5 mmol) were added to the mixture in the above step. After the mixture was stirred at 20 ° C for 2 hours, a thin layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 2 / 1) showed that the starting material was consumed completely. It was then extracted with ethyl acetate (50 mL × 2). Yield: 51.1%) as a yellow solid.

步驟C：在氮氣氛圍、-78攝氏度下，向正在攪拌的2-(4-溴苯基)吡咯烷-1-甲酸第三丁酯(0.6克，1.839毫莫耳)的無水四氫呋喃(20毫升)溶液中加入n-BuLi(1.5毫升，2.76毫莫耳)。將反應混合物在-78攝氏度下攪拌30分鐘，然後將N,N-二甲基甲醯胺(192毫克，2.63毫莫耳)緩慢加入到混合物中。將所得混合物升溫至室溫，攪拌另外30分鐘，用3毫升碳酸氫鈉水溶液淬滅。用水稀釋(30毫升)，並用乙酸乙酯(25毫升×3)萃取。將合併的有機層用鹽水洗滌，用硫酸鈉乾燥，過濾並減壓蒸乾。將殘餘物通過矽膠色譜純化(石油醚：乙酸乙酯=15：1至10：1)，得到2-(4-甲醯基苯基)吡咯烷-1-甲酸第三丁酯(0.4g，收率：79.1%)，為無色油。 Step C: To a stirred solution of 2-(4-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.839 mmol) in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere at -78 °C. The solution was charged with n-BuLi (1.5 mL, 2.76 mmol). The reaction mixture was stirred at -78 °C for 30 minutes, then N,N-dimethylformamide (192 mg, 2.63 mmol) was slowly added to the mixture. The mixture was warmed to room temperature and stirred for additional 30 min then quenched with EtOAc EtOAc. It was diluted with water (30 ml) and extracted with ethyl acetate (25 ml). The combined organic layers were washed with brine, dried over sodium sulfate The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Yield: 79.1%) as a colorless oil.

MS(ESI)m/z：276.0[M+1+]。 MS (ESI) m / z: 276.0 [M+1 + ].

2-丁氧基-7-(4-(吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]2嘧啶-4-胺的製備：步驟D：根據實施例22，用步驟E、F的方法製備2-丁氧基 -7-(4-(吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 2-butoxy-7- (4- (pyrrolidin-2-yl) benzyl) -5 H - pyrrolo [3,2-d] 2 pyrimidin-4-amine: Step D: According to Example 22, Preparation of 2-butoxy-7-(4-(pyrrolidin-2-yl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine by the method of steps E and F .

MS(ESI)m/z：366.2[M+1+]。 MS (ESI) m/z: 366.2 [M+1 + ].

2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺的製備：步驟E：根據實施例25，用步驟G的方法製備2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 Preparation of 2-butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine: Step E: According to Example 25, Preparation of 2-Butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine by the procedure of Step G 4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.27(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.03(s,1H),4.30(t,J=7.4Hz,2H),3.97(s,2H),3.31-3.19(m,1H),3.07-3,03(m,1H),2.31-2.87(m,1H),2.18-2.15(m,1H),2.13(s,3H),1.89-1.72(m,5H),1.54-1.48(m,2H),0.98(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.27 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 4.30 (t, J = 7.4 Hz, 2H), 3.97 (s, 2H), 3.31-3.19 (m, 1H), 3.07-3, 03 (m, 1H), 2.31-2.87 (m, 1H), 2.18-2.15 (m, 1H), 2.13 (s, 3H), 1.89-1.72 (m, 5H), 1.54-1.48 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：380[M+1+]。 MS (ESI) m/z: 380 [M+1 + ].

實施例27Example 27 1-(4-((4-胺基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮 1-(4-((4-Amino-2-butoxy- 5H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazine- 2-ketone

4-(4-甲基-2-氧代哌嗪-1-基)苯甲醛的製備： Preparation of 4-(4-methyl-2-oxopiperin-1-yl)benzaldehyde:

步驟A：向4-溴-苯甲醛(1.8克，9.73毫莫耳)、4-甲基哌嗪-2-酮(1.44克，12.6毫莫耳)、Pd2(dba)3(768毫克，0.84毫莫耳)、 Xantphos(435毫克，0.75毫莫耳)和碳酸銫(5.48克，16.8毫莫耳)的二噁烷(30mL)溶液中加入水(1滴)。將混合物在氮氣氣氛、90攝氏度下攪拌1.5小時。冷卻後，將該混合物過濾。將濾液在真空下濃縮至乾，殘餘物通過矽膠色譜法純化，得到4-(4-甲基-2-氧代哌嗪-1-基)苯甲醛(1.8克，84.8%)，為白色固體。 Step A: To 4-bromo-benzaldehyde (1.8 g, 9.73 mmol), 4-methylpiperazin-2-one (1.44 g, 12.6 mmol), Pd 2 (dba) 3 (768 mg, Water (1 drop) was added to a solution of Xantphos (435 mg, 0.75 mmol) and cesium carbonate (5.48 g, 16.8 mmol) in dioxane (30 mL). The mixture was stirred under a nitrogen atmosphere at 90 ° C for 1.5 hours. After cooling, the mixture was filtered. The filtrate was concentrated to dryness <RTI ID=0.0> .

MS(ESI)m/z：219[M+H+]。 MS (ESI) m / z: 218 [M+H + ].

1-(4-((4-胺基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮的製備：步驟B：根據實施例22，用步驟E、F的方法製備1-(4-((4-胺基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮。 1-(4-((4-Amino-2-butoxy- 5H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazine- Preparation of 2-ketone: Step B: Preparation of 1-(4-((4-amino-2-butoxy- 5H -pyrrolo[3,2-]- d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one.

1 HNMR(Methanol-d4,400MHz)δ7.36(s,1H),7.30(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),4.52(t,J=6.4Hz,2H),4.02(s,2H),3.72-3.69(m,2H),3.27(s,2H),2.89-2.86(m,2H),2.44(s,3H),1.83-1.79(m,2H),1.54-1.48(m,2H),1.00(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz) δ 7.36 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.52 (t, J = 6.4 Hz) , 2H), 4.02 (s, 2H), 3.72-3.69 (m, 2H), 3.27 (s, 2H), 2.89-2.86 (m, 2H), 2.44 (s, 3H), 1.83-1.79 (m, 2H) ), 1.54-1.48 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：409[M+H+]。 MS (ESI) m / z: 409 [M+H + ].

實施例28Example 28 2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

7-甲醯基-3,4-二氫異喹啉-2(1H)-羧酸第三丁酯的製備路線： Preparation route of 7-mercapto-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester:

步驟A：在氮氣氣氛、0攝氏度下，向2-(4-溴苯基)乙胺(27克，0.13莫耳)和三乙胺(16.4克，0.16莫耳)的無水二氯甲烷(300毫升)溶液中滴加入三氟乙酸酐(34克，0.16莫耳)。將反應混合物在室溫下攪拌1小時，然後用水稀釋。將有機層分離並在真空下濃縮至乾，得到N-(4-溴苯乙基)-三氟乙醯胺(37克，96.1%)，為白色固體。 Step A: Toluene dichloromethane (300 g of 2-(4-bromophenyl)ethylamine (27 g, 0.13 mol) and triethylamine (16.4 g, 0.16 m) in a nitrogen atmosphere at 0 ° C. Trifluoroacetic anhydride (34 g, 0.16 mol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water. The organic layer was separated and evaporated to dryness mjjjjjjjj

MS(ESI)m/z：296,298[M+H+]。 MS (ESI) m / z: 296, 298 [M+H + ].

步驟B：向N-(4-溴苯乙基)-三氟乙醯胺(37克，0.12毫莫耳)的濃硫酸(200毫升)/乙酸(300毫升)攪拌懸浮液溶液中分批加入多聚甲醛(10.2克，0.34莫耳)。加完後，該反應混合物在室溫下攪拌12小時，然後倒入冰水(1升)中，用乙酸乙酯(400毫升×2)萃取。將合併的有機層依次用飽和碳酸氫鈉水溶液和鹽水洗滌，用無水硫酸鎂乾燥，並減壓濃縮。將殘餘物用矽膠柱色譜法純化(洗脫劑：5%乙酸乙酯的石油醚溶液)，得到1-(7-溴-3,4-二氫異喹啉-2(1H)-基)-三氟乙酮(33克，89.3%)。 Step B: Adding a suspension solution of N-(4-bromophenethyl)-trifluoroacetamide (37 g, 0.12 mmol) in concentrated sulfuric acid (200 mL) / acetic acid (300 mL) Paraformaldehyde (10.2 g, 0.34 mol). After the addition was completed, the reaction mixture was stirred at room temperature for 12 hr, then poured into ice water (1 liter) and extracted with ethyl acetate (400 ml × 2). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by silica gel column chromatography (eluent: 5% ethyl acetate in petroleum ether) to give 1-(7-bromo-3,4-dihydroisoquinolin-2( 1H )-yl. )-Trifluoroethanone (33 g, 89.3%).

MS(ESI)m/z：308,310[M+H+]。 MS (ESI) m/z: 308, 310 [M+H + ].

步驟C：向1-(7-溴-3,4-二氫異喹啉-2(1H)-基)-三氟乙酮(30克，0.1莫耳)的無水甲基吡咯烷-2-酮(300毫升)溶液中加入氰化亞銅(18克，0.2莫耳)。將反應混合物在180攝氏度、氮氣氣氛下攪拌4小時。在冷卻到室溫後，將該混合物慢慢地倒入冰水(500毫升)中，並用乙酸乙酯(200毫升×2)萃取。將合併的有機層用水洗滌，經無水硫酸鈉乾燥並在真空下濃縮，得到25克粗品2-三氟乙醯基-四氫異喹啉-7-甲腈，其直接用於下一步驟。 Step C: To a solution of 1-(7-bromo-3,4-dihydroisoquinolin-2(1 H )-yl)-trifluoroethanone (30 g, 0.1 mol) of anhydrous methylpyrrolidine-2 To the ketone (300 ml) solution was added cuprous cyanide (18 g, 0.2 mol). The reaction mixture was stirred at 180 ° C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was slowly poured into ice water (500 ml) and extracted with ethyl acetate (200 ml × 2). The combined organic layers were washed with EtOAc EtOAc m.

MS(ESI)m/z：255[M+H+]。 MS (ESI) m / z: 495 [M+H + ].

步驟D：將2-三氟乙醯基-四氫異喹啉-7-甲腈(25克，0.1莫耳)和碳酸鉀(25克，0.18莫耳)溶解在甲醇(300毫升)和水(60毫升)的混合溶劑中，在室溫下攪拌2小時。然後在10分鐘內將二碳酸二第三丁酯(26克，0.12莫耳)分批加入。將反應混合物在室溫下再攪拌4小時後，用水(200毫升)稀釋，並用乙酸乙酯(200毫升×2)萃取。將合併的有機層用鹽水洗滌，用無水硫酸鈉乾燥，並在真空下濃縮。將殘餘物用矽膠柱色譜法純化(洗脫劑：5%乙酸乙酯的石油醚溶液)，得到7-氰基-3,4-二氫異喹啉-2(1H)-羧酸第三丁酯(14克，54%)，為白色固體。 Step D: Dissolving 2-trifluoroethenyl-tetrahydroisoquinolin-7-carbonitrile (25 g, 0.1 mol) and potassium carbonate (25 g, 0.18 mol) in methanol (300 mL) and water (60 ml) of a mixed solvent was stirred at room temperature for 2 hours. Dibutyl succinate (26 grams, 0.12 moles) was then added in portions over 10 minutes. After the reaction mixture was stirred at room temperature for additional 4 hr, then diluted with EtOAc. The combined organic layers were washed with brine w... The residue was purified by silica gel column chromatography (eluent: 5% ethyl acetate in petroleum ether) to afford 7-cyano-3,4-dihydroisoquinoline-2( 1H )-carboxylic acid Tributyl ester (14 g, 54%) was obtained as a white solid.

MS(ESI)m/z：259[M+H+]。 MS (ESI) m / z: 259 [M+H + ].

步驟E：在-10攝氏度、氮氣氣氛下，向7-氰基-3,4-二氫異喹啉-2(1H)-羧酸第三丁酯(1克，3.9毫莫耳)的無水四氫呋喃(20毫升)溶液中滴加二異丁基氫化鋁(1M，6毫升，6.0毫莫耳)。加完後，將反應混合物在0攝氏度下攪拌5小時，並用水(0.24毫升)淬滅。然後，將15%的氫氧化鈉水溶液(0.24毫升)加入，再加入0.6毫升水。將所 得混合物在室溫下進一步攪拌15分鐘後，用無水硫酸鎂乾燥並過濾。將濾液在真空下濃縮，殘餘物用矽膠柱色譜法純化(洗脫劑10%的乙酸乙酯石油醚溶液)，得到7-甲醯基-3,4-二氫異喹啉-2(1H)-羧酸第三丁酯(700毫克，70%)，為黃色油狀物。 Step E: To a solution of 7-cyano-3,4-dihydroisoquinolin-2(1 H )-carboxylic acid tert-butyl ester (1 g, 3.9 mmol) at -10 ° C under a nitrogen atmosphere. A solution of diisobutylaluminum hydride (1 M, 6 mL, 6.0 mmol) was added dropwise over anhydrous THF (20 mL). After the addition, the reaction mixture was stirred at 0 ° C for 5 hr and then quenched with water (0.24 mL). Then, a 15% aqueous sodium hydroxide solution (0.24 ml) was added, followed by 0.6 ml of water. The resulting mixture was further stirred at room temperature for 15 minutes, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting H )-Dicarboxylic acid tert-butyl ester (700 mg, 70%) as a yellow oil.

MS(ESI)m/z：262[M+H+]。 MS (ESI) m / z: 262[M+H + ].

2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的製備：步驟F：根據實施例22，用步驟E、F的方法製得2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine Preparation: Step F: According to Example 22, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl) was obtained by the procedure of steps E and F. -5 H -pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.49(s,2H),7.23-7.15(m,3H),7.10(s,1H),4.44(t,J=6.5Hz,2H),4.30(s,2H),3.98(s,2H),3.47(t,J=6.1Hz,2H),3.08(t,J=6.1Hz,2H),1.83-1.76(m,2H),1.55-1.49(m,2H),1.01(t,J=7.4Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.49 (s, 2H), 7.23 - 7.15 (m, 3H), 7.10 (s, 1H), 4.44 (t, J = 6.5 Hz, 2H), 4.30 (s) , 2H), 3.98 (s, 2H), 3.47 (t, J = 6.1 Hz, 2H), 3.08 (t, J = 6.1 Hz, 2H), 1.83-1.76 (m, 2H), 1.55-1.49 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：352[M+H+]。 MS (ESI) m / z: 352[M+H + ].

實施例29Example 29 2-丁氧基-7-((2-甲基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine 4-amine

以2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺為原料，根據實施例25，用步驟G的方法製備2-丁氧基-7-((2-甲基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4- 胺。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine As a raw material, according to Example 25, 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl) was prepared by the method of Step G. -5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.11-7.09(m,1H),7.03-7.00(m,3H),4.32(t,J=6.4Hz,2H),3.92(s,2H),3.55(s,2H),2.91-2.88(m,2H),2.73-2.71(m,2H),2.43(s,3H),1.80-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J=7.6Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.11-7.09 (m, 1H), 7.03-7.00 (m, 3H), 4.32 (t, J = 6.4 Hz, 2H), 3.92 (s, 2H), 3.55 (s, 2H), 2.91-2.88 (m, 2H), 2.73-2.71 (m, 2H), 2.43 (s, 3H), 1.80-1.73 (m, 2H), 1.56-1.52 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H).

MS(ESI)m/z：366[M+H+]。 MS (ESI) m / z: 366 [M+H + ].

實施例30Example 30 2-丁氧基-7-((2-乙基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine 4-amine

以2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺為原料，根據實施例25，用步驟G的方法製得2-丁氧基-7-((2-乙基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine As a raw material, according to Example 25, 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl was obtained by the method of Step G. -5 H -pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.43(s,2H),7.25-7.18(m,3H),7.10(s,1H),4.45(t,J=6.4Hz,2H),4.34(s,2H),3.99(s,2H),3.51(t,J=6.0Hz,2H),3.32-3.26(m,2H),3.15(t,J=6.0Hz,2H),1.84-1.77(m,2H),1.58-1.48(m,2H),1.42(t,J=8.0Hz,3H),1.01(t,J=6.0Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.43 (s, 2H), 7.25-7.18 (m, 3H), 7.10 (s, 1H), 4.45 (t, J = 6.4 Hz, 2H), 4.34 (s) , 2H), 3.99 (s, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.32-3.26 (m, 2H), 3.15 (t, J = 6.0 Hz, 2H), 1.84-1.77 (m, 2H), 1.58-1.48 (m, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.01 (t, J = 6.0 Hz, 3H).

MS(ESI)m/z：380[M+H+]。 MS (ESI) m/z: 380[M+H + ].

實施例31Example 31 2-丁氧基-7-((2-異丙基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d] Pyrimidine-4-amine

以2-丁氧基-7-((1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺為原料，根據實施例25，用步驟G的方法製備2-丁氧基-7-((2-異丙基-1,2,3,4-四氫異喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine As a raw material, according to Example 25, 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl was prepared by the method of Step G. )-5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.10-7.08(m,1H),7.03-7.00(m,3H),4.32(t,J=6.4Hz,2H),3.93(s,2H),3.70(s,2H),2.90-2.86(m,3H),2.83-2.80(m,2H),1.80-1.73(m,2H),1.56-1.50(m,2H),1.17(d,J=6.4Hz,6H),1.01(t,J=7.6Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.10-7.08 (m, 1H), 7.03-7.00 (m, 3H), 4.32 (t, J = 6.4 Hz, 2H), 3.93 (s, 2H), 3.70 (s, 2H), 2.90-2.86 (m, 3H), 2.83-2.80 (m, 2H), 1.80-1.73 (m, 2H), 1.56-1.50 (m, 2H), 1.17 (d, J = 6.4 Hz) , 6H), 1.01 (t, J = 7.6 Hz, 3H).

MS(ESI)m/z：394[M+H+]。 MS (ESI) m / z: 394 [M+H + ].

實施例32Example 32 2-丁氧基-7-((1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

N-第三丁氧羰基1,2,3,4-四氫異喹啉-6-甲醛的製備路線： Preparation route of N-tert-butoxycarbonyl 1,2,3,4-tetrahydroisoquinoline-6-formaldehyde:

步驟A：向6-溴異喹啉(10克，48毫莫耳)的N,N-二甲基甲醯胺/甲醇(V/V=1/1)(200毫升)混合溶液中加入乙酸鈉(5.0克，61毫莫耳)、三苯基膦(3.0克，11.4毫莫耳)和醋酸鈀(2.8克，12毫莫耳)。混合物處於通入有300千帕一氧化碳的高壓釜中，並加熱至100攝氏度。攪拌15小時後，通過LC-MS判定反應完成，其反應物通過矽藻土過濾(用乙酸乙酯洗脫)。將所得混合物濃縮，在減壓下將殘餘物通過矽膠柱色譜純化(洗脫劑：石油醚/乙酸乙酯=5/1)。得到異喹啉-6-羧酸甲酯(8.9克，收率：98%)。 Step A: Add acetic acid to a mixed solution of 6-bromoisoquinoline (10 g, 48 mmol) of N,N-dimethylformamide/methanol (V/V = 1/1) (200 mL) Sodium (5.0 g, 61 mmol), triphenylphosphine (3.0 g, 11.4 mmol) and palladium acetate (2.8 g, 12 mmol). The mixture was placed in an autoclave with 300 kPa carbon monoxide and heated to 100 degrees Celsius. After stirring for 15 hours, the reaction was completed by EtOAc (EtOAc). The resulting mixture was concentrated, and the residue was purifiedjjjjjjjjjjj Methyl isoquinoline-6-carboxylate (8.9 g, yield: 98%) was obtained.

MS(ESI)m/z：188[M+H+]。 MS (ESI) m/z: 188 [M+H + ].

步驟B：在氮氣保護下，向正在攪拌的異喹啉-6-羧酸甲酯(10克，53.5毫莫耳)的甲醇(100毫升)溶液中加乙酸(2毫升)和PtO2(200毫克)。在氫氣氣氛中，將該混合物在40攝氏度下攪拌反應3小時，然後將催化劑通過矽藻土過濾掉，並在真空下濃縮，得到1,2,3,4-四氫異喹啉-6-羧酸甲酯(9克，收率：88%)無需進一步純化。 Step B: Under nitrogen, to a stirred suspension of isoquinoline-6-carboxylate (10 g, 53.5 mmol) in methanol (100 mL) was added acetic acid (2 mL) and PtO 2 (200 Mg). The mixture was stirred at 40 ° C for 3 hours under a hydrogen atmosphere, then the catalyst was filtered off through celite and concentrated under vacuum to give 1,2,3,4-tetrahydroisoquinoline-6- Methyl carboxylate (9 g, yield: 88%) was obtained without further purification.

MS(ESI)m/z：192[M+H+]。 MS (ESI) m/z: 192[M+H + ].

步驟C：根據實施例25，用步驟C的方法製備N-第三丁氧羰基1,2,3,4-四氫異喹啉-6-羧酸甲酯。 Step C: According to Example 25, N-tert-butoxycarbonyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester was prepared by the procedure of Step C.

MS(ESI)m/z：292[M+H+]。 MS (ESI) m / z: 292 [M+H + ].

步驟D：根據實施例22，用步驟C、D的方法製備N-第三丁氧羰基1,2,3,4-四氫異喹啉-6-甲醛。 Step D: According to Example 22, N-tert-butoxycarbonyl 1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde was prepared by the procedure of Steps C and D.

MS(ESI)m/z：262[M+H+]。 MS (ESI) m / z: 262[M+H + ].

2-丁氧基-7-((1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的製備：步驟E：根據實施例22，用步驟E、F的方法製備2-丁氧基 -7-((1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine Preparation: Step E: According to Example 22, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)- 5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.12-7.09(m,1H),7.08(s,1H),7.04(s,1H),6.96(d,J=7.6Hz,1H),4.32(t,J=7.4Hz,2H),3.98(s,2H),3.93(s,2H),3.13(t,J=6.2Hz,2H),2.85-2.82(m,2H),1.79-1.73(m,2H),1.58-1.48(m,2H),1.01(s,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.12-7.09 (m, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.32 (t , J = 7.4 Hz, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.13 (t, J = 6.2 Hz, 2H), 2.85-2.82 (m, 2H), 1.79-1.73 (m, 2H), 1.58-1.48 (m, 2H), 1.01 (s, 3H).

MS(ESI)m/z：352[M+H+]。 MS (ESI) m / z: 352[M+H + ].

實施例33Example 33 2-丁氧基-7-((2-甲基-1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine 4-amine

以2-丁氧基-7-((1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺為原料，根據實施例25，用步驟G的方法製備2-丁氧基-7-((2-甲基-1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine As a raw material, according to Example 25, 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl) was prepared by the method of Step G. -5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.10-7.09(m,2H),7.03(s,1H),6.96(d,J=8.4Hz,1H),4.32(t,J=6.6Hz,2H),3.93(s,2H),3.60(s,2H),2.92-2.89(m,2H),2.77-2.74(m,2H),2.46(s,3H),1.81-1.73(m,2H),1.58-1.48(m,2H),1.01(t,J=7.4Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.10-7.09 (m, 2H), 7.03 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H) ), 3.93 (s, 2H), 3.60 (s, 2H), 2.92-2.89 (m, 2H), 2.77-2.74 (m, 2H), 2.46 (s, 3H), 1.81-1.73 (m, 2H), 1.58-1.48 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

MS(ESI)m/z：366[M+H+]。 MS (ESI) m / z: 366 [M+H + ].

實施例34Example 34 2-丁氧基-7-((2-乙基-1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine 4-amine

以2-丁氧基-7-((1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺為原料，根據實施例25，用步驟G的方法製備2-丁氧基-7-((2-乙基-1,2,3,4-四氫異喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine Preparation of 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl) by the procedure of Step G according to Example 25 -5 H -pyrrolo[3,2-d]pyrimidin-4-amine.

1 HNMR(Methanol-d4,400MHz)：δ7.11-7.08(m,2H),7.03(s,1H),6.97(d,J=8.0Hz,1H),4.32(t,J=6.6Hz,2H),3.94(s,2H),3.63(s,2H),2.93-2.88(m,2H),2.79-2.76(m,2H),2.65-2.60(m,2H),1.79-1.75(m,2H),1.56-1.52(m,2H),1.21(t,J=7.2Hz,3H),1.01(t,J=7.2Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 7.11 - 7.08 (m, 2H), 7.03 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H) ), 3.94 (s, 2H), 3.63 (s, 2H), 2.93-2.88 (m, 2H), 2.79-2.76 (m, 2H), 2.65-2.60 (m, 2H), 1.79-1.75 (m, 2H) ), 1.56-1.52 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：380[M+H+]。 MS (ESI) m/z: 380[M+H + ].

實施例35Example 35 7-苄基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺 7-Benzyl-2-(2-methoxyethoxy)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

步驟A：根據實施例1，用步驟C、D、E的方法製備(4-胺基-2-(2-甲氧基乙氧基)-5-((2-(三甲基矽基乙基)-5H-吡咯[3,2-d]嘧啶-7-基)(苯基)甲醇。 Step A: Preparation of 4-amino-2-(2-methoxyethoxy)-5-((2-(trimethyl decyl) Base-5-5- H -pyrrole[3,2-d]pyrimidin-7-yl)(phenyl)methanol.

MS(ESI)m/z：445[M+H+]。 MS (ESI) m / z: 445 [M+H + ].

步驟B：根據實施例1，用步驟G的方法製得7-苄基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 Step B: According to Example 1, Step G using methods to give 7-benzyl-2- (2-methoxyethoxy) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine Formate.

1 HNMR(Methanol-d4,400MHz)：δ8.39(s,1H),7.29-7.19(m,6H),4.61-4.58(m,2H),4.00(s,1H),3.79-3.76(m,2H),3.42(s,3H)。 1 H NMR (Methanol-d 4, 400 MHz) : δ 8.39 (s, 1H), 7.29-7.19 (m, 6H), 4.61-4.58 (m, 2H), 4.00 (s, 1H), 3.79-3.76 (m, 2H), 3.42 (s, 3H).

MS(ESI)m/z：299[M+H+]。 MS (ESI) m / z: 299 [M+H + ].

實施例36Example 36 2-(2-甲氧基乙氧基)-7-((6-甲基吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-(2-methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

根據實施例35，用步驟A、B的方法製得2-(2-甲氧基乙氧基)-7-((6-甲基吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 According to Example 35, 2-(2-methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5 H -pyrrole was obtained by the method of Steps A and B. [3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.34(s,3H),7.66(dd,J=2.4Hz/J=8.0Hz,1H),7.31(s,1H),7.24(d,J=8.0Hz,1H),4.57-4.55(m,2H),4.01(s,2H),3.77-3.75(m,2H),3.41(s,3H),2.51(s,3H)。 1 H NMR (Methanol-d 4, 400 MHz) : δ 8.34 (s, 3H), 7.66 (dd, J = 2.4 Hz / J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.57-4.55 (m, 2H), 4.01 (s, 2H), 3.77-3.75 (m, 2H), 3.41 (s, 3H), 2.51 (s, 3H).

MS(ESI)m/z：314[M+H+]。 MS (ESI) m / z: 314 [M+H + ].

實施例37Example 37 7-((5-氯吡啶-2-基)甲基)-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺 7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

根據實施例35，用步驟A、B的方法製得7-((5-氯吡啶-2-基)甲基)-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 According to Example 35, 7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3] was obtained by the procedure of Steps A and B. , 2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.45(s,1H),8.40(s,1H),7.77(dd,J=2.4Hz/J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.32(s,1H),4.52(t,J=4.0Hz,2H),4.17(s,2H),3.75(t,J=4.0Hz,2H),3.42(s,3H)。 1 H NMR (Methanol-d 4, 400 MHz) : δ 8.45 (s, 1H), 8.40 (s, 1H), 7.77 (dd, J = 2.4 Hz / J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 4.52 (t, J = 4.0 Hz, 2H), 4.17 (s, 2H), 3.75 (t, J = 4.0 Hz, 2H), 3.42 (s, 3H).

MS(ESI)m/z：334[M+H+]。 MS (ESI) m / z: 344 [M+H + ].

實施例38Example 38 2-(2-甲氧基乙氧基-)-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-(2-methoxyethoxy-)-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5 H -pyrrolo[3,2- d]pyrimidine-4-amine

根據實施例35，用步驟A、B的方法製得2-(2-甲氧基乙氧基)-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 According to Example 35, 2-(2-methoxyethoxy)-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl was obtained by the method of Steps A and B. ))-5 H -pyrrolo[3,2-d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.62(s,1H),8.41(s,2H),7.79-7.76(m,1H),7.36(d,J=8.4Hz,1H),7.28(s,1H),4.49-4.44(m,4H),4.05(s,2H),3.74-3.72(m,2H),3.39(s,3H),3.33-3.30(m,4H),2.10-2.07(m,4H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.62 (s, 1H), 8.41 (s, 2H), 7.79-7.76 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (s) , 1H), 4.49-4.44 (m, 4H), 4.05 (s, 2H), 3.74-3.72 (m, 2H), 3.39 (s, 3H), 3.33-3.30 (m, 4H), 2.10-2.07 (m , 4H).

MS(ESI)m/z：383[M+H+]。 MS (ESI) m / z: 381 [M+H + ].

實施例39Example 39 1-(4-((4-胺基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮 1-(4-((4-Amino-2-(2-methoxyethoxy)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)- 4-methylpiperazin-2-one

根據實施例35，用步驟A、B的方法製備1-(4-((4-胺基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮。 Preparation of 1-(4-((4-amino-2-(2-methoxyethoxy))- 5H -pyrrolo[3,2-d] by the procedure of Steps A and B according to Example 35 Pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one.

1 HNMR(Methanol-d4,400MHz)：δ7.35(s,1H),7.31(d,J=8.4Hz,2H) ,7.22(d,J=8.4Hz,2H),4.65-4.62(m,2H),4.01(s,2H),3.77-3.76(m,2H),3.70-3.67(m,2H),3.35(s,3H),3.32-3.28(m,2H),2.90-2.88(m,2H),2.45(s,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.35 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.65-4.62 (m, 2H) ), 4.01 (s, 2H), 3.77-3.76 (m, 2H), 3.70-3.67 (m, 2H), 3.35 (s, 3H), 3.32-3.28 (m, 2H), 2.90-2.88 (m, 2H) ), 2.45 (s, 3H).

MS(ESI)m/z：411[M+H+]。 MS (ESI) m / z: 411 [M+H + ].

實施例40Example 40 2-丁氧基-7-((5-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺 2-butoxy-7-((5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine

根據實施例22的流程，製得2-丁氧基-7-((5-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸鹽。 According to the procedure of Example 22, 2-butoxy-7-((5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-5 H -pyrrolo[3,2 was obtained. -d]pyrimidine-4-amine formate.

1 HNMR(Methanol-d4,400MHz)：δ8.61(s,1H),8.46(brs,2H),7.91(d,J=8.0Hz,1H),7.47(d,J=7.6Hz,1H),7.37(s,1H),4.44(t,J=6.4Hz,2H),4.35(s,2H),4.22(s,2H),3.33-3.27(m,4H),2.09-2.06(m,4H),1.83-1.76(m,2H),1.57-1.50(m,2H),1.01(t,J=7.6Hz,3H)。 1 H NMR (Methanol-d 4, 400 MHz): δ 8.61 (s, 1H), 8.46 (brs, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.37(s,1H), 4.44(t, J =6.4Hz, 2H), 4.35(s,2H), 4.22(s,2H),3.33-3.27(m,4H),2.09-2.06(m,4H) , 1.83-1.76 (m, 2H), 1.57-1.50 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H).

MS(ESI)m/z：381[M+H+]。 MS (ESI) m / z: 381 [M+H + ].

實施例41Example 41 4-胺基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈 4-amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine -6-carbonitrile

實施例41流程： Example 41 process:

實施例41流程Example 41 Process

步驟A：在氮氣氛、-78℃下，向7-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(10.00克，24.07毫莫耳)的無水四氫呋喃(200毫升)溶液中加入n-BuLi(6.17克，96.28毫莫耳)。將混合物在-78℃下攪拌1小時。然後將6-氯煙醛(10.22克，72.21毫莫耳)的四氫呋喃(200毫升)溶液逐滴加入。將反應混合物在-78℃下再攪拌1小時，慢慢地倒入水(150毫升)中，在室溫下攪拌20分鐘，然後用乙酸乙酯(100毫升×3)萃取。將合併的有機相用飽和鹽水(50毫升×2)洗滌，經無水硫酸鈉乾燥，過濾並真空濃縮。殘餘物通過矽膠色譜法純化(洗離線：石油醚/乙酸乙酯=5/1到1/3)，得到(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-氯吡啶-3-基)甲醇(5.00克，43.45%)，為黃色固體。 Step A: 7-Bromo-2-butoxy-5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrole in a nitrogen atmosphere at -78 °C [3,2-d]pyrimidin-4-amine (10.00 g, 24.07 mmol) in anhydrous tetrahydrofuran (200 mL) was added n-BuLi (6.17 g, 96.28 mmol). The mixture was stirred at -78 °C for 1 hour. A solution of 6-chloronicotinaldehyde (10.22 g, 72.21 mmol) in tetrahydrofuran (200 mL) was then added dropwise. The reaction mixture was stirred at -78.degree. C. for further 1 hour, poured slowly over water (150 ml), and then stirred at room temperature for 20 min, then ethyl acetate (100 ml x 3). The combined organic phases were washed with EtOAc EtOAc m. The residue was purified by silica gel chromatography (washing off: petroleum ether / ethyl acetate = 5/1 to 1/3) to give (4-amino-2-butoxy-5-((2-(trimethyl)) Methoxyalkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)(6-chloropyridin-3-yl)methanol (5.00 g, 43.45%), Yellow solid.

1 HNMR(400MHz,CHLOROFORM-d)δ8.52(d,J=2.3Hz,1H),7.87 (dd,J=2.4,8.2Hz,1H),7.34(d,J=8.0Hz,1H),6.65(s,1H),6.14(s,1H),5.97(br.s.,2H),5.39-5.26(m,2H),4.31(t,J=6.7Hz,2H),3.62-3.49(m,2H),1.86-1.71(m,2H),1.51(qd,J=7.5,14.9Hz,2H),1.28(t,J=7.2Hz,1H),1.06-0.87(m,5H),0.00(s,9H)。 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 2.4, 8.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 5.97 (br.s., 2H), 5.39-5.26 (m, 2H), 4.31 (t, J = 6.7 Hz, 2H), 3.62-3.49 (m, 2H), 1.86-1.71 (m, 2H), 1.51 (qd, J = 7.5, 14.9 Hz, 2H), 1.28 (t, J = 7.2 Hz, 1H), 1.06-0.87 (m, 5H), 0.00 (s) , 9H).

MS(ESI)m/z：478[M+H+]。 MS (ESI) m / z: 478 [M+H + ].

步驟B：在室溫下，向(4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-氯吡啶吡啶-3-基)甲醇(5.00克，10.46毫莫耳)的三氟乙酸(50毫升)溶液中分批加入三乙基矽烷(6.08克，52,30毫莫耳)。將反應混合物在環境溫度下攪拌24小時，倒入碳酸氫鈉飽和水溶液(150毫升)，並進一步攪拌20分鐘，然後用乙酸乙酯(100毫升×3)萃取。將合併的有機相用鹽水(20毫升×2)洗滌，經無水硫酸鈉乾燥，過濾並真空濃縮。殘餘物通過矽膠色譜法(洗脫劑：石油醚/乙酸乙酯=3/1)純化，得到2-丁氧基-7-((6-氯吡啶-3-基)甲基)-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(2.30克，47.59%)，為黃色固體。 Step B: To a solution of (4-amino-2-butoxy-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3 , 2-d]pyrimidin-7-yl)(6-chloropyridin-3-yl)methanol (5.00 g, 10.46 mmol) in trifluoroacetic acid (50 ml) 6.08 grams, 52, 30 millimoles). The reaction mixture was stirred at ambient temperature for 24 hr then EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc:EtOAcEtOAcEtOAc ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine (2.30 g, 47.59%) as a yellow solid.

1 HNMR(300MHz,CHLOROFORM-d)δ8.52(d,J=2.3Hz,1H),7.88(dd,J=2.4,8.1Hz,1H),7.35(d,J=8.3Hz,1H),6.64(s,1H),6.14(s,1H),5.89(br.s.,2H),5.40-5.23(m,2H),4.31(t,J=6.6Hz,2H),3.66-3.47(m,2H),1.88-1.70(m,2H),1.60-1.46(m,2H),1.07-0.82(m,5H),0.00(s,9H)。 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.52 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 2.4, 8.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.14 (s, 1H), 5.89 (br.s., 2H), 5.40-5.23 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.66-3.47 (m, 2H), 1.88-1.70 (m, 2H), 1.60-1.46 (m, 2H), 1.07-0.82 (m, 5H), 0.00 (s, 9H).

MS(ES1)m/z：462[M+H+]。 MS (ES1) m/z: 462[M+H + ].

步驟C：向2-丁氧基-7-((6-氯吡啶-3-基)甲基)-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-D]嘧啶-4-胺(2.30克，4.98毫莫耳)的N,N-二甲基甲醯胺(15毫升)溶液中加入醋酸鈀(111.75毫克，0.5毫莫耳)、1,3-雙二苯基膦丙烷(205.30毫克，0.5毫莫耳)、三乙胺(1.51 克，14.93毫莫耳)和甲醇(797.43毫克，24.89毫莫耳)。將懸浮液抽真空，充一氧化碳數次。將混合物加熱到100攝氏度，在一氧化碳氣氛(3兆帕)下攪拌24小時。薄層色譜板(展開劑：石油醚/乙酸乙酯=1/1)檢測顯示原料完全消耗。過濾掉不溶物，並濃縮。將粗產物經矽膠色譜法純化(洗脫劑：用石油醚/乙酸乙酯=1/1)，得到5-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(1.10克，45.48%)，為黃色固體。 Step C: To 2-butoxy-7-((6-chloropyridin-3-yl)methyl)-5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 Add palladium acetate (111.75 mg, 0.5) to a solution of H -pyrrolo[3,2-D]pyrimidine-4-amine (2.30 g, 4.98 mmol) in N,N-dimethylformamide (15 ml) Millol), 1,3-bisdiphenylphosphinepropane (205.30 mg, 0.5 mmol), triethylamine (1.51 g, 14.93 mmol) and methanol (797.43 mg, 24.89 mmol). The suspension was evacuated and charged with carbon monoxide several times. The mixture was heated to 100 ° C and stirred under a carbon monoxide atmosphere (3 MPa) for 24 hours. A thin layer chromatography plate (developing agent: petroleum ether/ethyl acetate = 1/1) showed complete consumption of the starting material. The insoluble material was filtered off and concentrated. The crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 5-((4-amino-2-butoxy-5-((2-) Methyl(meth)alkyl)ethoxy)methyl)-5- H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (1.10 g, 45.48%) as a yellow solid .

1 HNMR(400MHz,CHLOROFORM-d)δ8.76(d,J=1.8Hz,1H),8.06(d,J=8.0Hz,1H),7.85(dd,J=2.0,8.0Hz,1H),6.82(s,1H),5.71(br.s.,2H),5.35(s,2H),4.33(t,J=6.5Hz,2H),4.19-4.08(m,3H),4.00(s,3H),3.60-3.51(m,2H),1.85-1.74(m,2H),1.53(qd,J=7.4,15.0Hz,2H),1.28(t,J=7.2Hz,2H),1.02-0.90(m,5H),0.00(s,9H)。 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 2.0, 8.0 Hz, 1H), 6.82 (s, 1H), 5.71 (br.s., 2H), 5.35 (s, 2H), 4.33 (t, J = 6.5 Hz, 2H), 4.19-4.08 (m, 3H), 4.00 (s, 3H) , 3.60-3.51 (m, 2H), 1.85-1.74 (m, 2H), 1.53 (qd, J = 7.4, 15.0 Hz, 2H), 1.28 (t, J = 7.2 Hz, 2H), 1.02-0.90 (m , 5H), 0.00 (s, 9H).

MS(ESI)m/z：486[M+H+]。 MS (ESI) m / z: 486 [M+H + ].

步驟D：在低於0攝氏度下，向5-((4-胺基-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(800.00毫克，1.65毫莫耳)的四氫呋喃(10毫升)溶液中分批加入溴代丁二醯胺(293.18毫克，1.65毫莫耳)。將反應混合物在0攝氏度下攪拌1小時，用水(30毫升)稀釋並用二氯甲烷(20毫升×2)萃取。將合併的有機相用硫酸鎂乾燥並在真空下濃縮。殘餘物通過製備薄層色譜板純化，得到5-((4-胺基-6-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(160.00毫克，17.18%)，為黃色固體。 Step D: below 0 degrees C, a solution of 5 - ((4-amino-2-butoxy-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H To a solution of methyl pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (800.00 mg, 1.65 mmol) in tetrahydrofuran (10 mL) 293.18 mg, 1.65 mmol. The reaction mixture was stirred at 0.degree. C. for 1 h, diluted with water (30 mL) The combined organic phases were dried with MgSO4 and evaporatedEtOAc. The residue was purified by preparative thin-layer chromatography to give 5-((4-amino-6-bromo-2-butoxy-5-((2-(trimethylmethyl)alkyl)ethoxy)methyl Methyl 5- H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (160.00 mg, 17.18%) as a yellow solid.

1HNMR(400MHz,CHLOROFORM-d)δ8.83(s,1H),8.03(d,J=8.0Hz,1H),7.86(d,J=8.0Hz,1H),5.85(br.s,,2H),5.55(s,2H),4.34(t,J=6.5Hz,2 H),4.10(s,2H),4.00(s,3H),3.71-3.60(m,2H),1.84-1.72(m,4H),1.59-1.47(m,2H),0.98(q,J=7.8Hz,5H),0.01(s,9H)。 1H NMR (400MHz, CHLOROFORM-d) δ8.83 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 5.85 (br.s, 2H) , 5.55 (s, 2H), 4.34 (t, J = 6.5 Hz, 2 H), 4.10 (s, 2H), 4.00 (s, 3H), 3.71-3.60 (m, 2H), 1.84-1.72 (m, 4H), 1.59-1.47 (m, 2H), 0.98 (q, J = 7.8 Hz, 5H), 0.01 (s, 9H).

MS(ESI)m/z：565,567[M+H+]。 MS (ESI) m / z: 565, 565 [M+H + ].

步驟E：在氮氣氛、-78攝氏度下，向正在攪拌的5-((4-胺基-6-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(150.00毫克，0.266毫莫耳)的無水四氫呋喃(8毫升)溶液中滴加入二異丁基氫化鋁(56.28毫克，0.396毫莫耳)。加完後，將該反應混合物在-78攝氏度下攪拌1小時。隨後將反應混合物用甲醇(5毫升)淬滅，用水稀釋(20毫升)，並用乙酸乙酯(30毫升×2)萃取。合併的有機層在真空下濃縮至乾，得到約150毫克粗品5-((4-胺基-6-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶醛，無需進一步純化。 Step E: 5-((4-Amino-6-bromo-2-butoxy-5-((2-(trimethylmethyl)alkyl)) was stirred under a nitrogen atmosphere at -78 °C. Methyl oxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (150.00 mg, 0.266 mmol) in anhydrous tetrahydrofuran (8 mL) Diisobutylaluminum hydride (56.28 mg, 0.396 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were concentrated to dryness <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI><RTIID=0.0> Oxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridine aldehyde without further purification.

1 HNMR(400MHz,CHLOROFORM-d)δ10.05(s,1H),8.87(s,1H),7.96-7.80(m,2H),5.72(br.s,2H),5.56(s,2H),4.34(t,J=6.5Hz,2H),4.12(s,2H),3.71-3.62(m,2H),1.84-1.72(m,2H),1.56-1.48(m,2H),1.06-0.81(m,5H),0.01(s,9H)。 1 H NMR (400 MHz, CHLOROFORM-d) δ 10.05 (s, 1H), 8.87 (s, 1H), 7.96-7.80 (m, 2H), 5.72 (br.s, 2H), 5.56 (s, 2H), 4.34 (t, J = 6.5 Hz, 2H), 4.12 (s, 2H), 3.71-3.62 (m, 2H), 1.84-1.72 (m, 2H), 1.56-1.48 (m, 2H), 1.06-0.81 ( m, 5H), 0.01 (s, 9H).

MS(ESI)m/z：535,537[M+H+]。 MS (ESI) m / z: 535, 537 [M+H + ].

步驟F：向5-((4-胺基-6-溴-2-丁氧基-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7基)甲基)吡啶醛(150.00毫克，0.281毫莫耳)、吡咯烷(29.94毫克，0.421毫莫耳)、乙酸(0.2毫升)的四氫呋喃(5毫升)溶液中加入氰基硼氫化鈉(35.27毫克，0.561毫莫耳)，並在室溫下攪拌12小時。然後倒入冰/水(體積比=1/1，15毫升)混合物中攪拌20分鐘，並用乙酸乙酯(40毫升×3)萃取。用鹽水(20毫升×2)洗滌合併的有機相，用無水硫酸鈉乾燥，過濾並在減 壓濃縮。殘餘物通過製備型HPLC純化，得到150毫克的6-溴-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺，為黃色固體。 Step F: To 5 - ((4-amino-6-bromo-2-butoxy-5 - ((2- (trimethylsilyl silicon group) ethoxy) methyl) -5 H - pyrrolo [3,2-d]pyrimidin-7-yl)methyl)pyridine aldehyde (150.00 mg, 0.281 mmol), pyrrolidine (29.94 mg, 0.421 mmol), acetic acid (0.2 mL) in tetrahydrofuran (5 mL) Sodium cyanoborohydride (35.27 mg, 0.561 mmol) was added to the solution and stirred at room temperature for 12 hr. It was then poured into a mixture of ice/water (volume ratio = 1/1, 15 ml) for 20 minutes and extracted with ethyl acetate (40 ml × 3). The combined organics were washed with brine (20 mL EtOAc) The residue was purified by preparative HPLC to give 150 mg of 6-bromo-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5- ((2-(Trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidin-4-amine as a yellow solid.

MS(ESI)m/z：589,591[M+H+]。 MS (ESI) m / z: 589, 591 [M+H + ].

步驟G：將6-溴-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基矽基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(150.00毫克，254.39微莫耳)、Pd2(dba)3(23.30毫克，25.44微莫耳)、1,1’-雙(二苯基膦)二茂鐵(14.10毫克，25.44微莫耳)、二氰化鋅(59.74毫克，508.78微莫耳)和鋅(33.27毫克，508.78微莫耳)加到無水N,N-二甲基甲醯胺(2毫升)中，置換氮氣，然後在氮氣氣氛下加熱到110攝氏度並保持3小時。冷卻後，該混合物用水稀釋(30毫升)，並用乙酸乙酯(25毫升×3)萃取。將合併的有機相用鹽水(30毫升)洗滌，經無水硫酸鈉乾燥並在真空下濃縮，殘餘物用製備TLC純化，得到4-胺基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(120毫克，88.05%) Step G: 6-Bromo-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5-((2-(trimethyl)) silicon based) ethoxy) methyl) -5 H - pyrrolo [3,2-d] pyrimidin-4-amine (150.00 mg, 254.39 micromolar), Pd 2 (dba) 3 (23.30 mg, 25.44 micro Mohr), 1,1'-bis(diphenylphosphino)ferrocene (14.10 mg, 25.44 micromolar), zinc dicyanide (59.74 mg, 508.78 micromolar) and zinc (33.27 mg, 508.78 micron) Moor) was added to anhydrous N,N-dimethylformamide (2 mL), replaced with nitrogen, and then heated to 110 ° C for 3 hours under a nitrogen atmosphere. After cooling, the mixture was diluted with H.sub.2 (30 mL). The combined organic phase was washed with EtOAcqqqqqqqqqqlili Pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5-((2-(trimethylcarbinyl)ethoxy)methyl)-5 H -pyrrolo[3,2 -d]pyrimidine-6-carbonitrile (120 mg, 88.05%)

MS(ESI)m/z：536[M+H+]。 MS (ESI) m/z: 536[M+H + ].

步驟H：將4-胺基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲矽烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(120毫克，0.224毫莫耳)的三氟乙酸(5毫升)溶液在20攝氏度下攪拌12小時，然後在真空下濃縮至乾，殘餘物通過製備型HPLC純化，得到8.7毫克的4-胺基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈。 Step H: 4-Amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5-((2-(tri-) a solution of mercaptoalkyl)ethoxy)methyl)-5 H -pyrrolo[3,2-d]pyrimidine-6-carbonitrile (120 mg, 0.224 mmol) in trifluoroacetic acid (5 mL) After stirring at 20 ° C for 12 hours, it was concentrated to dryness in vacuo and the residue was purified by preparative HPLC to afford 8.7 mg of 4-amino-2-butoxy-7-((6-(pyrrolidine-1-) Methyl)pyridin-3-yl)methyl)-5 H -pyrrolo[3,2-d]pyrimidine-6-carbonitrile.

1 HNMR(Methanol-d4,400MHz)：δ8.52(s,1H),7.79(d,J=8.0Hz,1H) ,7.43(d,J=8.0Hz,1H),4.33(t,J=6.8Hz,2H),4.17(s,2H),3.76(s,2H),2.61(s,4H),1.82-1.72(m,6H),1.54-1.49(m,2H),1.02-0.99(t,J=7.2Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 8.52 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 4.17 (s, 2H), 3.76 (s, 2H), 2.61 (s, 4H), 1.82-1.72 (m, 6H), 1.54-1.49 (m, 2H), 1.02-0.99 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：406[M+H+]。 MS (ESI) m / z: 406 [M+H + ].

實施例42Example 42 4-胺基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidine-6-carbonitrile

4-胺基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈按照實施例41的流程製備，具體步驟見實施例41的步驟A、B、C、D、E、F、G、H。 4-amino-2-butoxy-7- (4- (pyrrolidin-1-ylmethyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidine-6-carbonitrile as described in The procedure of Example 41 was prepared. For the specific steps, see steps A, B, C, D, E, F, G, and H of Example 41.

1 HNMR(Methanol-d4,400MHz)：δ7.34-7.32(d,J=8.4Hz,2H),7.26-7.24(d,J=8.4Hz,2H),4.36-4.33(t,J=6.8Hz,2H),4.13(s,2H),3.62(s,2H),2.57(brs,4H),1.82-1.77(m,6H),1.52-1.49(m,2H),1.00(t,J=7.2Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.34 - 7.32 (d, J = 8.4 Hz, 2H), 7.26-7.24 (d, J = 8.4 Hz, 2H), 4.36 - 4.33 (t, J = 6.8 Hz) , 2H), 4.13 (s, 2H), 3.62 (s, 2H), 2.57 (brs, 4H), 1.82-1.77 (m, 6H), 1.52-1.49 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：405[M+H+]。 MS (ESI) m / z: 405 [M+H + ].

實施例43Example 43 4-胺基-2-丁氧基-7-(4-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈 4-amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidine-6-carbonitrile

4-胺基-2-丁氧基-7-(4-(嗎啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈鹽酸鹽按照實施例41的流程製備，具體步驟見實施例41的步驟A、B、C、D、E、F、G、H。 4-Amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carbonitrile hydrochloride according to the examples The procedure of 41 is prepared. For the specific steps, see steps A, B, C, D, E, F, G, and H of Example 41.

1 HNMR(Methanol-d4,400MHz)：δ：7.55(d,J=7.8Hz,2H),7.43(d,J=7.8Hz,2H),4.60(t,J=6.5Hz,2H),4.38(s,2H),4.23(s,2H),4.06-4.02(m,2H),3.80-3.73(m,2H),3.47-3.35(m,2H),3.28-3.14(m,2H),1.89-1.82(m,2H),1.59-1.51(m,2H),1.03(t,J=7.4Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ: 7.55 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 4.60 (t, J = 6.5 Hz, 2H), 4.38 ( s, 2H), 4.23 (s, 2H), 4.06-4.02 (m, 2H), 3.80-3.73 (m, 2H), 3.47-3.35 (m, 2H), 3.28-3.14 (m, 2H), 1.89- 1.82 (m, 2H), 1.59-1.51 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H).

LCMS(ESI)m/z：421[M+H+]。 LCMS (ESI) m / z: 421 [M + H +].

實施例44Example 44 4-胺基-2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈 4-amino-2-butoxy-7- (4 - ((4-methylpiperazin-1-yl) methyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidine - 6-carbonitrile

4-胺基-2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈鹽酸鹽按照實施例41的流程製備，具體步驟見實施例41的步驟A、B、C、D、E、F、G、H。 4-amino-2-butoxy-7- (4 - ((4-methylpiperazin-1-yl) methyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidine - 6-Methonitrile hydrochloride was prepared according to the procedure of Example 41. For the specific procedure, see Steps A, B, C, D, E, F, G, H of Example 41.

1 HNMR(Methanol-d4,400MHz)：δ：7.61(d,J=7.8Hz,2H),7.42(d,J=7.8Hz,2H),4.60(t,J=6.5Hz,2H),4.47(s,2H),4.23(s,2H),3.89-3.45(m,8H),3.02(s,3H),1.92-1.80(m,2H),1.61-1.44(m,2H),1.03(t,J=7.3Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ: 7.61 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 4.60 (t, J = 6.5 Hz, 2H), 4.47 ( s, 2H), 4.23 (s, 2H), 3.89-3.45 (m, 8H), 3.02 (s, 3H), 1.92-1.80 (m, 2H), 1.61-1.44 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H).

LCMS(ESI)m/z：434[M+H+]。 LCMS (ESI) m/z: 437 [M+H + ].

實施例45Example 45 4-胺基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲醯胺 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5 H -pyrrolo[3,2-d]pyrimidin-6-carboxamide

實施例45製備流程： Example 45 Preparation Process:

步驟A：將4-胺基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(90毫克，0.22毫莫耳)和氫氧化鈉(34毫克，0.85毫莫耳)溶於甲醇(10毫升)和水(10毫升)的混合溶劑，在80攝氏度下攪拌12小時。冷卻後，用水(10毫升)稀釋，並用乙酸乙酯(15毫升×2)萃取。將合併的有機層在真空下濃縮至乾，然後通過製備型HPLC純化，得到10毫克的4-胺基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲醯胺。 Step A: 4-amino-2-butoxy-7- (4- (pyrrolidin-1-ylmethyl) benzyl) -5 H - pyrrolo [3,2-d] pyrimidine-6 Methanol (90 mg, 0.22 mmol) and sodium hydroxide (34 mg, 0.85 mmol) were dissolved in a mixed solvent of methanol (10 ml) and water (10 ml), and stirred at 80 ° C for 12 hours. After cooling, it was diluted with water (10 mL) The combined organic layers were concentrated to dryness in vacuo then purified by preparative HPLC to afford &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& Base)-5 H -pyrrolo[3,2-d]pyrimidine-6-carboxamide.

1 HNMR(Methanol-d4,400MHz)：δ7.46(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),4.58(t,J=6.4Hz,2H),4.39(s,2H),4.34(s,2H),3.34-3.32(m,2H),3.18-3.16(m,2H)2.17-2.16(m,2H),2.03-2.00(m,2H),1.86-1.82(m,2H),1.56-1.50(m,2H),1.02(t,J=7.2Hz,3H)。 1 H NMR (Methanol- d 4, 400 MHz): δ 7.46 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 4.39 ( s, 2H), 4.34 (s, 2H), 3.34-3.32 (m, 2H), 3.18-3.16 (m, 2H) 2.17-2.16 (m, 2H), 2.03-2.00 (m, 2H), 1.86-1.82 (m, 2H), 1.56-1.50 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

MS(ESI)m/z：423[M+H+]。 MS (ESI) m / z: 422 [M+H + ].

實驗例1：Toll樣受體7和Toll樣受體8體外受體結合活性篩選方案Experimental Example 1: In vitro receptor binding activity screening protocol for Toll-like receptor 7 and Toll-like receptor 8

試劑：HEK-blue hTLR7細胞和HEK-blue hTLR8細胞(來源於InvivoGen公司) Reagents: HEK-blue hTLR7 cells and HEK-blue hTLR8 cells (from InvivoGen)

DMEM培養基 DMEM medium

熱滅活胎牛血清 Heat inactivated fetal bovine serum

抗支原體試劑NormocinTM Antimycoplasma reagent Normocin TM

博來黴素 Bleomycin

殺稻瘟菌素 Rice blasticidin

方案： Program:

1. 96孔化合物板的準備：利用液體工作站POD將化合物從10毫莫耳/升濃度起始，用DMSO做3倍梯度稀釋，共稀釋10個點(從第2列到第11列，每個點2個重複)。在第12列加入1微升5毫克/毫升的陽性化合物R848作為陽性對照，在第1列加入1微升DMSO作為陰性對照。每孔中含有的DMSO體積都是1微升。 1. Preparation of 96-well compound plate: Start the compound from a concentration of 10 mM/L using a liquid workstation POD, and make a 3-fold gradient dilution with DMSO, and dilute a total of 10 points (from column 2 to column 11, each 2 points are repeated). In the 12th column, 1 μl of 5 mg/ml of the positive compound R848 was added as a positive control, and in the 1st column, 1 μl of DMSO was added as a negative control. The volume of DMSO contained in each well was 1 microliter.

2. 收取細胞培養瓶中的細胞，將細胞密度稀釋成250,000個細胞/毫升。 2. Charge the cells in the cell culture flask and dilute the cell density to 250,000 cells/ml.

3. 加入200微升(50,000個細胞/孔)細胞懸液至準備好的化合物板中。每孔中DMSO終濃度為0.5%。 3. Add 200 μl (50,000 cells/well) of cell suspension to the prepared compound plate. The final concentration of DMSO in each well was 0.5%.

4. 將含有細胞和化合物的培養板放入CO2培養箱中培養24小時，培養條件為37攝氏度，5%CO2濃度。 4. The culture plate containing the cells and the compound was cultured in a CO 2 incubator for 24 hours under the conditions of 37 ° C and 5% CO 2 concentration.

5. 培養24小時後，從細胞培養板中每孔取出20微升上清液轉移到一塊96孔透明檢測板中。然後向檢測板中每孔加入180微升Quanti-Blue試劑，并置於37攝氏度，5%CO2培養箱孵育1小時。 5. After 24 hours of culture, remove 20 μl of supernatant from each well of the cell culture plate and transfer to a 96-well clear assay plate. Each well was then added to the assay plate in 180 [mu] L Quanti-Blue reagent, and incubated at 37 ° C, 5% CO 2 incubator for 1 hour.

6. 1小時後，用酶標儀OD650讀板檢測20微升上清液中鹼性磷酸酶的含量。 6. After 1 hour, the alkaline phosphatase content in 20 μl of the supernatant was measured using a microplate reader OD650.

7. 利用Prism軟體分析資料，得出各化合物的EC50。 7. Using the Prism software analysis data, the EC 50 of each compound was obtained.

實驗結果如表1所示： The experimental results are shown in Table 1:

注：1nMA100nM；100nM<B1000nM；1000nM<C50μM。 Note: 1nM A 100nM; 100nM<B 1000nM; 1000nM<C 50 μM.

實施例21化合物與對照品Toll樣受體7促效劑GS-9620頭對頭測試實驗結果如表2所示： The results of the head-to-head test of the compound of Example 21 and the reference Toll-like receptor 7 agonist GS-9620 are shown in Table 2:

結論：本發明的實施例21化合物，展現出比對照品Toll樣受體7促效劑GS-9620更高的與Toll樣受體7體外受體結合活性，和比對照品Toll樣受體7促效劑GS-9620更低的與Toll樣受體8體外受體結合活性。 Conclusion: The compound of Example 21 of the present invention exhibited higher in vitro receptor binding activity to Toll-like receptor 7 than the control Toll-like receptor 7 agonist GS-9620, and the Toll-like receptor 7 compared to the control. The agonist GS-9620 has a lower in vitro receptor binding activity to Toll-like receptor 8.

實驗例2：外周血單個核細胞試驗方案Experimental Example 2: Peripheral blood mononuclear cell test protocol

本方案的目的在於檢測利用現有化合物物刺激人外周血單核細胞(PBMC)24h後細胞因子的表達水準。檢測時細胞上清液不稀釋，直接檢測IFN-α和TNF-α的水準。實驗過程中首先將化合物配製成20mM的DMSO儲存液，用細胞培養基做10倍梯度稀釋，總共稀釋11個點。取其中9個稀釋點的化合物(化合物的最高濃度為200微摩/升)加入96孔板中，每孔50微升，然後接種新鮮的人外周血單核細胞，每孔接種150微升體系，其中含有450,000個細胞。將細胞培養板置於37℃和5%CO2培養箱中培養24小時，培養結束後將培養板以1200rpm的速度離心5分鐘，隨後收集上清並將其儲存於-20℃以待檢測。細胞因子的檢測利用BD公司的流式液相多重蛋白定量技術(CBA)，在流式細胞儀上完成檢測。利用上述檢測方法，我們將刺激產生最低檢測限至少3倍以上細胞因子水準的最低藥物濃度，定義為該化合物在該細胞因子刺激實驗上的MEC(Minimal Effective Concentration)值。 The aim of this protocol was to detect the level of expression of cytokines after 24 h of stimulation of human peripheral blood mononuclear cells (PBMC) with existing compounds. The supernatant of the cells was not diluted at the time of detection, and the levels of IFN-α and TNF-α were directly detected. During the experiment, the compound was first formulated into a 20 mM DMSO stock solution, and a 10-fold serial dilution of the cell culture medium was used to dilute a total of 11 points. Take 9 dilutions of the compound (the highest concentration of compound is 200 μM / liter) into a 96-well plate, 50 μL per well, then inoculate fresh human peripheral blood mononuclear cells, inoculate 150 μl per well It contains 450,000 cells. The cell culture plates were incubated at 37 ° C in a 5% CO 2 incubator for 24 hours, and after the completion of the culture, the plates were centrifuged at 1200 rpm for 5 minutes, and then the supernatant was collected and stored at -20 ° C for detection. Cytokine detection was performed on a flow cytometer using BD's Flow Cyclic Multiple Protein Assay (CBA). Using the above detection method, we will stimulate the lowest drug concentration that produces a minimum detection limit of at least 3 times the cytokine level, defined as the MEC (Minimal Effective Concentration) value of the compound in the cytokine stimulation experiment.

實驗結果如表3所示： The experimental results are shown in Table 3:

注：0.01nMA1nM；1nM<B10nM；10nM<C100μM。 Note: 0.01nM A 1nM; 1nM<B 10nM; 10nM<C 100 μM.

實施例21化合物與對照品Toll樣受體7促效劑GS-9620頭對頭測試實驗結果如表4所示： The results of the head-to-head test of the compound of Example 21 and the control Toll-like receptor 7 agonist GS-9620 are shown in Table 4:

結論：本發明的實施例21化合物展示出相對於對照品Toll樣受體7促效劑GS-9620更好的體外PBMC的IFN-α誘導活性以及相當的TNF-α的誘導活性。 Conclusion: The compound of Example 21 of the present invention exhibited better IFN-α-inducing activity and comparable TNF-α-inducing activity of PBMC in vitro relative to the control Toll-like receptor 7 agonist GS-9620.

實驗例3：大鼠藥代動力學實驗Experimental Example 3: Rat pharmacokinetic experiment

試驗用雄性SD大鼠共12隻，分成四組，每組3隻SD大鼠。2組動物靜脈注射給藥，分別注射對照品Toll樣受體7促效劑GS-9620和實施例21化合物的10%羥丙基-β-環糊***溶液(濃度0.5mg/mL)1mg/kg。另外2組口服給藥，分別口服GS-9620和實施例21化合物的0.5%甲基纖維素/0.2%吐溫80純水混懸液(濃度1mg/mL)5mg/kg。靜脈注射後的每隻大鼠於給藥後2、15、30分鐘和1、2、4、8、24小時連續採集全血樣本并製備血漿；口服給藥後的每隻大鼠於給藥後15、30分鐘和1、2、4、8、24小時連續採集全血樣本並製備血漿。應用LC-MS/MS方法，分別測定GS-9620和實施例21化合物血漿濃度。結果如表5所示。 A total of 12 male SD rats were tested and divided into four groups of 3 SD rats each. Two groups of animals were administered intravenously, and the control substance Toll-like receptor 7 agonist GS-9620 and the compound of Example 21 were mixed with 10% hydroxypropyl-β-cyclodextrin aqueous solution (concentration 0.5 mg/mL) 1 mg/ Kg. The other two groups were orally administered, and 5 mg/kg of a 0.5% methylcellulose/0.2% Tween 80 pure water suspension (concentration 1 mg/mL) of GS-9620 and the compound of Example 21 was orally administered. Each rat after intravenous injection continuously collected whole blood samples and prepared plasma at 2, 15, 30, and 1, 2, 4, 8, and 24 hours after administration; each rat after oral administration was administered. Whole blood samples were continuously taken at 15, 30 minutes and 1, 2, 4, 8, 24 hours and plasma was prepared. The plasma concentrations of the compounds of GS-9620 and Example 21 were determined by LC-MS/MS method, respectively. The results are shown in Table 5.

結論：本發明的實施例21化合物展示出在同等條件下，相對於對照品Toll樣受體7促效劑GS-9620在大鼠中有更長的半衰期和更高的曝露量。 Conclusion: The compound of Example 21 of the present invention exhibited a longer half-life and higher exposure in rats relative to the control Toll-like Receptor 7 agonist GS-9620 under the same conditions.

實驗例4：乙型肝炎感染雛鴨模型體內藥效學試驗Experimental Example 4: Pharmacodynamic test in duckling model of hepatitis B infection

實驗設計和方法：實驗採用一日齡北京鴨靜脈注射鴨乙型肝炎病毒陽性鴨血清，7天後開始分組給藥，每組6隻鴨。對照組：生理鹽水。供試樣品為GS-9620、實施例21化合物，每個樣品2個劑量組：20mg/kg和5mg/kg。供試樣品均為灌胃給藥，20mg/kg組為隔2天給1次藥(每3天給1次藥)，5mg/kg組為連續每天給藥，每天給藥1次。共給16天。陽性對照藥物拉米夫定由葛蘭素史克藥業公司生產，50mg/kg，為灌胃給藥，每天給藥2次，連續給藥16天。對於鴨乙型肝炎病毒感染對照組，以溶劑代替藥物。於感染後 7天給藥前(T0)、給藥後8天(T8)、給藥後16天(T16)和停藥後3天(P3)取血，分離鴨血清，冷凍保存。鴨血清用於鴨乙型感染病毒DNA(DHBV-DNA)的檢測，比較GS-9620、實施例21化合物和陽性對照拉米夫定對鴨乙型肝炎病毒的療效。鴨血清DNA(DHBV-DNA)的檢測方法：同批不同鴨血清用即時螢光定量PCR法測定鴨血DHBV-DNA的水準。統計學處理：採用配對和成組分析統計法，計算藥物對鴨血清DHBV-DNA抑制作用的顯著性，判斷效果。藥效結果見表6。 Experimental design and method: The experiment used a day-old Beijing duck intravenous injection of duck hepatitis B virus-positive duck serum, 7 days after the start of group administration, each group of 6 ducks. Control group: normal saline. The test samples were GS-9620, the compound of Example 21, and two dose groups per sample: 20 mg/kg and 5 mg/kg. The test samples were administered by intragastric administration. In the 20 mg/kg group, one dose was given every other day (one drug was given every three days), and the 5 mg/kg group was administered continuously every day, once a day. Give a total of 16 days. The positive control drug lamivudine was produced by GlaxoSmithKline Pharmaceutical Co., Ltd., 50 mg/kg, administered intragastrically, twice a day for 16 days. For the duck hepatitis B virus infection control group, the solvent was substituted for the drug. After infection Blood was taken before 7 days of administration (T0), 8 days after administration (T8), 16 days after administration (T16), and 3 days after withdrawal (P3), and duck serum was isolated and stored frozen. Duck serum was used for the detection of duck-type infected virus DNA (DHBV-DNA), and the efficacy of GS-9620, the compound of Example 21 and the positive control lamivudine against duck hepatitis B virus was compared. Duck serum DNA (DHBV-DNA) detection method: the same batch of different duck serum was determined by real-time fluorescent quantitative PCR method for duck blood DHBV-DNA level. Statistical analysis: The paired and group analysis statistical methods were used to calculate the significance of the drug's inhibition on duck serum DHBV-DNA, and the effect was judged. The results of the drug efficacy are shown in Table 6.

成組t檢驗，同一時間點同病毒對照組相比。*p<0.05，**p<0.01。 Group t test, at the same time point compared to the virus control group. *p<0.05, **p<0.01.

結論：相對於對照品Toll樣受體7促效劑GS-9620，本發明的實施例21化合物在同等條件下在乙肝感染雛鴨模型上展示出更優的藥效：20mg/kg隔2天給藥一次，抑制率大致相當；5mg/kg每天給藥一次連續給藥，實施例21化合物抑制率優勢十分明顯；停藥3 天後，GS-9620的20mg/kg隔2天給藥一次組出現HBV-DNA複製反彈，而對應實施例21化合物組沒有。 Conclusion: Compared with the control Toll-like receptor 7 agonist GS-9620, the compound of Example 21 of the present invention exhibited superior drug efficacy in the hepatitis B infected duckling model under the same conditions: 20 mg/kg every 2 days. Once administered, the inhibition rate was roughly equivalent; 5 mg/kg was administered once a day for continuous administration, and the inhibition rate of the compound of Example 21 was very obvious; After day, HBV-DNA replication rebound occurred in the group administered with 20 mg/kg of GS-9620 every 2 days, while the compound group corresponding to Example 21 did not.

實驗例5：HDI(hydrodynamic injection)乙型肝炎感染小鼠模型體內藥效學試驗Experimental Example 5: In vivo pharmacodynamic test of HDI (hydrodynamic injection) mouse model of hepatitis B infection

實驗設計和方法：給藥途徑：灌胃 Experimental design and method: route of administration: gavage

給藥時間：第1天到第7天，實驗週期共7天 Dosing time: from day 1 to day 7, the experimental cycle is 7 days in total

給藥組：第一組：載體(Vehicle)：10% HP-β-CD；第二組：GS-9620，20mg/kg；第三組：實施例21，20mg/kg。 Drug-administered group: First group: Vehicle (Vehicle): 10% HP-β-CD; Group 2: GS-9620, 20 mg/kg; Group 3: Example 21, 20 mg/kg.

實驗第1、3、5、7天給藥4小時後收集血漿樣本，第7天給藥4小時後收集肝樣本。詳情見表7。 Plasma samples were collected 4 hours after the first, third, fifth, and seventh days of the experiment, and liver samples were collected 4 hours after the seventh day of administration. See Table 7 for details.

HDI(hydrodynamic injection)乙型肝炎感染小鼠模型體內藥效學試驗藥效結果詳情見圖1和圖2。結論：血漿中的HBV拷貝數和肝臟中的HBV拷貝數檢測資料顯示，實施例21化合物在同等條件下藥效優於對照品Toll樣受體7促效劑GS-9620。 HDI (hydrodynamic injection) Hepatitis B infection in a mouse model. Pharmacodynamic test results are shown in Figure 1 and Figure 2. Conclusion: The HBV copy number in plasma and the HBV copy number detection data in the liver showed that the compound of Example 21 was superior to the control Toll-like receptor 7 agonist GS-9620 under the same conditions.

Claims (16)

一種式(I)所示化合物或其藥學上可接受的鹽， 式中，L1、L2分別獨立地選自-O-、-CH2-、-S-、-NH-、-NHC(=O)-、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O)2-、-NHS(=O)2-或-S(=O)2NH-，各自基團任選被一種或複數種R4取代；R1選自氫、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基，上述之C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；R2選自氫、鹵素、氰基、羥基、巰基、胺基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基，上述之羥基、巰基、胺基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；B選自C3-10環烴基、3-10員雜環烴基、芳基、雜芳基；L3選自C0-6亞烷基、亞胺基、-O-、-S-、-S(=O)-或-S(=O)2-，上述C0-6亞烷基、亞胺基任選被一種或複數種R4取代；R3選自氫、胺基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環 烴基、3-10員雜環烴基、芳基、雜芳基，上述之胺基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10環烴基、3-10員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；或R3、L3與B環上鄰位原子一起形成飽和或不飽和的5-8員環，上述之5-8員環任選被一種或複數種R4取代；n為0、1、2、3、4或5；R4選自鹵素、氰基、-R、-OR、=O、-SR、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、-NRC(=O)R、-NRC(=O)OR、-NRC(=O)NRR、-C(=O)NRR、-C(=O)OR、-OC(=O)NRR、-OC(=O)OR、-C(=O)R、-S(=O)2OR、-S(=O)2R、-OS(=O)2OR、-S(=O)2NRR、-S(=O)R、-NRS(=O)2R、-NRS(=O)2NRR、-NRS(=O)2OR、-OP(=O)(OR)2、-P(=O)(OR)2、-C(=O)R、-C(=S)R、-C(=O)OR、-C(=S)OR、-C(=O)SR、-C(=S)SR、-C(=O)NRR、-C(=S)NRR、-C(=NR)NRR或-NRC(=NR)NRR；R獨立地選自H、C1-8烷基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基、芳基烷基、雜芳基烷基；並且，當L1為-CH2-或-NH-時，R3不為H。 a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Wherein L 1 and L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-, -NHC(=O)-, -C(=O)-, -C(= O) NH-, -S(=O)-, -S(=O) 2 -, -NHS(=O) 2 - or -S(=O) 2 NH-, each group optionally being one or more R 4 is substituted; R 1 is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, Heteroaryl, the above C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally Substituted by one or more R 4 ; R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, amine, COOH, -CONH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2 - 10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, hydroxy, decyl, amine, COOH, -CONH 2 , C 1-10 alkyl, C 2 -10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally substituted by one or more R 4 ; B is selected from C 3 10 cyclic hydrocarbon group, 3-10 membered heterocycloalkyl, aryl, heteroaryl; L 3 is selected from C 0-6 alkylene, imine, -O-, -S-, -S(=O)- Or -S(=O) 2 -, The above C 0-6 alkylene group, imino group is optionally substituted by one or more kinds of R 4 ; R 3 is selected from hydrogen, amine group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 Alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, the above amino group, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl a C 3-10 cycloalkyl, a 3-10 membered heterocycloalkyl, an aryl, a heteroaryl optionally substituted by one or more R 4 ; or R 3 , L 3 together with an ortho atom of the B ring to form a saturated or An unsaturated 5-8 membered ring wherein the 5-8 membered ring is optionally substituted with one or more of R 4 ; n is 0, 1, 2, 3, 4 or 5; and R 4 is selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR 2 , =NR, -C(halogen) 3 , -CR(halogen) 2 , -CR 2 (halogen), -OCN, -SCN, -N=C =O, -NCS, -NO, -NO 2 , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C(=O)NRR, -C(=O )OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) 2 OR, -S(=O) 2 R, -OS(=O 2 OR, -S(=O) 2 NRR, -S(=O)R, -NRS(=O) 2 R, -NRS(=O) 2 NRR, -NRS(=O) 2 OR, -OP (=O)(OR) 2 , -P(=O)(OR) 2 , -C(=O)R, -C(=S)R, -C(=O)OR, -C(=S) OR, -C(=O)SR, -C(=S)SR, -C(=O) NRR, -C(=S)NRR, -C(=NR)NRR or -NRC(=NR)NRR; R is independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 a heterocyclic hydrocarbon group, an aryl group, a heteroaryl group, an arylalkyl group, a heteroarylalkyl group; and, when L 1 is -CH 2 - or -NH-, R 3 is not H. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中L1、L2分別獨立地選自-O-、-CH2-、-S-、-NH-、-C(=O)-、-S(=O)-或-S(=O)2-，上述之-CH2-、-NH-任選被一種或複數種R4取代。 The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein L 1 and L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-. And -C(=O)-, -S(=O)- or -S(=O) 2 -, the above -CH 2 -, -NH- are optionally substituted by one or a plurality of R 4 . 如請求項2所記載之式(I)所示化合物或其藥學上可接受的鹽，其中L1、L2分別獨立地選自-O-、-CH2-，上述之-CH2-任選被一種或複數種R4取代。 The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 2, wherein L 1 and L 2 are each independently selected from -O-, -CH 2 -, and -CH 2 - It is optionally substituted by one or more R 4 groups. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R1選自氫、C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基，上述之C1-6烷基、C2-6烯基、C2-6炔基、C3-6環烴基、3-6員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代。 A compound of the formula (I), wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or a pharmaceutically acceptable salt thereof, according to claim 1 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 The cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl group is optionally substituted with one or more R 4 groups. 如請求項4所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R1選自C1-6烷基，上述之C1-6烷基任選被一種或複數種R4取代。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a C 1-6 alkyl group, and the above C 1-6 alkyl group is optionally one or more R 4 is substituted. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R2選自氫、鹵素、氰基、羥基、胺基、-CONH2、C1-6烷基，上述之羥基、胺基、-CONH2、C1-6烷基任選被一種或複數種R4取代。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amine, -CONH 2 , C 1-6 alkyl The above hydroxyl group, amine group, -CONH 2 , C 1-6 alkyl group are optionally substituted by one or a plurality of R 4 groups. 如請求項6所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R2選自氫、氰基、-CONH2，上述之-CONH2任選被一種或複數種R4取代。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, cyano and -CONH 2 , and the above -CONH 2 is optionally one or more R 4 replaced. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中B選自芳基、雜芳基。 The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein B is selected from the group consisting of an aryl group and a heteroaryl group. 如請求項8所記載之式(I)所示化合物或其藥學上可接受的鹽，其中B選自苯基、吡啶基。 The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 8, wherein B is selected from the group consisting of a phenyl group and a pyridyl group. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中L3選自C0-6亞烷基，上述之C0-6亞烷基任選被一種或複數種R4取代。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from a C 0-6 alkylene group, and the above C 0-6 alkylene group is optionally one or A plurality of R 4 substitutions. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R3選自氫、胺基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8環 烴基、3-8員雜環烴基、芳基、雜芳基，上述之胺基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8環烴基、3-8員雜環烴基、芳基、雜芳基任選被一種或複數種R4取代；或R3、L3與B環上鄰位原子一起形成飽和或不飽和的5-8員環，上述之5-8員環任選被一種或複數種R4取代。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, an amine group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2 - 6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, the above amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne a C 3-8 cycloalkyl, a 3-8 membered heterocycloalkyl, an aryl, a heteroaryl optionally substituted by one or more R 4 groups; or R 3 , L 3 together with an ortho atom on the B ring to form a saturation or unsaturated 5-8-membered cycloalkyl, 5-8 membered ring of the above-described optionally substituted by one or a plurality of kinds of substituent R 4. 如請求項1所記載之式(I)所示化合物或其藥學上可接受的鹽，其中R4選自鹵素、氰基、-R、-OR、=O、-SR、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、-NRC(=O)R、-C(=O)NRR、-C(=O)OR、-OC(=O)NRR、-C(=O)R、-S(=O)2OR、-S(=O)2R、-OS(=O)2OR、-S(=O)2NRR、-S(=O)R、-NRS(=O)2R、-C(=O)R、-C(=O)OR或-C(=O)NRR。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR 2 , = NR, -C(halogen) 3 , -CR(halogen) 2 , -CR 2 (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , -NRC(= O) R, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -C(=O)R, -S(=O) 2 OR, -S(=O 2 R, -OS(=O) 2 OR, -S(=O) 2 NRR, -S(=O)R, -NRS(=O) 2 R, -C(=O)R, -C( =O)OR or -C(=O)NRR. 如請求項12所記載之式(1)所示化合物或其藥學上可接受的鹽，其中R4選自鹵素、氰基、-R、-OR、=O、-NR2、=NR、-C(鹵素)3、-CR(鹵素)2、-CR2(鹵素)。 The compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of halogen, cyano, -R, -OR, =O, -NR 2 , =NR, - C (halogen) 3 , -CR (halogen) 2 , -CR 2 (halogen). 一種下式表示的化合物或其藥學上可接受的鹽： A compound represented by the formula: or a pharmaceutically acceptable salt thereof: 一種如請求項1至14中任一項所記載之化合物或其藥學上可接受的鹽在製備治療病毒感染的藥物的用途。 A use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a viral infection. 一種藥物組合物，其包含治療有效量的如請求項1至14中任一項所記載之化合物或其藥學上可接受的鹽；及一種或複數種藥學上可接受的載體或賦形劑。 A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers or excipients.
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